Frederick O. Stephens, AM, MD,

Karl R. Aigner, MD

MS, FRCS (Ed), FACS, FRACS

Professor of Surgery

Emeritus Professor and

Department of Surgical Oncology

former Head of Department of Surgery

Medias Klinikum GmbH & Co. KG

The University of Sydney

Abt. Onkologische Chirurgie

Former Head of Surgical Oncology

Krankenhausstr. 1

The Royal Prince Alfred and Sydney Hospitals

84489 Burghausen

16 Inkerman Street

Germany

Mosman NSW 2088

Prof-aigner@medias-klinikum.de

Australia

fredstephens@optusnet.com.au

ISBN: 978-3-540-92924-6

e-ISBN: 978-3-540-92925-3

DOI: 10.1007/978-3-540-92925-3

Springer Dordrecht Heidelberg London New York

Library of Congress Control Number: 2008944024

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned,

specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction

on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof

is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current

version, and permission for use must always be obtained from Springer. Violations are liable to prosecution

under the German Copyright Law.

The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply,

even in the absence of a specific statement, that such names are exempt from the relevant protective laws and

regulations and therefore free for general use.

Product liability: The publishers cannot guarantee the accuracy of any information about dosage and applica-

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relevant literature.

Cover design: Frido Steinen-Broo, eStudio Calamar, Spain

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Contributing Authors

Tim Allen-Mersh, MD, FRCS

Tetsuo Taguchi, MD, PhD

Professor Division of Surgery,

Professor Department of

Oncology Reproductive

Oncologic Surgery

Biology and Anaesthetics

Research Institute for Microbial

Imperial College School of Medicine

Disease, Osaka University

Chelsea and Westminster Hospitals

Japan Society for Cancer

London

Chemotherapy

Osaka

Gabriel Hortobagyi, MD, FACP

Japan

Professor, Department of Breast

Medical Oncology

John F. Thompson, MD, FRACS,

The University of Texas,

FACS

MD Anderson Cancer Center

Professor, The University of Sydney,

Houston, TX, USA

Departments of Melanoma and

David Khayat, MD, PhD

Surgical Oncology, The Royal Prince

Professor Department of Medical

Alfred Hospital, Sydney,

Oncology Salpetrière Hospital

Melanoma Institute Australia

Paris, France

& The Sydney Melanoma Unit,

The Royal Prince Alfred Hospital,

Steven M. Picksley, BSc, PhD

The Mater, Royal North Shore,

Department of Biomedical Sciences

Westmead Hospitals, Sydney,

University of Bradford

Australia

Bradford, England

Paul Sugarbaker, MD, FACS, FRCS

Professor The Center for Surgical

Oncology, Washington Hospital Center

and Washington Cancer Institute

Washington, DC

USA

Dedication

Working in oncology is a very satisfying career. It is particularly satisfying to

be able to help people with this most distressing and worrying health problem.

Most patients are cured but for some cure is not a possibility with our present

state of knowledge. All can be helped.

In most cases our patients become our friends and some become very special

friends. They honour us with their friendship and trust and this makes our work

feel more than worthwhile, indeed a special reward.

We are also grateful for our teachers of the past and for our present colleagues

without whose cooperation our work would be of limited value and progress

would be difficult.

Like all teachers, we are inspired by our students. We not only pass on knowl-

edge to them, we also learn from them. To have interested and enthusiastic

students is a real stimulus and privilege.

As is obvious from the authorship of this book we have been privileged to

make close and lasting friendships across national borders and across borders of

traditional disciplines. We treasure these friendships dearly from their personal

aspects as well as being able to learn from each other and to stimulate each other

in clinical work and research. It is sad that so much cancer is still with us, but the

constant mutual commitment to improving methods of care and discovering new

information on prevention and treatment for the betterment of people everywhere

is itself a reward, which we all share with respect and gratitude.

Finally we acknowledge that our work is demanding of time and energy. This

is time and energy in which our wives, families and friends have so often had to

make allowances for our absence. Without their love, support and acceptance of

the conditions of our work, this work and our efficiency would be severely com-

promised. They have often joined us and at other times have had to stand by with-

out us when we were concentrating on other things we could not always share

with them. We especially owe our loved ones a debt of thanks and gratitude.

We proudly dedicate this book to all of these people.

vii

Preface

Who Should Read This Book

In Western societies and other developed countries, cancer is the leading cause

of death, after cardiovascular disease. It is therefore a major component of

medical undergraduate curricula and of primary concern to nurses and allied

health-workers.

Presently most undergraduate students learn about cancer from a broad range

of general and specialist books and journals. Medical students read about cancer

in textbooks of surgery, pathology and cancer medicine as well as in general and

specialist journals and from time to time in newspaper reports, magazines and

from various other sources.

We the authors teach, practise and conduct research in different specialty

areas in different parts of the world. We agreed that we should write this book

as an easily understood and general overview of cancer for students of medicine,

nurse oncologists, students of medical sciences and other health professionals in

all parts of the world. It is intended to serve as a basis for more detailed or spe-

cialised studies that will be needed in different areas of practice and in different

countries. Different countries will emphasise different aspects according to their

more specific community needs, incidence, traditions and available health-care

facilities and systems.

What This Book Is About

This book is intended to give an introduction to the scientific and clinical aspects

of cancer, that is the broad range of concepts of causes, pathology, clinical

features, possible investigations, treatments and outcomes both for cancers in

general and for the common cancers in different countries. It should be a basis

for further study as appropriate for all areas of oncology no matter where it is

practised or in what particular professional discipline. The purpose of this book

is not to cover all social, personal, environmental or financial aspects of cancer

nor to discuss details of supportive services available. These important aspects

will differ in different countries with different social, medical and administrative

services and facilities as well as different traditional practices and requirements.

Preface

Ideal comprehensive facilities and services may or may not be available. Other

books, specifically written for students and practitioners in different countries

with different curriculum requirements, may be needed to cover these aspects.

Objective of This Book

The objective of this book is to develop graded information from very basic to

more sophisticated understanding of present knowledge about cancer. For some

students this may well meet all their needs, but for students wishing to undertake

further studies in cancer this book will serve as a sound basis for more detailed

or specific studies.

To achieve this, the book will

^● Cover basic medical, scientific and clinical aspects of cancer

^● Explain how and why people develop cancer

^● Indicate how the body reacts to cancer

^● Describe how cancer presents

^● Outline principles of cancer prevention, investigation, diagnosis and management

This information applies in all countries. It is the essential requirement for

understanding cancer no matter where studied or practised. We believe this basic

information about cancer is best introduced early in a student’s career before

other details of personal, psychological, social, management practices and tradi-

tions are studied in detail in different communities.

More detailed and comprehensive information on specialised areas of knowl-

edge, research and practice is expanded in more specialised books and publica-

tions, some of which are listed in the final section of this book.

Sydney, Australia

Frederick O. Stephens

Burghausen, Germany

Karl R. Aigner

Acknowledgements

The authors wish to acknowledge the help of a number of friends and colleagues.

Under the direction of Mr Ray Barbour all members of the audio-visual

department of the Royal Prince Alfred Hospital, Sydney, were most generous

and skilled in helping provide the illustrations. In particular we want to thank

Mr Anthony Butler for preparing the clinical illustrations and artist,

Mr Bob Haynes, who converted our rough diagrams into meaningful illustrations.

We are grateful to Oxford University Press for permission to reproduce illustra-

tions first published in All About Prostate Cancer, All About Breast Cancer and

The Cancer Prevention Manual written by one of us (FOS).

Dr Jean Philippe Spano, assistant to Professor Khayat in Paris, kindly read the

manuscript and made a number of helpful suggestions.

Dr Murray Brennan, Professor and Chairman of the Department of Surgery at

the Memorial Sloan-Kettering Cancer Center, New York, read the original manu-

script and kindly made a number of helpful suggestions.

Dr David Pennington, Senior Surgeon in Plastic and Reconstructive Surgery at

the Royal Prince Alfred Hospital, Sydney, provided the illustrations of breast

reconstruction of one of his patients.

Professor Graham Young, Director of The Kanematsu Institute at the Royal

Prince Alfred Hospital, gave helpful advice with regard to Chap. 19.

Some of the case reports were provided by distinguished friends and colleagues. For

these we are especially grateful to Professor Graham Young, Dr Jean-Philippe Spano,

Professor Jonathan Carter, Dr Michael Stevens, Dr Robin Saw, Dr Robert Stephens,

Dr Chris Hughes, Dr Ian Kalnins, Dr Andrew Parasyn, Professor John Watson,

Professor Bruce Barraclough and Dr Graeme Brazenor.

The authors are indebted to Belinda Bonham for editorial help in preparing the

manuscript and Renata Atkins for help in design and presentation.

Contents

Part I The Cancer Problem

What Is Malignancy ?

1.1

Nature of a Malignancy

1.2

What is the Prevalence of Cancer?

1.3

Tumours Benign and Malignant?

1.4

Dangers of Malignant Tumours

1.5

What Causes Cancer

1.5.1

Is There a Single Cause Or a Single Common Pathway?

1.5.2

Apoptosis

1.5.3

Carcinogens

1.5.4

Tobacco Smoking

1.5.5

Alcohol

1.5.6

Betel Nut

1.5.7

Sunshine

1.5.8

Other Forms of Irradiation: X-rays and Atomic Irradiation ...

1.5.9

Industrial Irritants and Carcinogens

1.5.10

Chemical Carcinogens

1.5.11

Hormones

1.5.12

Viruses

1.5.13

Bacteria

1.5.14

Pre-Existing Abnormalities

1.5.15

Nutritional Deficiencies and Food Habits

1.5.16

Estimate of Known Risk Factors and Associations

with Cancer

Epidemiology

2.1

Comparative Cancer Incidence

2.2

People Most at Risk

2.3

Viral and Other Infection Associations

2.4

Heredity and Genetic Factors

2.4.1

Tumour Suppressors, Proto-Oncogenes and

Cancer-Oncogenes

2.4.2

Tumour Suppressor Genes

2.4.3

Cell Cycle Regulatory Genes

xiii

xiv

Contents

2.5

Molecular Biological Changes in Controlling

Cell Division

2.5.1

Inherited Cancer Genes: Inherited and Familial Cancers

2.6

Age

2.6.1

Infants

2.6.2

Children, Adolescents and Young Adults

2.6.3

Increasing Age

2.7

Predisposing and Pre-Malignant Risk Factors

2.7.1

Skin

2.7.2

Oesophagus

2.7.3

Stomach

2.7.4

Bowel

2.7.5

Mouth and Throat

2.7.6

Stones: Gallstones, Kidney and Bladder Stones

2.7.7

Chronic Inflammation

2.7.8

Acute Injury

2.7.9

Pre-Existing Lumps and Benign Tumours

2.7.10

Congenitally Abnormal Tissues

2.7.11

Gender

2.8

Diet and Cancer: Special Dietary

Preventive Ingredients

2.9

Stomach Cancer

2.10

Bowel Cancer: Cancers of the Colon and Rectum

2.11

Other Cancers

2.12

Vegetarian Diets

2.13

Special Dietary Ingredients: Phytoestrogens and Lycopene

2.14

Vitamins, Anti Oxidants and Trace Elements

2.15

Race

2.16

Geographic Associations

2.17

Environment

2.17.1

Sunshine

2.17.2

Air Pollution

2.17.3

Ionising Irradiation

2.17.4

Goitre Belts

2.18

Occupation

2.19

Habits and Lifestyle

2.19.1

Smoking

2.19.2

Alcohol

2.19.3

Sun-Exposure

2.19.4

Betel Nut

2.19.5

Pregnancies and Breast Cancer

2.19.6

Cultural and Social Customs

2.20

Psychological Factors: The Possible Role of

Stress or Emotion in Cancer Development

2.21

Cancer Registries

Contents

3 Summary of Practical Measures to Prevent Cancer

3.1

Smoking

3.2

Viral and Bacterial Protection

3.3

Genetic Protection

3.4

Skin Cancers

3.5

Diets: Stomach and Bowel Cancer, Breast Cancer

3.5.1

Prostate Cancer

3.5.2

Thyroid Cancer

3.5.3

Dioxins

3.5.4

Breast Cancer

3.6

Industrial Cancers

3.7

Ionising Irradiation

3.8

Treatment of Pre-Malignant and Potentially

Malignant Lesions

3.8.1

Pre-Malignant Conditions

Part II General Features of Cancer-Presentation and Management

Symptoms of Cancer: Local and General

4.1

Lump

4.2

Ulcer

4.3

Pain

4.4

Bleeding

4.5

Weight Loss

4.6

Interference with Tissue or Organ Function

4.7

Symptoms of Metastatic Spread

4.7.1

Lymph Nodes

4.7.2

Liver

4.7.3

Lungs

4.7.4

Bones

4.7.5

Fat and Muscles

4.7.6

Bowel

4.7.7

The Brain

4.7.8

The Unknown Primary Syndrome

Signs of Cancer: Local and General

5.1

Lump

5.2

Ulcer

5.3

Bleeding and Evidence of Blood Loss

5.4

Lymph Node Enlargement

5.5

Other Swellings

5.6

Findings of a General Examination Including

Mouth, Throat, Abdomen, Rectum and Anus

5.7

Rare and Seemingly Unrelated Indications of Cancer

xvi

Contents

Clinico-Pathology of Cancers

6.1

Typing, Grading and Staging of Cancer

6.2

Cancer Typing

6.3

Cancer Grading

6.4

Clinico-Pathological Staging of Cancer

6.5

Clinical Decisions Based on Pathology Information

Investigations That May be Useful in Detecting Cancer1

7.1

Screening Programs

7.2

Screening Tests

7.2.1

The Cervical Smear or “Pap” (Papanicolaou) Test

7.2.2

Occult Blood Tests

7.2.3

Gastro-Oesophageal Screening

7.2.4

Breast Screenings: Mammography

7.2.5

Skin Cancer Screening: Especially the “Mole Check”

7.2.6

PSA Screening Test

7.2.7

Genetic Testing

7.3

Organ Imaging

7.3.1

X-Rays

7.3.2

Barium (Baryum) and Iodine Contrast X-Rays

7.3.3

Radiographic Screening

7.3.4

Mammography

7.3.5

Chest X-Ray

7.3.6

Skeletal X-Rays

7.3.7

Angiography

7.3.8

Isotope Scans (Nuclear Scintigraphy)

7.3.9

CT Scan or CAT Scan (Computerised Axial Tomography)

7.3.10

Ultrasound Scans

7.3.11

MRI (Magnetic Resonance Imaging)

7.3.12

PET (Positron Emission Tomography) Scan

7.4

Endoscopic Examinations: Rigid and Flexible Scopes

7.4.1

Rigid Scopes

7.4.2

Sigmoidoscopy

7.4.3

Proctoscopy

7.4.4

Vaginal Speculum

7.4.5

Laryngoscopy and Bronchoscopy

7.4.6

Oesophagoscopy

7.4.7

Cystoscopy

7.4.8

Echo-Endoscopy

7.4.9

Flexible Scopes

7.4.10

Gastroscopy or Endoscopy

7.4.11

Colonoscopy

7.4.12

Laparoscopy (Peritoneoscopy) and Thoracoscopy

7.4.13

Culdoscopy

Contents

xvii

7.5

Indirect Evidence of Cancer

7.5.1

Blood and Serum Tests

7.5.2

White Cell Count (WCC)

7.5.3

Erythrocyte Sedimentation Rate (ESR)

7.5.4

Serum Biochemistry

7.5.5

Tumour Markers

7.5.6

The Future

7.6

Direct Evidence of Cancer

7.6.1

Biopsy

7.6.2

Needle Aspiration or “Punch Out” Biopsy

7.6.3

Aspiration Cytology

7.6.4

Bone Marrow Biopsy

7.6.5

Standard Paraffin Section Biopsy and

Frozen Section Biopsy

Treating Cancer

8.1

Can Cancer Be Cured? An Outline of Prognosis

8.2

In Western Societies More Cancers are

Cured than Not Cured

8.3

Methods of Treatment

8.3.1

Principles of Treatment of Potentially Curable

Regional Cancers

8.3.2

Surgery

8.3.3

Radiotherapy

8.3.4

Chemotherapy (Cytotoxic Drug Treatment)

8.4

Other Important Treatments

104

8.4.1

Hormone Therapy

104

8.4.2

Immunotherapy

107

8.5

Some Further Treatments Under Study

111

8.5.1

Heat Therapy

111

8.5.2

Gene Therapy

112

8.6

General Care

113

8.6.1

Care of General Health

113

8.6.2

Treatment of Complications

114

8.6.3

Supportive Care and Supportive Care Teams

115

8.6.4

Pain Relief

115

8.6.5

Psychological and Spiritual Help

116

8.6.6

Follow-Up Care

117

8.6.7

The Specialty of Palliative Care

118

8.6.8

Alternative Medicine

118

Relationship Between Patients, Their Doctors

and the Healthcare Team

121

xviii

Contents

Part III Most Common Cancers

Skin Cancers

125

10.1

Skin Cancer Prevention

125

10.2

Basal Cell Carcinoma (BCC)

126

10.2.1

Treatment

128

10.3

Squamous Cell Carcinoma (SCC)

128

10.3.1

Treatment

129

10.4

Melanoma

133

10.4.1

Pathology

133

10.4.2

Causes and Incidence

133

10.4.3

Early Features of Melanoma

134

10.4.4

Treatments of Melanoma

137

10.4.5

Investigations to Guide Surgical Treatment

137

10.4.6

Other Treatments

138

10.4.7

Vaccine Studies

139

Lung Cancer (Bronchogenic Carcinoma)

143

11.1

Symptoms

144

11.2

Investigations

145

11.3

Significance of Histological Findings

146

11.4

Treatments

146

11.5

Mesothelioma

148

11.6

Metastatic Cancer in the Lung

148

Breast Cancer

151

12.1

Hormone Replacement Therapy (HRT)

153

12.2

Symptoms

154

12.3

Inflammatory Breast Cancer

156

12.4

Cancer of the Male Breast

156

12.5

Signs

157

12.6

Investigations

157

12.6.1

Breast Cancer Staging

158

12.7

Treatments

158

12.8

Prevention

158

12.9

Pathology

160

12.10

Early Breast Cancer

161

12.10.1

Surgery and/or Radiotherapy

161

12.10.2

Adjuvant Chemotherapy

163

12.10.3

Hormone Sensitivity Tests

163

12.10.4

Options in Management of Early Breast Cancer

164

12.11

Locally Advanced and Metastatic Breast Cancers

164

12.12

Physical and Emotional Needs

165

12.12.1

Breast Prostheses and Breast Reconstruction

165

Contents

xix

12.12.2 Breast Clinics

167

12.12.3 Cancer Societies and Breast Cancer Support Groups

167

Cancers of the Digestive System (Alimentary Tract)

171

13.1

Cancer of the Oesophagus

171

13.1.1

Pathology

172

13.1.2

Symptoms

172

13.1.3

Signs

172

13.1.4

Investigations

172

13.1.5

Treatment

173

13.2

Cancer of the Stomach

175

13.2.1

Pathology

175

13.2.2

Symptoms

176

13.2.3

Signs

176

13.2.4

Investigations

176

13.2.5

Treatment

177

13.3

Cancers of the Liver

179

13.3.1

Primary Liver Cancer (Hepatoma or

Hepatocellular Carcinoma)

179

13.3.2

Secondary (Metastatic) Liver Cancer

182

13.4

Cancer of the Gall Bladder and Bile Ducts

186

13.4.1

Symptoms

186

13.4.2

Signs

186

13.4.3

Pathology and Treatment

187

13.5

Cancer of the Pancreas

187

13.5.1

Presentation

187

13.5.2

Investigations

188

13.5.3

Treatment

188

13.6

Cancers of the Small Intestine

190

13.6.1

Carcinoid Tumour

190

13.7

Cancer of the Large Bowel (Colon and Rectum)

191

13.7.1

Clinical Features

193

13.7.2

Investigations

193

13.7.3

Treatment

194

13.7.4

Follow-Up Care

195

13.8

Cancer of the Anus

195

13.8.1

Presentation and Pathology

195

13.8.2

Treatment

197

Head and Neck Cancers

199

14.1

Cancers of the Lips

200

14.2

Cancers of the Floor of the Mouth (Under the Tongue),

Anterior Two-Thirds of the Tongue, and Buccal Mucosa

(Inside the Cheek)

200

Contents

14.3

Cancer in the Posterior Third of Tongue, Tonsillar

Region and Pharynx

206

14.4

Cancers of the Post-Nasal Space (The Air Passage

at the Back of the Nose)

207

14.4.1

Presentation

208

14.4.2

Treatment

208

14.5

Cancer of the Larynx

208

14.5.1

The Lost Cords Club

210

14.6

Salivary Gland Cancers

210

14.7

Cancers of the Thyroid Gland

213

14.7.1

Causes and Presentation

213

14.7.2

Accidental Irradiation

214

14.7.3

Investigations

214

14.7.4

Types of Thyroid Cancer

214

14.7.5

Papillary Cancer

214

14.7.6

Follicular Cancer

215

14.7.7

Medullary Cancer

215

14.7.8

Anaplastic Cancer

215

14.7.9

Other Types

216

Cancers of Female Genital Organs

217

15.1

Cancers of the Uterus

217

15.2

Cancer of the Cervix

217

15.2.1

Presentation and Risk Factors

217

15.2.2

Investigations

218

15.2.3

Treatment

218

15.2.4

Prevention

219

15.3

Cancer of the Body of the Uterus (Endometrial Cancer)

221

15.3.1

Presentation

221

15.3.2

Investigations

221

15.3.3

Treatment

221

15.4

Choriocarcinoma

223

15.5

Cancer of the Ovary

223

15.5.1

Presentation

224

15.5.2

Investigations

224

15.5.3

Treatment

224

15.5.4

Prevention

225

15.5.5

Metastatic Cancer of the Ovary

225

15.6

Cancer of the Vagina

228

15.7

Cancer of the Vulva

229

Cancers of the Male Genital Organs

231

16.1

Cancer of the Penis

231

16.2

Cancer of the Testis

232

16.2.1

Presentation

232

Contents

xxi

16.2.2

Investigations

233

16.2.3

Pathology

233

16.2.4

Treatment

233

16.3

Cancer of the Prostate Gland

234

16.3.1

Presentation

235

16.3.2

Investigations

236

16.3.3

Screening Tests: The PSA (Prostate-Specific Antigens)

and the DRE (Digital Rectal Examination)

236

16.3.4

Controversies in Management of Men with

Prostate Cancer

237

16.3.5

Treatments

239

16.3.6

Treatment of Bone Metastases

241

Cancers of Bladder and Kidneys

245

17.1

Bladder Cancer

245

17.1.1

Investigations

246

17.1.2

Types of Bladder Cancer (Pathology)

246

17.1.3

Treatment

246

17.2

Kidney Cancers

247

17.2.1

Wilm’s Tumour (Nephroblastoma)

247

17.2.2

Adenocarcinoma (Hypernephroma or Grawitz Tumour)

247

17.2.3

Carcinoma of the Renal Pelvis Or Ureter

(Transitional Cell Carcinoma)

248

17.2.4

Investigations

248

17.2.5

Treatment

248

Cancers of the Brain and Nervous System

251

18.1

Brain Cancers

251

18.1.1

Clinical Features (Symptoms and Signs)

252

18.1.2

Pathology Types

253

18.1.3

Investigations

253

18.1.4

Treatment

253

18.2

Secondary Cancers in the Brain

257

18.3

Nerve Cell Cancers

258

18.3.1

Neuroblastoma

258

18.3.2

Presentation

258

18.4

Retinoblastoma

258

18.4.1

Presentation

258

The Leukaemias and Lymphomas

259

19.1

The Leukaemias

259

19.1.1

Incidence and Prevalence of Leukaemias

260

19.2

The Acute Leukaemias

261

19.2.1

Clinical Presentation

261

19.2.2

Investigations

262

xxii

Contents

19.2.3

Treatment

262

19.3

Chronic Lymphocytic (Lymphatic) Leukaemia

265

19.3.1

Clinical Presentation

265

19.3.2

Investigations

265

19.3.3

Treatment

265

19.4

Chronic Myeloid Leukaemia (CML)

266

19.4.1

Clinical Presentation

266

19.4.2

Investigations

266

19.4.3

Treatment

267

19.4.4

Hairy Cell Leukaemia

268

19.5

The Lymphomas

271

19.5.1

Causes of Lymphoma

271

19.6

Hodgkin Lymphoma

272

19.6.1

Presentation

272

19.6.2

Investigations

272

19.6.3

Staging and the Staging Laparotomy

273

19.6.4

Treatment

274

19.7

Non-Hodgkin Lymphomas

275

19.7.1

Presentation

275

19.7.2

Investigations

276

19.7.3

Treatment

277

19.8

Multiple Myeloma

279

19.8.1

Investigations

279

19.8.2

Treatment

279

Soft-Tissue Sarcomas

281

20.1

Classification: Pathological Types

283

20.1.1

Fibrosarcoma

283

20.1.2

Liposarcoma

283

20.1.3

Rhabdomyosarcoma

284

20.1.4

Leiomyosarcoma

284

20.1.5

Neurosarcoma

284

20.1.6

Malignant Fibrous Histiocytoma (MFH)

285

20.1.7

Angiosarcoma

285

20.1.8

Synovial Sarcoma (Synoviosarcoma or

Malignant Synovioma)

285

20.1.9

Presentation

286

20.1.10

Investigations

286

20.1.11

Treatment

286

Malignant Tumours of Bone and Cartilage

291

21.1

Osteosarcoma

291

21.1.1

Presentation

291

21.1.2

Investigations

292

21.1.3

Treatment

292

Contents

xxiii

21.1.4

Intra-Operative Irradiation

294

21.2

Osteoclastoma (Central Giant Cell Tumour of Bone)

295

21.2.1

Presentation

295

21.2.2

Investigations

295

21.2.3

Treatment

295

21.3

Ewing’s Tumour

296

21.3.1

Presentation

296

21.3.2

Investigations

296

21.3.3

Treatment

296

21.4

Chondrosarcoma

297

21.4.1

Presentation

297

21.4.2

Investigations

297

21.4.3

Treatment

297

22 Metastatic (Secondary) Cancer

299

Part IV Making Progress

Techniques and Evidence of Progress

307

23.1

Evidence-Based Medicine

307

23.1.1

Randomised Trials

307

23.1.2

Other Historic Methods of Gathering Evidence

308

23.2

Clinical Trials

312

23.2.1

Ethics Approval

313

Future Directions

315

24.1

Prevention

316

24.2

Improved Cancer-Screening and Diagnostic

Techniques

317

24.2.1

MRS (Magnetic Resonance Spectroscopy)

318

24.2.2

Combined Imaging Using PET and CT or PET

and MRI

318

24.2.3

Magnetic Resonance-Guided Focused Ultrasound

Surgery

318

24.3

Vaccines

318

24.4

Improved Treatment Agents

319

24.5

Self Rescuing Concept (SRC)

319

24.6

New Agents

320

24.7

Therapeutic Viruses

320

24.8

Targeted Therapies

320

24.9

Improvements in Radiotherapy

321

24.9.1

Improvements in Focussing Radiotherapy

322

24.10

More Effective Use of Chemotherapy and

Radiotherapy Integrated with Surgery

322

24.11

Prevention of Metastases

323

What Is Malignancy?

In this chapter you will learn about:

› Prevalence of cancer

› Benign and malignant tumours

› Dangers of malignant tumours

› What causes malignancy

A malignant growth is characterised by a continuing, purposeless, unwanted,

uncontrolled and damaging growth of cells that differ structurally and function-

ally from the normal cells from which they developed.

The commonly used term for a malignant growth is a cancer - cancer is Latin

for crab. The condition was called cancer in ancient times because an advanced

cancer was thought to resemble a crab, with “claws” reaching out into surrounding

tissues.

All living plants and animals are composed of living cells that often need to

Cancer is Latin

divide to produce more cells for growth and development, and also to replace

for crab.

cells that have been damaged or have died. The process of cell proliferation (cell

division and cell growth) is controlled by genes in the DNA of the cell nucleus.

The genes are inherited from parents and bestow particular features in the off-

spring, including height, colour, weight and countless other distinctive features

and functions of the tissues. The process is normally under remarkably well-

balanced control. A cancer forms when this genetic control is damaged or lost in

one or more cells, which then continue to divide and divide again producing more

abnormal cells that continue to divide and increase in number when and where

they should not. The masses of unwanted dividing cells cause damage to other

cells and tissues in the body. They are no longer controlled by normal genes that

stop division after normal body needs have been met. They just go on dividing

in spite of causing damage to other tissues and body functions. This is a cancer.

All the causes of cancer are now known to directly, or indirectly, damage these

normal genes that regulate cell division.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_1, © Springer-Verlag Berlin Heidelberg 2009

1 What Is Malignancy?

One obvious factor is that the longer we live the more chance there is for the

genes that regulate cell proliferation to become damaged by exposure to agents

that damage the genetic blueprint, DNA. So most cancers become more common

the longer we live; most cancers are more common in old age. Another factor

is the rate of division for growth and replacement of tissues. Tissues like skin,

bowel lining or lining of air passages (especially in the lungs), and blood cells are

constantly being shed and replenished. Breast cells are constantly changing due

to hormone activity over a woman’s years of fertile life. With all this constant cell

proliferation there is more likelihood of mistakes being made in the process of

copying the genetic blueprint to daughter cells, especially as the process becomes

less accurate as we get older. A mistake or error in copying the genetic blueprint

is called a genetic mutation. These then are the tissues most likely to undergo

malignant change. Bone growth is greatest in growing young people and testicu-

lar activity is greatest in young adult males and these are the periods of life most

prone to cancers of these tissues. As men grow old the slow but constant changes

in the prostate gland make it more likely that factors causing a change in cells

might go wrong after years of exposure to the driving force of male hormones.

So prostate cancer becomes increasingly common in old age.

The remarkable thing is not that something goes wrong from time to time in

the delicate process of cell division but that things don’t go wrong more often. In

all life there is a continuous delicate living process involving countless genera-

tions of cell division. The better we care for our bodies with good living practices

the greater the likelihood of preventing something, possibly uncontrollable, from

seriously going wrong.

These good living practices include having good nutrition, healthy exercise,

safe sex and avoiding exposure to potentially damaging agents in our environ-

ment. All of these practices serve to reduce the exposure of the genetic material

in cells to agents that could cause changes in the genetic blueprint.

In the normal

Whilst most normal body tissues are composed of cells that have the ability

genetic

to grow or reproduce, they normally only do so when there is a need. When this

make-up there

need has been satisfied they stop reproducing. In the normal cell there is a brak-

is a braking

ing mechanism to stop cell division when the need for more cells has been satis-

mechanism

fied. Cells in such tissues as the skin or blood or the lining of the mouth, throat

to stop cell

or alimentary tract, wear out quickly and are constantly being replaced. They

division when

are normally replaced only to meet the immediate need of the body, after which

the need for

reproduction stops. Also, after injury or cell death, surrounding cells reproduce

more cells has

to replace and repair damaged tissues but there is an in-built mechanism that

been satisfied.

stops the cell reproduction once the injury has been repaired and the wound has

healed. The “switch on” and “switch off” mechanisms are governed by two

different types of genes, whose functions are either to promote or to suppress

cell division and cell growth. These are called proto-oncogenes and tumour sup-

pressors. Proto-oncogenes respond to growth signals and are positive regulators

of cell proliferation, only in the presence of appropriate growth signals. Tumour

1.1 Nature of a Malignancy

suppressor genes conversely act as negative regulators of cell growth and sup-

press or check the unregulated growth of cells. So in the normal cell the “switch-off”

mechanism is the response to the absence of specific growth signals.

Some, but not all, body tissues retain a lifelong ability to replicate themselves

to meet the body needs. For example, after surgical removal of as much as three

quarters of a normal liver, the remaining liver will grow back to its original size

within about 6 weeks and then stop. The nature of the “switch off” mechanism

is not fully understood - but it is clearly a critically important process that is

normally under genetic control.

In the case of a malignancy there is no “switching off” mechanism. Some of

the proto-oncogenes have now acquired mutations that mean they promote cell

growth even in the absence of appropriate growth signals, i.e. they become onco-

genes (cancer promoting genes) and some of the tumour suppressor genes are

inactivated, such that abnormal growth goes unchecked. Abnormal and unwanted

cells then invade into surrounding tissues and possibly blood and lymph vessels,

or body cavities, thereby spreading to other parts of the body, where they estab-

lish new damaging colonies of unwanted growing cells. These colonies are called

secondary or metastatic cancers, known as secondaries or metastases.

1.1

Nature of a Malignancy

A malignancy is therefore totally different from an infection, which is caused by

organisms from outside the body invading body tissues and causing damage. The

body defences recognise invading organisms as foreign and protective measures

are set in train to destroy them. Invading cancer cells, on the other hand, are

abnormal cells that have developed from the body’s own cells and are therefore

allowed to further develop and infiltrate other tissues without the control nor-

mally provided by natural body defences.

Cancer cells also have different features and take on a different microscopic

appearance from the cells from which they developed. Cancer cells become

bizarre in size, shape and other features. As a rule, the more bizarre they become,

the more aggressive and malignant is their behaviour. Cancer cells are usually

derived from a single original cell, and are said to show a clonal origin. The

nucleus is often irregular, larger and darker in colour and may even be duplicated

in the one cell. The cytoplasm is often relatively smaller, irregular in size and

shape and without the special features of the cell of origin. There may be cells

not only of different sizes and shapes but also with different staining properties

(pleomorphic). These changes are brought about by changes in the tumour sup-

pressor genes and oncogenes that are responsible for the control of cell division.

1.3 Tumours Benign and Malignant?

most prevalent in a community will vary with the age, sex distribution and race

of people in the community, as well as the geographical situation, the economic

and environmental situation and habits of the people including their diets. (See

Appendix showing incidence of different cancers in different countries.)

In developed countries cancer is responsible for about 25-30% of deaths. It

is second to cardiovascular disease as a cause of death. Young people in devel-

oped societies are much more at risk of dying from causes other than cancer

such as infectious diseases (including AIDS) or as a result of trauma (espe-

cially accidents in homes or on the roads, gunshot wounds or suicide), than

from cancer. Although cancer can occur at any age it is relatively uncommon

before the age of 40 years but as people grow older the risk of cancer progressively

increases.

1.3

Tumours Benign and Malignant?

Non-malignant or benign tumours are much more common than malignant

tumours. A benign tumour is a limited growth of cells that seems to be under

some sort of control. Although there is no apparent purpose in the growth,

the cells are more mature and closely resemble the cells from which they

developed. Once the growth reaches a certain size, it usually slows or stops,

such as a mole on the skin. All the cells of a benign tumour stay together as

a lump or swelling that is usually confined by a capsule or lining of fibrous

tissue. They do not spread to other parts of the body and are generally easily

removed by surgery.

There are two broad groups of solid tissue malignant tumours, commonly

called cancers. They are carcinomas and sarcomas. Carcinomas are malignant

tumours of epithelial origin, such as lining cells of skin, the alimentary tract,

respiratory tract, bladder or glands such as pancreas, thyroid or salivary glands.

Sarcomas are malignant tumours of connective tissue such as bone, cartilage,

muscle, fat, fascia, nerve or blood vessel. Carcinomas are much more common

than sarcomas.

In a malignant tumour the cells look less like the cells from which they

developed. The term anaplasia is used to describe cells that have lost their

distinctive features. The multiplication of cells also continues without control

(Fig. 1.2).

Very occasionally benign tumours can be life-threatening simply because

of their size and location. An example is meningioma, which is a benign,

slowly growing tumour that arises from the meninges covering the brain. It

can eventually prove fatal if not removed because it compresses the surround-

ing normal brain tissue and eventually interferes with vital brain functions.

A meningioma is nevertheless classified as a benign tumour because its cells

do not invade surrounding tissues or spread to other parts of the body via

the bloodstream or the lymphatic system and its removal by surgery should

result in cure.

1 What Is Malignancy?

Fig. 1.2. Illustrations of degrees of

cell degeneration into cancer

1.4

Dangers of Malignant Tumours

If a malignant tumour is detected while it is still small and before it has metas-

tasised, it can usually be completely removed surgically or destroyed by radio-

therapy or other means, before any serious damage has been done. The danger

it poses will have been eliminated and the patient will have been cured.

Malignant tumours become dangerous when they damage surrounding tissues

and when they establish metastases in other organs and tissues. To metastasise

cancer cells have an ability to break away from where they arose and penetrate or

spread into other tissues including blood and lymph vessels. Some cancers, like

basal cell cancers (BCCs) of skin have a low grade of malignancy. They almost

never metastasise but others, like some melanomas, produce malignant cells with

much greater ability to invade, break free and penetrate into blood and lymph

vessels relatively early in the disease. Such cancers become highly aggressive

and high grade and may establish early metastases. The ability of some cancers

to metastasise is not completely understood. It appears to be related to imperfect

intercellular cementing substances and is acquired through alterations in genes

that cause proteases, angiogenic factors and dysregulation of adhesion factors.

Proteases allow penetration of cells through tissues, angiogenic factors promote

development of new cancer capillaries for nutrition of the malignant cells and

dysregulation of adhesion factors “set cells free” to allow individual cell penetra-

tion rather than being held together as one tissue. The more of these factors asso-

ciated with a cancer, the greater will be its malignancy and degree of spread.

Cancer cells have been likened to seeds of a weed growing in a garden. Just as

some seeds will grow in some soils and some need special soil conditions, so too,

some cancer cells tend to grow more readily in some tissues as opposed to other tis-

sues. Some tissues seem to be disposed to different types of metastatic cell growth.

For example breast and prostate cancer cells are very likely to form metastases

1.5 What Causes Cancer

in bone; sarcoma cells and kidney cancers seem to grow preferentially in lung;

and alimentary tract cancer cells are most likely to grow as metastases in the liver.

Lymph nodes are the most common sites for metastatic spread of most cancers but

are not often the site of metastases of sarcomas. Other tissues appear to have general

resistance to metastases. The spleen and muscles are rarely the site of metastatic cell

growth except for melanoma cells, which seem to grow readily in virtually any tis-

sue including lung, liver, brain and bone as well as lymph nodes. Squamous cancers

from skin and other tissues spread most often to nearby lymph nodes, then to more

distant lymph nodes but further spread seems to be delayed. However sooner or later

they will metastasise further to lungs or other organs or tissues.

Metastatic growths damage and destroy the organ or tissue in which they

are growing. For example, metastases in the liver interfere with the function of

the liver, metastases in the lung block air passages leading to lung infection or

pneumonia and metastases in the brain often result in headaches first and eventu-

ally convulsions or coma. Bone metastases often cause pain and weakness of the

bones that may then collapse or break.

1.5

What Causes Cancer

1.5.1 Is There a Single Cause Or a Single Common Pathway?

For generations doctors, researchers, other health workers, philosophers, uncon-

Smoking is a

ventional practitioners and sometimes “quacks” have been trying to find a single

major cause of

cause for all cancers, and consequently a single cure. No such cause has been

many health

found and probably none exists. Many different factors initiate changes in cells

problems and

that lead to cancer. Current evidence would suggest that all causes of cancer

in modern

act by generating damage to the genetic blueprint of cells, specifically causing

societies it is

mutations in proto-oncogenes and tumour suppressor genes. In many cases the

the foremost

mutations in such genes can be linked directly to the types of DNA damage

preventable

associated with the agents that cause cancer e.g. UV-light and tobacco tar, and

cause of

each has its own signature form of DNA damage, providing evidence of “direct

cancers.

cause and effect”. Even tumour viruses cause cancer by altering the cell’s

genetic blueprint, either by directly altering the expression of proto-oncogenes,

or indirectly, through the inactivation of tumour suppressor proteins, in effect,

over-riding the genetic blueprint. Today it is believed that cancer arises from a

single cell that has acquired 6-12 genetic changes (mutations) in key tumour

suppressor and proto-oncogenes. This explains the clonal origin of cancers, and

why cancer incidence increases with age, due to the sequential accumulation of

these mutations; and also why some familial cancers are inherited at an earlier

age, as such individuals would already have one of these pre-disposing mutations

at birth. While we can minimise our own risk of cancer by adopting a healthy

life-style, we cannot completely eliminate the risk, as within all our cells are

natural metabolites that can potentially cause such mutations.

1 What Is Malignancy?

1.5.2 Apoptosis

While so far cancer has been discussed simply in relation to uncontrolled cell

proliferation, there is another important counter-balance to cell growth, namely

that of cell death. Cell death is a natural feature of cells that occurs in damaged

cells, and also during development, for example, in the foetus the development

of our fingers arises from the death of the web of cells between the fingers. This

process of cell death is known as apoptosis. It is a highly regulated and biochemi-

cally defined process, distinct from simple necrosis (where cells simply spill out

their contents). Cells that have extensive genetic damage often spontaneously

undergo apoptosis, and in effect “commit suicide” for the greater good of the host.

This is an important mechanism for suppressing tumour development. Indeed,

the main aim of chemotherapy and radiotherapy is to induce such extensive

genetic damage in tumours that the cancer cells undergo apoptosis. Cells that

escape, or evade, this apoptotic process form tumours that are more resistant to

chemotherapy and radiotherapy, and are associated with poor prognosis.

1.5.3 Carcinogens

There are many known cancer causing agents (carcinogens) but whatever the

end result of their actions they all cause genetic mutations resulting in different

types of cancers.

1.5.4 Tobacco Smoking

Smoking is a major cause of many health problems and in modern societies it is

the foremost preventable cause of cancers. Tobacco smoking is responsible for

an increased incidence of cancers of the lung, mouth, throat and larynx as well

as cancers of the oesophagus, stomach, pancreas, kidney, bladder, cervix uteri

and in the long term even the breast.

EXERCISE

Study Fig. 1.3 and list the potential long-term effects of cigarette smoking.

1.5 What Causes Cancer

Fig. 1.3. (a, b) Tobacco smoking is responsible for many health problems including

many cancers

1.5.5 Alcohol

The association between alcohol and cancer is not so clear. There is an obvious

association in heavy drinkers, especially of strong spirits, with cancers in the

oesophagus. The incidence of oesophageal cancer is significantly increased in

both heavy drinkers and tobacco smokers in any of its forms (whether it be ciga-

rettes, pipes or cigars). However people (especially males) who are both heavy

drinkers and heavy smokers have a much higher incidence than with just alcohol

alone or tobacco alone. Such an increased risk association is seen in cancers of

the alimentary tract from pharynx to colon and including the pancreas.

There is a secondary association between alcohol and primary liver cancer.

Alcohol causes cirrhosis of the liver and cirrhosis sometimes predisposes the

patient to primary liver cancer.

1.5.6 Betel Nut

In some countries a locally grown nut, betel nut, is cheaply produced and is

often chewed. It may become habit forming rather like chewing gum rather than

1 What Is Malignancy?

in itself being addictive. When not being chewed, betel nut is often held in the

cheek area of the mouth, lined by buccal mucosa. It has carcinogenic proper-

ties that commonly cause cancers of the mucous membrane lining the mouth,

especially in the buccal mucosa. When mixed with tobacco leaf or lime, or both,

the carcinogenic properties are increased.

The habits of chewing betel nut or tobacco leaf are responsible for a consid-

erably increased incidence of cancer in the mouth of people who live in India,

Pakistan, South East Asia and New Guinea, where these habits are common.

1.5.7 Sunshine

Excessive ultra-violet light from sunshine is predominantly responsible for a

greatly increased incidence of skin cancers, especially in fair-skinned people

who live in sunny tropical or sub-tropical climates. UV light of solariums can

be equally damaging in even shorter periods of time (Figs. 1.4 and 1.5).

1.5.8 Other Forms of Irradiation: X-rays and Atomic Irradiation

Increased incidence of cancers in the skin of the hands in people who held X-ray

plates in their hands during the early use of X-ray machines was the first evidence

that irradiation with X-rays would cause certain cancers. An increased incidence

of other cancers, including thyroid cancer and leukaemias, followed the atomic

irradiation exposure after the World War 2 atomic bomb explosions at Hiroshima

and Nagasaki and the atomic energy plant accident in Chernobyl (Russia) in 1986.

This confirmed the risk of these forms of irradiation in causing cancer.

Fig. 1.4. Diagram illustrating simple preventive

measures to protect against skin cancers. People

and communities should be encouraged to adopt

such lifestyle practices as a routine. Note the hat,

protective-cream and long sleeved shirt

1.5 What Causes Cancer

Fig. 1.5. (a–c) Photographs showing early, late and extremely late effects of sun damage

with increasing hyperkeratoses, BCCs and SCCs

1.5.9 Industrial Irritants and Carcinogens

The first cancer in Western countries found to be caused by a chemical agent was

cancer of the scrotum. This cancer commonly developed in chimney sweeps in

Britain in the eighteenth century. The cause was found to be soot that collected in

the scrotal area. Later, certain dyes used by German workers in chemical factories

and excreted in the urine were found to be associated with an increased incidence

of bladder cancer. People using phosphorus to paint luminous dials on clocks and

watches were also found to have a high incidence of bone cancer (osteosarcoma).

The phosphorus was absorbed from the habit of the workers wetting the tips of

their paintbrushes with saliva by putting the brushes in their mouths.

1.5.10 Chemical Carcinogens

A number of chemical agents can cause cancer in experimental animals. Simi-

larly chemical agents are known to be present in tobacco tars and in products

of the petroleum and other industries.

1.5.11 Hormones

Increased hormones or prolonged hormone exposure can be associated with

increased risk of some cancers. There is an increased risk of breast cancer in

women having hormone replacement therapy (HRT) for postmenopausal symp-

toms. Prostate cancer in men is known to be an androgen dependent tumour.

Without androgens prostate cancer will not grow. Other cancers that are some-

times linked to hormones include cancer of the body of the uterus.

1 What Is Malignancy?

1.5.12 Viruses

Viruses have been extensively studied as possible causes of human cancers.

These investigations have been stimulated by evidence that certain viruses cause

cancers in animals and that human warts, which are benign tumours, are known

to be caused by a virus. A “human papilloma virus” (HPV) may also sometimes

cause wart-like papillomas in the skin of people and these can become malignant.

One form of HPV is sexually transmitted and can cause cancer of the uterus,

vagina or vulva in women or cancer of the penis in men. HPV is now known to

be the most common cause of cancer of the cervix.

There is now evidence that some other viruses appear to be responsible for

some other human cancers. For example, there is cancer that arises in the back of

the nose, most common in Chinese who live in or near the Quantong province of

China near Hong Kong. In these people there is a high incidence of infection with

the Epstein-Barr virus that probably plays a part in the development of this can-

cer. The malignant tumour Burkitt’s lymphoma, most common in certain parts

of Africa and New Guinea, is also associated with a high incidence of infection

with the Epstein-Barr or a similar virus.

Convincing evidence that viruses play a role in the development of some

cancers comes from analysis of the incidence of cancer in patients who have

received solid organ transplants (e.g. kidney, heart, liver). These patients receive

lifelong immunosuppression to prevent rejection of their transplanted organ, and

apparently as a result of this have an increased incidence of cancers but especially

of those cancers known to be associated with viral infections. In Australian renal

transplant recipients, for example, the incidence of squamous cell carcinoma is

100 times that in the rest of the population - and a clear association with HPV

has been demonstrated. Similarly increased is the incidence of carcinoma of

the cervix (also known to be associated with HPV), hepatoma (associated with

the hepatitis B and hepatitis C viruses), non-Hodgkin lymphoma (sometimes

associated with the Epstein-Barr Virus) and Kaposi’s sarcoma (associated with

Cytomegalovirus infection). Similar tumours are seen in patients with AIDS

whose immune systems are damaged, not by drugs, but by the virus that causes

immune-deficiency.

1.5.12.1 Recent studies of viruses at a molecular level

At a molecular level viruses have been shown to cause cancer in a number of

ways. Firstly, many viruses encode proteins that directly target and inactivate

host tumour suppressor genes such as the p53 and retinoblastoma (RB) tumour

suppressors. This allows the virus to kick start cells into dividing so they can

replicate their genetic material using the host replication machinery in S-phase of

the cell cycle. Viruses through having to compete with the host cell have strongly

expressed genes to assist their propagation, and sometimes they inappropriately

activate the expression of host proto-oncogenes, or are indirectly associated

1.5 What Causes Cancer

with chromosomal re-arrangements that place the host proto-oncogenes under

the genetic regulation of the virus.

1.5.13 Bacteria

Evidence of a direct link between bacteria and cancer is unclear although prolonged

inflammation of ulcers caused by prolonged bacterial activity can predispose to

malignant change. Perhaps the most apparent association of a link between bacteria

and cancer is the common finding of helicobacter organisms in gastric cancer.

1.5.14 Pre-Existing Abnormalities

It is a common observation that congenitally abnormal tissues, chronically irri-

tated tissues, chronically atrophic or degenerate tissues, chronically inflamed or

ulcerated tissues, or severely scarred tissues are more likely to develop malig-

nant cells than are normal tissues. Examples include cancer that develops in an

undescended testis, and squamous cell cancer that develops in a chronic ulcer

resulting from a severe burn. Also, pre-existing benign tumours such as polyps,

papillomas and adenomas have a propensity to undergo malignant change; some

types more than others.

1.5.15 Nutritional Deficiencies and Food Habits

Deficiencies of certain vitamins, trace elements, anti-oxidants, naturally occur-

ring plant hormones and other plant products including natural fibre have been

linked to increased risk of several cancers of different types, in different body

systems and in different communities and racial groups often living in different

parts of the world. High animal fat content of food appears to be associated with

increased risk of some cancers; whilst a diet rich in fresh fruit and vegetables

appears to be protective. Details of these associations are discussed later in

this chapter under the heading diet and in the chapters of the various cancers

concerned, especially Chaps. 12, 13 and 16.

1.5.16 Estimate of Known Risk Factors and Associations with Cancer

The association of the most common skin cancers with ultraviolet light is clear.

Of the other known and potentially avoidable cancer risk factors it has been

variously estimated that food, alcohol and tobacco might be associated with about

70%, viruses and bacteria about 10%, heredity about 10%, physical factors (e.g.

chemicals, irradiation, chronic trauma) about 5% and other factors about 5%.

Epidemiology

In this chapter you will learn about:

› Comparative cancer incidence

› People most at risk

› Viral and other infection associations

› Heredity and genetic factors

› Age

› Predisposing and pre-malignant risk factors

› Gender

› Diet

› Race

› Geographic associations

› Environment

› Occupation and cancer

› Habits and lifestyle

› Possible psychological factors

› Cancer registries

2.1

Comparative Cancer Incidence

The incidence of cancers is very different in different countries (see Appendix).

The incidence

The most obvious differences are between developed and developing countries.

of cancers is

Cancers of the lung, prostate, breast, colo-rectum and pancreas are all much more

very different

common in developed countries and cancers of oesophagus and liver are much

in different

more common in developing countries. Other cancers that are at least twice as

countries (see

common in developed countries are cancers of skin, uterus, ovary, bladder, kidney,

Appendix). The

testis, brain, the lymphomas, leukaemias and multiple myeloma. Nasopharyngeal

most obvious

cancers are more than twice as common in developing countries.

differences

Table 2.1 shows the year 2001 incidence of the most common internal cancers

are between

in the United States and the incidence of death rates from these cancers.

developed and

developing

countries.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_2, © Springer-Verlag Berlin Heidelberg 2009

2 Epidemiology

able 2.1 The year 2001 incidence of the most common internal cancers in the United

States and the incidence of death rates from these cancers

Cancer

Incidence

Deaths

Prostate

198,100

31,500

Breast

193,700

40,600

Lung

169,500

157,400

Colon and rectum

135,400

56,700

2.2

People Most at Risk

Although the risk of developing cancer is much lower in young people cancer

can affect people of any age, race or occupation in any part of the world. People

who have been cured of one cancer often ask about the risk of developing a

second cancer. Whilst it is true that some people have an increased predisposi-

tion towards developing cancer, in most cases people who have already had one

cancer cured have only a slightly greater risk of developing a second cancer

than do people who have never had a cancer. For example, a woman who has

been cured of breast cancer has an increased risk of developing cancer in the

other breast and a somewhat increased risk of developing cancer of the uterus or

ovary, but the majority of these people never develop any other serious cancer.

Again, people who have been treated and apparently cured of one bowel cancer

do have an increased risk of developing a second cancer elsewhere in the bowel

but most do not. It is also true that people who have been cured of one type of

cancer have a slightly increased risk of developing a second cancer, not only of

the same system but of another system of the body, but the increased risk is small.

However, the risk of developing a second cancer is increased if they continue

to indulge in an obviously cancer-causing habit such as cigarette smoking or if

they inherit a mutation in a tumour suppressor or proto-oncogene. There is also

an increased risk of developing a leukaemia in some people 20 years or so after

treatment of another cancer with a prolonged chemotherapy program.

2.3

Viral and Other Infection Associations

In the normal

In the normal course of events cancer cannot be passed directly from one

course of events

individual to another. The present day worldwide scourge of acquired immune

cancer cannot

deficiency syndrome (AIDS) is caused by a virus infection that can predispose

be passed

to cancer but AIDS is not itself a cancer. In this disease the sufferer’s natural

directly from

immune defences against infection and cancer are damaged, resulting in a higher

one individual

incidence of cancer developing in affected people. Several cancers are now

to another.

commonly associated with HIV infection or AIDS. These include a sarcoma of

2.4 Heredity and Genetic Factors

soft tissues called Kaposi’s sarcoma, lymphomas of the central nervous system,

non-Hodgkin lymphoma and cancer of the cervix. Each of these is described

and discussed in Part 3 of this book.

Similarly, liver cancer is not infectious but a common precursor of liver cancer

is the chronic inflammatory changes in the liver due to hepatitis B or hepatitis

C infection. These hepatitis infections do spread easily from person to person,

mainly from food or intimate contact. In the case of hepatitis C, blood transfusion

or sharing of intravenous needles is also a common method of spread. Liver

cancer therefore develops more commonly in people who have been infected.

However in many cases the liver cancer doesn’t develop until at least 20 years

after infection. This is known as “the latency period” and is consistent with

the clonal origin of cancers and that five to eleven other genetic alterations are

required for cancer to develop.

The human papilloma virus is sometimes responsible for papillomas or

squamous cell carcinomas of skin or genitals of either sex. It is often transmitted

during the sexual intercourse and is particularly associated with cancer of the

cervix. The latency period for the development of cervical cancer from human

papilloma virus is 5-30 years.

Viruses can act by modulating the function of proto-oncogenes and tumour

suppressors. These original findings provided initial molecular insights into the

genetic basis of cancer.

2.4

Heredity and Genetic Factors

Molecular biology and studies of association of genes with cancer is one of the

About 10% of

most stimulating, challenging and exciting fields of cancer research.

breast cancers

At this stage information about three genetic concepts is important. These still

result from

evolving concepts are about cancer proto-oncogenes, tumour suppressor genes

breast tissue

and cell cycle regulation genes. It is certain that these concepts will be modi-

changes due to

fied, changed or added to fairly rapidly as more information is gathered in this

one of several

relatively new but exciting area of study being carried out in many laboratories

specific genes

in many parts of the world. It is not known whether all the different carcinogenic

that have been

factors already described all activate “biological triggers” in cells. Whatever the

inherited from

mechanism or combination of mechanisms, it seems that cancers are ultimately

a parent.

caused by changes in tumour suppressor genes or proto-oncogenes that convert

them into oncogenes, i.e. genes that can cause cancer.

2.4.1 Tumour Suppressors, Proto-Oncogenes and Cancer-Oncogenes

The many functions of our body cells are controlled by genes. Genes are coded in

the DNA that makes up the chromosomes or genetic library of our cells. Like the

genes that determine features like eye colour and blood group, we inherit these

2 Epidemiology

controlling genes from our parents. There is a link between genetic make-up

and some cancers.

Different genes are associated with different cancers for example the BRCA1

gene is often associated with either breast cancer or ovarian cancer. The BRCA2

gene can be associated with either breast cancer or pancreas cancer. Recent

studies have also shown a link between the BRCA2 gene and prostate cancer,

particularly prostate cancer in younger men.

The p53 gene is the gene most commonly associated with a broad spectrum of

cancers. This gene is responsible for coordinating the cellular response to DNA

damage, be it a transient growth arrest to allow the cell to repair the DNA damage,

or to instruct the cell to commit suicide via apoptosis if the damage was too

great. p53 protein is a transcription factor that switches on expression of genes

that regulate the cell cycle and cause growth arrest and apoptosis. Accordingly,

it has been called the guardian of the genome because of its role in indirectly

maintaining the coding integrity of the genetic blueprint. Approximately half

of all cancers carry an abnormal (mutated) p53 gene, and have lost the other

normal copy. Every normal cell has two copies of every gene (except some genes

of the Y chromosome in males). The mutation of one p53 gene, leaves the other

one potentially active and able to regulate cell growth and apoptosis. However,

the mutant p53 gene makes a protein that inactivates the normal p53 by binding to

the normal protein and inactivating the normal p53 protein. Since the protective

role of normal p53 protein is now overcome the genetic material is unstable and

the remaining normal p53 gene is deleted from its position on chromosome 17.

The mutation of one gene followed by the loss of the remaining normal gene is a

common feature of tumour suppressor genes. The mutant p53 gene by indirectly

promoting cancer behaves as an oncogene, so the p53 gene, can behave as both a

tumour suppressor or an oncogene depending on whether or not it is mutated.

BRCA1 and BRCA2 are also tumour suppressor genes and like the p53 gene

make a protein that has a role in switching on gene expression, and is involved

with DNA repair and regulation of the cell cycle.

All tumour suppressor genes, play a modulating or inhibitory role in cell

growth and differentiation. Factors that impair or damage these genes can there-

fore be carcinogenic.

Cells also contain special genes called proto-oncogenes. These proto-oncogenes

are responsible for programmed growth in development or repair. They play a

major role in co-ordinating our growth from a single fertilized egg cell into an

adult with 10¹³ cells. When development or tissue repair is complete, the cell

growth is switched off. Cancer-causing agents or spontaneous genetic mutation

change the proto-oncogenes into potentially cancer-causing oncogenes, as they

promote growth where and when they should not. Spontaneous genetic mutation

increases as we get older as our DNA repair processes become less efficient.

When an oncogene is active in a cell, the cell doesn’t require growth signals

to grow so that the “switched-on” mechanism of growth and repair continues

instead of being “switched off ” as it should be, and the cells that are produced do

not later undergo apoptosis (self destruction) when they are not wanted. Unlike

2.4 Heredity and Genetic Factors

tumour suppressors only one genetic change is associated with these genes

becoming oncogenes, as a mutation leads to the activation of the gene function

in the absence of the appropriate cell growth signal. Proto-oncogenes or oncogenes

are genes that encode proteins involved in all aspects of the cell signalling pathway

that promote the social behaviour of cells and their growth.

Cancer causing oncogenes or defective tumour suppressors may be inherited;

or result from cancer-causing agents changing proto-oncogenes into oncogenes;

or result from accidental genetic mutation caused by errors in copying the genetic

material in dividing cells or by genetic damaging agents within the cell (e.g.

oxygen free radicals) or by external agents such as UV irradiation of sunlight.

Occasionally, these errors allow cells to divide without correctly partitioning the

genetic complement of cells equally between the daughter cells, such that cells

now have multiple copies of the genetic material contributed by both parents, and

become polyploid (have more DNA content per cell). This is a typical feature of

cancer cells at times of rapid cell growth in some tissues or after the many years

of cell division during the course of a normal life.

In colon cancer, molecular oncologists have identified the sequential genetic

changes in specific oncogenes and tumour suppressors that lead a normal cell

into becoming a cancer cell.

From breast cancer studies it has been shown that about 10% of breast cancers

result from breast tissue changes due to one of several specific genes that have

been inherited from a parent. Most of the remaining 90% are probably the result

of an accidental genetic mutation after constant and repeated changes in breast

tissue over many years during cyclical hormonal stimulation.

2.4.2 Tumour Suppressor Genes

As opposed to proto-oncogenes or cancer-oncogenes these inherited genes,

tumour suppressor genes, play a modulating or inhibitory role in cell growth

and differentiation. Factors that impair or damage these genes can therefore be

carcinogenic.

2.4.3 Cell Cycle Regulatory Genes

In laboratory culture cancer cells can grow and divide every 24 h, however, in

patients regulatory processes restrict cell doubling times to between 5 and 700

days depending on the cell type and tumour stage. The control of cell growth

and division has been well studied. The cell growth cycle consists of five stages.

Stage 1 starts at the end of mitosis (M) and ends at the point the genetic mate-

rial is copied, and is called the G ₁ phase (G = gap). This copying of the genetic

material defines the next phase, known as the S phase (S = synthesis). The next

stage starts at the end of DNA synthesis and ends with the cell starting mitotic

division into daughter cells. The gap between the S phase and mitosis (M) is

2 Epidemiology

DNA SYNTHESIS

RNA SYNTHESIS

PROTEIN SYNTHESIS

G₂

G₁

RNA SYNTHESIS

PROTEIN SYNTHESIS

Fig. 2.1. Diagram illustrating the cycle of cell division and the sites of controlling genetic

and molecular biological activity. Normal cells and cancer cells divide in a similar way

but normal cells stop dividing when sufficient new cells have been made. Cancer cells

keep dividing uncontrollably. The new abnormal and unwanted cells become invasive and

dangerous, damaging other cells and tissues. Because they are constantly dividing, they are

therefore more constantly exposed to anti-cancer drugs that predominantly affect dividing

cells when they are in one or more of the stages of cell division (see Sect. 8.3.4 in Chap. 8)

known as G ₂. Cells not in cycle or undergoing differentiation, are said to be in

G ₀, as they are no longer in cycle.

The cycle cannot proceed without a series of successive events occurring. If

an event fails, then the cell arrests at defined checkpoints to allow adjustments

to be made. The most notable checkpoints occur at the G _1-S and G _2-M transition

points. The G _1-S checkpoint allows the cell to repair any DNA damage before it is

copied in the S-phase, to prevent mutations becoming fixed in the genetic mate-

rial. The second, G _2-M checkpoint allows the cell to ensure that the chromosomes

are arranged correctly prior to segregation to the daughter cells (Fig. 2.1).

Molecular Biological Changes in Controlling Cell Division

The cell cycle control system is based on two partners, cyclins and cyclin-

dependent kinases. Cyclins, are regulatory proteins expressed at specific

stages of the cell cycle, that interact with specific cyclin-dependent kinases.

2.5 Molecular Biological Changes in Controlling Cell Division

The partnerships between the cyclins and the kinases they specifically activate,

ensure that environmental factors and the cell’s readiness to divide directly influ-

ence progress through the cell cycle. The basis of the G _1-S checkpoint is well

understood. Cells can enter S phase only if a certain protein (called the retino-

blastoma protein after the eye cancer it is associated with) is phosphorylated by

a specific cyclin activated kinase. The multiply phosphorylated RB protein then

releases specific transcription factors, previously bound in an inactive form to

itself, to allow them to switch-on genes involved in DNA synthesis.

In times of genetic damage, p53 tumour suppressor protein blocks the G _1-S

transition by switching on expression of a protein, p21, that inhibits this kinase

to block DNA synthesis, and stop the cells entering the S phase.

Since cancer cells exhibit unregulated growth it is not surprising that they

have been shown to have genetic changes in cyclins, cyclin-dependent kinases,

p53 and RB protein, to allow the cancer cells to proliferate. The nature of the

genetic changes varies from cancer to cancer, which is why it has been difficult

to identify the mechanisms of how cells become cancer cells.

More recently discovered are genes that inhibit or stimulate cell reproduction

according to need. Impairment of these genes and their active roles in cell repro-

duction management can also lead to cancer.

2.5.1 Inherited Cancer Genes: Inherited and Familial Cancers

From an immediate practical and clinical point of view in some relatively

uncommon cancers there is a strong hereditary factor while in other cancers,

there is a less obvious hereditary factor, but for most there is no evidence of an

hereditary factor at all. Among the most obvious cancers with a strong hereditary

factor as a condition called familial polyposis coli in which, by transmission

of a responsible oncogene, half the children of an affected parent are likely to

develop the condition of multiple polyps in the large bowel. All those affected

who do develop these particular polyps will eventually develop cancer in the

bowel, usually by the age of 40.

With a rare but inherited familial condition called Xeroderma pigmentosa

there is a high incidence of development of skin cancer.

Another rare but most often inherited condition is called the Li-Fraumeni

syndrome. This syndrome is caused by germ-line mutations in the p53 gene.

This condition has provided a model to understand further the pathogenesis of

genetic cancers. Patients with this syndrome are defective in one allele of the

p53 (“the guardian of the genome”) or were born with one non-functional allele

of it. Therefore if the other p53 allele is affected during their life, cancer will

develop.

Among the more common cancers with an increased familial incidence are

cancers of the breast, stomach and bowel. Although the increased risk for rela-

tives of sufferers is not great in most families, occasionally it may be considerable.

For example there have been rare reports of families in which about half the

female blood relatives have developed breast cancer. What is responsible for this

2 Epidemiology

apparent increased risk in a few families was largely unknown until recent

discoveries of inherited genes called BRCA1 and BRCA2 (the names are derived

from BR of Breast and CA of cancer). The BRCA1 gene is on chromosome 17

and the BRCA2 gene is on chromosome 13. These genes behave as oncogenes on

breast cells (see hereditary and genetic factors). Families with a high incidence

of breast cancer may carry one or both of these genes, alternatively it may be

simply that members of these families have similar lifestyle habits and have been

affected by similar environmental factors.

Cancers of the stomach, colon or rectum have a significantly increased risk

of developing in relatives of sufferers from these conditions, but this risk is very

high only in patients with an obvious genetic predisposing cause such as familial

polyposis coli. In most cases it is likely that members of these families had similar

diets and other environmental factors.

Another indication of the genetic influence in association with stomach cancer

is the fact there have been reports of a slightly higher risk of people with blood

Group A developing cancer of the stomach than there is of people of other blood

groups. Such information is well documented but the risk is so small that it is

of little practical value to anyone other than statisticians and scientists studying

cancer. The fact is that thousands of people of different blood groups had to be

studied before any difference in cancer incidence could be substantiated and

some studies have indeed not detected any difference. For the individual with

blood group A the risk of being any more likely to develop stomach cancer is

almost negligible.

2.6

Age

In general, the risk of developing most cancers increases with age but there

are exceptions. For example it is a feature of familial cancers that they usually

present at an earlier age and are more likely to be bilateral or multiple than

cancers without a familial association. Also, although cancer in young people

is uncommon, no age group is entirely free from risk.

2.61

Infants

Cancers that occur

An uncommon cancer of the kidney, known as a Wilm’s tumour (or nephroblastoma)

in younger age

occurs almost exclusively in infants less than 5 years of age, and may, in fact,

groups are often

even be present at birth. Other malignant tumours, which although uncommon,

in those tissues

are more likely to occur in infants and young children, are retinoblastomas

that tend to divide

(eye), neuroblastomas (nerve tissue), rhabdomyosarcomas (voluntary muscle)

and grow more

and medulloblastomas (brain).

in early life.

2.6 Age

2.6.2 Children, Adolescents and Young Adults

The acute leukaemias, especially acute lymphoblastic leukaemia, are more likely

to occur in children and adolescents than adults. Teenagers and young adults

have the highest incidence of osteosarcomas as well as the highest incidence

of the lymphoma known as Hodgkin lymphoma or Hodgkin disease. Burkitt’s

lymphoma is a tumour that predominantly affects the jaw of children most

commonly in tropical Africa and New Guinea.

2.63

Increasing Age

Malignant tumours of the testis are not common but when they do occur it is

most often in men younger than 40 years with a peak incidence at about 25

years for germ-cell testicular cancers of the teratoma (or non-seminoma) type.

For seminoma type germ-cell cancers of the testis the peak incidence is at about

35 years of age. Ovarian cancer and cancer of the cervix most commonly affect

women between the ages of 40 and 60 years, but cancer in the endometrial lining

of the uterus, is more likely to occur in women over 60 years.

Lung cancer has become increasingly common in communities where ciga-

rette smoking is prevalent. It most frequently occurs between the ages of 40 and

60, because it takes some years for the damaging effects of tobacco carcinogens

to cause changes in the air passages that lead to cancer.

Breast cancer may affect women of any age but it is uncommon in women

under the age of 30. Thereafter it increases in incidence with increasing age,

having a mean of about 60 years.

The incidence of stomach and colo-rectal cancers increases with age, reach-

ing a peak between 60 and 75 years.

Cancer of the prostate gland is essentially a disease of increasing age. It is not

often seen before the age of 50 but other than skin cancer it is the most common

cancer affecting men over the age of 65 and almost all men who reach the age of

90 years will have at least some low-grade prostate cancer cells.

Skin cancers and head and neck (mouth and throat) cancers become more

common with increasing age. Although the sun damage to skin may have occurred

many years previously and, in the case of mouth and throat cancers, the most

common association is with smoking that began many years before. Melanoma

is rare before puberty but after puberty it affects all age groups. It then becomes

a little more common with increasing age. Unlike other skin cancers that most

often occur in the skin of the face (because that skin is most constantly exposed

to the sun), melanoma is not so directly related to prolonged sunlight exposure.

Melanoma occurs most commonly on the trunk, thighs and lower limbs; sites

not constantly exposed to the sun but areas more likely to be acutely damaged by

intermittent episodes of sunburn, especially sunburn in childhood.

The strongest association with age is that for most cancers the risk of develop-

ing a cancer is greater in the older age groups. More than 70% of cancers are first

2 Epidemiology

detected in people over 65 years. This is probably because of the potential for

more genetic mutation mistakes to be made with increasing age and because these

may be made more frequently after years of exposure to toxins like tobacco.

Cancers that occur in younger age groups are often in those tissues that tend

to divide and grow more in early life including brain, nerve and blood-forming

cells and growing bone. In young adults during the most active reproductive age

groups, the testis and ovary are at increased risk.

2.7

Predisposing and Pre-Malignant Risk Factors

Abnormal tissues in general have an increased risk of malignant change.

27.1

Skin

The UV-A and B wavelengths are the major carcinogenic factors of sunlight.

Repeated sun damage to skin is often followed by thickening and crustiness of

the surface layers of the skin called “hyperkeratosis”. This can be a pre-malignant

condition and usually precedes the development of skin cancer. Hyperkeratosis

of the lips also predisposes to cancer on the lips, most commonly the lower lip

(see Figs. 14.1 and 14.2).

Melanoma commonly develops in a pre-existing pigmented naevus, or mole,

although sometimes a melanoma develops in skin where there has not been a

mole. Fair-skinned and redheaded people have a greater risk of skin cancers

including melanoma because of lack of protective pigment in their skin.

27.2

Oesophagus

Cancer of the oesophagus is more common in developing countries where

food contamination is common. However the incidence of cancer of the lower

oesophagus is now increasing in Western countries. This is often associated with

a “Barret’s ulcer”, an ulcer in the lower oesophagus likely to be associated with

persistent gastric reflux.

27.3

Stomach

People who have pernicious anaemia or chronic atrophic gastritis are six times

more likely to develop stomach cancer than other people. People with gastric-

ulcer disease do have an increased risk of stomach cancer although this was

long disputed by some gastroenterologists who believed that gastric lesions

2.7 Predisposing and Pre-Malignant Risk Factors

were either benign or malignant from their onset. Most agree, however, that the

Helicobacter pylori bacterium does sometimes cause gastric cancer as well as

gastric ulcers and that effective eradication of this bacillus with antibiotics may

well reduce the incidence of gastric cancer. The more common duodenal ulcer

does not show an increased tendency to develop into cancer.

27.4

Bowel

Polyps in the large bowel (colon or rectum) predispose to an increased incidence

of bowel cancer. A chronically inflamed bowel, such as in ulcerative colitis, has

an increased risk of developing cancer. The younger the patient at the onset of

the disease, the longer the disease has been present, and the greater the extent

of the disease in the colon, the greater will be the risk of cancer developing. In

general about 10% of people with ulcerative colitis will develop a colon cancer

after about 10 years. The risk of cancer developing in Crohn’s disease, another

chronic inflammatory condition of bowel, sometimes called granular colitis, is

also increased but not to the same degree.

27.5

Mouth and Throat

Chronic irritation of the lining of the mouth and throat, as especially seen in

smokers and sometimes in diabetics, may lead to a thickening of the surface cell

layer that shows as white patches called leukoplakia. These white patches also

have a predisposition towards the development of cancer (see Figs. 14.4a).

2.7.6 Stones: Gallstones, Kidney and Bladder Stones

Cancer of the gall bladder is not common particularly in Western countries, but

when it does occur it is almost always in a gall bladder containing stones, with

chronic irritation and inflammation in the wall of the gall bladder. Irritating stones

may also cause cancer of the pelvis of the kidney and cancer in the bladder.

27.7

Chronic Inflammation

Any chronically inflamed, chronically irritated or injured, or chronically degen-

erate (atrophic) tissue has a somewhat increased risk of developing cancer after

some years. Examples include chronically discharging wounds, burn scars, and

varicose ulcers of the lower legs, which occasionally develop malignant change,

as well as the chronically irritated lining of the mouth, throat, and air passages

of smokers in which malignant change is relatively common.

2 Epidemiology

27.8

Acute Injury

Whether malignancy follows acute trauma is not clear. There are a number of inci-

dences where tumours, especially sarcomas, have been found in tissues after some

well-documented injury such as a kick in the thigh or calf, or a blow to a bone at

football. Whether the tumour followed the injury or whether the injury simply drew

attention to a tumour that was already present is often impossible to determine.

Certainly, it must be very rare indeed for a malignant tumour to follow such an injury,

as these types of injury are very common and sarcomas of this type are rare.

2.7.9 Pre-Existing Lumps and Benign Tumours

In the case of benign tumours, there is sometimes a risk that a benign tumour

may become malignant. With some types of benign tumours, such as warts, the

risk is negligible. With the common fatty tumour, lipoma, the risk is so small

that removal of the lipoma is usually not justified. However, with others there is a

somewhat greater (but still small) risk of malignant change and surgical removal

is usually recommended. Such lesions include papilloma in the mouth or papil-

loma in a duct of a breast, or some soft tissue tumours, or adenomas of glands, or

some benign tumours of bone or cartilage. With still other benign tumours, such

as polyps of stomach or colon, papillomas in the bladder or especially papilloma

of the rectum, the risk of malignant change is of real significance and surgical

removal of these tumours is virtually always indicated.

2.7.10 Congenitally Abnormal Tissues

Congenitally abnormal tissues all have a greater risk of developing cancer than

do normally developed tissues. These include, a thyroglossal cyst (a congeni-

tal remnant of thyroid tissue high in the neck or in the back of the tongue), a

branchial cyst (a cyst resulting from a congenital developmental abnormality

in the neck) and an undescended testis (a testis that has not descended into the

scrotum at birth). The increased risks of these tissues developing a cancer are

of varying degrees. The risk is very small in the case of branchial cysts but in

the case of an undescended testis the risk is relatively high.

2.7.11 Gender

The incidence of

Obviously, cancers that occur in organs unique to one gender occur only in that

lung cancer in

gender For example, cancers of the uterus, vagina or ovary are unique to females,

women is now

and cancers of the prostate or testes are unique to males, however breast cancer,

approaching

often assumed to be associated with female breasts only, does sometimes occur

that in men.

in males. About 1% of breast cancers are in men.

2.8 Diet and Cancer: Special Dietary Preventive Ingredients

The incidence of lung cancer has increased some ten times over the past 60 or

70 years. This increase, initially in men, has been due to increased use of tobacco

products. Thirty years ago, lung cancer was ten times more common in men

than in women. However, following the trend in recent years for increased use of

cigarettes by women, the incidence of lung cancer in women is now approaching

that in men. In most Western countries, after skin cancer, breast cancer is the

most common cancer in women. However recent statistics show that in some

countries, including the US, the incidence of lung cancer in women is approaching

that of breast cancer and may become more common within a few years.

Skin cancers are more prevalent in men than in women because of the increased

exposure to the sun of men working and playing out of doors, often without a

hat or a shirt (see Figs. 10.2–10.7]. On the other hand, many cancers have a sig-

nificantly different incidence in the sexes for no apparent reason. For example in

most Western countries, but not all, cancer of the stomach is three times more

likely to occur in men than in women and cancers of the colon and rectum are

more common in males. Cancer of the oesophagus is more common in men, espe-

cially cancer of the middle and lower oesophagus; however, cancer of the upper

oesophagus is more likely to occur in women. Primary liver cancer is four times

more common in men than women. For some unknown reason, the incidence of

cancer of the pancreas has increased in the US and in other Western countries,

especially in men and mostly in men who smoke cigarettes. It is now also being

seen more frequently in women, especially in women who are smokers.

2.8

Diet and Cancer: Special Dietary Preventive Ingredients

There is an association between diet and some cancers A high fibre diet is protective

A high fibre diet

against bowel cancer. Whether this is a mechanical effect of the bulk of high fibre

is protective

alone or some other factor is uncertain. The widely accepted theory is that diets

against bowel

high in meat, animal fats and highly refined foods as in Westernised, industrialised

cancer.

countries, can produce cancer-inducing substances (carcinogens). The absence of

fibre from the diet results in a relative constipation that is thought to allow these

carcinogens to stay in contact with the bowel wall for prolonged periods.

In developing countries, the diet generally contains a great deal more roughage

and fibre with less meat, animal fat and refined foods. The already low carcinogen

content of the stool is further diluted by the bulky quantity of stool and rapidly

passed by the frequent bowel motions, resulting in a low incidence of large-bowel

cancer.

More recent studies have shown that the effect of fibre may be more than just

increasing bulk and rapid passage of bowel contents. Fibre is basically composed

of a complex carbohydrate glucan that can stimulate macrophages in healing

wounds and may stimulate immune protective macrophages in the bowel wall.

Glucan is found in high-fibre foods such as grains, fruit and vegetables but is not

present in meat, dairy products or fatty foods (Fig. 2.2).

2 Epidemiology

Fig. 2.2. Asian diets

are protective against

certain cancers

In addition to lower rates of bowel cancer associated with high fibre diets,

Asians and others who eat predominantly plant products, also have a lower

incidence of a number of other health problems that are common in Western

societies. Particularly if these diets are high in legumes like peas, beans and soy,

they contain abundant quantities of naturally occurring plant hormones called

phytoestrogens. Communities having such diets have not only less bowel cancer

but also a lower incidence of both breast cancer and prostate cancer. They also

have a low incidence of a number of other health problems in women including

osteoporosis, pre-menstrual tension and postmenopausal syndrome.

Although the evidence of a direct association between diet and cancer is

strong for cancer of the large bowel, for other cancers statistical proof that diet

is a major factor is highly suggestive but has not yet been confirmed. There are

so many variable factors between people of different population groups that it is

always difficult to prove which particular factor or factors were responsible for

any difference in the incidence of cancer. For example, as well as differences in

2.9 Stomach Cancer

diet there may be genetic differences, racial differences, environmental diffe-

rences, or differences in social habits or customs such as smoking, differences

in the incidence of parasites or infections or even in occupational stress or

psychological factors.

However the different incidences of cancer of some tissues, such as breast

and prostate, between Asians and Caucasians appear to be related to diet.

Traditionally Asians have a diet with a high content of legumes, especially peas

and soybeans. Legumes have a high content of phytoestrogens. Several studies

suggest that this may a significant factor in the relatively low incidence of breast

diseases (including cancer) in Asian females and the relatively low incidence of

prostate cancer in Asian males. This belief is supported by evidence that before

Europeans, with increasing affluence, changed from diets high in plant foods,

including legumes, to present diets high in animal products, the incidence of

breast and prostate cancer was lower than at present and that Asians who change

their diets after migrating to the US acquire an incidence of breast and prostate

cancer, approaching that of other US citizens.

Dietary phytoestrogens may also play a protective role against colon cancer

and pancreas cancer but evidence for this is less clear.

Studies especially from France, Italy and Greece have shown that anti-oxidant

properties of red wine (in moderation) and mono-unsaturated fat properties of

olive oil may also have cancer protective properties, especially in relation to breast

cancer. More recently there has been considerable interest in a substance called

lycopene found in tomatoes and some other red fruits. Lycopene is one of the

beta-carotene anti-oxidants and is responsible for the red colour of tomatoes. Labo-

ratory studies suggest it may have protective properties against a number of cancers

including cancers of the prostate, breast, lung, stomach, pancreas and bowel.

2.9

Stomach Cancer

Early in the twentieth century, cancer of the stomach was much more common

Early in the

than it is today. The reason for the decreasing incidence is not completely under-

twentieth century,

stood but it has been suggested that it may be associated with the increased use

cancer of the

of refrigeration and less use of artificial chemical preservatives such as pickling

stomach was much

and salt curing of meats and vegetables.

more common

Stomach cancer is seven times more common in Japan and Korea than in the

than it is today.

US, Canada, Britain, Australia or New Zealand. This may be genetic or due to

the high consumption of smoked fish or chemical preservatives or other food

additives or both in Japan and Korea.

An interesting comparison is the high incidence of stomach cancer in northern

Iceland where crude smoked salmon is part of the staple diet, compared to a lower

incidence in southern Iceland where the residents prepare their fish differently.

In other studies, a higher incidence of stomach cancer has been found in peo-

ple who have a highly refined starch diet and high animal fat diet as opposed to

2 Epidemiology

a lower incidence in people who eat a diet with a high content of nuts, grains,

fruit and vegetables.

2.10

Bowel Cancer: Cancers of the Colon and Rectum

In contrast to stomach cancer, for reasons already stated, large bowel cancer is

more common in Europe, the US, Britain, Canada, Australia and New Zealand

than in Asian and African countries. It has been called one of the “Western can-

cers” and is associated with a Western type diet. In Australia and New Zealand,

after skin cancer, cancers of the colon and rectum are now the most common

cancers in both sexes. As discussed above people who eat little animal fat or

refined foods and have a high intake of plant food, crude fibre and roughage

with increased phytoestrogens, have a lower incidence.

2.11

Other Cancers

Several reports have suggested a relationship between high consumption of ani-

mal fat with increased risk of several cancers not only bowel, breast and prostate

cancers but, possibly also pancreas cancers.

2.12

Vegetarian Diets

Members of the Seventh Day Adventist Church have a lower than average inci-

dence of most cancers, including cancers of the oesophagus, stomach, pancreas,

prostate, colon and rectum. However, as well as being vegetarians with a high-fibre

and low meat and animal fat consumption, these people are usually non-smokers

and non-consumers of alcohol which may well be more significant. One study

in male members of the Seventh Day Adventist Church found that those church

members whose diet included eggs, cheese and milk had a greater incidence of

prostate cancer than did those who refrained from all animal products.

2.13

Special Dietary Ingredients: Phytoestrogens and Lycopene

All plant foods contain phytoestrogens. Studies now suggest that these, especially

the isoflavone phytoestrogens of legumes, have protective properties against

breast and prostate cancers, as well as colon and possibly pancreas cancer.

In tissue culture and animal models, prostate and breast cancer cells appear

to be especially inhibited by lycopene, the anti-oxidant red-colouring matter of

2.15 Race

tomatoes and some other plant products. Laboratory studies also suggest that

increased and synergistic cancer-cell inhibitory properties are achieved if lyco-

pene is used in conjunction with beta-carotenes or vitamin D. Whether lycopene

and isoflavone phytoestrogens might also have anti-cancer synergistic activity is

also under study. Possible clinical or cancer preventive use of these agents used

synergistically is awaited with interest.

2.14

Vitamins, Anti Oxidants and Trace Elements

Direct anti-cancer protective qualities of additional vitamins, anti-oxidants, and

trace elements, are the subject of many claims, counter-claims and special studies.

Some claims of protection and cure with vitamins are undoubtedly exagger-

ated, but there is some evidence that the anti-oxidant vitamins A and C and

possibly E as well as selenium may offer some protection. More clearly however

there is general agreement that a deficiency of any of these dietary ingredients

will make people more susceptible to health problems including a greater risk

of cancer.

There is a direct relationship between the level of economic development in

a country, its diet and the incidence of cancers, especially large bowel cancer.

In developed Western countries with more dairy products, meat and animal-fat,

and less fibre, large bowel cancer is common in men and women whilst in many

developing countries with more predominantly vegetarian diets, large-bowel

cancer is rarely seen.

However the association of diet with cancers in parts of the digestive system

other than stomach and large bowel is less clear because other factors appear to

be of major significance, especially alcohol and tobacco. For example cancer

of the oesophagus, pancreas and head and neck, as well as the stomach, are all

more common in smokers but the risk is greater if they are also heavy drinkers of

alcohol. In Western countries primary liver cancer is most often seen in alcoholics

with cirrhosis of the liver although in Asian countries it is usually associated with

a history of hepatitis infection.

2.15

Race

Some cancers are more prevalent in people of some races than in other races.

Whether the significant factor is genetic or racial or whether it is more likely

due to environmental factors, diet, social habits like smoking, or other influences

such as the general health and age of the people, is often uncertain.

There are many examples of increased incidence of certain cancers in some

races and some parts of the world. These include a high incidence of stomach

cancer in Japan, Korea, and to a lesser extent in Scandinavia, Holland and

Czechoslovakia, and the high incidence of cancer of the post-nasal space in

2 Epidemiology

Chinese. There is also a high incidence of cancer of the oesophagus in certain

African tribes including the Bantu in South Africa but not in the white popula-

tion. There is a high incidence of primary liver cancer in Malaysians, East Asians

and Africans. Europeans and people of European decent have a high incidence

of breast, prostate and large bowel cancer so much so that these are sometimes

known as “The Western Cancers”.

The high incidence of melanoma and other skin cancers in northern Europeans

and especially people of northern European descent, who live in tropical and

sub-tropical climates, is due to genetic factors associated with fair skin that does

not tan readily plus the environmental factor of sunshine.

In Israel, a country with one of the highest incidences of thyroid cancer, the

disease is more common amongst Jews born in Europe than in those born in Asia.

In South Africa, Bantus have a distinctly higher incidence of thyroid cancer than

do blacks from other regions.

Whilst there are genetic influences that predispose people of different races to

develop different cancers, it is hard to know with any particular cancer whether

the most significant factors are genetic or environmental.

2.16

Geographic Associations

The incidence of a particular type of cancer varies from country to country and

even varies within countries according to geographic conditions but it is often diffi-

cult to know whether geography is the predominant cause of this difference.

The association of skin cancer and melanoma with fair-skinned people living

in a sunny climate is obvious. The incidence is highest in fair-skinned people

living in sunny climates in Australia and in the sunny southern parts of the

United States. In Australia, not only is there the world’s highest incidence of skin

cancer and melanoma but the incidence varies from state to state. It increases

proportionately with the proximity of the state to the equator. For the more

common forms of skin cancer (squamous and basal cell carcinoma) the inci-

dence is directly related to areas of skin most often exposed to the sun. These

skin cancers thus occur most frequently on the face, neck and on the backs of the

hands and arms. On the other hand, as noted above, the distribution of melanoma

is not closely related to the areas of skin most constantly exposed they are most

common on the trunk in men and on the thighs and lower limbs in women. For

melanoma the association is not especially the amount of direct exposure of skin

to sunlight but the intensity of episodes of acute sunburn, especially if episodes

of sunburn occurred in childhood.

Primary cancer of the liver (hepatoma or hepato-carcinoma) is common in

South-East Asia and East African countries but whether there is a racial predis-

position or a dietary or some other environmental factor is not known. However

it is clear that longstanding infection with hepatitis B or C are significant. It is

2.17 Environment

uncertain whether the high incidence of stomach cancer in Japan and Korea is

mainly genetic or dietary.

2.17

Environment

2.17.1 Sunshine

See Sect. 2.7.1.

217.2

Air Pollution

In Western societies, city dwellers living in a more highly polluted atmosphere

have a slightly higher incidence of lung cancer than their country cousins. This

factor, however, is not nearly as significant as the smoking habits of the people

concerned. Atmospheric pollution with asbestos in some workplaces in mining

and building industries was, in the past, responsible not only for increased lung

cancer but also for development of an aggressive cancer of pleura or peritoneum

called mesothelioma. This is further discussed below under Sect. 2.18.

Paradoxically, atmospheric pollution may produce a reduction in skin cancer rates

by reducing the amounts of ultraviolet radiation reaching the surface of the earth.

217.3

Ionising Irradiation

The increased incidence of leukaemia and some other cancers (including breast,

thyroid and skin cancers) in the survivors of Hiroshima and Nagasaki atom

bomb explosions and the Chernobyl atomic energy plant disaster, confirms the

environmental effect of ionising irradiation as a cause of some cancers.

217.4

Goitre Belts

Cancer of the thyroid is more common in communities where goitre (thyroid

gland enlargement) is common. Goitres are most common in places where there

is a deficiency of iodine in local food and water supplies. Such areas are known

as goitre belts and are usually found in mountainous regions where iodine has

been washed out of the soil over millions of years. Goitre belts are found particu-

larly in the Swiss Alps, the Rocky Mountains, the Andes, the Himalayas and

the mountainous regions of New Guinea. The Great Lakes district in the United

States is also a goitre belt. It is believed that the iodine has been washed out of

the soil in the region into the Great Lakes and lost through the rivers into the

2 Epidemiology

sea. It is also likely that in some areas, after many years of cultivation of crops,

iodine has been leached out of natural soils. Eventually it is transferred into the

sea where fish is a good source of iodine in food.

2.18

Occupation

Present-day industrial laws should protect workers against most industrial

dangers, including the risks of exposure to carcinogens. A number of cancers

were previously linked to working conditions (as discussed), but these have now

been largely eliminated.

Industrial laws compelling stringent improvements in working conditions

now protect asbestos workers from their otherwise high incidence of lung cancer

and mesothelioma.

Another less obvious risk is the increased incidence of cancer in the air

passages under and around the nose (the para-nasal sinuses) in wood workers,

leather workers, metal workers, and especially nickel workers. This is probably

due to constantly breathing small particles of these materials. There was also

said to have been an increased risk of cancer of the larynx in people who misused

their voices, such as old time bookmakers who would shout a great deal in calling

the odds, and in clergymen who would spend hours using a high-pitched chant.

However, if they truly existed, these risks would be very small in comparison to

the risk of cigarette smokers developing the same sort of cancer.

2.19

Habits and Lifestyle

2.19.1 Smoking

Lung cancer

Certainly the most striking carcinogen in present day society is tobacco. As well

in cigarette

as causing a lot of other health problems the habit of smoking outweighs all other

smokers is

known influences as a cause of serious cancer in present day men and women.

increased ten

Lung cancer in cigarette smokers is increased ten times compared to non-smokers

times compared

and the risk is directly related to the amount of tobacco smoked and inhaled.

to non-smokers.

Similarly, cancers in the mouth and throat are closely associated with smoking.

It has been estimated that heavy smokers have about six times the risk of develop-

Similarly,

ing cancer in the mouth and throat than non-smokers. The risk is increased to 15

cancers in

times if the smokers are also heavy drinkers.

the mouth

In the case of lung cancer, the risk appears to be greater in cigarette smokers

and throat

than in pipe or cigar smokers, whereas with mouth cancers there is no apparent

are closely

difference whether the smokers use cigarettes, pipes or cigars. Cigarette smokers

associated

are more likely inhale smoke into their lungs but there is a similar risk of tobacco

with smoking.

products entering the mouth with all forms of smoking.

2.19 Habits and Lifestyle

Apart from tissues in direct contact with tobacco smoke, a number of other

cancers also have increased incidence in smokers. These include cancer of the

oesophagus, stomach, pancreas, kidney, bladder, cervix and even breast cancer.

2.19.2 Alcohol

Heavy alcohol drinkers have an increased incidence of cancer of the mouth and

Alcohol does

throat, oesophagus, stomach, liver and pancreas and breast but the risk is greater

seem to

in those heavy drinkers who are also smokers. Alcohol is sometimes considered

potentiate

to be a co-carcinogen as it does seem to potentiate carcinogenic effects of other

carcinogenic

products especially tobacco.

effects of

other products

especially

2.19.3 Sun-Exposure

tobacco.

See Sect. 2.7.1.

219.4

Betel Nut

The habit of some Asian and Oriental people of chewing betel nut or tobacco leaf

or especially both together, sometimes with lime, is associated with an increased

incidence of cancer in the buccal mucosal lining of the cheek.

2.19.5 Pregnancies and Breast Cancer

The incidence of breast cancer is lowest in women who have given birth to babies

at an early age and have had multiple pregnancies. In communities where the

custom is for women to marry early and have their first babies whilst still in

their teens, the incidence of breast cancer is low, whilst in Westernised societies

where first babies are commonly born to women over the age of 30 years, the

incidence of breast cancer is higher. There may also be some protection against

breast cancer by prolonged breast feeding as is common in most developing

countries, although the evidence for this is less clear. Women who have never

had a child, such as nuns, have the highest incidence of breast cancer.

2.19.6 Cultural and Social Customs

Cultural and social customs may also have a relationship with development of

cancer.

Cancer of the penis is extremely rare in Jewish males who are circumcised

at birth but is occasionally seen in Muslim males who are not circumcised until

2 Epidemiology

about the age of 10 years. Although not a common cancer, the incidence is greatest

in uncircumcised males.

Nuns, who practice chastity, have a low incidence of cancer of the cervix of

the uterus but an increased incidence of breast cancer. On the other hand, cancer

of the cervix is more common in women who commenced intercourse at an early

age and who have had multiple male partners. Prostitutes are especially at risk of

cervical cancer. The single most significant factor, especially in prostitutes, is the

incidence of the sexually transmitted human papilloma virus.

Women who have taken the contraceptive pill for some years appear to have

a somewhat reduced incidence of developing both cancer of the ovary and

cancer of the uterus. On the other hand, prolonged use of contraceptive pills, and

especially the high-dose oestrogen contraceptive pill formerly used, has been

associated with a slightly higher risk of developing breast cancer. The low-dose

contraceptive pill presently in general use has not been shown to have any signifi-

cant association with breast cancer, some studies suggest that it may even have

some protective value.

Lifestyle in strict vegetarian, teetotal and non-smoking communities and in

different geographic, economic and racial communities has been discussed.

2.20

Psychological Factors: The Possible Role of Stress or Emotion

in Cancer Development

Among the more unusual theories for causes of cancer has been a suggestion

that like emotional and some mental (psychosomatic) illnesses, cancer may be

triggered by an unnatural suppression of the “fight or flight” response to anxi-

ety or stress. It has been suggested that if a stressful situation persists over a

long period and the person concerned feels that whatever action he or she takes

will be wrong, a subconscious decision to escape through death by cancer may

result. There is no substantial evidence to support such a theory although some

retrospective studies have indicated that a high proportion of cancer patients

have experienced some form of severe stress in the period 6 months to 2 years

before the onset of their illness.

Most

Most psychologists would not claim that stress is a direct cause of cancer

psychologists

but some consider that it may play a part alongside known chemical, genetic,

would not claim

dietary, geographic, viral or radiation causes. People become psychologically

that stress is a

disturbed on hearing a diagnosis of cancer and many need additional psycho-

direct cause of

logical support by psychiatrists, clinical psychologists, specially trained and

cancer but some

experienced nurses, social workers and other trained medical or paramedical

consider that it

health workers.

may play a part.

The belief of many “alternative” health practitioners that stress may stimulate

cancer is given as a reason by a variety of such practitioners to support practices

in faith healing, meditation or other alternative treatments.

2.21 Cancer Registries

2.21

Cancer Registries

The value of having accurate cancer records in registries kept on a national or

The value of

state basis must be stressed. Most countries try to keep registries of cancer inci-

having accurate

dence categorised by age, gender, race, income, geography, environment, culture

cancer records

and/or other relevant group, (see Appendix). They do so with different levels of

in registries

detail and different levels of success and accuracy. However it is through these

kept on a

registries that information is gathered that can often lead to valuable indications

national or

of causes of specific cancers, knowledge of people at high risk and introduction

state basis must

of appropriate public health measures to either prevent such cancers or facilitate

be stressed.

their early diagnosis and treatment. One example is knowledge of the relatively

high incidence of breast cancer in women in Western countries that has lead to

knowledge of lifestyle associations of this cancer and establishment of an aware-

ness among women, especially of the value of mammography screening clinics

and specialised breast-cancer detection and treatment centres. This has resulted

not only in better treatment outcomes but also a greater interest in supporting

research in breast cancer causes, preventive measures and treatment.

EX ERCISE

List the factors that are known to contribute to an increased cancer risk.

Summary of Practical Measures

to Prevent Cancer

Is this chapter you will learn about:

› Smoking

› Viral and bacterial protection

› Genetic protection

› Skin cancers

› Diets - cancers of stomach, bowel, breast, prostate and thyroid cancer

› Breast cancer - other potential preventive measures

› Industrial cancers

› Ionising irradiation

› Early detection and treatment of pre-malignant or potentially

pre-malignant conditions

Prevention is so much better than cure. There are many cancer preventive

measures that should become lifestyle habits but one of the most important is

for people to seek medical advice if they have any suspicion of anything going

wrong (Fig. 3.1).

3.1

Smoking

The most

obvious

The most obvious preventive measure in reducing the risk of serious cancer is to avoid

preventive

smoking. By not smoking, the risk of developing many cancers is greatly reduced.

measure in

Even spending frequent long periods in a smoky atmosphere (passive smoking) is

reducing the

associated with increased cancer risk and should therefore be avoided.

risk of serious

cancer is to

avoid smoking.

3.2

Viral and Bacterial Protection

Condoms have been the most practical way of providing an immediate practi-

cal protection against the human papilloma virus (HPP). However Professor Ian

Frazer working in Brisbane, Australia, has shown in recent trials that a vaccine

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_3, © Springer-Verlag Berlin Heidelberg 2009

3 Summary of Practical Measures to Prevent Cancer

Fig. 3.1. People should be

encouraged to seek early

advice about any suspicious

lesion

against the human papilloma virus has given a 100% effectiveness in immunity

to the virus that is responsible for most cancers of the cervix and some skin

cancers. Hence in the future people at risk, especially girls and young women

who are sexually active or approaching sexual maturity, will be advised to have

immunization against the human papilloma virus.

Vaccination against Hepatitis B is also a cancer-protective measure. Wide-

spread vaccination programs are currently being conducted in several countries.

3.3

Genetic Protection

Expert advice is now realistically worthwhile for avoiding or reducing the risk

of inheriting or passing on a genetic risk (Chap. 2).

3.4

Skin Cancers

The risk of the common skin cancers - basal cell carcinoma (BCC) and squamous

cell carcinoma (SCC) - can be greatly reduced by avoiding unnecessary direct

exposure to sunshine or other forms of ultra-violet light such as in solariums.

Nature’s protection is pigment in the skin in coloured races. For fair-skinned

people, the use of wide-brimmed hats, long-sleeved shirts and other appropriate

clothing plus ultra-violet filtering skin lotions or creams offers considerable

protection. The same measures may help to avoid melanoma to some extent but,

intermittent and severe episodes of sunburn should especially be avoided by

young people. Sunburn causes permanent damage to the immune defence cells

in skin called Langerhan’s cells.

3.5 Diets: Stomach and Bowel Cancer, Breast Cancer

3.5

Diets: Stomach and Bowel Cancer, Breast Cancer

3.5.1 Prostate Cancer

As previously discussed important factors of diet are the proportions of natural

fibre and animal fat and the presence of chemical preservatives or other chemicals

in food. Diets that are high in fibre (including cereals, nuts, grains, fresh fruit

and vegetables) and low in meat, animal fat, highly refined foods and chemically

preserved foods, offer some protection against development of stomach, bowel

and possibly pancreatic cancers as well as breast and prostate cancers. Apparently

protective factors may include the dietary amounts of phytoestrogens, lycopenes,

anti-oxidants, certain vitamins and trace elements. These and some other ingre-

dients are under study but as yet no firm conclusions can be made.

The amount of fat in the diet, especially saturated animal fat, ideally should be

lower than in most present Western diets. Omega-3 oils present in oily fish (e.g.

salmon, sardines, mackerel, tuna) and soya beans and kidney beans, may have

some protective effect against the development of cancer and also against the

latter stages of some cancers where there is dramatic loss of weight.

3.5.2 Thyroid Cancer

The addition of iodine to the diet (usually as iodised salt) in iodine-deficient “goitre belt”

areas reduces the incidence of goitre and to some degree the risk of thyroid cancer.

3.5.3 Dioxins

Plastic containers of foods and fluids, especially fatty foods, have been under

study as having possible carcinogenic potential. There have been recent recom-

mendations to avoid heating fatty foods in plastic containers in microwave ovens.

It has been recommended that plastic containers are better avoided for long-term

storage of fatty foods; glass or ceramic containers are recommended.

3.5.4 Breast Cancer

Encouragement of breast-feeding may be of some help in reducing the inci-

HRT can

dence of breast cancer, so too is regular exercise, avoiding obesity, not smoking

slightly

and attention to diet. Especially breast-screening is widely encouraged as an

increase

anti-breast-cancer measure. Whilst regular self-examination is encouraged and

the risk of

may reveal an otherwise unnoticed breast lump women should be advised that

subsequent

it must not be regarded as an alternative to regular mammography in screening

development of

for early cancer; that is women and doctors too, should not assume that cancer

breast cancer.

cannot be present because they have not felt a breast lump (Fig. 3.2).

3 Summary of Practical Measures to Prevent Cancer

Fig. 3.2. Palpation of breasts in the bath

or shower with wet soapy fingers is a

good method of self-examination

In the past it was common practice to help relieve post-menopausal symptoms

with small doses of hormone replacement therapy (HRT). It is now known that

if used over 5 years or more HRT can slightly increase the risk of subsequent

development of breast cancer so that if such treatment is now prescribed at all, it

is only to treat postmenopausal women with symptoms that cannot be relieved in

some other way. Even then it is given for a limited period of time only.

3.6

Industrial Cancers

Industrial laws that protect workers from a number of known industrial carcino-

genic agents, such as asbestos and certain chemicals especially in the petroleum

and pest control industries, play a significant role in cancer prevention.

3.7

Ionising Irradiation

The lessons of irradiation from atomic bomb explosions and the Chernobyl

atomic plant disaster in causing cancers have been well documented, as has the

need to avoid excessive irradiation from X-ray plants or nuclear energy plants.

There has also been much discussion and study about risks of living near high

voltage wires, microwave irradiation and of mobile telephones (cell phones) but

as yet the studies are inconclusive.

3.8 Treatment of Pre-Malignant and Potentially Malignant Lesions

3.8

Treatment of Pre-Malignant and Potentially Malignant Lesions

3.8.1 Pre-Malignant Conditions

Treatment of any long-standing ulcers or chronically inflamed or irritated lesions

All people

may prevent development of cancer. This may involve such different lesions as

affected

long-standing varicose ulcers and ulcers in the mouth from a jagged tooth. Good

by familial

care should also be given for gastric ulcers, persistent gastric reflux, ulcerative

polyposis coli

colitis of the colon or rectum, long-standing gallstones, kidney or bladder stones

will eventually

or chronically discharging sinuses such as from osteomyelitis. Certain skin

develop colon

lesions may also need attention including a pigmented skin lesion that is chroni-

cancer.

cally irritated by virtue of its position under a belt or bra strap or a pigmented

lesion under a fingernail or on the sole of the foot.

Another preventive measure is to remove or otherwise properly treat known

pre-malignant conditions such as polyps, papillomas, hyperkeratotic skin lesions,

leukoplakia in the mouth or moles that show any sign of irritation or change,

especially in irregular dysplastic lesions.

Benign tumours that show any evidence of enlarging or that are known to

have a risk of malignant change, should be removed to reduce the risk of cancer

developing. Such tumours might include dysplastic naevi on the skin, adenomas

in the parotid or thyroid glands, papillomas or adenomas in the breast, cysts in

the ovary, papillomas or polyps in the stomach, colon, rectum or uterus, papil-

lomas in the bladder, or enlarging soft-tissue tumours of fat (lipomas), nerve

tissue (neuromas), muscle (myomas), tumours of blood or lymph vessels (heman-

giomas or lymphangiomas) and occasionally of cartilage (chondromas) or bone

(osteomas).

Total removal of the colon and rectum before cancer has developed will

prevent cancer in those people affected by familial polyposis coli.

Symptoms of Cancer: Local and General

In this chapter you will learn about:

› Lump, ulcer, pain, bleeding, interference with tissue or

organ function, unexpected weight loss

› Symptoms of metastatic spread: lymph-nodes, liver,

lungs, bones, fat and muscles, bowel, the brain, the

“unknown primary” syndrome

A symptom is something that is reported or felt by a patient. A sign is something

that can be observed, felt, measured or otherwise demonstrated by another per-

son. Symptoms may result from two effects of a cancer - first the local effects of

the cancer itself, and second, the more general effects of the cancer as it affects

the person’s body as a whole.

Usually local effects are noticed first. The main local effects include one or

more of the following - a lump; an ulcer that does not heal; a persistent cough

possibly with blood stained sputum; persistent local pain; abnormal bleeding

from the stomach, bowel, bladder, vagina or elsewhere; or interference with

function of the organ or tissue involved. Such functional interference may be

seen in obstruction of the bowel in the case of bowel cancer, persistent cough or

interference with breathing in the case of lung cancer, difficulty with swallowing

with oesophageal cancer or difficulty with passing urine in the case of prostate

cancers. These symptoms of local trouble will thus depend upon the site of the

cancer; the organ or tissue in which it started; the type of cancer cells that have

developed; the size of the tumour; and the possible involvement of other organs

or tissues near to the cancer.

The main general effects that may be noticed by a person with cancer are

lassitude, malaise, fatigue and loss of energy, anorexia and weight loss. General

symptoms are usually related to advanced cancers and may result from damage

to, or interference with, function of any organ or tissue involved, as well as the

body’s reaction to the presence of cancer.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_4, © Springer-Verlag Berlin Heidelberg 2009

4 Symptoms of Cancer: Local and General

In Part 3 each of the above features will be mentioned in more detail in

relation to various cancers, but some general features are outlined below.

4.1

Lump

A lump, swelling or tumour of some sort is present in virtually every cancer but

the lump may or may not be noticed by the patient or be able to be felt by the

doctor. The lump may be obvious if it is in the skin, head and neck (e.g. mouth

or tongue), breast, lymph nodes or fat, muscles or bone (especially in an arm

or leg). On the other hand, most lumps are non-malignant, but if a new lump is

found anywhere in the body it is important to determine what it is. The most

common symptom of breast cancer, for example, is finding a lump in the breast.

The lump is often felt whilst the patient is in the bath or shower, because most

breast lumps are more easily felt with wet soapy fingers.

4.2

Ulcer

If there is any

An ulcer in the skin that does not heal readily may be a cancer and should be

doubt about

examined carefully. Skin ulcers are usually noticed easily but ulcers in the mouth

the origin

or throat may be less obvious, especially if they are painless. Any such ulcer may

of an ulcer

be of potential concern if it has been present for more than 2 or 3 weeks with no

arrangements

evidence of healing. However, it should be remembered that most long-standing

should be made

ulcers are not malignant. Chronic ulcers may be caused by such conditions as

to perform

varicose veins or poor arteries giving poor blood supply to the lower legs or by

a biopsy.

repeated trauma such as a jagged tooth, ill-fitting dentures or infections in the

mouth. If there is any doubt about the origin of an ulcer arrangements should be

made to perform a biopsy. This involves taking a small piece of tissue, usually

from the edge of the ulcer, and examining it microscopically to be sure exactly

what cells are present and what sort of ulcer it is and what has caused it.

In general, a

4.3

Pain

small painless

lump is more

Most cancers are painless in their early stages. Pain may develop after a tumour

likely to be a

has become big enough to invade or to press upon and damage surrounding

cancer than a

tissues or nerves. In general, a small painless lump is more likely to be a cancer

small painful

than a small painful lump and people should not wait for pain to develop before

lump.

seeking medical advice.

4.5 Weight Loss

4.4

Bleeding

Intermittent bleeding can be a feature of many cancers of surface tissues. For

some internal cancers such as the stomach, bowel, kidney, bladder, uterus or

lung, bleeding is often the earliest or one of the earliest features. Any evidence

of abnormal bleeding should be investigated. For example, bleeding from the

bowel may be fresh blood that is bright red or it might be altered blood that is

dark red or black. Other sites of bleeding may be in the urine, from the vagina

(especially between periods or after the menopause), in the sputum (either from

the mouth or throat or from the lung after coughing), from a mole in the skin,

or from a nipple. While bleeding may be an indication of cancer, it does not

necessarily mean cancer; there are many other causes of bleeding. Bleeding or

bruising at several sites or small haemorrhagic spots in the skin (petechial spots)

may be an indication of a blood disorder including those caused by leukaemias

or lymphomas.

Weight loss

4.5

Weight Loss

is due to

abnormal and

Approximately two-thirds of all cancer patients will experience weight loss,

inefficient

and in many cases this is the first symptom that prompts them to visit their doctor.

metabolism

An involuntary weight loss of greater than 5% in 6 months is often a prognostic

of glucose.

indicator for cancer.

The weight loss is often associated with anorexia (premature satiety or lack of

Weight loss is

interest in food), but this is not the cause, as the weight loss is much more dramatic

pre-dominantly

than the actual reduction in calorific intake. The weight loss is due to a condition

from adipose

known as cancer cachexia, and the patients look gaunt and malnourished. Cancer

tissue and

cachexia is caused by a tumour becoming metabolically adapted to the anaerobic

skeletal muscle,

utilisation of glucose (glycolysis), such that it consumes a lot of glucose and

but it is the

produces a lot of lactic acid (as muscles normally do under intense activity). The

loss of muscle

lactic acid is taken away by the blood and is used in the liver to newly synthesize

mass that

glucose (by gluconeogenesis) and requires three times as much energy as that

causes death.

yielded by glucose consumed anaerobically. In effect glucose becomes part of

a futile and expensive cycle (the Cori cycle) in addition to anaerobic utilisation

representing only ~6% of the energy yielded from glucose in aerobic conditions.

With generally a reduced energy intake and an increased energy expenditure (to

recycle the glucose) the body needs energy and it obtains it via breaking down

fat reserves in adipose tissue and proteins in skeletal muscle. Patients can lose up

to 30% of their pre-illness weight, and up to 75% of skeletal muscle protein. It is

the loss of skeletal muscle that leads to asthenia (muscle weakness), which can

affect breathing and heart function, and is often the cause of death. The weight

4 Symptoms of Cancer: Local and General

loss is not related to the size of tumour because it is directly related to cytokines

(small proteins that act like hormone) produced by either the tumour and/ or the

host immune system. Cancer cachexia is most commonly seen in children and

the elderly, and cancers such as gastric, pancreas, lung and prostate cancers, but

is rare in breast cancer and sarcomas. This involuntary weight loss is associated

with poor prognosis and a poor response to chemo- and radio-therapy.

4.6

Interference with Tissue or Organ Function

These symptoms vary a great deal depending upon the site of a cancer. For

example a cancer in the mouth or throat may make speaking or swallowing

difficult. A cancer of the larynx will usually cause hoarseness or change in voice.

A cancer of the oesophagus is usually first noticed because of difficulty with

swallowing, initially of solid food and later of liquids. A cancer of the stomach

may cause difficulty with eating or a change in appetite or vomiting, and a cancer

of the bowel may cause a change in bowel habits (diarrhoea or constipation

or alternatively intermittent diarrhoea and constipation) or may partially or

fully obstruct the bowel causing colic, in the first instance and possibly bowel

perforation in the second.

Cancer of the prostate may interfere with the passage of urine, and cancer of

the bladder may also cause difficulty or frequency of passing urine.

Cancer of the lung may cause a persistent cough, local obstruction of air

passages or localised pneumonia.

Cancers of the liver, bile ducts or pancreas may block the flow of bile from the

liver, causing jaundice.

Obviously, there are many other causes of these symptoms but if any of them

is noticed for the first time in someone who was otherwise well, especially if the

symptoms persist, they should be investigated promptly and thoroughly.

4.7

Symptoms of Metastatic Spread

These symptoms will depend upon the tissues or organs into which the cancer

has metastasised.

Enlargement

of lymph nodes

47.1

Lymph Nodes

may sometimes

be the first

A common site of spread is to nearby draining lymph nodes in the neck, axillae,

feature of the

groins or elsewhere depending on the site of the primary cancer. Enlargement

presence of a

of lymph nodes may sometimes be the first feature of the presence of a cancer

cancer nearby.

nearby (see Fig. 22.1).

4.7 Symptoms of Metastatic Spread

47.2

Liver

Spread of cancer to the liver may cause jaundice or pain as well as swelling in

the upper abdomen under the ribs on the right side. It may also lead to malnutri-

tion with wasting and weight loss, or to fluid (ascites) collecting in and possibly

filling the abdominal cavity.

47.3

Lungs

Cancer that spreads to the lungs may cause a cough, difficulty with breathing,

fever, pneumonia or chest pain.

47.4

Bones

Spread of cancer to bones may cause bone pain or a fracture. Metastases in

spinal vertebrae risk spinal cord compression and paralysis. Bone metastases

sometimes cause anaemia due to destruction of the blood-forming bone marrow

tissues and hypercalcaemia may result from release of calcium from damaged

bones.

47.5

Fat and Muscles

Metastases to soft tissues may cause swelling or lumps that may be felt under

the skin.

47.6

Bowel

Spread to bowel or elsewhere in the abdominal cavity may cause bowel obstruc-

tion with colic or swelling and fluid in the abdominal cavity (ascites).

47.7

The Brain

Cancer that spreads to the brain may cause severe headaches, vomiting, blurred

vision, confusion, fits or unconsciousness, convulsions or coma.

4.7.8 The Unknown Primary Syndrome

A patient will sometimes notice symptoms associated with a cancer metastasis

without being aware of trouble at the site of a primary cancer. For example a

woman may first complain of a lump in her axilla. A biopsy has shown this not

to be a primary lymph node tumour, but a lymph node containing metastatic

breast cancer, although she was not aware of any breast problem, and no lump

can be felt in the breast. A patient may complain of a lump in the neck that is

found to be caused by metastatic involvement of nodes from a cancer in the

Signs of Cancer: Local and General

In this chapter you will learn about:

› Lump, ulcer, bleeding and evidence of blood loss,

lymph node enlargement

› Other swellings

› Findings of general examination including examination

of mouth, throat, abdomen, rectum and anus

› Rare and seemingly unrelated indications of cancer

Physical signs of cancer include local lumps or other abnormal swellings, ulcers,

tender or painful areas, evidence of blood loss from bowel, urine, uterus, etc.

and general effects on the patient such as weight loss, pallor, and general unwell

appearance. There may also be evidence of cancer spread to other organs or tis-

sues (metastases). Different cancers tend to spread in a usually predictable way

to different organs or tissues but no matter what signs are present the only proof

of cancer depends on a biopsy demonstrating the presence of malignant cells.

5.1

Lump

It is important to recognise features of lumps that are most likely to be associ-

Cancer lumps

ated with cancer in general and particular forms of cancer. For example, cancer

are usually not

lumps are usually harder than lumps from other causes. Cancer lumps usually

tender unless

are not cystic (although on occasions they may be) and they are usually not

quite advanced.

tender unless quite advanced. As they enlarge, cancer lumps adhere to and invade

nearby structures and therefore become less mobile.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_5, © Springer-Verlag Berlin Heidelberg 2009

5 Signs of Cancer: Local and General

5.2

Ulcer

Malignant ulcers often have raised or heaped up edges. They tend to grow into

nearby tissues on which they lie and there is usually surrounding swelling and

induration. They may bleed easily but usually not profusely. They may or may

not be tender. Ulcers due to skin cancer are usually not tender, whereas malignant

ulcers in the mouth and throat, usually become quite tender in the later stages.

5.3

Bleeding and Evidence of Blood Loss

There may be obvious blood loss or hidden (occult) blood loss with evidence of

anaemia due to chronic blood loss. Blood in the faeces may be detected chemi-

cally even when it is not obvious to the naked eye and this may be an early feature

of cancer of the stomach or bowel. In fact occult blood loss is often used as a

screening test for people with a high risk of developing gastric or bowel cancer

even though they may have no symptoms.

Blood in the urine may sometimes be found on microscopic examination of

the urine even when it is not obvious to the naked eye. This can be a feature

of cancer of the kidney or bladder although there are also other more common

causes of blood in the urine.

5.4

Lymph Node Enlargement

Evidence of

Evidence of metastatic spread of cancer may be revealed by examination of the

metastatic

draining lymph-node areas. For example, if a head and neck cancer is suspected

spread of the submandibular, submental and cervical (neck) nodes must be examined

cancer may be

(Fig. 5.1a, b). If breast cancer or cancer of the skin of the arm or chest wall is

revealed by suspected, the axillary lymph nodes must be examined. If cancer in the lower

examination limb or of the skin of the abdomen or lower back, scrotum, anus or vulva, is

of the draining

suspected the inguinal lymph nodes must be examined.

lymph-node

Abdominal lymph nodes may be involved from cancers of the stomach, bowel,

areas.

pancreas, testes, uterus, ovaries or elsewhere in the abdominal cavity but these

are usually not palpable unless very large. Nowadays they are often first seen in

CT studies. Sometimes lymphatic channels allow a tumour to spread from the

abdominal organs to supraclavicular lymph nodes in the neck (usually the left

side), so these too need to be examined; they are easily felt if enlarged. The name

given to a palpable metastatic lymph node in the lower neck from a primary

cancer in the abdomen or pelvis is Virchow’s node. Finding this node to be pres-

ent is called Trousseau’s sign.

Lymph nodes in the chest may be involved from cancers of the lung or oeso-

phagus or sometimes the breast. Although these cannot be felt with the hands,

5.6 Findings of a General Examination Including Mouth, Throat, Abdomen, Rectum and Anus

Fig. 5.1. (a, b) Enlarged cervical (neck) lymph nodes that became obvious 3 years after

apparently successful treatment of a squamous cell cancer of upper lip

evidence of mediastinal node enlargement can sometimes be seen in a chest

X-ray or in CT studies.

Lymph nodes may also be enlarged in the lymphomas or leukaemias. If

enlarged, these lymph nodes are usually somewhat rubbery, and less hard than

nodes involved with cancer. They are also likely to be smoother in outline, less

likely to become fixed to other structures and often lymph nodes on both sides

of the neck or lymph nodes in other places may also be involved. The spleen also

behaves like a large lymph node, and although a normal spleen cannot be felt, it

may become enlarged and palpable in patients with a lymphoma or leukaemia.

5.5

Other Swellings

There can sometimes be evidence of lumps or swellings due to metastases in

other parts of the body, especially a subcutaneous lump or a lump in the

abdomen, the liver or any other tissue or organ. Metastases in such sites can

arise from virtually any cancer.

5.6

Findings of a General Examination Including Mouth,

Throat, Abdomen, Rectum and Anus

Part of the examination of the alimentary tract should be an examination of the

mouth, tongue and throat, and most importantly, an examination inside the anus

with a gloved finger. Most cancers of the rectum can be felt with a gloved finger

in the rectum and many other conditions such as an enlarged or lumpy prostate,

5 Signs of Cancer: Local and General

an enlarged uterus or tumour in the pelvis can be felt by this simple examination

or by a bi-manual examination: a finger in the rectum (or vagina) and the other

hand palpating the lower abdomen. Also by examining the glove used, the colour

and nature of the faeces and presence of blood that can be seen and an abnormal

finding might give a clue about the possibility of a cancer being present.

5.7

Rare and Seemingly Unrelated Indications of Cancer

Very occasionally an apparently unrelated health problem may be the first evi-

dence of an occult cancer. An unexplained anaemia is the most common, but

a neuropathy or other neurological disorder or the onset of herpes zoster in an

elderly person may indicate a weakened immune response possibly associated

with an undetected malignancy. An unexplained deep vein thrombosis with

no obvious initiating factors may occasionally be the first clinical feature of a

cancer (Fig. 5.2).

Fig. 5.2. A typical out-

break of herpes zoster

(shingles) that was the

first evidence of this

72-year-old man’s cancer

of pancreas

EXERCISE

List patient signs that are commonly associated with cancers.

Clinico-Pathology of Cancers

In this chapter you will learn about:

› Typing, grading and staging of cancer

› Clinical decisions based on pathology information

The ultimate diagnosis of any benign or malignant tumour will depend upon a

pathologist’s examination of a specimen of tissue. This can be a surface scrap-

ing of tissue, a small sample of cells taken by aspiration with a syringe, a small

core of tissue taken with a small core cutting instrument, a small sample of

representative tissue (incision biopsy) taken by a surgeon using a scalpel or other

cutting instrument or even the whole tumour mass (excision biopsy) taken by

a surgeon. The ultimate diagnosis is sometimes not confirmed until after death

of the patient with specimens taken at autopsy.

No matter how the tissue sample is taken, the pathologist will, if possible,

report on the macroscopic as well as the microscopic features of the tissue

and its cells. Before the pathologist can report on the microscopic features of

the tissue and cells in it, the tissue must be prepared in a solid block, usually a

wax block, so that fine sections can be cut. The prepared tissue will be stained

with appropriate stains to best display special features. Unless immediate

cell smears or frozen section specimens (described later in this chapter) are

prepared, most tissue preparations and staining procedures require at least

24 h and usually 2-3 days.

The pathologist will be able to report not only on the type of tissue but whether

it is normal or abnormal tissue and if abnormal, whether it shows features of a

tumour - benign or malignant.

If it is found to be a malignant growth the pathologist will report on the range

of relative normality and maturity of cells in it (i.e. the degree of anaplasia), and

other more abnormal and aggressive features. If possible, a sample of surround-

ing tissue should be taken with the biopsy specimen so the pathologist can also

report on the degree of invasion or infiltration of cancer cells into surrounding

or underlining tissues.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_6, © Springer-Verlag Berlin Heidelberg 2009

6 Clinico-Pathology of Cancers

6.1

Typing, Grading and Staging of Cancer

Best management of cancer will depend on many factors including patient fac-

tors (age, state of health, family, social and emotional considerations), hospitals

or other treatment facilities with or without specialised nursing care and allied

health professionals, as well as particular factors of the cancer itself.

The cancer factors include three special pathology considerations: the type,

grading and staging of the cancer. These will be made with information provided

by both the pathologist and the cancer treatment team.

6.2

Cancer Typing

The treatment team depends on the pathologist for confirmation of the presence

of cancer, the cancer type and other features of the cancer. The most common

malignancies are carcinomas from cells of epithelial surface or glandular type

and usually retaining some of the features of these types of cells.

Other malignancies include those of connective-tissue cell origin (sarcomas),

germ-cell origin (testicular cancers and some ovarian cancers) and blood-

forming cell origin (leukaemias and lymphomas). Malignancies that do not

readily fit into any of the preceding group types include gliomas of brain and

myeloma, an uncommon tumour that develops in bone but is not of bone cells.

Myeloma or multiple myeloma is a malignancy of plasmacytes in bone.

The pathologist will recognise features of these various types of cells. Often

they are obvious to the expert and closely resemble their tissue of origin but

sometimes there is so much anaplastic change it can be very difficult or impos-

sible to recognise the original cell type. Special facilities such as use of special

stains, electron-microscopy or immunochemistry can be helpful in making a

more accurate tissue typing determination.

In cases where the site or history of an original primary cancer is uncertain

the pathologist might also be of special help in deciding whether malignant

tissue in a biopsy is from a primary cancer or has features indicating that it is

more likely to be metastatic tissue.

6.3

Cancer Grading

Cancer grading gives an indication of the likely aggressiveness of the cancer.

In general, highly differentiated tumour cells that closely resemble their cells of

origin may be either benign or may be very low-grade cancers with little tendency

to grow rapidly or to metastasise early. Whereas poorly differentiated, anaplastic

cancer cells that have often lost all special features of their tissue of origin are

6.4 Clinico-Pathological Staging of Cancer

much more likely to behave in an aggressive fashion and invade nearby tissues

as well as to metastasise to other sites.

In general, cancers that remain localised, or invade surrounding tissues by

pushing into them and infiltrating only as a continuous growth, are less aggres-

sive than cancers with cells that break free from the original tissue of origin and

invade more deeply into surrounding tissues.

Nuclear pleomorphism is the degree to which cell nuclei vary in size, shape

and in staining patterns. The more pleomorphic the cell nuclei, the more aggres-

sive the likely behaviour of the cancer.

Along with the number of pleomorphic cells, the number of mitotic figures

(indicating dividing cells) gives an additional indication of the aggressive poten-

tial of the cancer.

Sometimes the cancer growth is surrounded to a greater or lesser degree of

infiltration by lymphocytes. Such lymphocytic infiltration may give an indication

of natural body immunological defence against the cancer and therefore a poten-

tially lower grade of cancer than one with no evidence of a protective reaction.

With these features all considered: well differentiated or poorly differentiated

cancer cells, presence or absence of cancer cells separating from the primary

cancer site and infiltrating into surrounding tissues, the degree of nuclear pleo-

morphism, the number of mitotic figures and the amount of lymphocytic reaction,

the pathologist will be able to give an indication as to the potential for aggres-

sive behaviour of the cancer. That is the grade of the cancer from low grade and

less aggressive to high grade and a potentially more aggressive cancer. This all

depends on a truly representative biopsy sample being made available to the

pathologist. The grade of the cancer may be different in different samples of

tissue. In general the cancer growth pattern is likely to follow the highest grade of

tissue sample rather than the lowest so that the grade report given by the patholo-

gist will depend on the highest grade of cancer tissue seen.

6.4 Clinico-Pathological Staging of Cancer

Cancer type and cancer grading will depend on findings of the pathologist. The

Cancer staging

third important pathology information is the staging of the cancer and this will

expresses

depend on combined information of pathologist and surgeon or clinical team.

how much the

Cancer staging expresses how much the cancer has grown and has spread

cancer has

from its site of origin. The important elements of the most commonly used clini-

grown and has

cal staging indices are:

spread from its

site of origin.

1. Local primary growth: The size of the tumour and the extent of its spread

into local tissues is indicated by the letter “T” and the scale of 1-4; T1 being

a small localised cancer; T4 being an advanced cancer that is destroying

surrounding tissues and unlikely to be curable.

6 Clinico-Pathology of Cancers

2. Lymph-node involvement: The extent of spread into the nearest local lymph

nodes or more distant lymph nodes in the region is indicated by the letter “N” and

the scale 0-3. NO indicates no lymph node involvement; N1 indicates involve-

ment of adjacent lymph nodes only; N2 indicates that a further set of lymph

nodes is involved; and N3 indicates distant involvement of lymph nodes.

3. Metastatic growth: Evidence of metastatic spread (usually by bloodstream)

into distant organs or tissues is indicated by the letter M and the scale 0-1.

MO indicates no evidence of metastatic growth in distant tissues and M1

indicates metastatic spread into one or more distant sites.

The best prognosis cancers are T1, N0, M0 and the worst prognosis cancers are

T4, N3, M1.

The symbol X is used to indicate an uncertainty of classification. When there

is insufficient information to classify one or more of the clinico-pathological

stages the symbol X is used. TX suggests that there was not sufficient informa-

tion to make a staging of the primary tumour; NX indicates that node staging was

not known; and similarly MX suggests that evidence for or against the presence

or absence of metastases was not known.

Tumour staging can be based on clinical assessment compiled after all clinical

information is known. This is clinical staging. Alternatively staging may be based on

the pathologist’s examination of tissue biopsies. This is pathological staging. Clinical

staging is more readily available to the examining doctor but ultimate decisions are

better based on pathological staging which should be more accurate.

6.5

Clinical Decisions Based on Pathology Information

All of these pieces of pathology and clinical pathology information together

with knowledge of the habits of cancers of different tumour types will allow the

medical team responsible for the patient’s care, to make an assessment of the

prognosis for the patient as well as the most appropriate treatment schedule and

likely response to treatment. However in each case advice must be modified by

the knowledge that not every tumour will respond in a predictable way. With

few exceptions, advice about likely response should be guarded and given in

general terms only. Usually statistical likelihood is the most appropriate method

of making clinical decisions and in giving clinical or prognostic advice.

Sometimes special tests on biopsy tissue will indicate appropriate treatment

choices. For example tests of breast biopsy tissue for hormone receptor activity,

oestrogen receptor ER or Progesterone receptor PR can indicate a likely response

to hormonal management if positive. ER +ve and PR +ve cancers are more likely

to respond to hormone management than ER −ve and PR −ve breast cancers.

Another more recent test, an immuno-histochemistry test for HER2 growth

receptors, is for likely response of breast cancers to Herceptin. If there is an over-

expression of extracellular growth receptors on the cell surface then Herceptin is

recommended for treatment, as it targets the cancer cells for destruction.

Investigations That May be Useful

in Detecting Cancer

In this chapter you will learn about:

› Screening tests

› Organ imaging

− X-rays, isotopes, CT, ultrasound

− MRI (magnetic resonance imaging)

› PET (positron emission tomography)

› Indirect evidence of cancer blood and serum tests

› Direct evidence of cancer biopsy

A large range of tests is now available to help detect cancer. Some of the

most useful of these became available only during the last decade or two of

the twentieth century. These range from screening tests, that may help detect

the possibility of cancer in people who are at risk but without any symptoms,

to organ-imaging tests when symptoms are being investigated. Helpful tests

include X-rays, CT scans, ultrasound scans, isotope scans, MRI scans and

PET scans. Each of these may reveal the presence, the site and likely dimen-

sions of a deep-seated tumour. Endoscopic tests that use flexible mirrored

endoscopic tubes allow the operator to look at, photograph and even biopsy

lesions in the alimentary tract, thorax, peritoneal cavity or in other body

cavities. A number of blood and serum tests may reveal evidence of reactions

to a tumour somewhere in the body. The ultimate investigation, however,

is a biopsy because microscopic examination of biopsied material can very

often tell the type of malignant cells and the organ or tissue from which they

originally developed, as well as the degree of anaplasia or potential aggres-

siveness of the cancer.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_7, © Springer-Verlag Berlin Heidelberg 2009

7 Investigations That May be Useful in Detecting Cancer

7.1 S creening Programs

Screening programs are simple, non-invasive and relatively inexpensive methods

of detecting early cancers in people in high-risk categories. Early detection before

symptoms or signs of cancer have become evident results in significantly better

prospects of cure. When certain cancers are known to have a high incidence

in a community, governments and health authorities have established on-going

screening programs in many countries.

7.2 S creening Tests

7.2.1 The Cervical Smear or “Pap” (Papanicolaou) Test

One of the first, and still one of the most useful, specific screening tests is the

Papanicolaou (cervical smear) test for detecting early cancer of the cervix of the

uterus. Cancer of the cervix is the most common cancer of the uterus. Women

over the age of 40 and especially those who have had several sex partners or

several pregnancies are at increased risk for this type of cancer, and many

such women now have a cervical smear test every year. Women who have been

exposed to infection with the human papilloma virus, especially sex workers

who have had multiple male partners, have the greatest risk and should be tested

more frequently. This test has the advantage of being simple, painless, cheap, and

in most cases, highly reliable. In this test a swab or scraping is taken from the

uterine cervix through the vagina. Fluid from the swab or scraping is smeared

over a glass slide and examined for cells. If malignant cells are found, cancer

may be detected early and treated with good results. Other abnormal cells may

suggest pre-malignant changes that could become cancer if not treated, so simple

treatment at that stage can often prevent a cancer developing.

7.2.2 Occult Blood Tests

A number of chemical and other tests have been used to detect small amounts of

blood in the faeces. As stated earlier, blood in the faeces that is not obvious to the

naked eye, is called “occult blood”. Its presence indicates some abnormality in the

stomach or bowel that might be a cancer or possibly a pre-cancerous condition

such as a polyp. Occult blood tests are not always reliable and sometimes produce

false-negative and false-positive results. Positive tests can be caused by a number

of inflammatory or other benign conditions. However occult blood tests can be

useful screening tests to help detect people who are most at risk of cancer and help

determine those in need of further investigation. For people with a high risk of bowel

cancer regular screening of the colon and rectum by colonoscopy is advisable.

7 Investigations That May be Useful in Detecting Cancer

7.2.4 Breast Screenings: Mammography

Although there is no Other than skin cancer, breast cancer is the most common cancer in women

single screening test

in most Western countries. Although there is no single screening test that is

that is totally reliable,

totally reliable, a number of tests can be combined to help detect early breast

a number of tests cancer. These include the teaching of self-examination and examination for

can be combined lumps in screening clinics by a doctor or specially trained nurse. Mammog-

to help detect early

raphy, ultrasound studies and biopsy using a fine needle or similar instrument

breast cancer.

to aspirate or otherwise remove a sample of fluid or cells from any suspicious

lump for microscopic examination, are important screening tests. These are

often performed in special clinics supported by government-funded screening

programs. Most large cities in developed societies now have breast-screening

clinics in a city hospital or elsewhere in conveniently located central positions

(Figs. 7.1 and 7.2).

7.2.5 Skin Cancer Screening: Especially the “Mole Check”

In countries where skin cancer is common, annual “mole checks” are often

arranged for members of clubs or particular workforces. This is now commonly

practised in many Australian surf clubs. Although called “mole checks”, with

particular interest in detecting early melanoma, many “non-mole” pre-malignant

Fig. 7.2. Mammogram showing a

rather dense area of breast with a

cluster of spicules of calcification

suggestive of breast cancer

7.3 O rgan Imaging

or early malignant lesions of skin are detected, especially hyperkeratoses, basal

cell carcinomas and squamous cell carcinomas.

7.2.6 PSA Screening Test

Other than skin cancer, prostate cancer is the most common cancer affecting

men in Western societies. It is not common before the age of 50 but there-

after becomes increasingly common in older men. Previously, digital rectal

examination (DRE) with a gloved finger to detect evidence of a hard or lumpy

prostate was the only useful screening test but the prostate specific antigens

(PSA) blood test is now commonly used. The PSA is a simple test in which

a raised level is suggestive of a prostate disorder that might be cancer. PSA

tends to increase naturally with increasing age in all men. At age 50, the upper

level should not be above 3 ng/mL; at 60 it should not be above 4 ng/mL.

Higher levels indicate an abnormality of the prostate, most commonly benign

prostatic hyperplasia, but progressively increasing levels (up to 6, 8 or 10) or

greatly increased levels above about 12 are more suggestive of cancer. Prostate

biopsy might be indicated when there is a progressively rising PSA or when

the initial PSA is significantly elevated, even if no lump or other abnormality

can be detected by DRE.

7.2.7 G enetic Testing

The genetic basis for a familial incidence of some types of cancer such as some

cases of breast, prostate, ovary, and large bowel cancers is becoming better

understood. In most cases, cancers associated with inheritance of abnormal

tumour suppressors and oncogenes tend to appear at an earlier age than those

not found to have an hereditary association.

Genetic testing is time-consuming and, as yet, has not become available for

general cancer screening but there is potential for early detection and cancer

prevention in individuals with a strong family history of a particular cancer.

People found to be at special risk should be referred to special counselling and

risk-management clinics.

7.3 O rgan Imaging

7.3.1 X

-Rays

Radiological studies or X-rays are a relatively old but still useful method of

medical examination for cancer. Techniques are constantly being improved and

the doses of X-rays needed are becoming smaller. X-ray films are only able to

7 Investigations That May be Useful in Detecting Cancer

detect spots or lesions that have different permeability for X-rays than that of

normal tissue in the region. This difference is seen as a relatively light or rela-

tively dark shadow on a film. For example, X-rays pass easily through air in the

lungs or gas in large bowel and this is shown as a dark shadow on a film. If a

tumour is present in a chest X-ray, the X-rays will penetrate the tumour tissue

less well than the air-filled lungs so that the tumour will show as relatively

lighter or whiter part in the area normally showing as dark shadow from the

air-filled lungs. On the other hand, X-rays are blocked by dense bone that shows

as a white area on film. If a tumour is present in bone, the bone destruction may

show as relatively dark or grey areas in the bone that is otherwise white due

to lack of penetration of normal bone by X-rays. Other tissues such as muscle

and fat are intermediate between the dark shadow of air or the white shadow

of bone in their penetration by X-rays. These tissues are of similar consistency

and have similar penetration to X-rays as do tumours so that it is not so easy to

detect tumour shadows in soft tissues by simple X-rays, and more sophisticated

investigations may be required.

7.3.2 Barium (Baryum) and Iodine Contrast X-Rays

Barium (baryum) or iodine compounds and some other materials (often called

“dyes” or “contrast” material) are impervious to X-rays and these are often used

in the body to outline cavities that are otherwise not easily seen in a plain X-ray

film. A barium meal is a barium sulphate mixture swallowed into the stomach.

This outlines the shape of the stomach. If a cancer is present it may show as an

abnormality in the shape or in the outline of the stomach. Similarly, a barium

enema in the lower bowel may allow X-rays to help detect a cancer in the colon

or rectum (Figs. 7.3 and 7.4).

Iodine compounds are also used as “contrast” material as they are excreted

in the urine after injection into a peripheral vein. These may be used to show

the position, shape, size and outline of the kidneys or bladder. This is called an

intravenous pyelogram (IVP) or excretory urogram. Iodine compounds can also

be injected into the bladder or the kidneys from below, through the urethra and/

or the ureters, and X-rays taken. Such X-ray studies of the kidneys are called

retrograde pyelograms or retrograde urograms. Iodine compounds have in the

past been injected into other body cavities such as the fluid-filled space around

the spinal cord, and an X-ray called a myelogram may show some abnormality

of the filling if a tumour is present. Nowadays myelograms have been replaced

by CT or MRI studies.

Some iodine compounds are also excreted in bile into the gall bladder and

bile ducts. X-rays can then be used to outline the shape and contents of the

gall bladder (cholecystogram) and bile ducts (cholangiogram) that again may

show abnormalities if tumours or other defects, such as gallstones, are present.

Injection of contrast backwards up the biliary tree into the pancreatic duct is

7 Investigations That May be Useful in Detecting Cancer

possible if a fine tube is passed into the Ampulla of Vater in the duodenum

(through which bile and pancreatic juice normally pass). This test is known

as endoscopic retrograde cholangio-pancreatogram (ERCP). It is endoscopic

because passage of an endoscope through the mouth and down the oesophagus

and stomach into the duodenum is necessary to insert the fine tube into the

duodenal papilla.

7.3.3 R adiographic Screening

Whereas in years past all X-rays were recorded on a film as still photographs,

nowadays techniques are used to allow the radiologist to study on a television

screen the movement of a radio-opaque material (dye or contrast) such as barium

or iodine in a body cavity. After a barium meal or barium enema the patient is

taken into a dark screening room where the radiologist can change the position

of the patient to allow the radio-opaque material to flow into different parts of

the organ being examined. This manoeuvring helps to visualise more accurately

on the television screen the size, shape, position and outline of the organ under

study, and allows the radiologist to see, for example, if a lump in the bowel is

faeces that can be moved, or tumour attached to the bowel wall.

Air can be used to replace fluid in certain cavities and shows up as a dark

shadow in X-rays. Air is sometimes used in the large bowel together with barium

so that the barium coats onto the bowel wall and the air fills the bowel cavity. This

allows X-rays to show more precisely the shape of the wall of the bowel and any

lump projecting into the cavity of the bowel. This is called an air contrast barium

enema and can be a very useful examination to detect tumours or polyps attached

to the bowel wall. Air can also be used to replace some of the fluid in the cavities

(ventricles) of the brain. This allows X-ray films to detect evidence of some brain

lesions by the contrasting penetration of X-rays passing through air as compared

to a tumour that might be distorting the shape of the brain ventricles. This study

is known as an air encephalogram. This test was used much more often before

CT and MRI scanning facilities became widely available.

In most cases, the X-ray density of a cancer is similar to the X-ray density

of surrounding tissues and X-ray films alone are unlikely to show evidence of

a deep-seated cancer. For cancers that are not so deep-seated, however, such as

breast cancer, X-ray (mammograms) can be used to detect any small differences

in penetration of the tissues that may indicate the presence of a cancer.

A negative

mammogram

in a woman

with a breast

7.3.4 M ammography

lump does not

in itself negate

A mammogram is a special X-ray of the breast that may show the presence

the necessity

of cysts, dense fibrous tissue, or a cancer in the less-dense fatty tissue of the

of having

breast. Small amounts of X-rays only are needed so this examination is safe if

other tests.

not used excessively. Although mammograms produce some false negatives and

7.3 O rgan Imaging

some false positives they are nevertheless very useful, safe and inexpensive in

screening for breast cancer. However even the small doses of X-rays needed for

mammography are better avoided in women who may be pregnant or wish to

have further pregnancies as even this exposure to irradiation can cause genetic

mutation of foetal cells or of actively functioning ovarian tissue. This usually

means that mammography is not routinely recommended in women younger

than 40.

It is important to appreciate that, like any other test, a mammogram is not

infallible. A negative mammogram in a woman with a breast lump does not in

itself negate the necessity of having other tests such as ultrasound and, more

importantly, a fine needle biopsy.

7.3.5 C hest X-Ray

Chest X-rays are most useful investigations for detecting abnormalities in the

lungs, including tumours, which may show as white opacities within the dark

air-filled lungs (see Figs 11.1a, b, Figs. 11.2a, b). Sometimes the size and shape

of the lungs, or the tissues between the lungs (the mediastinum), may be altered.

Lymph nodes in the chest are grouped around the midline between the lungs.

If lymph nodes are enlarged as in the lymphomas, the normal mediastinum or

central area of white density in a chest X-ray may be widened.

7.3.6 Ske letal X-Rays

These will show the outline of bones and give an indication of their density.

Primary cancer of bone (i.e. cancer starting in the bone, called osteosarcoma)

may sometimes be seen as an abnormal shape and abnormal density of one part

of the bone, usually towards one or other end of a long bone. Sometimes a pri-

mary bone cancer may give a “sunray-like” appearance in an X-ray. Secondary

(metastatic) cancers in bone usually show as rounded less-dense areas in the bone

due to local destruction of bone tissue. They may sometimes show as fractures

in damaged bone (a form of pathological fracture). Some metastatic cancers

containing calcium may even show as rounded areas of increased density in the

bone. However, X-rays are not infallible and will not always detect malignant

lesions in bone, especially if the lesions are small.

7.3.7 An giography

Radio-opaque materials (dyes) may be injected into arteries, veins and even

lymph vessels for films to be taken or for immediate viewing on a television

screen. The radiologist can then determine whether the vessels are in their nor-

mal position or whether they may have been pushed aside by a lump of some

7 Investigations That May be Useful in Detecting Cancer

Fig. 7.5. An angiogram taken during injection

of an iodine compound into the upper end of

the femoral artery. A mass in the lower thigh

is seen to flush with blood due to a vascular

sarcoma seen to be distorting the normally

straight femoral artery. Such vascularity in a

tumour is known as a “tumour blush”

sort, which may be a cancer. Some cancers also develop a distinctive blood

supply showing, with this technique, as a cluster of small blood vessels called

a “tumour blush” (Fig. 7.5).

Modern angiography has allowed arteries in virtually every part of the body

to be outlined by radiographic (X-ray) techniques and may be helpful in detecting

and treating deep-seated tumours.

Lymphangiography, by injecting radio-opaque “dyes” into lymph vessels,

will also allow X-rays of the lymph nodes to be taken to determine whether they

are enlarged or partly replaced by abnormal tissue that may be cancer.

7.3.8 Isotope Scans (Nuclear Scintigraphy)

Isotope scans have some similarity to X-rays in that the shadows of a radioactive

source are recorded on a film plate. In this case the radioactive material is injected

into a peripheral vein and is distributed in the bloodstream. The radioactive dose

used is very small. The radioactive material is made of, or combined with, various

agents depending on which organ or tissue is to be examined. Radioactive iodine,

for example, is concentrated in the thyroid gland and the amount of uptake, size,

shape, position, and consistency of tissue in the thyroid gland can be determined

from such a test. Another such material, called technetium, is concentrated in bone,

particularly in areas of the bone with cellular activity or growth. Thus a bone scan

7.3 O rgan Imaging

Fig. 7.6. Radio-isotope bone scans showing many metastatic cancer deposits in bones

(dark spots). The patient had advanced metastatic prostate cancer

will not only outline the position, size and shape of bone but will also show areas

of abnormal cellular activity that may be due to cancer (Fig. 7.6).

Similar scans are used to outline the size, shape and any abnormal activity in

the liver and spleen. In these organs, cancer may show up as one or more areas

of decreased activity.

Similar radioisotope scan tests are now available for a number of other organs

or tissues including the brain, lungs and lymph nodes. An isotope of gallium can be

used to help delineate between normal and abnormal patterns of lymph nodes.

Scanning is carried out with the patient lying on a special table. Apart from a

needle prick to inject the material into a vein, it is quite painless.

7.3.9 CT Scan or CAT Scan (Computerised Axial Tomography)

In the early 1970s British workers developed a technique in which small doses

of X-rays were used to construct a picture of tissues in a cross-section of the

trunk, head and neck, or limbs. Many cross-sectional pictures of the abdomen

for example, are taken, thus allowing a three-dimensional image concept to be

developed. The position, size and shape of all the organs, major blood vessels,

bones and muscles in the abdomen can be seen and the position, size and density

of any abnormal tumour can often be assessed with considerable accuracy. CT

scanning requires highly specialised equipment and skilled personnel and is

7.3 O rgan Imaging

7.3.10 U ltrasound Scans

X-rays, nuclear scans and CT scans all depend on penetrating X-rays and gamma

rays. Although the small doses now required are safe if used with proper care,

there are occasions when even these are probably better avoided. One of these

situations is during pregnancy because the developing foetus is highly sensitive

to irradiation. The ovaries and testes of people of reproductive age are also better

not irradiated even with small doses of radiation.

In more recent years, use of ultrasound waves has been developed to give a

somewhat similar cross-sectional picture of body tissues and organs as does the

CT scan. The ultrasound waves are quite harmless and can be safely used in the

region of a pregnant uterus or active ovaries. The principle depends upon sound

waves being reflected or bounced back in different degrees by body tissues of

different densities somewhat like a radar or a depth sounder.

The degree to which sound waves bounce back depends on the nature or

qualities of the underlying tissues. The principle is similar to that used by fish-

ing crews to detect schools of fish or oceanographers to measure the depth of

the ocean floor. It is certainly not a new or original physical adaptation of sound

waves. Dolphins use a similar system to locate schools of fish. The same principle

is used by bats flying in the dark.

Ultrasound scans in general do not give as much information as CT scans

but for some lesions, for example cysts, they are more accurate in showing the

position and type of lesion. This is especially true in examining breasts of young

women because the ultrasound shows more information in the more dense breast

tissue of younger women. It is also completely safe in studies during pregnancy

or ovulation. Hence they may be used as an alternative to CT scans in some situ-

ations or in conjunction with CT scans in other situations.

Like taking X-rays and CT scans, ultrasound examinations are carried out

with the patient lying on a table with a small handpiece moving over the patient.

The procedure is harmless, painless and causes no discomfort.

EX ERCISE

Under what circumstances would ultrasound be preferable to

mammography in breast examination?

7 Investigations That May be Useful in Detecting Cancer

7.3.11 MRI (Magnetic Resonance Imaging)

A MRI scan shows tissues on cross sectional images similar in appearance to

those of a CT scan although based on quite different principles of physics.

The images are based on computer analysis of absorption and penetration of high

frequency radio waves by water molecules in a strong magnetic field. There is

no exposure to X-rays or other damaging forms of irradiation. In some parts of

the body and in some body tissues such as in bone, muscles and in the brain and

spinal cord an MRI scan may show more detail and provide more information

than a CT scan but in other situations a CT is preferred. Whereas a CT scan only

shows pictures horizontally, with MRI pictures can be taken from almost any

angle. MRI scanning is now recognised as the preferred method of imaging of

musculo-skeletal structures and of intra-cranial and spinal cord investigation. In

some situations both CT and MRI studies are used. They may complement each

other by giving different information about the size, shape and other character-

istics of a tumour and its possible extent of spread into surrounding tissues.

The scan is usually performed as an outpatient procedure. The patient must

lie still. It is painless and no anaesthetic is required, except possibly in children

to keep them perfectly still. Since the procedure is conducted in a powerful mag-

netic field it is important for the patient not to wear jewellery or metal objects.

7.3.12 PET (Positron Emission Tomography) Scan

The PET scan is the most recent of presently used non-invasive studies - that

is studies that do not require an instrument to be put inside the body or for a

piece of biopsy tissue to be removed or a surgical operation. At the time of writ-

ing this innovative but very costly equipment is available only in a relatively

small number of centres where intense research studies are being carried out to

determine exactly how it can help in the diagnosis and treatment of cancers and

other serious medical conditions.

PET scans are quite different to X-rays, CT or MRI studies. X-rays are used to

produce films that are shown as black/white shadows with shades of grey. These

are inexpensive and readily available but do not give nearly as much information

as CT or MRI scans. Both CT and MRI scans give more three dimensional

information about the position, size, shape and consistency of tumours or lumps

deep to the surface and their position in relation to other tissues like arteries,

nerves, muscles, bone and important organs. They are also produced in black

and white pictures with shades of grey. They are based on laws of physics using

penetration of X-rays and radio waves under different conditions including a

change in magnetic fields in the case of MRI.

Although PET scans produce three-dimensional pictures that may be in black

and white or in colour, they are based not so much on laws of physics but on

different chemical activity in different types of tissues and different cells. The

basic principle is that cancer cells use more glucose than normal cells. They

7.4 Endoscopic Examinations: Rigid and Flexible Scopes

demonstrate areas of activated uptake of glucose which is a feature of cancer

cells. PET scanning therefore represents functional as opposed to anatomical

imaging. PET scans are often able to show something of the activity of the

cancer such as its rate of growth and any changes made to the cancer by treat-

ment given. For some cancers, such as lung cancers, they are better able to show

whether the cancer has spread (metastasised) to other places. For lymphomas they

are better able to show the extent of the disease. They may also indicate whether a

cancer has totally responded to treatment or whether it might be starting to recur

after treatment.

PET scanning is a very safe study but it is expensive. The equipment costs the

equivalent of several million dollars. Because it is not yet known what help it can

give that cannot be given by less expensive methods, many more studies must be

made and costs contained before PET scanning can be made more widely avail-

able. However in the United States PET scanning it is now recognised as a unique

tool in cancer investigation and is supported financially by health authorities.

More recently combined imaging of PET and CT or PET and MRI have been

used to more precisely demonstrate both anatomical and functional activity of

cancer deposits.

7.4

Endoscopic Examinations: Rigid and Flexible Scopes

Some internal

7.4.1 R igid Scopes

organs such as

the oesophagus

Most people are familiar with a dentist using a mirror to examine the back of

or prostate

the teeth and the stereotypical image of a doctor using a head mirror to reflect

may be well

light waves into the mouth to examine the throat, larynx, or back of the nose.

examined

The principle of using mirrors and lenses with a light source to examine the

for presence

inside of body cavities has been extended and refined to remarkable degrees of

of cancer by

precision, that were inconceivable a few decades ago. Previously, non-operative

the use of an

examination of the inside of body cavities was limited to the larynx, trachea

ultrasound

and air passages (bronchi), oesophagus, stomach, rectum and lower large bowel,

probe passed

bladder and vagina, through rigid or semi-rigid tubes. These are still useful

through a

methods of examination as they allow ready visualisation of these organs. They

scope.

are reasonably simple to use, cheap to buy and are readily available both in

doctors’ surgeries and hospitals.

7.4.2 Si gmoidoscopy

Although largely replaced by more flexible colonoscopes, old-fashioned readily

available rigid metal sigmoidoscopes are still used in isolated country practices

and developing countries. Examination of the rectum and lower bowel by a

7 Investigations That May be Useful in Detecting Cancer

sigmoidoscope can still be a valuable examination for large bowel cancer. More

than half of all large bowel cancers are within reach of a rigid sigmoidoscope.

Sigmoidoscopy can be performed in a doctor’s surgery without anaesthesia and

a biopsy of any suspicious tissue can be taken at the time of examination. Some

precautions are first taken to empty the bowel of faeces. During the examination

the patient usually lies on one side and the sigmoidoscope is passed through the

anus. The instrument is fitted with a small light and air is blown into the bowel

to inflate it and so open up the lumen or bowel cavity. This air and the passage

of the instrument are uncomfortable but not unbearable.

7.4.3 Pr octoscopy

Examination of the anus and lower rectum can be carried out quite simply in a

doctor’s surgery with a small metal tube-like instrument called a proctoscope

or anal speculum. Although it does not penetrate far into the rectum, it is fitted

with a small light and can be useful for detecting or treating lesions in or near

the anus such as haemorrhoids or cancer of the anus, which is rather rare.

7.4.4 V aginal Speculum

A vaginal speculum is a metal instrument that allows a doctor to examine the

walls of the vagina or cervix of the uterus in the surgery without significant

discomfort to the patient.

7.4.5 Laryngoscopy and Bronchoscopy

The larynx can be examined indirectly with a mirror in the doctor’s surgery

but a more direct examination of the sensitive larynx or main air passages is

usually carried out with a rigid laryngoscope or bronchoscope in hospital under

general anaesthesia.

7.4.6 O esophagoscopy

Similarly, in the past, examinations of the oesophagus were usually carried out

in hospital under general anaesthesia using a rigid oesophagoscope.

7.4.7 C ystoscopy

The bladder too may be examined with a rigid cystoscope usually in hospital

under general anaesthesia

7.4 Endoscopic Examinations: Rigid and Flexible Scopes

7.4.8 E cho-Endoscopy

Some internal organs such as the oesophagus or prostate can be examined

for presence of cancer by the use of an ultrasound probe passed through a

scope. The combined use of scope and ultrasound probe is referred to as

echo-endoscopy.

7.4.9 F lexible Scopes

In recent years advances have seen great progress made in fitting a series of

lenses and mirrors and a light source to flexible fibre-optic endoscopes and

colonoscopes as well as a great variety of flexible scopes to replace many of the

rigid metal scopes previously used.

7.4.10 Gastroscopy or Endoscopy

Skilled gastroenterologists can pass the modern gastroscopes or endoscopes

without general anaesthesia. Provided the patient is suitably sedated these instru-

ments are passed with little discomfort. They allow examination, not only of the

oesophagus and stomach, but also of the first part of the duodenum. Through

the duodenum and at the ampulla of Vater they also allow examination of the

opening of the bile duct from the liver and gall bladder and the pancreatic duct.

Radio-opaque material (dye) can be injected into these ducts allowing ERCP

X-rays to be taken for more detailed examination.

7.4.11 C olonoscopy

The colonoscope is similarly a flexible instrument that can be passed through

the anus and around the whole length of large bowel to allow examination

of all the length of the large bowel. The instrument can be used to remove

pre-malignant polyps or to take biopsies of a suspected cancer. Special

preparation is required to empty the bowel clear of faeces before the colono-

scope is used. This instrument may be passed without undue discomfort if

the patient is well sedated, although for some patients general anaesthesia

may be preferred.

A less invasive bowel examination is by virtual colonoscopy in which the

bowel is prepared as for a colonoscopy, an enema mixture is given and the colon

is scanned by CT. Anaesthesia is not required and accuracy of detection of color-

ectal lesions is probably comparable but if a lesion is detected and biopsy or

removal of a polyp is required a true colonoscopy is still required.

7 Investigations That May be Useful in Detecting Cancer

7.4.12 Laparoscopy (Peritoneoscopy) and Thoracoscopy

The body cavities - the peritoneal cavity and the pleural cavities can also be

examined by passing an instrument called a laparoscope (or peritoneoscope) or a

thoracoscope through a small incision into the cavity. This is carried out under

general anaesthesia in the operating theatre. Through these instruments the surgeon

can examine the contents of the body cavities. First a harmless gas (CO₂) is used

to fill the peritoneal cavity to separate movable organs and allow manipulation of

the instrument between loops of bowel and other tissues and viscera. The examiner

may be able to take biopsies if suspicious lesions are seen. Special equipment is now

available to carry out some surgical operations using similar scopes with surgical

instruments passed through a second or third small opening in the abdominal or

chest wall. Some cancer operations can be carried out in this way.

7.4.13 C uldoscopy

Culdoscopy is a similar examination of the pelvis. The instrument is passed

into the pelvic cavity through a small incision made in the top of the back wall

of the vagina.

7.5

Indirect Evidence of Cancer

Blood tests may show either direct or indirect evidence of cancer.

7.5.1 Blood and Serum Tests

Haemoglobin and red cell count (RCC)

Most cancers eventually cause some degree of anaemia, which manifests as

decreased haemoglobin and red blood cell counts but some tumours might be

quite advanced before this becomes apparent.

7.5.2 White Cell Count (WCC)

The total white cell count might also show a reaction to some types of cancer

but most significantly the number and type of white cells might be the first direct

indication of leukaemia.

7.5 Indirect Evidence of Cancer

7.5.3 Erythrocyte Sedimentation Rate (ESR)

The ESR is an index of blood sedimentation and increases with elevation of

certain proteins in the blood due to ill-health. Many organic disease processes,

including cancer, are associated with a raised ESR, but apart from giving an

indication of the severity of disease, the test can be useful in giving an indica-

tion of response to treatment given. If a raised ESR falls after cancer treatment

it suggests that the treatment has been effective although it cannot be regarded

as a guarantee of complete cure.

7.5.4 S erum Biochemistry

Some types of cancer are likely to change biochemical components in the blood.

For example cancer of the prostate gland may cause an elevation of the enzyme

serum acid phosphatase, advanced breast cancer may cause elevation of serum

calcium and a particular type of large bowel cancer, papillary adenocarcinoma,

may cause loss of potassium from the bowel resulting in fall in serum potas-

sium. Cancers in the liver may cause a degree of liver failure which may also

be detected in changes in serum biochemistry after checking that the patient is

not suffering from cirrhosis.

7.5.5 T umour Markers

The potential for using biological tumour markers to help detect early cancer or

Valuable and

recurrent cancer is constantly under study. Many tumour markers are now use-

reliable tumour

ful in determining the presence of cancer. Some are already in regular clinical

marker tests,

use with varying degrees of reliability. The most regularly used are the PSA

indicating

for prostate cancer (as previously discussed); the carcino-embryonic antigen

the presence

(CEA) test for cancers of the alimentary tract, especially large bowel cancers;

or absence

and the alpha-foeto-protein (AFP), a test for primary liver cancer and germ-cell

of specific

cancers and the CA125 test for ovarian cancer. Useful markers in detection of

cancers will be

germ-cell cancers are AFP, human chorionic gonadotropin (HCG) and lactate

available for

dehydrogenase (LDH). No doubt further tumour markers will be found to be

more specific

clinically valuable in detecting early cancers as well as in determining response

clinical use in

to treatment or tumour recurrence.

the not too

Tumour markers are also used to estimate the success or otherwise of treat-

distant future

ment of the cancer. A fall will indicate a good initial result of therapy but a sub-

sequent rise might indicate the presence of recurrent or residual cancer either at

the original tumour site or elsewhere.

7 Investigations That May be Useful in Detecting Cancer

7.5.6 T he Future

As yet, no tumour marker test is totally reliable on its own, but a great deal

of work is being carried out in this field. The major issue is one of specificity

and sensitivity being inversely related - the more specific the criteria (higher

concentrations) for a tumour marker the less cancers are identified, and these

pre-dominantly are more advanced, conversely the less specific criteria identify

more cancers but there will be more false positves.

It seems certain that valuable and reliable tumour marker tests, indicating the

presence or absence of specific cancers, will be available for more specific clini-

cal use in the not too distant future.

7.6

Direct Evidence of Cancer

7.6.1 B iopsy

The ultimate test for cancer is in the tissue biopsy in which a piece of tissue is

taken from a suspected cancer and examined microscopically. Provided a truly

representative sample of tissue is taken, examination of the cells in the biopsy

specimen will usually allow the pathologist to determine not only whether a cancer

is present, but also the type of cancer, the tissue of origin of the cancer and even the

degree of malignancy. In some cancers the biopsy may also give a good indication

of the most appropriate treatment and likelihood of a cure being possible.

Ideally a biopsy is taken before any treatment, including surgical treatment, is

started. This helps the clinical team to decide upon most appropriate treatment.

Often biopsies are also taken by a surgeon during an operation. Usually the

surgeon will take a small representative sample of a suspected cancer (incision

biopsy) or if the tumour is small the surgeon may remove the whole tumour for

examination (excision biopsy). Sometimes the surgeon will biopsy tissues or an

organ nearest to the cancer to be sure that it does not have cancer cells spread

into it, that is to be sure of a “clear margin” of tissue free of cancer (Fig. 7.8).

A number of techniques have been developed to help make a diagnosis by biopsy.

EX ERCISE

List features of microscopic appearance that suggest a biopsy shows a

highly malignant tumour.

7.6 Direct Evidence of Cancer

Fig. 7.8. Diagrams illustrating microscopic features of (a) normal prostate gland, (b) changes of

early “in-situ” or “latent” prostate cancer and (c) more advanced, invasive prostate cancer.

7.6.2 Needle Aspiration or “Punch Out” Biopsy

For some tumours - as for example, some lumps in the breast, a special needle

can be inserted into the lump to aspirate or suck out sufficient cells or tissue for

biopsy examination. There is also a special needle called “Trucut” with a “punch

out” mechanism that allows a small core of tissue to be “punched out”. This might

be done under local anaesthesia without admission to hospital or sometimes a

general anaesthetic may be required. Provided a representative specimen is taken

and an expert team is readily available to examine the specimen, a diagnosis

might be made rapidly with little disturbance to the patient.

Needle aspiration or “punch out” biopsy may now be used for a number of

different types of tumours in a variety of other tissues such as the prostate gland,

the liver, the thyroid gland, or deep-seated tumours in the limbs or in the chest.

7 Investigations That May be Useful in Detecting Cancer

7.6.3 A spiration Cytology

This is similar to aspiration biopsy except that it applies to the examination for cells

in cysts or other fluid. A cyst in the breast or elsewhere may be aspirated and by

special preparation the contents are examined for the presence of malignant cells. If

malignant cells are found, a positive diagnosis of cancer can be made. If, however,

no malignant cells are found there may still be some doubt as to whether cancer is

present and a further biopsy may be necessary. It is still possible that cancer cells

could be in the cyst or adjacent lump but not in the sample of fluid taken.

7.6.4 Bone Marrow Biopsy

A similar aspiration technique is used to obtain specimens of bone marrow,

which is especially important in determining the presence and type of any

suspected leukaemia. Bone marrow biopsies can also be valuable in confirming

the presence of metastatic cancer in bones.

7.6.5 S tandard Paraffin Section Biopsy and Frozen Section Biopsy

Preparation and staining of a biopsy specimen for microscopic examination

usually takes several days. The tissue is prepared embedding it in a wax block

and staining it to reveal special features of the cells. In some circumstances it

may be important for the surgeon to know the diagnosis immediately, so that

any necessary cancer operation can be completed without delay. An experienced

pathologist can often make a diagnosis without delay by using the technique of

frozen section. In a frozen section examination the biopsy specimen is prepared by

immediately being frozen solid so that it can then be finely sliced. Fine slices are

then stained with a simple stain and examined microscopically. The pathologist

may then be able to give the surgeon an accurate diagnosis within a few minutes.

If the patient is anaesthetised and prepared for operation, the surgeon may then be

able to completely remove any cancer at the same operation. Frozen-section tech-

niques are now highly accurate for most cancers if used by skilled pathologists,

but for some cancers it may not be possible to determine an accurate diagnosis

until special pathology sections embedded in wax have been prepared some days

later. Sometimes a variety of special stains or even other tests, such as immuno-

histochemistry tests, using antibodies against tumour markers, are needed.

EX ERCISE

List the most useful investigations that help in establishing a diagnosis

of cancer.

Treating Cancer

In this chapter you will learn about:

› Can cancer be cured? An outline of prognostic factors

› Methods of treatment

› Surgery

› Radiotherapy, including brachytherapy

› Chemotherapy - anti-cancer drugs

› Hormone therapy

› Immunotherapy

› Cell mediated anti-cancer activity

› Other treatments under study

› General care

› Supportive care and supportive care teams

› Psychological and spiritual help

› Follow up care

› The specialty of palliative care

›

Alternative medicine”

8.1

Can Cancer Be Cured? An Outline of Prognosis

Although cancer is a frightening word, it is a fact that in modern developed

societies most cancers are cured. The possibility of cure of a cancer depends upon

a number of factors, especially the tissue from which it has grown and the type

of cancer cells in it, the size and position of the tumour in the body, the degree

of abnormality of the individual cancer cells, the structures into which the cancer

may have grown and the presence and site of any metastatic spread. The age and

general health of the patient are also significant. The patient’s natural defence

reactions may be highly significant although, as yet, not clearly understood and

not yet able to be measured with any confidence.

Many of the most significant factors will depend upon how quickly the cancer

is detected and treated. A small cancer detected early and before it has spread

or involved other tissues may be eminently curable whereas the same cancer

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_8, © Springer-Verlag Berlin Heidelberg 2009

8 T reating Cancer

neglected, perhaps for some months, until it has enlarged and spread to other

sites, may be quite incurable.

Many years ago a great American pathologist, Arthur Purdy Stout, said:

“The best chance of curing cancer lies in the hands of the therapist who makes

the first attempt”.

Nowadays this should be paraphrased as:

“The best chance of curing many advanced and aggressive cancers lies in the

hands of the team of therapists that makes the first attempt”.

That is, a cancer that has recurred after a failed attempt at treatment is more

difficult to cure than it would have been at the first attempt. The quality of treat-

ment given to the patient, especially in the initial treatment, is a most important

factor in determining whether or not a cure is likely. For difficult cancers, this is

often now best achieved with integrated treatment and a team approach.

8.2

In Western Societies More Cancers are Cured than Not Cured

This is certainly true because the most common cancers are basal cell cancers

of skin and squamous cell cancers of skin. Not only do these cancers grow rela-

tively slowly and spread relatively late, if at all, they are usually obvious to the

patient and doctor when they are quite small, and if properly treated at that stage

they are eminently curable. Even the more aggressive and dangerous pigmented

skin cancer, the melanoma, is usually eminently curable in its early stages. With

people becoming more aware of the danger of any change in a pigmented mole,

or other dark spot on the skin, most melanomas are now detected before they

have spread. If properly treated at this stage they are effectively cured.

All this is good news but, even better, is the fact that even excluding skin

cancers, more cancers can now be cured than not cured.

The common cancers of the breast and bowel and cancers of the uterus are

usually curable now that methods of early detection are widely practised. It is

most important that these cancers should be detected early as the outlook is so

much better if treatment is initiated when these cancers are small. For this reason,

a great deal of effort has been spent in establishing cancer screening clinics to

detect potentially curable cancers before they reach an incurable stage. This is

now likely to need a diagnostic and therapeutic team effort.

Cure can now be expected for most cancers in the head and neck region,

including the lips, mouth and throat, larynx, salivary glands and thyroid gland.

Until fairly recently, cancers that develop in cells scattered widely through-

out the body tissues, such as the lymphomas and leukaemias, were considered

incurable but with modern treatment methods, increasing numbers of patients

with these malignancies are being cured including the majority of children who

develop leukaemias.

The most common internal cancer in men, prostate cancer, can now usually

be diagnosed at a curable stage. However because most of these cancers are

8.3 Methods of Treatment

slowly growing and not necessarily life threatening during the patient’s other-

wise expected lifespan, there may be uncertainty as to whether radical treatment

to establish a cure is justified. Sometimes the outlook without curative treatment

does not justify the severe side effects of curative treatment, especially in elderly

men with other health problems.

The outlook for germ-cell cancers of the testis underwent dramatic change

over the last two to three decades of the twentieth century. From being cancers

with a poor prognosis except when treated at a very early stage, most are now

cured when treated with combined and integrated therapy programs using modern

chemotherapy, radiation therapy and surgery.

Integrated treatment methods have also improved the curability of a number of

other cancers including more advanced head and neck cancers, sarcomas, espe-

cially in limbs, and previously high-risk stomach and breast cancers.

Cancers with the worst prognosis (least likely to be cured) are often those that

develop in deep body tissues and are usually not obvious until they have spread to

lymph nodes or other tissues. These include cancers of the oesophagus, pancreas

and lung. Hence the search for methods of earlier detection of these cancers.

Other cancers with poor prognosis include those in organs that cannot be easily

dispensed with such as the liver or a major part of the brain.

With modern endoscopic techniques, stomach cancer can now also be detected

at a curable stage. In Japan, where this cancer is common and screening tests are

becoming a routine, most are now diagnosed at an early stage and are cured.

8.3

Methods of Treatment

The three mainstays of cancer treatment are surgery (meaning operative sur-

gery), radiotherapy and chemotherapy.

8.3.1 Principles of Treatment of Potentially Curable Regional Cancers

The main principle of treatment of any new and potentially curable cancer is to

treat one step beyond the apparent limits of the cancer.

With an inflammatory condition, such as an acutely inflamed appendix, only

The main

the appendix needs to be removed to cure the condition. Similarly in treatment

principle of

of benign lesions such as benign cysts, adenomas or polyps, only the lesion needs

treatment of

to be removed. Best treatment of cancer however, requires surgical removal of

any new and

more than just the apparent cancer. Tissues adjacent to the cancer into which

potentially

cancer cells might have spread are also removed. Similarly if treatment involves

curable cancer

radiotherapy, it is given to tissues beyond the apparent edge of the cancer, that is

is to treat one

tissues into which microscopic cancer cells might have spread. Chemotherapy is

step beyond the

often given in addition to surgery and/or radiotherapy if the cancer being treated

apparent limits

is one that has significant risk of having already spread beyond the local primary

of the cancer.

8 T reating Cancer

site or region being treated even though there may be no evidence of more distant

spread.

83.2

Surgery

The discipline of surgery is that part of medicine and medical practice that is

likely to involve need of a surgical operation. The word surgery is also often

used to mean operative surgery and it is in this context that the word surgery is

used in the following paragraphs.

Before the discovery of general anaesthesia and the first use of ether as a

general anaesthetic by Dr Crawford Long in America in 1842, operative surgery

was very primitive but nevertheless it was the only available effective cancer

treatment.

Early use of general anaesthesia for operative surgery was followed by

rampant cross infection with a high mortality rate. The situation changed after

the discovery of micro-organisms in infected wounds by great world scientists

Pasteur in France, Koch in Germany, Semmeilweiss in Hungary and Lister in

England (Fig. 8.1).

These changes in operating under general anaesthesia with aseptic condi-

tions allowed operative surgery to develop and progress to what it is today. Thus

operative surgery became the first widely used effective and generally applicable

anti-cancer treatment.

Surgery was thus the first effective form of cancer treatment. It is now used

to establish a diagnosis, to effect a cure or in some advanced or incurable cases,

to give good palliation and relief of symptoms. When possible the surgeon’s

primary objective is to excise the cancer in its entirety, together with all adjacent

tissues into which cancer cells may have spread. For many cancers, especially

for early skin cancers and small cancers on lips or in the mouth, surgery offers a

relatively simple, straightforward, quick and effective method of eradicating

cancers. A complete cure can be expected without any residual problem. For

more advanced cancers that have spread to or are likely to have spread into drain-

ing lymph nodes, the surgeon removes not only the primary cancer but all the

draining lymph nodes likely to be involved. The primary cancer and lymph nodes

are best removed in continuity in one block of tissue where this is feasible. This

is called a “block dissection” and a high incidence of long-term cure can also be

expected. If a great deal of tissue has to be removed, the surgical team may need

to do some form of plastic or reconstructive surgical procedure to leave as little

defect or deformity as possible. The surgical removal of a tumour is also the most

effective cure for the cancer associated weight loss (cancer cachexia), as the

cellular source of the abnormal metabolism driving the weight loss is removed.

Used alone successful surgery depends upon establishing diagnosis and treat-

ment early in the disease and before the cancer has spread into tissues that cannot

be resected with the primary cancer.

8 T reating Cancer

For breast cancer that is confined to the breast with possible early involvement

of lymph nodes in the axilla, the most common surgical treatment over the past

100 years has been total removal of the affected breast and lymph nodes from

the axilla as one block of tissue. This operation, called a radical mastectomy, has

cured many women with breast cancer over the years but nowadays less radical

operations have been equally successful.

For deep-seated cancers the whole or part of the involved organ is usually

excised together with nearby draining lymph nodes. Such has been standard

treatment for cancer of the stomach, colon, rectum, uterus, ovary, oesophagus,

lung, and sometimes the pancreas. For some the cure rate by surgery alone has

been good but for others the cure rates by surgery alone have been dismal.

Sarcomas in limbs tend to recur locally in the limb unless widely excised and

sometimes the best chance of cure by surgery, especially for big sarcomas, has

been by amputation of the affected limb. Newer techniques of combined treat-

ment (discussed later in this chapter) have reduced the need for amputation in

many cases.

EXERCISE

What are the possible objectives of surgical operations in treatment of

cancer?

83.3

Radiotherapy

Radiotherapy is the second oldest effective form of treatment for cancer but has

been clinically available only since about the year 1900 following the work of the

Curies in France and Dr Roentgen in Germany. Treatment depends upon the sen-

sitivity of dividing cells being destroyed by X-rays or gamma rays emitted from

a radioactive source. Treatment, equipment and computer assisted techniques are

constantly being improved with improved results in eradicating cancer cells and

causing minimal damage to surrounding tissues and cells (Fig. 8.2).

Radiotherapy has the advantage of avoiding a surgical operation but in many

cases treatment over 5-8 weeks is required. Radiotherapy has the disadvantage

of causing some damage to normal tissues and cells covering and surrounding

the cancer in the area treated (the irradiation field). The radiotherapist must have

the patient in a correct position so that the radiation beams will include the whole

tumour in the irradiated field with minimal exposure of normal tissue. This will

8.3 Methods of Treatment

Fig. 8.2. Photograph of a patient

ready for treatment with super-

voltage external radiotherapy

allow greatest destruction of tumour cells with as little as possible damage to

surrounding normal tissues and cells.

Radiotherapy alone is effective treatment for many skin cancers, some head

Radiotherapy is

and neck cancers and for some deep-seated cancers that cannot be totally removed

now often used

by surgery. It is also used as a palliative treatment to give relief by reducing the

in combined,

size of some cancers that cannot be cured by surgery or other means.

integrated

The dose of radiotherapy used is critical and must be given by experts. Too

treatment

little will not destroy cancer cells but too much will destroy normal tissues and

programs,

may result in loss of tissue sometimes with painful ulceration of overlying skin

especially with

which may not heal, and other long-term local problems such as damage to an

surgery and/or

underlying lung or other tissue. The dose is also cumulative, that is, that once

chemotherapy.

radiotherapy has been given to a part of the body in a therapeutic dose it cannot

ever be given again to the same site without risk of serious tissue damage.

The actual administration of radiotherapy is quite painless although it may

leave some skin changes, like an erythema resembling sunburn, and may make the

patient feel listless and tired, adding to his or her feeling of depression. Depres-

sion is a natural feature of having a cancer. Radiotherapy sometimes adds to the

depression but it usually improves when active treatment has been completed.

Although the red flush of skin change settles a few weeks after radiotherapy,

some minor skin changes with small, visible blood vessels called telangiectasia

are often a permanent feature of an area that has in the past been irradiated.

8 T reating Cancer

8.3.3.1 Brachytherapy

Brachytherapy is a form of radiotherapy in which radio-active needles or “seeds”

are inserted into a tumour to give a measured dose of irradiation directly to

the cancer. The dose of irradiation given by such needles (withdrawn after the

required dose has been administered) or “seeds” (left permanently in place in

the cancer) is critical. It is also critical to place the radioactive material in such

a position that all of the cancer tissue receives a satisfactory dose of irradiation.

Traditional external irradiation can more reliably cover the needed irradiation

field but will irradiate surrounding tissues. Brachytherapy will more specifically

deliver a dose of irradiation into the cancer but has a greater risk of missing some

of the outlying cancer cells. In some clinics, combined use of these two forms of

radiotherapy can be used in treating some cancers. In some clinics brachytherapy

or combined external irradiation with brachytherapy is becomingly increasingly

used in treating prostate cancer when there is a localised limited cancer focus.

Results are now believed to be equivalent to radical surgery but with the advan-

tage of fewer side effects.

Radiotherapy is now often used in combined, integrated treatment programs,

especially with surgery and/or chemotherapy. For many advanced and aggres-

sive cancers combined and integrated treatment will effect cures that would have

been unlikely by using one treatment modality alone. This is why it is becoming

increasingly important for patients with aggressive or advanced cancers to be

seen by clinicians working in cooperative multidisciplinary teams.

EXERCISE

What are the advantages and disadvantages of treating a cancer by

brachytherapy as opposed to external radiotherapy?

8.3.4 Chemotherapy (Cytotoxic Drug Treatment)

Doctors, scientists and others have been searching over the centuries for chemical

substances that might cure cancer. The first effective such treatment was

reported by Dr George Beatson from the Glasgow Royal Cancer Hospital early

in the twentieth century. Dr Beatson reported that oophorectomy (removal of

the ovaries) depressed growth of some breast cancers. Hormonal management

8.3 Methods of Treatment

of breast cancer followed that observation. Next was a report in 1941 by two

Americans doctors, Charles Huggins and Clarence Hodges that some prostate

cancers responded to treatment with the female hormone stilboestrol. Four years

later in 1945 it was first observed that a gas that had been used during World War

I, destroyed dividing cells, and so nitrogen mustard was discovered as being a

drug that could be used clinically against cancer cells in patients. This was the

beginning of modern anti-cancer chemotherapy. Since that time a large number

of effective anti-cancer drugs have been developed. These drugs have their

greatest effect on dividing cells and because cancer cells are more constantly

dividing than normal cells, they are more likely to be affected than normal body

cells. The present anti-cancer drugs are grouped or classified according to how

they affect dividing cells (Fig. 8.3).

Fig. 8.3. Diagram illustrating the sites of greatest activity on dividing cells of some of

the anti-cancer agents

E XE R C I S E

Why are cancer cells more likely to be affected by chemotherapy than

normal cells?

8 T reating Cancer

8.3.4.1 Anti-Cancer Drugs

Just as details of surgical procedures must be left to trained surgeons and the

details of the best use of radiotherapeutic procedures must be left to specialist

radiotherapists, so too details of best use of anti-cancer agents are highly com-

plex. The use of complex anti-cancer agents is best guided by experts who are

appropriately trained and experienced in their use. However some knowledge

of the agents most commonly used should be helpful as a basis for further

understanding.

The number of anti-cancer drugs is constantly increasing as newer agents

with more selective actions against particular tumour types are discovered.

In general they are grouped as:

Antimetabolites. This group of anti-cancer agents predominantly interfere

most with synthesis and metabolism of DNA and, to some extent, RNA. They

include methotrexate, 5FU (5-fluorouracil), cytarabine, gemcitabine and 6MP

(6 mercaptopurine).

DNA damaging agents. These include alkylating agents like cyclophosphamide

and ifosfamide and melphalan; antibiotics like adriamycin, actinomycin D and

bleomycin; nitrosoureas (such as BCNU and CCNU) and platinum derivatives

like cisplatin and carboplatin.

Mitosis inhibitors. This group includes vinca alkaloids (like vincristine and

vinblastine) and taxanes (Taxol).

Cancer cell enzyme inactivators. This is a new class of anti-cancer agent recently

discovered and undergoing much research. The first, code-named STI 571 (trade

name Gleevec or Glivec), is the enzyme tyrosine-kinase inhibitor. Tyrosine-

kinase is an essential for cancer cell reproduction. STI 571 was first found to

counteract the Philadelphia chromosome of chronic myeloid leukaemia and, in

treating this leukaemia, results have been very encouraging. STI 571 is now being

used in trials of treating other cancers, particularly with certain gastrointestinal

stromal cancers and renal cancers, with encouraging results. There may be a

place for similar management of some breast cancers and prostate cancers.

All effective

Unfortunately all effective anti-cancer drugs presently available have side effects

anti-cancer

that affect some people more than others. Some become manifest early as acute

drugs presently

toxic side effects. Some are long-term or late side effects and may not be apparent

available have

for months or even years. Until all adverse side effects of such agents are well

side effects.

understood experienced specialists should oversee their clinical use.

8.3.4.2 Using Combined Anti-Cancer Agents

In treating cancers, the specialist cancer clinician (oncologist) selects drugs that

are known to be effective against the type of cancer being treated with least

possible damage to normal body cells. In general, appropriate combinations of

effective drugs are more effective than large and increasingly toxic doses of

8.3 Methods of Treatment

Fig. 8.4. Diagram indicating the principle of use of multiple agents in combination

in treating a cancer rather than using larger and more toxic doses of just one agent.

As illustrated, provided the drugs are known to be active against the type of cancer

being treated, a selection of two or more agents should have increased activity against

the target cancer cell. It is like hitting the cancer cell in two or more places at the same

time. It is safer to avoid using drugs with the same side effects so that normal cells are

less likely to be damaged by multiple agents

one drug only. Much research is constantly being carried out to discover the

most effective and safest combinations and dose and timing schedules of drugs

against different types of cancer with minimal damage to normal dividing cells

(Fig. 8.4).

8.3.4.3 Time and Concentration of Anti-Cancer Cytotoxic Drugs

on Different Cancer Cell Types

Another aspect of the use of anti-cancer drugs is the sensitivity of the cancer

There is also

cells being treated in relation to the length of time of their exposure to the drugs

much to

and their relative sensitivity to drug concentration. For example 5FU is gener-

be learned

ally more effective if given by continuous infusion over several days whereas

about when

melphalan seems to have a greater impact given in greater concentration over

anti-cancer

a shorter period, possibly an hour or so. Similarly cancers of different types

cytotoxic

respond differently to different periods of exposure and to different concentra-

drugs are best

tions of agents. Gastrointestinal cancers and mouth and throat cancers seem to

integrated with

respond best to continuous prolonged drug exposure over days or weeks whereas

radiotherapy

melanoma responds best to a more intense concentration of agents that can

or surgery.

only be given over a short period. There is still much to be learned about dose,

combinations, length of time of exposure and concentration of agents to achieve

8 T reating Cancer

greatest effect on the type of cancer being treated with minimal side effects.

There is also much to be learned about when anti-cancer cytotoxic drugs are

best integrated with radiotherapy or surgery.

8.3.4.4 Palliative Chemotherapy

The most widely applied use of the anti-cancer drugs is in treating widespread

cancers or cancers that for one reason or another cannot be treated effectively

by surgery or by radiotherapy. Although some drugs will, on occasions, cure

some widespread cancers, in general this form of treatment is palliative.

Palliation means that the cancer may be reduced in size and the patient may be

given relief of symptoms for some time, but almost invariably the cancer will

re-develop sooner or later, at which time it will be more resistant to anti-cancer

agents. Eventual death from the cancer is likely.

Palliative chemotherapy, by reducing the cancer, will usually prolong life and

should make the patient more comfortable. Sometimes, however, because of the

inconvenience and problems associated with treatment and the possible distress

of side-effects (see “side effects” below) there is doubt as to whether palliative

chemotherapy is worthwhile. In each case the medical attendants should discuss

the likely benefits and possible problems with the patient and members of the

patient’s family before a final decision is made about having this form of treat-

ment. Although it is the doctor’s responsibility to give informed advice, the final

decision as to whether to have palliative chemotherapy should be made by the

patient. If doubt exists in the patient’s mind about the desirability of having such

treatment, a trial course of treatment may be appropriate, that is, that treatment

be commenced with the proviso that if the patient finds treatment too distressing,

treatment can be modified or stopped at any time.

8.3.4.5 Adjuvant Chemotherapy

Adjuvant chemotherapy is chemotherapy given following surgery or radio-

therapy and is used to treat cancers where it is known there is a significant risk

that scattered cancer cells may be present somewhere even though they cannot

be detected.

The most proven value of adjuvant chemotherapy is in treating women who

have had a breast cancer treated by surgery (mastectomy, segmentectomy or

lumpectomy) or a combination of surgery and radiotherapy to the breast region.

These are patients who have certain prognostic factors that suggest that, although

undetectable, there is a significant risk of some cancer cells already having spread

beyond the treated region. Adjuvant chemotherapy is also given as part of the

treatment for people (usually young people) who have had bone cancer (osteo-

sarcoma) treated by surgery. The surgery may have been amputation of a limb.

Post-operative chemotherapy is now standard even with small osteosarcomas

because there is a high risk that some cancer cells will have already escaped from

the local tissues and formed micro-metastases in the lungs. Treatment of ovarian

8.3 Methods of Treatment

cancers and some colo-rectal cancers also now often includes administration of

adjuvant chemotherapy to get best long-term results.

8.3.4.6 Systemic and Regional (Intra-Arterial) Chemotherapy

(a) Systemic chemotherapy

The most convenient and simplest way of giving a measured dose of chemo-

therapy is by intravenous delivery, either by bolus injection or by slow infusion

into a vein. After intravenous delivery, drugs are distributed by the bloodstream

more or less equally to all parts of the body and should affect cancer cells

wherever they may be.

Whilst surgery is limited to treating cancers localised in a particular region

that can be excised, and radiotherapy is limited to treating cancer cells in a lim-

ited radiation field, chemotherapy is generally given systemically, that is, to treat

the body as a whole. Some anti-cancer drugs can be given by mouth but most

are given by intravenous injection or infusion. This method of chemotherapy is

likely to be the most effective as adjuvant therapy when there is a significant risk

that there may be widespread cancer cells remaining somewhere after a primary

cancer has been eradicated.

(b) Regional (intra-arterial) chemotherapy Fig. 8.5

When cancers appear to be limited to one particular body region and that region is

It is sometimes

supplied with blood by one particular artery, it is sometimes possible to concentrate

possible to

anti-cancer drugs to the cancer by injecting or infusing the drugs directly into the

concentrate

artery supplying blood to the cancer. This is called regional or intra-arterial che-

anti-cancer

motherapy. The initial activity of the agents is concentrated in the tissues supplied

drugs to the

by the artery infused before most of it flows into the systemic circulation and then

cancer by

functions as systemic chemotherapy. An alternative to this intra-arterial infusion

injecting or

chemotherapy is intra-arterial perfusion chemotherapy, with regional vascular

infusing the

isloation. With perfusion chemotherapy, carried out under general anaesthesia, a

drugs directly

“closed circuit” pump is often used and the part containing the cancer (usually a

into the artery

limb) has its circulation separated or isolated from the general circulation. A high

supplying

dose of the drugs is thus concentrated in the isolated tissues containing the cancer

blood to the

without flowing into the general circulation where in such high concentration they

cancer.

would cause severe toxicity. This is a form of delivery used in treating some cancers

that may be confined to a limb but respond only to a high concentration of an anti-

cancer drug, such as some cases of melanoma or some limb sarcomas.

8.3.4.7 Other Regional Chemotherapy

Chemotherapy is sometimes used to achieve a greater regional effect by intra-

thecal or intra-ventricular injection, or by intrapleural or intraperitoneal injec-

tion. Some drugs do not pass the blood/brain barrier so that to be effective

100

8 T reating Cancer

Fig. 8.5. Diagram illustrating the principle of

intra-arterial chemotherapy. If all active anti-cancer

agents are infused into a small artery that supplies

the cancer with all its blood (illustrated in the

bottom of the diagram) the cancer will be exposed

to a greater initial concentration than if the agents

are infused into the venous circulation. Infused

into the venous circulation they will be distributed

more or less equally but in lower concentration

to all body tissues. The value of this technique

depends on the agents used being active in the

form in which they are given. Some agents, e.g.

cyclophosphamide, need to be activated by passage

through the liver so that for them intra-arterial

infusion has no advantage. For some other agents

exposure over a prolonged period of time may be

of greater importance than a more concentrated

exposure

against tumours in the brain they must be given intrathecally (i.e. directly into

the cerebro-spinalfluid). Some drugs can be effective in treating skin cancers

when incorporated into creams or ointments for local (topical) application.

EXERCISE

Under what circumstances might there be potential advantages in delivering

chemotherapy to a cancer by the intra-arterial route?

8.3 Methods of Treatment

101

Intraperitoneal chemotherapy is a form of regional chemotherapy that can be

useful in treating some intra-abdominal cancers. The activity of the agents is

first concentrated in the peritoneal cavity but some is then absorbed into the

general circulation as systemic chemotherapy.

8.3.4.8 Combined Integrated Treatment

For relatively small and uncomplicated localised cancers that can be readily and

effectively treated by surgery or radiotherapy, these forms of treatment are best

used in a straightforward and usually simple fashion.

For some cancers, however, surgery alone or radiotherapy alone or even sur-

gery and radiotherapy together may not be able to cure most of the patients. Or

possibly, a surgical operation required to eradicate the cancer may be so mutilat-

ing as to be unacceptable to the patient. In these circumstances, better results

can sometimes be achieved by combining surgery and/or radiotherapy and/or

chemotherapy.

Present-day treatment of some breast cancers is an example of a widely

accepted use of combined treatment. Often nowadays, for women with moder-

ately advanced breast cancer, the breast and axillary lymph nodes are removed

surgically and radiotherapy is given to the breast region after surgery. Nearby

lymph nodes if not removed at operation may be treated by radiotherapy. How-

ever adjuvant chemotherapy is given systematically to control any cancer cells

that may have escaped further than draining lymph nodes into the circulation

and could be the seeds of future metastatic growths in distant organs or tissues.

With such combined and integrated treatment programs survival rates have

been improved considerably.

Treating advanced cancer of the cervix is an example where statistics

have now shown improved survival rates for women treated by integration of

chemotherapy with radiotherapy and surgery rather than by radical surgery

alone.

8.3.4.9 Induction Chemotherapy

Induction chemotherapy (sometimes called neoadjuvant, primary, initial, basal,

Both surgery and

or reducing chemotherapy) is chemotherapy given before any other treatment in

radiotherapy

order to induce tumour changes. In treating some cancers that appear to remain

will damage

localised to the site of origin but which are so advanced locally that they are

blood vessels and

unlikely to be cured by surgery or radiotherapy alone, induction chemotherapy

compromise blood

given first can reduce the size and extent of the cancer. This may make it possible

flow through

to totally remove the reduced tumour either by surgery or using with radiotherapy

tumours.

or using a combination of both.

The primary advantage of administering induction chemotherapy is to allow

the chemotherapy to flow into the cancer before its vascularity has been compromised.

Both surgery and radiotherapy will damage blood vessels and compromise blood

102

8 T reating Cancer

flow through tumours. If the chemotherapy flows through undamaged arteries

supplying the cancer with blood, the cancer should be maximally affected and

reduced in size and viability, thus improving the chance of success by subsequent

surgery or radiotherapy as well as being immediately effective as systemic pre-

operative adjuvant chemotherapy.

If induction chemotherapy can be given by regional infusion, directly into

the tumour arterial supply, with its greater concentration, it should have an

even greater impact on the primary cancer and most of it will still flow off

throughout all body tissues and should be effective as immediate systemic

“adjuvant” chemotherapy. This means that both the concentrated induction

chemotherapy reducing the primary cancer and the immediate pre-operative

systemic adjuvant effect on possible micro-metastases are given to best advan-

tage. Hopefully in this way the primary cancer is reduced and small undetected

clusters of cancer cells distant from the primary site are completely or par-

tially destroyed before curative surgery or radiotherapy of the primary cancer

is carried out. Work investigating this form of combined treatment is showing

encouraging results especially in treating some cancers in the head and neck

(including the mouth and throat), some stomach cancers, some breast cancers

and some cancers and sarcomas in limbs.

In treating locally advanced cancers whether or not induction chemotherapy

can be given by regional infusion there should be an advantage in giving at least

some chemotherapy before surgery. This should reduce and destroy as much of

the cancer as possible whilst its blood supply is still intact, and avoid waiting for

a surgical or radiotherapy procedure to be completed before adjuvant chemo-

therapy is started.

8.3.4.10 Side Effects of Chemotherapy

The risk of using cytotoxic anti-cancer drugs that cells in normal tissues may be

damaged. Expert supervision should ensure maximum damage to cancer cells

and minimum damage to normal cells and normal body tissues.

Because cancer cells are the most constantly dividing of all cells, they are

more susceptible to chemotherapeutic agents than normal cells. However, a num-

ber of cells in normal tissues are at risk because they also divide frequently.

These include blood-forming cells (in the bone marrow), surface skin and grow-

ing hair cells, mucosal cells lining the mouth, throat, stomach and bowel, and

cells lining the air passages.

Using

The most serious acute or short-term side effect of most anti-cancer agents

chemotherapy

is a fall in the white cells or platelets in the blood - this may lead to reduced

and radio-

ability to resist infection or to bleeding problems (granulocyte stimulating fac-

therapy over

tor or G-CSF, stem-cell infusion and bone marrow transfusion are methods of

the same treat-

helping to correct this side-effect in more severe cases). Hence regular blood

ment period,

counts are taken and doses of drugs may need to be adjusted. Other common

has been shown

acute side effects are mouth and throat ulcers, nausea and vomiting, hair loss,

or bleeding from the bowel. Whilst some side effects are common, provided the

8.3 Methods of Treatment

103

patient survives their toxicity, almost all of them are reversible and they abate

to be more

after drugs have been stopped.

effective than

A small number of anti-cancer drugs may affect function of the heart, lungs,

using the two

kidneys, central nervous system or peripheral nerves, but these effects are not

treatment

often seen because they are unlikely to occur with normal doses of drugs. Even

modalities

so, it is still necessary to watch closely and stop treatment at any sign of these

separately.

problems. With proper supervision by oncologists, the risk of very serious prob-

However

lems is small (Fig. 8.6).

potential

If chemotherapy is infused intra-arterially or otherwise given regionally, the

damage to

risk of damaging local tissues with local or regional side effects will be greater

surrounding

because the chemotherapy is concentrated in tissues near the cancer that are sup-

normal tissues

plied by the artery that is infused. Such regional infusions should be given only

is also greater.

by clinicians experienced in these techniques.

Fig. 8.6. Major side effects of diffe-

rent anti-cancer agents are often

different. This chest X-ray shows

pulmonary fibrosis that developed

as a serious side-effect in a patient

being treated with bleomycin

ertilisation and Pregnancy

Cells in the ovaries of young women and cells in the testes of men are con-

stantly dividing to produce ova or spermatozoa for potential reproduction and

development of a new embryo. If chemotherapy is necessary for such people,

they are advised to avoid pregnancy during treatment and for at least 12 months

afterwards due to the risk of abnormal ova or spermatozoa. There is even a

risk of permanent sterility. In the case of young males, keen to become fathers,

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8 T reating Cancer

spermatozoa can be produced and kept in cold storage (in liquid nitrogen) before

chemotherapy is started so that it can be used for fertilisation at a later date.

Sometimes it may also be possible to take and store ova from young females

before commencing chemotherapy. These can be fertilised and implanted into

the uterus at a later date if subsequent cancer treatment has been successful.

Late or long-term side effects of chemotherapy have been less apparent than

the more acute side effects and in fact not all long-term side effects have been

confirmed. Such delayed side effects as impairment of hearing or balance, bone

marrow dysplasias and delayed haematological toxicity are becoming well

documented although fortunately they are not common. Prolonged use of some

anti-cancer drugs can even cause a second cancer. All alkylating agents can be

associated with bone marrow dysplasia (myelodysplastic syndrome) or rarely

acute leukaemia. This small risk is highest with the alkylating agent melphalan.

A second group of drugs (the topoisomerase II inhibitors doxorubicin, epirubicin,

etoposide, teniposide etc) can also be associated with a mild increased risk of

myelodysplastic syndrome or acute leukaemia. The risk of leukaemia is further

increased when chemotherapy is combined with radiotherapy.

8.3.4.11 Concomitant Chemotherapy and Radiotherapy:

The So Called “Sandwich Treatment”

Using chemotherapy and radiotherapy over the same treatment period, has been

shown to be more effective than using the two treatment modalities separately.

Some chemotherapeutic agents e.g. cisplatinum, appear to sensitise cells to

radiotherapy. Although responses in the cancer are likely to be significantly

greater, it is apparent that the potential damage to surrounding normal tissues

is also greater, thus greater regional side effects. Programs for such concomitant

treatment schedules are under study but until further clarified they should be

used with great care and limited to experts in specialised cancer centres. Some

reports of using intra-arterial chemotherapy concomitant with radiotherapy in

treating locally advanced primary and secondary melanoma masses have also

been encouraging but because there is potential for serious tissue damage such

treatment schedules must be restricted to specialised centres.

8.4

Other Important Treatments

8.41

Hormone Therapy

8.4.1.1 Breast Cancer

Since 1896 when Dr George Beatson observed regression of breast cancer after

removal of the ovaries, it has been shown that in a number of women, especially

young (pre-menopausal) women, breast cancer is to a greater or lesser extent

8.4 Other Important Treatments

105

dependent upon the female sex hormone oestrogen. Just as removal of the major

source of the patient’s own circulating oestrogen (by oophorectomy) results in

regression of breast cancer in many patients, giving more oestrogen to women

with breast cancer can result in the cancer growing more rapidly. Removal of the

ovaries is still sometimes used in treating cancer of the breast in pre-menopausal

women (i.e. women with active ovaries) if the cancer is widespread or is so

advanced that it cannot be cured by surgery or by radiotherapy. Unfortunately,

removal of the ovaries or other hormone treatments rarely, if ever, results in

complete cure, although it often results in a period of worthwhile regression.

When the cancer enlarges again in younger women whose ovaries have

been removed, or in older women whose ovaries are not actively functioning,

a further improvement may be gained by giving male hormones, the androgens.

An even greater number may respond to one of the more recently developed anti-

oestrogen products. The first and still most widely used anti-oestrogen agent is

called Tamoxifen.

Hormone manipulation has a distinct advantage over other forms of chemo-

therapy because hormones are less likely to cause serious side effects. However,

the male hormone, androgen, will cause most female patients to develop certain

male characteristics such as a deepening of the voice and growth of hair on the

face. It may also cause an increase in sexual desire (libido) that can be distress-

ing for some patients such as women without a partner. Modified androgens with

reduced side effects are an improvement but none is without any side effects.

Another form of hormone therapy used in the past was to remove or other-

wise put out of action other glands - the adrenal or pituitary that are responsible

for oestrogen production after the ovaries have ceased to function or had been

removed. Nowadays their actions can be suppressed by the use of luteinising

hormone releasing hormone (LH-RH) agonists and aromatase inhibitors. If this

is done, other precautions must be taken and medications given to replace other

essential functions of these glands.

The original hormonal treatments of breast cancer have now been largely

replaced by more modern hormone treatment schedules that should be adminis-

tered carefully by specialist oncologists.

Anti-Oestrogens: Tamoxifen

The anti-oestrogen compound, Tamoxifen, has a somewhat similar effect to

androgen but has the distinct advantage of being relatively free from side effects.

Tamoxifen is also more likely to be effective in a larger number of patients

(including older women), than androgens or other agents.

Whilst Tamoxifen is often effective and is the most widely used hormonal

agent (actually it acts in competition with oestrogen) it rarely causes any upset to

the patient in the short term. When used over several years there is some risk that

it may alter the uterine mucosa and can even stimulate a cancer in the uterus. This

risk is small but most doctors now limit the use of Tamoxifen to 5 years unless

it is clearly essential to use it for longer periods. Studies have now shown that

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8 T reating Cancer

used as adjuvant chemotherapy, after treatment of breast cancer in women with

hormone receptor positive cancers, hormone therapy can significantly reduce the

risk of both recurrent disease and mortality.

Cortisone

The adrenal gland hormone, cortisone, may also suppress some cancers. It is

often used in combination with cytotoxic chemotherapeutic agents in treatment

of breast cancer, some cases of leukaemia, the lymphomas, especially Hodg-

kin disease, (Chap. 19), adenocarcinoma of the kidney (Chap. 17.2.2), advanced

prostate cancer (Chap. 16.2.4) and a rare cancer of plasmocytes in bone called

multiple myeloma (Chap. 19.8).

Hormone Side Effec ts

Most patients tolerate hormone therapy better than chemotherapy. However

hormones may sometimes have some serious long-term side effects after pro-

longed use. Oestrogens can cause thrombosis and, in males, some feminising

effects. Androgens in females can cause hypertension as well as troublesome

mascularising effects. Removal of the adrenals or pituitary glands also leaves

problems of endocrine balance that must be managed.

Hormone treatment is often more readily accepted by patients and the medical

profession as being more “natural”, more scientific, and less toxic than cytotoxic

chemotherapy. Unfortunately, however, the good responses of hormone treat-

ment of widespread cancer are usually relatively short-lived and eventually most

of the cancers re-develop. Each time they re-develop they are less responsive to

other forms of hormone management and eventually become unaffected by all

forms of hormone management.

Long-Term Hormone Therapy

Small doses of oestrogen were commonly given to menopausal and post-

menopausal women to relieve hot flushes, depression, vaginal dryness loss of

sexual libido and other menopausal symptoms. This hormone replacement

therapy (HRT) given over a prolonged period, was known to be associated with

a slightly increased risk of breast cancer as well as a small risk of deep vein

thrombosis. Oestrogen therapy was then replaced by medications combining

small doses of oestrogen with progesterone. However it has now been shown

that there is still a small risk of side effects from oestrogen which are possibly

even greater, from the combined medication, including increasing the risk of

osteoporosis, thrombosis and cardiac problems. From recent studies there is no

apparent increased risk of breast cancer if HRT is given to post menopausal

women for no longer than 2 years and very little risk if given for no more than

5 years. However women who have already been treated for breast cancer or

women in other high-risk groups are not given such treatment.

8.4 Other Important Treatments

107

New Agents

New more effective agents are constantly being developed and tested. Herceptin

is discussed in a later chapter (Sect. 12.7 in Chap. 12). Tests on biopsy specimens

indicate likely response to Herceptin if needed.

8.4.1.2 Prostate Cancer

In 1941 Charles Huggins and Clarence Hodges, showed that a large percentage

of cancers of the prostate regressed after either the removal of male hormone (by

castration) or administration of a female hormone (oestrogen). This was the first

study that showed that some hormone dependent cancers can be influenced by

giving the patient an antagonistic hormone. Castration is sometimes still used in

treatment of prostate cancer, and can be worthwhile, but it gives only temporary

control in the majority of patients. Oestrogen is no longer used because there

are better hormonal agents now available that don’t cause the desire and ability

to have sexual activity to be so suppressed and there is less likelihood of other

changes in sexual characteristics such as enlargement of the man’s breast tissue.

Anti-androgen drugs luteinising hormone releasing hormone agonists (LH-RH)

have a similar cancer suppressive activity with fewer side effects than with

oestrogens (see Chap. 16).

8.4.1.3 Other Possible Hormone Sensitive Cancers

Other cancers that respond to hormones include cancer in the male breast,

which often responds to castration, although a more acceptable treatment

is Tamoxifen to which it will often respond. Cancer of the lining inside the

uterus (endometrial cancer) may respond to progesterone. Sometimes cancer

of the kidney will respond either to male or female hormones, and some

cases of thyroid cancer will be at least temporarily suppressed by the thyroid

hormone, thyroxine.

8.42

Immunotherapy

The body’s natural defence against invasion by organisms and other foreign

matter is through its immune defence system. The body also has some immune

defences against malignant cells and, possibly, development of cancer may be

caused by some fault or breakdown in these protective mechanisms. (Some

present concepts of these defence mechanisms are discussed below under Cell

mediated anti-cancer activity.)

Attempts have been made to develop immunity against cancer but the only

real success has been vaccines against viruses that are associated with cancer

directly against HPV (the human papilloma virus) and indirectly by immunising

against Hepatitis B.

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8 T reating Cancer

Three groups of

A great deal of research is concerned with determining the nature of these

immunological

immunological defence mechanisms and trying to improve them or assist them

substances

in people with cancer. These approaches will one day be of considerable practical

of particular

value in cancer treatment.

interest are

Injections of certain relatively harmless organisms such as the cowpox virus,

interferon, the

BCG or (Corynebacterium parvum). Both are harmless bacteria and have been

interleukins

used in trials in the treatment of some malignancies to stimulate natural immune

and tumour

defence mechanisms. Some isolated successes have been reported, especially in

necrosis

the treatment of melanoma and lymphomas. Unfortunately as yet for most cancers,

factor (TNF).

little if any clinical benefit has resulted although further worthwhile studies are

in progress, especially in vaccine treatment of advanced melanoma. There is

still a place for clinical use of BCG in treatment of some bladder cancers and

prolonged cancer control is well established in many of these patients.

8.4.2.1 Monoclonal Antibodies

Many attempts have been made to develop antibodies with specific activity

against a particular cancer. In animal studies this has been possible in a number

of different models, especially with several tumours types in mice. There have

been three somewhat different therapeutic objectives:

1. One is to develop “killer antibodies” that specifically act against a particular

cancer.

2. Another is to develop “magic bullets” where antibodies are used to carry

an anti-cancer chemotherapeutic agent or a radioisotope or other such agent

directly to the cancer cells wherever they might be.

3. The third potential use of monoclonal antibodies is to identify the presence

of cancer cells by reaction to specific antibodies.

The application of these principles to treatment of clinical cancers in humans

has met with some encouraging results, especially in treating metastatic breast

cancer.

Recently developed techniques in biotechnology have made it possible to

manufacture so called monoclonal antibodies that are aimed at specific vital targets

in certain cancers. These include malignant lymphoma, breast and bowel cancers.

The use of these antibodies is relatively new, e.g. mabthera for lymphoma, herceptin

in breast cancer and erbitux for bowel cancer. In general these antibodies are used

in combination with chemotherapy. Despite their great expense they are showing

considerable effectivity, although their final role is still being evaluated.

Herceptin (trastuzumad) is a commercially available humanised monoclo-

nal antibody medication that specifically targets cancer cells. In fact it specifi-

cally targets a certain protein, human epithelial growth factor (HER2). HER2

is responsible for normal cell growth and cell division but HER positive cancer

cells have raised HER receptors on their surface and grow more quickly than

normal cells. Herceptin can also activate the immune system to kill HER2

8.4 Other Important Treatments

109

positive cancer cells. This explains why cancer growth is more specifically

retarded by Herceptin. In some patients Herceptin is considerably more effec-

tive if used in combination with chemotherapy, especially taxones. Herceptin is

expensive but is relatively non-toxic in clinical doses.

Three groups of immunological substances of particular interest are inter-

feron, the interleukins and tumour necrosis factor (TNF).

8.4.2.2 Interferon

It was first recognised in the 1930s that infection of animal cells with one virus

would for a time “interfere” with infection by other viruses. Thirty years later it

was discovered that a protein substance was released from cells infected with a

virus and this substance protects other cells against other viral infections. This

interfering substance is called “interferon”.

Interferon is found to be species specific. That is, interferon produced by chicken

cells is protective to other chicken cells against virus infection but is not protective

for cells of any other animal species. Similarly, interferon produced from human

cells is protective for other human cells but not for cells of other animal species.

Because it is difficult and expensive to prepare large quantities of interferon,

trials to study its clinical value in large numbers of patients have been difficult

to arrange. There is evidence that it may be protective in some viral infections

but is too expensive for general use. A rare form of leukaemia called “hairy cell”

leukaemia is one malignancy that often does respond well to interferon treatment

(Chap. 19).

AIDS (acquired immune deficiency syndrome), is due to a virus infection.

This condition is an infection and not a cancer but a particular type of cancer

called Kaposi’s sarcoma was found to develop in some of the first patients with

AIDS. Over a longer term some types of lymphoma, cancers of the cervix and

some other cancers have been found to develop more commonly in AIDS patients

than in the community at large. Early hopes that AIDS might respond well to

Interferon or any other immune treatment has so far not been fulfilled.

8.4.2.3 The Interleukins

The interleukins are protein substances, known as cytokines, and are produced

from white cells and are found to activate the immunological defence system.

The first interleukins were Interleukin 1 which is produced from macrophages

(giant white cells) and Interleukin 2 that is produced from lymphocytes (small

white cells). They stimulate reproduction and activity of immune cells against

a cancer to which the cells have been specifically sensitised. In experimental

animals, interleukins have been shown, under certain conditions, to stimulate the

animal’s natural lymphocyte activity against implanted cancers to such an extent

that the cancers have been eradicated. At the time of writing this book neither

Interleukin I nor Interleukin 2 nor several more recently discovered Interleukins

have made any widespread impact on cancer treatment.

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8 T reating Cancer

However some cancers, including melanoma and kidney cancers, sometimes

appear to have increased response when certain interleukins are used in conjunc-

tion with other treatments.

8.4.2.4 Tumour Necrosis Factor (TNF)

TNF is a more recent cytokine protein product of immunological research. TNF

does cause cancer cell destruction in some experimental models but is too toxic

for direct use in human patients. However recent work has shown that TNF

enhances the anti-cancer effect of certain other chemotherapeutic agents and

can be used safely and effectively when given exclusively to a limited part of the

body. At the time of writing this book it can be given with safety only in a closed

circuit by regional perfusion or regional infusion to treat malignancies such as

melanoma and sarcoma when confined to a limb (as discussed under “Regional

Chemotherapy”) but it can not be used systemically with safety.

TNF in combination with Interleukins 1 and 6 has been implicated in promo-

ting cancer cachexia. Indeed, TNF was originally called cachetin, as the agent

that caused cachexia. Drugs that suppress the production of TNF, e.g. corticos-

teroids and thalidomide, have shown promise as agents that suppress cachexia

and tumour growth, respectively. The omega-3 oils are thought to work by sup-

pressing Interleukin 6, which promotes breakdown of adipose tissue and skeletal

muscle.

Small Molecule Target Inhibitors

Basic cancer research has identified a number of key signalling pathways that

co-ordinate cancer cell growth. Growth signalling cytokines circulate in the

blood and bind to cancer cells via special receptor molecules. Receptors become

activated by the binding cytokine, and send a complex series of chemical signals

to the cell nucleus stimulating cell growth and division The principle oncogene

proteins responsible have been identified and successfully targeted for direct

inhibition by small molecules (low molecular mass compounds) that specifi-

cally inhibit the enzyme activity that stimulates growth. Examples are: Imatinib

mesylate (Gleevec), inhibit the tyrosine kinases, c-ABL + PDGF and c-KIT,

that are activated in chronic leukaemia and gastrointestinal stromal tumours

respectively. Small molecules can also inhibit other protein functions or block

regulatory protein-protein interactions.

8.4.2.5 Cell-Mediated Anti-Cancer Activity

Cell-mediated anti-cancer activity starts with a dendritic cell, a specialised

type of white blood cell produced in bone marrow and lymph nodes. Dendritic

cells are responsible for initiating and coordinating the body’s defence and

immune system. They stimulate macrophage activity. Macrophages have scavenger

(phagocytic) activity and are present in connective tissues and many organs

8.5 Some Further Treatments Under Study

111

including bone marrow, lymph nodes, spleen, liver and the central nervous

system. Macrophages are also called antigen-presenting cells (APC). They pro-

cess antigens for presentation to “T” (tissue) lymphocytes.

Helper “T” cells recognise foreign antigen on the surface of foreign cells and

stimulate the production of cytotoxic “T” lymphocytes or killer cells. The killer

cells destroy cancer cells and virus-infected cells by targeting foreign antigen

that has been presented by macrophages.

This is all like a rather interdependent cycle of immune-cell activity and many

of the immune therapy factors described in this chapter are derived from dif-

ferent cells involved in this intriguing cycle. Each is aimed at boosting natural

defences against cancer cells.

8.5

Some Further Treatments Under Study

85.1

Heat Therapy

Because cancer cells are more sensitive to heat than normal cells heat-therapy is

now used in conjunction with chemotherapy in treating some tumours confined

to a limb, for example melanoma. When chemotherapy and heat can be confined

to the limb circulation there is a greater anti-tumour impact than with the use of

chemotherapy alone. However the safe and effective level of temperature eleva-

tion must be kept in a narrow range and even then there is an increased risk of

damage to normal muscles, skin and other tissues in the limb.

Investigations continue into methods of applying localised heat selectively

to internal organs or tissues containing cancer in a manner that will safely

destroy the cancer cells without damaging the normal body tissues. This

approach could be particularly valuable for treating cancer cells in a vital organ

that cannot be safely removed (such as in the liver). Several types of microwave

emitting machines have been designed for this purpose. A number of problems

have yet to be solved, particularly in maintaining the heat at a critical level

for a significant period without overheating the patient or causing damage to

normal tissues and cells. Studies are continuing but after several years the

most that can be said is that some interesting and hopeful results continue to

be reported.

8.5.1.1 Cryosurgery

This is another technique of destroying tumour tissue by using an extremely

cold temperature application to freeze-thaw and so destroy the tissue. It has been

used topically for years to treat small skin pre-malignant lesions (CO ₂ snow,

or liquid nitrogen) but more recently an internal probe has been developed to

destroy metastatic deposits of cancer cells, especially in the liver. Good results

have been reported from cancer centres specialising in this treatment.

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8 T reating Cancer

8.5.1.2 Laser Surgery

In general the somewhat romantic objective of developing a laser gun that could be

specifically aimed at cancer cells and initiate their destruction sadly still remains

largely in the realm of science fiction. However some studies using laser in treating

some early cases of prostate cancer are encouraging, otherwise to date the closest

application of this principle is with photodynamic surgery as discussed below.

In its more general application, laser surgery is simply development of surgi-

cal technique in cancer treatment in which laser light is used to cut tissues in

some ways similar to diathermy. However studies of the use of laser light in

combination with other agents such as in photodynamic therapy continue and

their future expanded clinical application is almost certain. These techniques

have already be used in some clinical areas such as vascular surgery in which

endoscopic tubes are used to reach pathological lesions or tumours in organs or

tissues of otherwise difficult access.

8.5.1.3 Photodynamic Therapy

This is a type of light sensitive treatment being further investigated for some

cancers.

The small new capillary blood vessels that develop with a cancer to supply it

with blood are poorly formed and fragile. They easily break down if damaged

and also allow some chemicals to leak out into the cancer tissues. In photo-

dynamic therapy patients are injected with certain photo-sensitising chemical

substances, that leak out of the fragile blood vessels in the cancer. The cancer

is then subjected to laser light of certain wavelengths. The reaction of the sub-

stances to laser light destroys the cancer cells. As laser light does not penetrate

any distance into tissues this treatment has so far only been used to treat certain

surface cancers, such as skin cancers and cancers in the mucous membrane

lining the mouth. Studies to date are being carried out only in specialised clinics

as precautions must be taken to avoid side effects, especially general sunlight

hypersensitivity from photosensitising agents.

Any advantages of this treatment over other more standard treatments are as

yet uncertain but in the future there may be potential for developing similar tech-

niques to treat other less accessible cancers, for example bladder cancers.

Dermatologists have now developed an effective photodynamic therapy for

skin cancers using a local application of a photosensitive cream and a strong light

wave, not necessarily laser light. Many superficial skin cancers are now treated

very effectively by this relatively simple technique.

85.2

Gene Therapy

Among the more exciting areas of progress of both understanding cancer and treat-

ing cancer is the study of genes and their activity and genetic abnormalities. In the

near future genotypic tumour changes will be relevant in deciding treatment.

8.6 General Care

113

Gene therapy is in its infancy, but the Chinese Government has licensed in 2005

a recombinant adenovirus that produces a functional p53 protein when the virus is

injected into head and neck squamous-cell carcinoma (HNSCC), and it has shown to be

effective in combination with radiotherapy (to induce apoptosis and tumour regression).

8.5.2.1 Matching Treatment to Cancer-Associated Genes

and Molecular Characterisation of Cancers

As well as traditional matching of treatment to histological features of cancer

cells, progress is now being made in matching treatment to cancer-associated

genes and molecular typing. Progress is especially being made in using the

tyrosine-kinase inhibitor STI 571 or imatinib (Gleevec) with successful treat-

ment of chronic myeloid (or myelocytic or granulocytic) leukaemia and gastro-

intestinal stromal tumours as mentioned in Chap. 19.4.3.

More of this progress is outlined in Chap. 24.19 under the heading “Molecular

Characterisation in Future Cancer Treatment”.

8.5.2.2 Anti-Angiogenesis

Following the principles mentioned in photodynamic therapy, agents are now being

developed specifically aimed at damaging or preventing development of the small

blood vessels (capillaries) that supply the cancers with blood. Without a blood sup-

ply the tumours can’t grow or survive. At this stage successful experiments have

been conducted against tumours in mice and other animals. One such product is

called “angiostatin” but it is likely that a number of new agents, aimed specifically

at tumour blood vessels, will be developed in the near future.

People who remember the deformed limbs of some babies born about in the early

1960s to some mothers who took the anti-nausea drug thalidomide, may be interested

to know that thalidomide caused the defects in the growing foetus precisely as a result

of interfering with the important blood vessels growing in the developing foetus limbs

in at a crucial time of foetal development. Thalidomide and similar products are now

being investigated to destroy the small blood vessels in some growing cancers.

8.6

General Care

8.6.1 Care of General Health

The ability

of the body’s

The presence of cancer in the body sooner or later will have a profound effect

natural defence

on the sufferer’s general state of health. Anorexia (loss of appetite), weight loss,

mechanisms to

anaemia, lassitude, and general malaise and debility are common general features

control cancer

and specific problems will develop according to the site of the cancer and the tis-

is affected by

sues or organs involved. The ability of the body’s natural defence mechanisms to

the patient’s

control cancer is affected by the patient’s general state of health, as will the patient’s

general state

mental and emotional state and ability to tolerate the various forms of treatment.

of health.

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8 T reating Cancer

For these reasons, it is important that special attention should be paid to

the patient’s general health and well-being. The diet should be nutritious yet

tempting and interesting. Adequate vitamins must be provided either in the

food or in vitamin supplements and omega oils should be part of the treatment

of cachexia. Any anaemia should be appropriately treated and there should be

provision for adequate rest and gentle healthy exercise. There must be adequate

provision for pain relief. Emotional support from family, friends and the treat-

ment team including friendly concern and support of a good family doctor

make a big difference in the prospects of the patient living comfortably and

making achievable progress.

8.62

Treatment of Complications

Special problems associated with particular forms of cancer will need appro-

priate attention. These include nutrition for patients with obstructive cancer

of oesophagus or stomach. Surgical measures can give relief of obstruc-

tion for patients with obstructive bowel cancer or patients with pancreatic

cancer obstructing the bile duct and causing jaundice. Surgical relief can

also be given for urinary obstruction of patients with obstructive cancer

of the prostate gland. Local treatment and dressing is essential for cancers

fungating through the skin. Diuretics and some other measures sometimes

give partial relief from pressure on the lungs with breathlessness caused by

fluid accumulated around the lungs in the pleural cavity (pleural effusion).

However removal of pleural fluid or ascites fluid accumulated in the chest or

abdominal cavity may be needed to achieve temporary relief from pressure

in the abdomen and chest.

Raised intra-cranial pressure may cause headaches, vomiting, papilledema

(with blurred vision) convulsions or coma. This may be caused by tumours

with surrounding swelling in the brain and the patient can often be relieved by

radiotherapy or the use of certain drugs, especially steroid drugs, that reduce the

swelling.

Complicating infections due to cancer, such as pneumonia associated with

cancer obstructing the air passages or infections associated with weakened

leukocyte defences of leukaemias, will also require appropriate attention.

Bleeding, bruising or thrombosis also commonly associated with blood dis-

orders of leukaemias will also require special attention.

Anaemia is also a common association with many cancers including the

leukaemias; cancers of stomach, bowel or uterus with abnormal bleeding; or

primary or secondary cancers destroying or replacing bone marrow. Anaemia

secondary to chemotherapy can be improved with judicious use of the bone

marrow protective agent erythropoietin. Haemoglobin should be maintained at

or above 12 g/L. This reduces the need for blood transfusion and improves the

patient’s quality of life.

8.6 General Care

115

Bones involved with cancer may not only be painful but may fracture sponta-

neously - known as pathological fracture. The use of bisphosphonates has been

shown to decrease the risk of complications (fractures, hypercalcaemia, spinal

cord compression etc) as well as relieving bone pain. Bisphosphonates become

incorporated in the weakened area of bone, restoring some strength to the bone

and helping it to resist further destruction. Bisphosphonate treatment requires the

patient to attend the hospital or oncology unit for a couple of hours. A slow drip of

fluid containing the drug is infused into a vein. The patient simply sits comfort-

ably during the procedure, possibly reading a book or watching television. The

treatment should not worry the patient or cause side effects and can be repeated

at about monthly intervals if necessary. Bisphosphonates are used to advantage

in managing metastases from breast, prostate and lung cancers.

Pathological fractures need to be treated on their merits but healing is often

helped by local radiotherapy. Metastatic cancers not only in bones but also in

liver, lungs, brain, bowel and other situations may also need special treatment.

8.6.3 Supportive Care and Supportive Care Teams

Because of the complexity of cancer treatments, their inevitable side-effects,

and the need for both acute and long-term specialised care, professional “sup-

portive care” teams have been established in some clinics. These teams consist

of doctors, nurses, allied health professionals, social, psychological and spiritual

helpers. These teams have particular skills and interest in care of cancer patients

who have developed complications of treatment and patients who have residual

complications but an otherwise good, long term prognosis. The skills of these

teams range from administration of haemopoetic growth-factors and blood trans-

fusions to restore depressed bone marrow activity, management of infections or

nutritional problems as well as longer term restoration of physical activity, long-

term pain relief and restoration of social and income producing activity.

This is an area of care that has been historically shared between the cancer

treatment team and the palliative care team.

In most clinics “supportive care” is still provided either by the cancer treat-

ment team or the palliative care team but in some clinics, especially where the

clinical workload is increasing, specialised supportive care teams have become

a valuable asset in cancer care.

8.6.4 Pain Relief

Nothing is more wearing, debilitating and distressing for people than to suffer

constant and unrelieved pain. Whilst most cancers causing severe pain are usually

advanced and some are incurable, at least patients suffering severe pain can be

given relief. For curable cancers, the best pain relief is achieved by eradicating

the cancers, but for incurable cancers many pain-relieving measures are available.

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8 T reating Cancer

Radiotherapy will often give pain relief by reducing the size of the tumours and

surrounding swelling and pressure. This is especially so for metastatic cancers

in bones and the brain. Operations to relieve obstruction of bowel, bladder or

other organs will give pain relief. Hormones or anti-cancer drugs that reduce

the size of tumours, thus reducing any associated pressure, may also be used on

occasions to effect pain relief.

Nerves that transmit pain may also be put out of action by injecting them with

local anaesthetic or with alcohol or possibly by cutting them surgically. Occasion-

ally the nerve pathway in the spinal cord that conducts pain sensation to the brain

can be cut to give permanent loss of pain sensation from a region of the body.

Meditation, hypnotherapy or even acupuncture is used at times for pain relief.

Whilst they are undoubtedly helpful for some patients, for others, their greatest

value may be in providing emotional support rather than physical relief of severe

or constant pain.

The most common and quickest method of pain relief is with simple pain-

relieving drugs (analgesics) or the stronger and addictive pain relieving drugs

(narcotics). Simple analgesics such as aspirin and aspirin-like products, para-

cetamol and the like, are usually used first. If not effective, agents containing

small amounts of the least dangerous narcotic agent, codeine, are often used.

The stronger narcotic agents, Pethidine (meperidine), methadone, and the opium

derivative, morphine, may be given for immediate relief of severe pain usually as

a temporary measure until other treatment has given more permanent pain relief.

They may also be given on a permanent basis for pain-relief in people, who have

a limited life expectancy, from an incurable cancer.

One of the most frequent treatment errors in oncology is under-treatment

of pain, especially chronic pain in a palliative setting. Combination analgesic

therapy, with narcotic and non-narcotic drugs, as well as tricyclic drugs for stress

relief is an important aspect of management for people with advanced incurable

cancer. In some countries heroin is also used very effectively in these circum-

stances but only when life expectancy is strictly limited.

8.6.5 Psychological and Spiritual Help

As mentioned in Chap. 2.20, some psychologists, alternative medicine practi-

tioners and well-qualified psychiatrists postulated that sometimes cancer may

be a result of anxiety, emotional trauma or depressive states. This may or may

not be so but at least it must be acknowledged that such emotional states are

detrimental to the patient’s well-being and often do have an adverse effect on

the progress of the disease and response to treatment. Perhaps more importantly,

people who rightly or wrongly believe that they have a cancer become anxious

and emotionally disturbed even if they were not previously. This is a natural and

understandable reaction to what they often regard as a death sentence at worst,

or a very serious illness requiring radical or prolonged treatment, and possibly

with disfigurement at best.

8.6 General Care

117

Such emotional distress will often cause patients to seek alternative medica-

tions or fringe medicine therapists, unconventional “faith healers” or tragically

unqualified “quacks”, especially if they have been told that traditional medicine

has nothing to offer.

Every doctor who cares for cancer patients should anticipate these natural

reactions and readily support the emotional needs of the patient and the patient’s

family in all situations. Sometimes this can be given effectively by the respon-

sible clinical specialists with the cooperation and help of the family doctor

experienced nurses and other qualified helpers including social workers or

psychologists. For most people, support of a member of the clergy can be a great

comfort. Sometimes the help of an understanding psychiatrist experienced in this

field is mandatory and certainly it is extremely valuable for a cancer treatment

team to have the services of an interested and experienced psychiatrist and/or

clinical psychologist and a social worker readily available.

Some psychiatrists and paramedical workers have claimed that some patients

who have learned techniques of relaxation and meditation or hypnotherapy have

shown not only emotional and physical benefit but even regression of the size of the

cancer. In some patients such benefits may be real but they are difficult to prove.

A strong wish for improvement may cloud any measurable judgment, and very

occasional cases of spontaneous cancer regression have been reported in response

to no particular therapy. However, an invaluable benefit of an experienced

psychiatrist or clinical psychologist and social worker is to help the cancer sufferer

and members of his or her family adjust to the new situation with all the emotional,

social and other problems associated. An experienced social worker is of great

help in advising of financial and other supportive agencies that may be available

to help a patient’s readjustment and other needs. For many people, especially those

with advanced or incurable cancer, member of the clergy or other spiritual adviser

will be of great value in helping in this re-adjustment process in which the patient

has to come to terms with a changed and possibly fatal situation.

8.6.6 Follow-Up Care

No matter what treatment is used in cancer management it is important that

No matter what

all patients should undergo regular medical follow-up examinations. This is

treatment is

mainly to detect and treat, at an early stage, any problem that might arise but

used in cancer

also gives most patients confidence that they are not being neglected and that

management

any new problem will be detected and treated early. It is also important for

it is important

doctors to keep accurate and continuing records of the long-term success or

that all patients

otherwise of treatment given so that improved treatments can be recorded and

should undergo

further developed.

regular medical

For some cancers if 2 years has passed since treatment with no evidence of

follow-up

cancer, it can be very hopeful that the cancer has been cured. Indeed for most

examinations.

cancers a period of 5 years free of cancer indicates that cure of that cancer is very

likely. Two of the more common cancers however require a longer period of regular

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8 T reating Cancer

follow up as evidence of disease can show up years later. These are melanoma

and breast cancer. It seems that for these two cancers in particular, the body’s

natural “immune” defences can keep the cancer under control for many years until

something causes it to show up again, sometimes as a lump under the skin or in

a lymph node, or somewhere else. These recurrent or residual cancers are often

slowly growing and may be curable provided they have been detected whilst still

small and localised. Hence the special need for regular and long-term follow-up of

cancer patients.

8.6.7 The Specialty of Palliative Care

In recent years palliative care has developed into a specialty service in its own

right. It is especially relevant to the field of oncology.

When cure is beyond all probability and remaining life is, or is likely to become,

increasingly miserable, doctors, nurses and other associated experts who develop

special expertise in relieving distressing symptoms and making remaining life

more comfortable and tolerable make up the palliative care team. Rather than

leave the family doctor, or specialist surgeon, physician, radiation oncologist or

other specialist oncologist either individually or collectively to do their best to

relieve distress, the experts in palliative care form a team dedicated to studying and

administering methods to best make life more comfortable for suffering patients.

These teams specialise in relieving acute or chronic pain, bladder or bowel inconti-

nence, feeding, respiratory, speech and mobility problems and sleeping difficulties.

They are aware of and help avoid problems of prolonged ill health or confinement to

bed such as pressure sores, pulmonary congestion or deep-vein thrombosis.

These caring specialists have now become most valuable associates for cancer

treatment teams attending to special needs of the patient not only medical and

physical but also needs of a social, emotional and spiritual nature. They help

families and friends adjust to different circumstances and different needs -

specially when there is no prospect of curing the cancer.

Palliative-care specialists initially began their work in hospitals and nursing

homes but now many are able to offer services in other institutions or in family

homes. In some countries, separate institutions have been established for specia-

lised services in palliative care.

Most

unconventional

“cures”

have been

8.6.8 Alternative Medicine

investigated

one way or

8.6.8.1 Ranging from Unproven Naturopathic and Herbal Medicine

another and

Remedies To Unscrupulous “Quack” Practises

found to be

lacking when

There are almost limitless numbers of “cancer cures” promoted by a variety of

analysed

people ranging from thoughtful, well-intentioned and knowledgeable alternative

scientifically.

medicine practitioners on the one hand to misguided “quacks” and unscrupulous

8.6 G eneral Care

119

charlatans on the other. These “cures” range from large doses of vitamins (espe-

cially vitamin C), to pure or blended mixtures of herbs and a variety of plant

extracts. One of the most publicised plant extracts is an extract of apricot kernels

called Laetrile. Diets (especially low-protein diets) are commonly advocated.

Other common recommendations are meditation, acupuncture, hypnotherapy

and faith healing.

There are also some contemptible, deceitful unqualified practitioners who use

For some

sleight-of-hand manoeuvres in which they pretend to extract cancers painlessly

patients

from sufferers and produce a handful of bloodstained tissue as evidence of this.

alternative or

Some of these alternative remedies are undoubtedly based on incidental

un-orthodox

observations. Some are based on reasonable observations or hypotheses, as may

therapy can

be so for vitamin C therapy and the other anti-oxidant vitamins A and E. Others

be comforting

however are devoid of any logical or scientific basis. Some of these are based

and supportive

on a figment of imagination or a “one-off” incidental observation in an isolated

even though

cancer sufferer who happened to undergo a spontaneous remission.

specific cancer

Unfortunately sometimes a “cancer cure” promotion is purely based on a

healing

desire to get rich on the part of the practitioner, at the expense of the cancer suf-

properties

ferer and his or her family. Sometimes cancer cures have been claimed in patients

are either

in whom a diagnosis of cancer was never established.

non-existent,

Most unconventional “cures” have been investigated one way or another

not known

and found to be lacking when analysed scientifically. None has been more thor-

or not

oughly studied than Laetrile and, although no medicinal value has been found,

understood.

it is entirely understandable that people who find themselves unable to face the

reality of having an incurable condition or of requiring radical surgery or other

radical treatments, will search for a more acceptable alternative. This must be

appreciated by cancer treatment teams who need to be prepared to spend time in

advising and helping cancer sufferers in their mental and emotional as well as

physical distress.

At the same time, medical practitioners should not close their minds to the

possibility that one day an idea might be proposed or an observation made by a

non-traditional practitioner that could be of value in cancer treatment.

Many valuable medications, including some anti-cancer agents, have been

found in plants. Undoubtedly more will be found in the future. The medical

profession and research scientists are aware of these possibilities, so that most

proposed new or alternative but unproven “cancer cures” undergo some form of

examination by appropriate authorities.

For some patients alternative or unorthodox therapy can be comforting and

supportive even though specific cancer healing properties are either non-existent,

not known or not understood. Provided such therapy is helping or comforting for

the patient, is not harmful either physically or financially, and does not conflict

with necessary treatment, it should not be dismissed for this patient by the cancer

treatment team.

Relationship Between Patients, Their Doctors

and the Healthcare Team

In this chapter you will learn about:

› The importance of selecting appropriate specialists for patient care

› The importance of developing an honest and compassionate relationship

between doctor and patient

› Skills in delivering worrying news to patients and their families

› Differences that often exist between men and women in dealing with

health issues.

Nowhere in the field of medical practice is it more important for the patient to

The occasion

have good personal relationships, trust and understanding, than between each

of breaking

patient with cancer, or suspected cancer, and his or her medical advisers. Breast

bad news to

cancer and prostate cancer stand out as having special need for good relation-

any patient

ships. In the case of breast cancer different possible courses of action are likely

with cancer

to achieve similar long-term results and the patient’s preferred treatment option

must be

should be discussed. In the case of prostate cancer there may be a question of

handled

advisability of any attempt at cure so that the patient’s personal life priorities

with

must be considered.

gentleness,

The occasion of breaking bad news to any patient with cancer must be handled

compassion

with gentleness, compassion and understanding. It must not be hurried and pref-

and under-

erably the patient’s wife or husband or a particular friend or family member

standing.

should be present. Questions must be answered truthfully and carefully but with-

out unnecessarily stressing pessimistic aspects.

There is no simple answer and each patient’s special needs and priorities and

his or her family and social relationships and circumstances are all important in

the decision making.

By the time women reach the age of having need for advice about a cancer

problem most will know a family doctor in whom they have trust and confi-

dence.

Men are usually less ready than women to seek medical advice and often need

to be persuaded by a wife or a friend.

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122 9

Relationship Between Patients, Their Doctors and the Healthcare Team

After a comfortable, unhurried and mutually thoughtful and honest discus-

sion about the problem with the family doctor, and, at least on one occasion with

the patient accompanied by his or her wife, husband, partner or other close fam-

ily member or friend, arrangements will usually be made for consultation with

a specialist.

The specialist is unlikely to be an old family friend, as the family doctor may

well be. However it is equally important for the family doctor to arrange referral

of the patient to a skilled but compassionate, supportive and understanding

specialist who is prepared to listen to the patient’s anxieties and take time to

answer many asked or unasked questions. The specialist should be chosen

because he or she has special skills, facilities and expertise and is also readily

able to communicate comfortably with an anxious, worried and often confused

patient and his or her family. This is not the occasion for the family doctor to

arrange consultation with a specialist predominantly because he or she was an

old school mate or one who has just come back from overseas with good training

and needs support. The relationship between specialist and patient will probably

be prolonged over several months or years. In fact there should be a close three-

way relationship with good understanding and communication between special-

ist or treatment team, family doctor and patient.

Certainly the specialist must have the appropriate skills and facilities and must

be up to date with latest information. But over and above this, it is most important

for the specialist, and members of the treatment team, to be able to communicate,

explain and be ready to answer questions freely and in an unhurried atmosphere

and be readily accessible, possibly by telephone, if or when problems or ques-

tions arise. Discussions about the most appropriate treatment should not sound

like an edict from above but be mutually considered and arranged, having taken

into account many factors unique to the individual patient. The specialist must

also appreciate that no matter how clearly he or she has explained everything to

the patient it is unlikely that the patient will be able to “take it all in” in one visit.

One or more further visits are almost essential for probably every patient, if not

to the specialist, then at least to the well-informed family doctor.

Skin Cancers

In this chapter you will learn about:

› Skin cancer prevention

› BCC (basal cell carcinoma)

› SCC (squamous cell carcinoma)

› Melanoma

Cancer of the skin is the most common cancer affecting people of European

descent. It is especially common in fair-skinned people who live in sunny climates.

Australians and New Zealanders have the world’s highest incidence of skin cancer,

followed by the white populations of the southern regions of the United States.

In fact more than half of the white-skinned people living in these climates can

expect to get one or more of the common skin cancers during their lifetime.

There are three common types of skin cancer - basal cell carcinoma (BCC),

squamous cell carcinoma (SCC) and melanoma. BCC is by far the most common

and fortunately, the least dangerous. SCC is the next most common but is more

aggressive than BCC. Melanoma is fortunately the least common of the three but

is the most dangerous.

10.1

Skin Cancer Prevention

As for any health problem, the best treatment for skin cancer is prevention.

BCCs and SCCs of skin can be largely prevented by avoiding too much

ultraviolet irradiation from strong sunlight or artificial light in solariums. It is

particularly important for fair-skinned people, and especially fair and red-headed

people, who live in sunny tropical or subtropical climates, to take preventative

measures in their everyday lives. If exposed to strong sunlight they are advised

to wear protective clothing, broad brimmed-hats, long-sleeved shirts, and long

skirts or trousers, and apply sun-screening lotions on exposed skin if any time is

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DOI: 10.1007/978-3-540-92925-3_10, © Springer-Verlag Berlin Heidelberg 2009

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10 Skin Cancers

Fig. 10.1. The best preventative measure against skin cancers is to protect the skin, espe-

cially fair sensitive skin, against sunshine and other forms of ultraviolet irradiation. A

large shady hat, protective skin creams, ointments or lotions and other forms of protective

clothing all give protection. The very fair skinned girl pictured is wearing a large shady

hat but would have been even better protected if she had worn a long-sleeved dress

spent in strong sunlight. They are advised to confine outdoor swimming or beach

activities to early mornings or late afternoons. They are especially advised to

protect nose, lips and face in general and the backs of their forearms and hands,

because of the risk of long periods of exposure. By taking such measures, the

risk of developing BCCs and SCCs can be greatly reduced.

Protective measures against risk of melanoma are similar with special empha-

sis on the need to avoid getting sunburnt. This applies especially to children and

young people who may like to remove clothing from chest, backs and limbs thus

exposing relatively white skin when days are sunny and beaches are available.

The skin of young people is especially vulnerable to changes that reduce protec-

tive cells in skin (Langerhans cells), leading to an increased risk of melanoma

later in life (Fig. 10.1).

10.2

Basal Cell Carcinoma (BCC)

A BCC is usually first noticed as a small, crusty patch or pearly grey nodule or

an ulcer on the skin surface. These cancers occur most commonly in skin that has

been constantly exposed to sunshine over many years. Hence they are not com-

mon before the age of 40 and become increasingly common with increasing age.

More than 70% occur on the face because the skin of the face is most constantly

10.2 Basal Cell Carcinoma (BCC)

127

exposed to the sun. The next most common sites are on the skin of the neck, the

backs of the hands or forearms, lower legs, chest, shoulders and back.

BCCs are painless, usually slowly growing and may have been noticed for

months or even a year or more before medical attention is sought. If neglected, they

usually develop as slowly enlarging ulcers, sometimes called rodent ulcers because

of the appearance that may look as though a rat had gnawed out a piece of skin.

Although, fortunately, they almost never metastasise to lymph nodes or other distant

tissues, they do tend to erode locally into tissues around them. Thus if neglected for

a long time they may become incurable or even fatal by causing destruction to such

tissues as underlying cartilage of the nose or ear, underlying bone of the skull, or

large blood vessels in the neck. They can sometimes invade the orbit and paranasal

sinuses and may even erode into the brain (Figs. 10.2 and 10.3).

Fig. 10.2. A typical

BCC on the face

Fig. 10.3. This photograph shows a

woman with a tragically neglected

advanced BCC on her face. Such

neglect before seeking medical attention

is extremely rare. When seen it is

usually in someone who has been living

in isolation. This case does demonstrate

that even slowly growing BCCs can

become mutilating if improperly treated

or neglected for some years

128

10 Skin Cancers

10.2.1 Treatment

Very small superficial BCCs are often treated by cryotherapy, usually with a

liquid nitrogen spray. If larger or extending deeper, they are better treated by

simple surgical excision, usually under local anaesthesia. The tissue excised is

examined by a pathologist to confirm that it was a BCC and that it was com-

pletely excised with an adequate margin of normal tissue. Radiotherapy can also

be an effective method of treating BCCs but preferably after a small biopsy has

been taken to confirm the diagnosis. Radiotherapy has the advantage of avoid-

ing a surgical operation and of being a painless procedure. Radiotherapy has

the disadvantage of requiring expensive specialised equipment and personnel,

requiring several treatment attendances (often 20 or more) and leaving some

permanent radiation damage to a small patch of skin. It also has the disadvantage

that if no tissue is removed, there may be some doubt about the exact diagnosis

of the lesion and whether it was completely eradicated. Nevertheless, for many

small lesions, especially in elderly patients and in difficult places such as over

a lacrimal duct, it may be the most appropriate form of treatment. Sometimes

small BCCs are removed by dermatologists using cauterisation or a small curette.

These techniques should be left to experienced specialists because a mistake in

diagnosis or incomplete removal can lead to a greater problem.

BCCs that have recurred after previous attempts at treatment or BCCs that

occur close to vital structures such as a lacrimal duct or in an eyelid, present

special problems and require expert attention.

Large BCCs invading bone or other tissues may require extensive surgical

procedures including reconstructive surgery. Very occasionally they may even

be incurable and are possibly best treated by palliative radiotherapy. (Palliative

treatment will give a patient relief by reducing the tumour or lessening its symp-

toms without being likely to cure). Although such advanced lesions are not com-

mon, they are disastrous when they do occur and can easily be prevented by

correct treatment of BCCs in their early stages. Hence it is important for people

with small lesions to seek medical help early, at which time BCCs are easily and

completely curable.

10.3

Squamous Cell Carcinoma (SCC)

SCCs are also most common on the skin of the face, especially the lower part

of the face and lower lip. However they also commonly occur on the neck, the

backs of the hands or forearms, or skin of other frequently exposed areas such

as the lower legs, back or chest.

They often develop in skin lesions called hyperkeratoses that are small, crusty

or flaky thickened areas of skin, resulting from previous repeated sun-damage

over a long period.

An SCC is usually first noticed as a small painless, often crusty, lump growing

on the surface of the skin or as an ulcer in the skin. Intra-epithelial hyperplasia

10.3 Squamous Cell Carcinoma (SSC)

129

(Bowen’s disease) is a very early non-penetrating SCC confined to the most

superficial skin layer. It is a carcinoma “in-situ” and often presents as a small red

patch of skin, possibly superficially ulcerated.

SCCs usually grow more rapidly than BCCs and, unlike BCCs, after a time

they do tend to metastasise to nearby draining lymph nodes. Later, they may

spread further to more distant lymph nodes or to other distant tissues or organs

such as the lung. They also grow locally and are likely to invade surrounding

tissues causing ulceration, bleeding and pain.

Fortunately, however, most SCCs of skin have not metastasised when first

diagnosed and treatment of draining lymph nodes is usually not required. How-

ever, draining lymph nodes must be kept under close observation and if they

enlarge they should be treated without delay - usually by surgical excision (Figs.

10.4–10.7).

10.3.1 Treatment

As for all cancers, the earlier SCCs are diagnosed and treated, the less radical

treatment they need and the greater the likelihood of cure.

For any lesion suspected of being an SCC, it is important for a biopsy to

be taken. In the case of a small lesion, this may be best achieved by surgi-

cal excision of the whole lesion - an excision biopsy. For a large lesion it is

usually more appropriate for a small piece of tissue to be taken from its edge

for microscopic examination - this is called an incision biopsy. A frozen

section examination of a biopsy specimen, (as described in Chap. 7.6.5), is

sometimes appropriate to allow immediate complete treatment to be carried

out without delay.

Fig. 10.4. A typical SCC (squamous cell cancer) on the scalp of a bald-headed elderly

man who had worked out of doors all his life as a gardener

10.3 Squamous Cell Carcinoma (SSC)

131

Fig. 10.7. An advanced SCC of the lower lip

Very superficial SCCs (Bowen’s disease) can now be treated effectively by

photodynamic therapy. The lesion is painted with a photosensitising cream and

subsequently exposed to a strong light beam. Cryotherapy is also effective.

Once the diagnosis of an invasive or potentially invasive SCC in skin is

established, treatment is usually by surgical excision or sometimes by radio-

therapy. Surgical excision is usually the most effective and appropriate treat-

ment. The lesion is widely excised and examined microscopically to confirm

that a margin of normal tissue surrounding the cancer has also been excised

to be sure that total removal of all the primary cancer has been achieved. If

draining lymph nodes are enlarged without evidence that this is due to infec-

tion, then the lymph nodes too should be removed in one block of tissue and

examined histologically. Depending on the site and how much tissue has to be

excised, cosmetic surgery such as a skin graft may be needed to repair the

tissue and close the defect.

As in the case of BCCs, radiotherapy is sometimes used to treat some SCCs

of skin, especially in elderly patients or in other patients in whom an operation

might be risky, or occasionally as palliative treatment when cure by surgery is

considered to be impossible.

People occasionally are seen with large SCCs of skin that appear not likely

to be curable by radiotherapy or surgery (or only curable by mutilating surgery

such as amputation of a limb). These can sometimes be reduced in size and

extent by first administering chemotherapy, especially when given regionally by

132

10 Skin Cancers

intra-arterial infusion or perfusion (as described under Sect. 8.3.4.6 and 8.3.4.9

in Chap. 8). After the use of chemotherapy, the tumours are usually so reduced

in size, extent and viability that they can then be cured by radiotherapy and/

or local surgical excision and usually with surgical excision of any involved

regional lymph nodes.

Occasionally when a SCC of skin is very advanced, possibly invading local

vital organs or tissues, or if there is metastatic spread into distant organs or tis-

sues, it may be incurable. However, it may still be appropriate to use anti-cancer

drugs and radiotherapy as part of a palliative-care program to reduce the extent

and size of the cancer and to relieve symptoms.

C AS E R E P O R T

Skin Cancer

Eric is a 64 year-old man of Northern European origin who has lived in

Southern California since he was 2 years of age and has spent most of his

life in out-door activities.

Between his 40th and 60th birthdays he had many hyperkeratotic skin

lesions on his face, neck and backs of hands treated by cryotherapy (liquid

nitrogen), four BCCs excised surgically and one SCC on his lower left

cheek excised surgically. At the age of 60 when he had many more crusty

lesions and a newly-developed reddish lesion, called Bowen’s disease

(superficial squamous carcinoma in-situ) on his lower right face, he was

referred to a specialist dermatologist. The dermatologist suggested that the

present lesions, including the patch of Bowen’s disease, be treated with a

chemotherapy cream called Efudix (Efudix is a skin cream containing the

chemotherapeutic agent fluorouracil). The dermatologist advised that the

cream should be applied to the lesions twice daily for three weeks during

which time Eric should avoid direct sun-exposure as his skin would have

increased photo-sensitivity. He explained that the lesions should flake off

leaving a clearer complexion.

When Eric returned in one month for follow-up consultation both he

and the dermatologist were pleased with the result. The lesions had disap-

peared and his face had a clear, fresh appearance.

Two years later three further crusty lesions had developed. These too

were treated with Efudix cream with a similar result. Now, four years after

first using the cream, two more lesions have developed and are to be treated

similarly. Eric is otherwise well and is pleased with the result.

10.4 Melanoma

133

10.4

Melanoma

Melanoma is the most dangerous form of skin cancer. A melanoma is a malignant

growth of pigment-forming cells in the skin or in an eye. Occasionally it may

occur in mucous membranes such as the lining of the mouth or anus.

Whilst melanoma is a highly malignant tumour, present-day general aware-

The outlook

ness, early detection and better management methods have greatly improved

nowadays has

the outlook. From being a lesion with a more than 50% mortality until the mid-

so improved

twentieth century, the outlook nowadays has so improved that 85-90% of people

that 85-90%

with melanoma can now be cured.

of people with

melanoma can

now be cured.

0.4.1 Pathology

There are three main pathological types of melanoma called “lentigo maligna”,

“superficial spreading melanoma” and “nodular melanoma”.

Lentigo maligna melanoma in situ develops in a freckle-type pigmented lesion

in which the pigment cells (melanocytes) are in the basal layer of skin as opposed

to common freckles which contain pigment in the superficial layers of skin. Len-

tigo maligna occurs most often in the skin of the face in older age group people

after years of sun exposure, when they are known as Hutchinson’s melanotic

freckles. These are superficial, non-invasive melanomas and are less aggressive

than invasive melanomas arising in the skin of the trunk and limbs.

Melanomas on invesive sites, especially on the trunk for men and the lower

limbs for women, are usually either superficial spreading melanoma (and not

penetrating deeply early in the disease) or nodular melanoma with somewhat

thickened or lumpy features and usually penetrating more deeply into underlying

skin layers. The deeper the penetration of melanoma the worse the likely progno-

sis and the more radical the treatment needed to achieve a cure.

0.4.2 Causes and Incidence

Melanoma is most common in fair-skinned people living in sunny tropical or

Melanoma rarely

sub-tropical climates but as opposed to BCCs and SCCs, melanoma does not

affects children

commonly occur on areas of the body most constantly exposed to sunshine. The

before puberty.

most usual sites of the more common and more often aggressive melanomas are

After puberty

on the back, particularly in men, or on the thigh or leg, particularly in women,

it affects

as opposed to the face that is the most common site of other cancers caused by

people of all

sunshine. However, like other skin cancers, the world’s highest incidence is in the

ages including

white populations of Australia and New Zealand, especially those living closest

teenagers and

to the equator and nearest to the seaside. In Australia about 10% of all registered

young adults.

134

10 Skin Cancers

cases of the more serious cancers are melanomas. The white population of the

sunny southern parts of the United States also have a high incidence of mela-

noma. In Europe the fair-skinned people of Scandinavia and Northern Europe

also have a relatively high incidence. Even though they do not live in a tropical

or subtropical climate they do tend to take their holidays in sunny climates and

often become sunburnt. People of dark-skinned races do occasionally develop

a melanoma but in these people it is much more common for the melanoma to

be at sites of less pigmentation such as the sole of the foot, under fingernails or

toenails or in the mucosa lining the mouth or anus.

Melanoma rarely affects children before puberty. After puberty it affects peo-

ple of all ages including teenagers and young adults but the incidence rises with

increasing age, especially in males. Whilst it affects males and females almost

equally in younger years, it becomes more common in males with increasing age.

Also the outlook for females is rather better than that for males. In Australia and

in Scandinavia it has been found to be more common in upper socio-economic

groups, possibly because these families can afford to spend more holiday time in

the sun or at the beach. It is also more common in native-born Australians than in

immigrants from the UK, Ireland or elsewhere, possibly because they were less

likely to have had sunburn in their childhood years in their countries of origin.

A strong family history is a significantly increased risk factor for melanoma

and the stronger the family history the greater the risk factor for other members

of the family. A previous history of other skin cancers is also an increased risk

factor for melanoma. There is also an increased risk in patients who are immu-

nosupply following organ transplants and in AIDS patients.

The danger of melanoma lies in the fact that it tends to metastasise early to

draining lymph nodes and to distant organs like liver, lungs, bowel and brain.

The outlook has improved in recent years mainly because people in general,

and doctors in particular, are becoming more aware of the early indications of

melanoma and the need to treat it as early as possible. Most melanomas develop

in pre-existing moles in the skin but almost as many develop in areas of skin

without any pre-existing mole.

Melanoma sometimes develops in a long-standing, slowly-growing freckle of

older age people called a Hutchinson’s melanotic freckle.

In 5-10% of cases a melanoma will develop without pigment. This is known

as an amelanotic melanoma and can be diagnosed with confidence only by

microscopic examination. Amelanotic melanomas behave in a similar way to

pigmented melanomas and require similar treatment.

10.4.3 Early Features of Melanoma

Any evidence of increasing pigmentation in a spot in the skin, especially on

increase in size or pigmentation of a mole, must be regarded with suspicion. Other

early features may be itching or crusting of a mole. Bleeding and ulceration are

10.4 Melanoma

135

usually late features. Any of these features occurring either in a pre-existing

mole or in a newly developed pigmented spot, require immediate attention and if

there is any doubt, a biopsy should be taken. In most cases the most appropriate

biopsy procedure is for a surgeon to excise the whole lesion as an excision biopsy.

If an infiltrating melanoma is confirmed by pathology, a wider excision with or

without lymphnode surgery should be scheduled. For large lesions, preliminary

incision biopsy is sometimes done. If the biopsy is positive, the surgeon can then

proceed with appropriate surgical treatment (Fig. 10.8).

Fig. 10.8. Photograph of two pigmented lesions in skin of a woman’s thigh. The larger lesion

proved to be a benign dysplastic junctional naevus but the smaller lesion was a melanoma.

This illustrates the need to obtain histological confirmation of suspicious lesions

E XE R C I S E

What features of a mole might indicate malignant change? (Sects. 10.8-10.11)

10.4 Melanoma

137

Fig. 10.11. A typical

nodular mela-

noma

0.4.4 Treatments of Melanoma

10.4.4.1 Surgical Treatment

Surgical excision of early lesions offers the best prospect of cure. The melanoma

must be excised with a wide margin of normal tissue surrounding the melanoma

(at least 1 cm and at least 2 cm for thicker, more deeply invasive tumorus)

because melanoma cells are sometimes present in tissues or even in lymphatic

vessels surrounding the tumour. To determine whether there is involvement of

drawing lymph nodes, “Sentical” lymph node biopsy may be recommended. If

there is evidence of meta melanoma a sentivel lymph node or if metastatic disease

ininvasive lymph node is clinically apparent, a complete surgical densure of the

lymph node field is the standard treatment.

10.4.5 Investigations to Guide Surgical Treatment

10.4.5.1 Skin Penetration

The likelihood of spread of melanoma is directly related to the thickness and skin

penetration or infiltration of the tumour. Thin melanomas, i.e. less than 1 mm in

thickness, are unlikely to have spread to lymph nodes, whereas half of all melano-

mas greater than 4.0 mm in thickness, may have metastasised, especially to lymph

nodes. Penetration of skin by a melanoma is also recorded by the level of skin

involvement measured as Clark’s levels 1-5: Level 1 being a surface lesion only

with good prognosis and Level 5 being a melanoma that has completely penetrated

all skin layers and has a very guarded prognosis as metastasis is likely.

Ultrasound studies of enlarged lymph nodes are becoming highly reliable in

determining whether the node enlargement is caused by metastases.

138

10 Skin Cancers

10.4.5.2 Sentinel Node Biopsy

Surgical

More recently, a test called “sentinel node biopsy” is used in specialised mela-

excision of

noma units. In cases where lymph nodes are normal size despite a distinct pos-

early lesions

sibility of melanoma having spread to them rather than excising all local lymph

offers the

nodes “just in case they are involved”, lymphatic mapping by lymphoscintigraphy

best prospect

may be carried out. This helps to detect localised nodes that are first in line for

of cure. The

lymph-node drainage from the site of the melanoma. These are called the sentinel

melanoma

nodes. In this test a radioactive isotope is injected adjacent to the melanoma and

must be excised

nuclear scanning over the regional nodes will show which node or nodes are first

with a wide

in line for drainage from the melanoma site. Marks are then made immediately

margin of

over the sentinel node or nodes so that the surgeon can remove these one or two

normal tissue

nodes for pathological examination. If melanoma cells are not found in sentinel

surrounding

nodes, no further nodes are removed. If malignant cells are found in sentinel

the melanoma

nodes then block dissection of all that group of nodes is carried out because of

the risk that adjacent nodes might also be involved.

As well as lymphatic mapping using a radioactive isotope, a “blue dye test”,

may be used. The test is similar in that a blue dye (Patent blue or isosulphan

blue) is injected adjacent to the melanoma just or before operation. At opera-

tion the surgeon can then identify the blue-stained lymph nodes that drain the

melanoma site and these nodes are removed for microscopic examination for

melanoma cells.

Usually the blue dye test and the radioactive isotope test are done together to

be more certain of identifying the appropriate node or nodes for biopsy.

0.4.6 Other Treatments

In general, melanomas are not particularly sensitive to radiotherapy although

radiotherapy may be helpful in achieving worthwhile palliation in some situa-

tions such as for a metastasis in the brain and sometimes for other metastatic

deposits. An exception is in treating the rather uncommon uveal melanomas in

the eye. Responses have been good using application of a radioactive plaque

(containing a radioactive isotope such as iodine 125) for 5-7 days. More recently

in some centres a special form of external radiotherapy, proton-beam irradiation,

is also being used with good effect in treating a primary melanoma in an eye.

When oculor melanoma metastasises it most commonly spreads to the liver.

Occasionally metastatic melanoma in the liver can be excised depending on the

number and sites of the metastatic deposits.

Chemotherapy has in general been disappointing in treating melanoma.

Occasional beneficial responses have been observed but they are infrequent.

When advanced melanoma appears to be confined to one limb, treatment by more

concentrated regional chemotherapy using a special technique of closed-circuit

perfusion of the limb with high dose chemotherapy, usually achieves worthwhile

tumour regression, (see Sect. 8.3.4 in Chap. 8). A newer technique of “closed

10.4 Melanoma

139

circuit infusion” without needing a perfusion pump may be as effective as closed-

circuit perfusion and is more easily carried out. In this technique a tourniquet is

applied to separate the circulation in a limb from the general circulation, the anti-

cancer drugs are mixed with blood drawn from a vein in the limb and reinjected

into the main artery in the limb. This process is repeated several times for upto

30 min or so, thus avoiding the need for a continuous infusion pump.

Regional chemotherapy treatment is more effective if heat is used with the

chemotherapy and appears to be even more effective if the immunotherapy agent

tumour necrosis factor (TNF) is used with chemotherapy.

Reports of effective use of concomitant radiotherapy and chemotherapy, so-

called “sandwich treatment” (see Sect. 8.3.4.11), have encouraged further studies

of this approach.

Immunotherapy is also sometimes used to treat advanced or widespread mel-

anoma. Although occasional responses have been observed with general (sys-

temic) immunotherapy, results have been inconsistent and early hopes of a pos-

sible new cure have not yet been fulfilled. Some encouraging results have been

reported in using Interleukin 2 in combination with other chemotherapy.

Work with chemotherapy and immunotherapy is continuing in large mela-

noma clinics in the hope of improving treatment techniques so that more reliable

treatment methods may be available for patients with advanced melanoma in

the future.

10.4.7 Vaccine Studies

There are also studies being conducted with the objective of finding an effective

protective anti-melanoma vaccine but as yet there is no preparation for safe,

reliable or effective clinical use.

C AS E R E P O R T

1. Thin Melanoma

Mr TD is a 46-year-old teacher. His grandparents had migrated from

Scotland to Australia. As a child, he had played outdoor sport and loved

the beach.

His wife noticed a new mole on his back about a year ago. Over the last

few months she noted that it was darker and had changed shape.

Mr TD went to his general practitioner (GP) who examined the mole and

found that it was 1 cm in diameter, was irregular in pigmentation and had

irregular borders. No axillary, groin or cervical lymphadenopathy was present.

(continued)

140

10 Skin Cancers

(continued)

The GP performed an excision biopsy of the whole lesion. The pathology

showed a melonoma 0.4 mm in thickness, Clark level 2, without ulcer-

ation and with only occasional mitotic figures (one mitosis per square

millimetre) indicating a comparatively low grade melanoma. A defini-

tive wider excision was performed taking a 1 cm margin down to muscle

fascia.

It is now 5 years since operation. Mr TD remains well and returns

yearly to his GP for follow-up of his melanoma and for a full skin check.

2. Intermediate Thickness Melanoma

Mr LB is a 58-year-old solicitor who had lived all his life in Southern

California. He went to his GP for an annual health check. He was on

anti-hypertensive medication but is otherwise well. His GP noticed a

pigmented nodule on the right upper chest which was 8 mm in diameter

and irregular in shape. An excision biopsy was performed and pathology

showed a melonoma 2.5 mm in thickness, Clark level 4, with ulceration

present and four mitoses per square millimetre. Mr LB was referred to a

specialist surgical unit.

The surgeon recommended a wider excision of the primary melanoma

site (taking a 2 cm margin) and a sentinel node biopsy for staging pur-

poses. Mr LB had a lymphoscintogram on the morning of his surgery and

then proceeded to the operating theatres. The lymphoscintogram showed

a single sentinel node in the right axilla.

Under general anaesthetic, Mr LB had 1 mL of Patent blue dye injected

intradermally around the primary melanoma site. The wider excision was

performed, then the sentinel node biopsy. The surgeon noted that there

was a blue lymphatic channel passing into the sentinel node, and the node

was blue stained and “hot” when measured with a gamma probe.

The pathology of the wider excision showed no further evidence of

malignancy and the sentinel node showed no evidence of metastatic mela-

noma. Mr LB was advised to present for regular follow-up for the mela-

noma. He remains well 3 years later with no evidence of residual mela-

noma and no evidence of metastatic decrease. Regular skin checks have

not found any new melanoma.

3. Metastatic Melanoma

Mr WM was a 66-year-old farmer. He had migrated to Australia from

Germany when he was 12 years old. He was a diabetic, controlled on

oral hypoglycaemics and was also on antihypertensive medication. He

had had a melanoma on his left lower thigh treated with a wider excision

only, 6 years earlier.

He visited his GP because he had noticed a lump in his left groin. The

GP found a 4 cm firm mass in the left groin, below the inguinal ligament.

(continued)

10.4 Melanoma

141

(continued)

It was mobile and not tender. The previous melanoma scar on the left lower

thigh appeared normal.

A fine needle biopsy of the mass showed cells consistent with meta-

static melanoma. He was referred to a specialist surgical unit.

The surgeon recommended a left groin dissection and staging CT scans

of the brain, chest, abdomen and pelvis. The CT scans showed no evidence

of metastatic disease and Mr WM underwent a left lymph inguinal node

dissection. Of 25 lymph nodes examined the pathology showed only one

4 cm node involved with metastatic melanoma.

Postoperatively, Mr WM had a prolonged lymphatic leak from his

groin drain and went home with the drain still in-situ. The drain remained

in for 1 month. He had no adjuvant therapy.

Mr WM failed to return for his regular follow-up visits but returned

18 months later when he found a 2-cm lesion, two 1-cm lesions and three

smaller nodules in the skin of his right thigh and two small nodules in the

skin just below his left knee. Needle biopsies confirmed the presence of

melanoma cells in these nodules. Mr WM had no other symptoms. Staging

CT scans of the brain, chest, abdomen and pelvis were again negative for

tumour. No other lesions were detected.

He was advised that it was almost certain that there would be other

undetected melanoma deposits elsewhere but especially in the left lower

limb. He was advised that rather than having many operations with in-

creasing difficulty to excise and control new lesions as they arose in the

limb, one closed circuit infusion of concentrated chemotherapy to his limb

would be likely to control the melanoma in his limb.

Mr WM agreed and a closed circuit infusion of his left lower limb was

carried out. In this treatment a closed circuit was achieved using a torniquet

applied high around his left thigh and the chemotherapy agent was injected into

the femoral artery. Blood was extracted from the femoral vein and reinjected

with the femoral artery repeatedly for 30 min. The chemotherapy agent of

choice was melphalan and the temperature in the limb was increased to 39°C.

Post infusion a marked red reaction of the whole lower limb accrued

but slowly regressed. Over the next few weeks the tumour lumps also

regressed and completely disappeared.

Mr MW remained well for 14 months but a routine chest X-ray then

showed a suspicious mass in the right lung. New staging CT scans identi-

fied multiple liver metastases and multiple lung metastases, the largest of

which corresponded to the lesion found on the chest X-ray.

He was referred to a specialist melanoma oncologist who offered treat-

ment with another chemotherapeutic agent (DTIC) but there was little

response and Mr WM died 5 months later from disseminated metastatic

melanoma.

Lung Cancer (Bronchogenic Carcinoma)

In this chapter you will learn about:

› Symptoms

› Investigations

› Pathology

› Treatments

› Mesothelioma

› Metastatic cancer in the lung

Cancer of the lung has increased from being an uncommon disease 100 years

ago to one that, in the Western world, now causes more deaths than any other

cancer. Worldwide about 1 million cases are diagnosed every year and the

reported death rates are about 90% of the diagnosis rates. This rapid increase in

incidence is directly related to the widespread habit of cigarette smoking. The

disease in smokers is eight to ten times more common than in non-smokers.

With greater numbers of females smoking in recent years, the incidence of lung

cancer in women is now approaching that of men. In the United States, other

than skin cancer, lung cancer is now the second most common cancer in both

sexes together. In fact, in the US, lung cancer now causes more cancer deaths

than all colorectal, breast and prostate cancers combined (see Table 2.1). The

increase in numbers of people with lung cancers has followed by 20 years or

more behind the increase in tobacco consumption. Due to a slowly reduced

incidence of smoking in men in many Western countries (including the US and

Australia) over the last 30 years of the twentieth century lung cancer passed its

peak incidence in men between 1985 and 1990. However it continues to rise in

women, in whom smoking did not decline when it did in men.

Although tobacco smoking is by far the most significant cause of lung cancer,

a number of other factors may also play a part in some cases. These include

industrial and automobile pollutant gases. Workers in certain industries includ-

ing chromium, arsenic and asbestos also have an increased incidence, especially

if they are also smokers.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

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144 1

1 Lung Cancer (Bronchogenic Carcinoma)

Diagnosis of lung cancers is most common in North America (especially in

black males) and in New Zealand (especially in Maoris). It is also very common

in the UK, Europe and Australia. It is least common in West and East Africa. It

is extremely rare under the age of 30 years and is rarely diagnosed before the age

of 40. Thereafter the incidence increases with increasing age. The median age of

diagnosis is between 65 and 70 years. In Western countries it is more common

in lower socio-economic groups than in higher socio-economic groups, probably

because smoking is more common in lower socio-economic group.

Pathological sub-types of lung cancer. There are four major histological types

of lung cancer. These are:

1. Small-cell lung cancer (SCLC)

2. Squamous cell cancer (SCC)

3. Adenocarcinoma and

4. Large-cell cancer

As the approach to clinical management of the last three cancer types is similar,

they are grouped together as non-small-cell lung cancers (NSCLC). Thus for clinical

and treatment purposes lung cancer is classified as either SCLC, or NSCLC.

SCLCs are generally more aggressive and patients have a median survival

time of about 18 months. Five-year survival is rare.

Localised NSCLC is potentially curable in its early stages by surgical resec-

tion but SCLC has invariably spread beyond resectable tissues when first diag-

nosed.

Not only is lung cancer now showing an increase in incidence in women due

to the relatively more recent uptake of the smoking habit by women, but women

with lung cancer also have a rather poorer prognosis than men with lung cancer.

This is because women have a higher proportion of SCLCs and adenocarcinoma

than men. Men have a higher proportion of SCCs of lung that are relatively less

aggressive and more likely to be resectable even though they are still potentially

curable in less than 25% of cases.

11.1

Symptoms

During its early

During its early stages, lung cancer causes few problems, so that it is usu-

stages, lung

ally not diagnosed until it is quite advanced and usually incurable. Perhaps

cancer causes

this is partly because of the nature of the sufferer who, being a smoker, is

few problems, so

adjusted to having a chronic cough and does not become aware of a change

that it is usually

in the cough until the disease is advanced. A cough is the most common

not diagnosed

single symptom of lung cancer but other features are shortness of breath,

until it is quite

coughing up blood or bloodstained sputum (haemoptysis), chest pain and

advanced and

attacks of chest infection or pneumonia that do not respond completely

usually

with treatment.

incurable.

11.2 Investigations

145

The first evidence of lung cancer can also be due to spread of the cancer

causing metastases in lymph nodes, bone, brain or elsewhere. Sometimes lung

cancers produce hormones or other substances that may affect the sufferer as

a whole. These may result in changes in other parts of the body such as swell-

ing of the breasts, changes in bones (osteoarthropathy), or fingernails (club-

bing), or loss of nerve function often causing numbness or tingling sensations

(neuropathies).

11.2

Investigations

Chest X-rays sometimes show a lung cancer that has not been causing symp-

toms but in most cases by the time symptoms are present, X-rays will show the

cancer.

CT scans may also show more clearly the position and the size of a lung cancer

and enlarged lymph nodes in the mediastinum.

Bronchoscopy (Sect. 7.4.5) will often allow the doctor to see a lung cancer

and, if so, a biopsy may be taken. The biopsy specimen will be examined micro-

scopically to confirm that cancer is present and to find out what sort of lung

cancer it is, and therefore how best to treat it (Fig. 11.1).

Sometimes a cancer cannot be seen through a bronchoscope but sputum can

be sucked out or coughed up and this can also be examined microscopically. This

is called cytology and this test will often show cancer cells if a cancer is present.

If a lump is seen on X-ray, sometimes it is possible to suck out cells for cytology

from the lump through a needle inserted through the chest wall.

Fig. 11.1. (a, b) Anteroposterior and lateral chest X-rays showing a primary lung cancer as

an increased white area in the apex of the right lung. Small metal sutures can be seen just

to the right of anterior-midline. These sutures remain after previous cardiac surgery

146 1

1 Lung Cancer (Bronchogenic Carcinoma)

11.3

Significance of Histological Findings

The several types of lung cancer are all usually smoking related but the distinc-

tion between the two main groups SCLC and NSCLC is convenient for plan-

ning treatment. SCLSs (about 20% of all lung cancers) are usually widespread

when first diagnosed and are therefore not treated by surgery. NSCLCs are

sometimes localised to their site of origin and some can be surgically excised

with a chance of cure. They are usually not very sensitive to chemotherapy

or radiotherapy.

11.4

Treatments

Unfortunately, most people with lung cancer do not go to a doctor until the

disease has spread from the lung into surrounding structures, lymph nodes

or other parts of the body. Most lung cancers are therefore probably incurable

at the time of diagnosis. For those with NSCCS, who do present for treat-

ment early and are diagnosed when their cancers are small, the best results

are achieved by an operation to remove all or part of a lung. Yet even for

people whose cancers appear to have been totally resected, only about 25%

are cured in the long term.

Radiotherapy is sometimes used when surgery is unsuitable, but cure by

radiotherapy alone is very uncommon.

Chemotherapy and immunotherapy have had disappointing results against

lung cancer although newer anti-cancer drugs used in certain combinations and

in certain treatment programs by experts, can produce worthwhile improve-

ment for some types of lung cancer. SCLCs will often respond temporarily to

chemotherapy or radiotherapy but long-term cure is a rarity. The improvement

may last for several months or even a year or two.

Studies continue to try to improve results with combined treatment schedules.

There is some hope that combinations of newer chemotherapy schedules used

with radiotherapy and/or surgery may have more to offer in the future. Such

combinations of drugs and other treatments are being investigated in a number

of leading cancer treatment centres throughout the world.

11.4 Treatments

147

C AS E R E P O R T

Lung Cancer

Alex was a 57-year-old man who attended his doctor because his “cough

would not settle down” and recently, after coughing, he had noticed

blood in his sputum. Alex had been a smoker for almost 30 years, using

20 cigarettes/day. His wife stated that she had been aware of his cough

for 2 or 3 years but it had become more persistent recently. He had lost

weight and had little energy over recent weeks. He recently had “the flu”

and in spite of taking antibiotics that were in the house the flu persisted

with his productive cough.

On examination the doctor could hear moist noises in both sides of

Alex’s chest and noticed some dullness with little air entry over the lower

right lung. An immediate chest X-ray showed a lesion in the lower right

mediastinum and lung.

Alex was referred to a thoracic surgeon who arranged a bronchoscopic

examination. A tumour growth was seen almost completely blocking the

right lower bronchus. A biopsy of the growth proved it to be a squamous

carcinoma.

The surgeon advised that he was prepared to attempt to resect the can-

cer but that would probably mean resecting the right lung and even then

the chances of cure would be less than 20%. The alternative treatments

would be radiotherapy or chemotherapy followed by radiotherapy with a

good chance of improving Alex’s symptoms for possibly a few months but

unlikely to achieve long-term success.

Alex chose to have operation but it proved not possible to resect the

cancer that had involved mediastinal lymph nodes. Alex was then given

chemotherapy but developed nausea, loss of hair and bone-marrow de-

pression (a fall in both platelets and white blood cells). Chemotherapy

was suspended with the intention of treating the cancer with radiotherapy

when Alex was well enough but Alex declined to have further treatment.

He died 4 months after the cancer was first diagnosed.

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1 Lung Cancer (Bronchogenic Carcinoma)

11.5

Mesothelioma

Mesothelioma is a rare form of cancer that predominantly affects males over 60

years. There is a male to female ratio of about 3-1. Mesothelioma is well known

to industrial workers because when it does occur it is often in people who have

been exposed to asbestos in their work. Asbestos workers who are also smokers

are particularly at risk. Protective industrial laws for asbestos workers have now

made this a less common cancer although the cancer can develop years after the

patient has stopped working with asbestos.

Mesothelioma is not truly a cancer of the lung; it is a cancer of the pleura

surrounding and lining the lungs. It may rarely occur in other lining tissues such

as the lining of the peritoneal cavity - the peritoneum. Mesothelioma may pres-

ent with cough, chest infection, difficulty with breathing or chest pain. A tumour

lump may be felt or seen on X-ray or CT studies.

Mesothelioma is difficult to diagnose and to treat. To confirm its diagnosis

requires a panel of immuno-histochemical stains. It is usually too widespread

and advanced to treat by surgery and it usually does not respond well to either

radiotherapy or chemotherapy. Combinations of chemotherapy, radiotherapy and

surgery are used but significant and worthwhile responses are uncommon.

Sadly the best treatment is often simply to give the patient best relief from

symptoms while the tumour slowly progresses.

11.6

Metastatic Cancer in the Lung

The lungs are among the organs most commonly the site of metastatic growths

spread from primary cancers that developed in other parts of the body. Cancers

from almost any primary site are likely to spread through the bloodstream to

the lungs, especially from cancers of the breast, kidney, bone, ovary or from a

sarcoma or a melanoma. These usually show as a number of rounded opacities

(white spots) seen in chest X-rays although sometimes, especially from the kid-

ney or a sarcoma, a metastasis may be single showing as just one round white

spot or lump resembling a “cannon ball” in the X-ray. Treatment depends upon

the type of cancer that has spread to the lung A solitary metastasis can sometimes

be resected with possible cure but solitary metastases are rare and in general

anti-cancer drugs are likely to be more helpful than any other anti-cancer treat-

ment. However, because cure is unlikely, treatment with risk of troublesome side

effects may or may not be considered worthwhile (Fig. 11.2).

Sometimes primary or metastatic cancer in the lung will cause fluid to collect

around the lung in the pleural cavity. This is a pleural effusion. Pleural effusion

causes shortness of breath and difficulty with breathing due to pressure on the

lung. Sometimes patients will achieve good, although temporary, relief if their

Breast Cancer

•

In this chapter you will learn about:

› Incidence, causes and general features

› Hormone replacement therapy (HRT)

› Symptoms

› Cancer of the male breast

› Signs

› Investigations

› Breast cancer staging

› Treatments

› Prevention

› Early breast cancer

› Surgery and/or radiotherapy

› Adjuvant chemotherapy

› Advanced breast cancer

› Physical and emotional needs

› Prostheses and breast reconstruction

› Breast clinics

› Breast cancer support organisations

Breast cancer became much more common in Western societies over the twentieth

century. Apart from skin cancer it is now the most common cancer affecting

women in most European countries, Britain, The United States, Canada, Aus-

tralia and New Zealand (see Appendix).

In some of the above countries, the incidence of breast cancer appears

to have levelled off but the incidence of lung cancer in women continues to

increase, so that the incidence of lung cancer is now approaching the incidence

of breast cancer. Because more women with breast cancer can be cured than

women with lung cancer, in some countries, including the US, lung cancer is

now responsible for more cancer deaths in women than breast cancer or any

F. O. Stephens and K. R. Aigner, Basics of Oncology,

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12 B reast Cancer

other cancer (see Table 2.1). Not only did the incidence of breast cancer con-

tinue to increase during the twentieth century, was also diagnosed at an earlier

stage, partly due to increased awareness and increased use of mamographic

screening. This resulted in a greater likelihood of the cancer being diagnosed

at a curable stage.

In North America, Northern Europe, Australia and New Zealand breast can-

cer is about five times more common than in women of most Asian or African

countries. However, women of Asian or African ethnic origin who have lived

all their lives in the US or other developed Western countries have a risk of

breast cancer similar to other women of those countries. This suggests that the

predominant influence is environment, social and other customs, or very likely

diet of those countries rather than a racial or genetic influence. About one in nine

American women will develop breast cancer during her lifetime, assuming a life

expectancy of 80 years.

Although occasionally seen in women in their 20s or even rarely in teenagers,

breast cancer is not common until after the age of 40 and becomes increasingly

common with age. The average age for women first presenting with breast cancer

is about 60 years.

The cause of breast cancer is unknown, but a number of associated factors

have been noticed. Probably the one most significant factor is the age of a woman

when she has her first baby. Having a baby at an early age seems to give some

protection to a mother. Breast cancer is least common in women who had their

first babies as teenagers and significantly more common in women who did not

have their first baby until after the age of 35 years. Women who have not had any

babies, such as nuns, have a greater risk of breast cancer.

The age of a woman when she experienced her first menstrual period and the

age at menopause are also significant. Early menstruation and late menopause are

both associated with increased risk of breast cancer. It does seem that the longer

the woman’s reproductive life cycle the greater the risk of development of breast

cancer. This may be due to a more repeated and prolonged exposure to ovarian

production of oestrogen.

A strong family

There may also be some protection in women who breastfeed their babies

history is a

although the evidence for this is less clear. Women who live in undeveloped coun-

prominent

tries tend to breastfeed their babies for many months and have a low risk of breast

risk factor for

cancer. However these women also usually have had their first baby at a young

breast cancer.

age and have a very different lifestyle including very different diets.

There is an association between breast cancer and being overweight, lack of

exercise and smoking tobacco, although the association with tobacco smoking is

not as strong as it is with lung cancer. Some studies have reported an association

of breast cancer with a high-fat diet, particularly saturated animal fats, although

this has not been found in all such studies. Breast trauma too has sometimes been

suspected but it is really not known whether injury may cause a breast cancer.

Although after injury some women first notice a lump that is found to be breast

cancer, it is likely that in most cases the injury simply drew attention to a lump

that was already present. Injuries may, of course, cause other types of lumps

12.1 Hormone Replacement Therapy (HRT)

153

in the breast that are not cancer, for example a haematoma or a lump due to fat

necrosis.

A strong family history is a prominent risk factor for breast cancer. The high-

est risk is related to having first-degree relatives with breast cancer, especially

if pre-menopausal at the time of diagnosis. About 10% of breast cancers are

considered familial, and of these BRCA1 and BRCA2 tumour suppressor genes

(Chap. 2) account for about two-thirds. There are probably additional higher risk

genes, as yet unidentified. Environmental influences including diet are also more

likely to be similar in women of these families, so that genetic relationships are

not always clear.

It was once believed that fibro-cystic disease (also known as fibro-adenosis-

cystica, benign mammary dysplasia, hormonal mastopathy or “chronic masti-

tis”) was a strong precursor of breast cancer but more recent studies have found a

modest increased risk only. However if there are histological features of atypical

hyperplasia the risk is substantially increased. Because both fibro-cystic disease

and breast cancer are common, making a diagnosis of breast cancer in a woman

who already has lumpy breasts from other causes may present difficulties.

After the atomic bomb explosions at Hiroshima and Nagasaki, an increase

in numbers of women with breast cancer was reported but the increase was not

apparent until some years after the event.

Tobacco smoking has also been associated with an increased incidence of

women with breast cancer but the increase is usually apparent only in women

who have been smoking for 20 or 30 years.

In practical terms, other than regular self-examination, routine mammogra-

phy every 2 years for women over 50, (or more often in women who belong

to special risk groups), remains the best early detection measure against breast

cancer at the present time. An annual mammogram may be advisable for women

with a previous history of breast cancer, or a strong family history of breast can-

cer. Increasingly, in some countries, breast cancer is being diagnosed by screen-

ing mammography before a lump can be felt and before the onset of discomfort

or other local feature. Ultrasound of the breast is mostly useful for patients with

a palpable mass that is not seen in mammograms or to help determine whether a

lump is solid or cystic. It is also more likely to help screening in pre-menopausal

women and safe to use in pregnancy. It is far superior to mammography or physi-

cal examination in evaluating lymph nodes for possible metastases and can be

helpful in directing a needle into a suspected lesion for needle biopsy.

12.1

Hormone Replacement Therapy (HRT)

Using oestrogen or oestrogen-progesterone medication to relieve menopausal

and postmenopausal symptoms, has been incriminated as increasing the risk

of breast cancer. The increased risk of small doses of hormones is small but

nevertheless significant in most women, and considerable for women with pre-

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disposing factors. Therefore HRT is reserved for women who experience severe

menopausal or postmenopausal problems that cannot be relieved in any other

way and even then, small doses are usually given for a limited period only and

the woman kept under regular monitoring. Meanwhile studies continue to try to

find something equally effective, but without risk, to relieve these menopausal

symptoms. One study under investigation is with the use of naturally occurring

hormones, the phytoestrogens which are present in all plant foods but especially

in legumes such as soybeans.

There is a reduced risk in women who have a high intake of fruit, vegetables,

nuts, grains and other plant foods, especially if they are complete vegans (see

Sects. 2.5 and 2.12 in Chap. 2).

12.2

Symptoms

Breast cancer is usually first noticed by a woman finding a painless lump in

one breast. The most common situation is in the upper outer quadrant of the

breast (Fig. 12.1a).

The majority of breast lumps are not cancer, but when a lump is first noticed in

a breast the woman should seek medical advice without delay. Usually she should

be sent for further investigation or a specialist opinion.

As a general rule a solitary breast lump first noticed in a woman under 50 is

rather more likely to be benign but a solitary lump first noticed in a woman over

50 is likely to be malignant. However any lump in a breast or any other change in

a breast should be checked out.

A reddish nipple that looks rather like an abrasion of the nipple may be early

Paget’s disease of the nipple and this may be an indication of an underlying breast

cancer (Fig. 12.1b).

Women with breast cancer may be aware of a change in the position or shape

of a nipple (called retraction or inversion) (Fig. 12.1c); redness, and puckering or

ulceration of skin over the breast (especially if over a lump).

These are sometimes features of breast cancer noticed either by the woman

herself or by her doctor. Other features may be discharge of blood from a nipple

or discharge of other fluid from a nipple not associated with a pregnancy or lacta-

tion, redness of a nipple or a change in size of one breast.

Occasionally breast cancer may first be discovered after finding a lump in an

axilla or a metastasis in another organ such as the lungs (seen in a chest X-ray),

liver or bone.

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12.3

Inflammatory Breast Cancer

Occasionally the first indication of breast cancer is a red inflamed breast very

like acute mastitis (Fig. 12.2). If this change develops for no apparent reason or

does not settle down after a week or 10 days of appropriate treatment (including

antibiotics), the possibility of an underlying cancer must be considered and a

biopsy taken.

Inflammatory breast cancer is an uncommon but aggressive form of cancer.

The diagnosis is more obvious when it occurs in older women not associated

with pregnancy or lactation but can be very difficult to diagnose in pregnant

or lactating women because it can easily be confused with mastitis. Treatment

needs to be aggressive as for other advanced breast cancers but the outlook must

be very guarded.

12.4

Cancer of the Male Breast

Less than one per cent of all breast cancers are in males, but when they do occur

they show up and behave in a similar way to cancer in female breasts. The outlook

for breast cancer in males is usually worse than for females, possibly because

men are more likely to delay seeking medical advice.

Fig. 12.2. Photograph showing an “inflammatory” cancer in the left breast of a young

woman. If it occurs during or after a recent pregnancy it can easily be confused with

mastitis

12.6 Investigations

157

12.5

Signs

Typical features of breast cancer are a lump that is hard, often irregular in outline

Typical features

and possibly fixed to skin, muscle or other tissue. Other signs include retraction of

of breast cancer

a nipple, Paget’s disease of a nipple, nipple blood stained discharge or a dimpling

are a lump that

of the skin over a lump (there may be multiple small dimples in an area of skin

is hard, often

like orange peel and known as peau d’orange). These may have first been noticed

irregular in

by the patient herself or first detected by her doctor. Lymph nodes in the axilla

outline and

or elsewhere must be examined for evidence of enlargement. Examination will

possibly fixed

include examination of the chest and abdomen for possible evidence of lumps

to skin, muscle

or spread into other organs such as lungs, liver, ovaries or bone.

or other tissue.

12.6

Investigations

Screening tests for breast cancer have been discussed in Chap. 7.

For a woman who presents with a breast lump, a number of investigations may

be arranged to discover whether it is cancer. Mammograms may show the size,

position and type of lump and the general condition of the breast. Ultrasound and

CT scans usually give little further information unless cysts are present. Ultra-

sound is safer to use in younger and pregnant women. Ultrasound is also better at

demonstrating lesions in the more dense breasts of younger women and it better

demonstrates the presence of cysts.

If a breast lump is thought to be cancer from the initial examination, and espe-

cially if it is an advanced cancer, other general investigations may be needed. These

may include chest X-rays, liver CT or scan and bone scan to look for evidence of

possible spread to lungs liver or bone. Results should be known before any major

breast surgery is carried out. Involvement of any of these organs may sometimes

indicate the need for some form of treatment other than removal of all or part of the

breast, because cure would not be achieved by removing the breast.

The most important investigation is a biopsy. In many cases a pathologist

will perform a needle biopsy on an outpatient basis. Sometimes it is better for a

surgeon to take a larger biopsy specimen taking a core of tissue with a special

instrument or even cutting out a piece of the lump in an operating theatre. This

is the most reliable method of diagnosis. If a surgical biopsy is carried out and

frozen-section pathology technique confirms a diagnosis of cancer, the surgeon

can operate without further delay provided the patient has been appropriately

prepared. However this approach is becoming less common. In most clinics it

is preferred to establish a diagnosis and staging of the cancer and, with this

information, discuss appropriate options with the patient before any treatment

intervention is started.

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12.6.1 Breast Cancer Staging

Clinicians depend on skilled pathologists to classify cancers and to decide on

likely prognosis and which treatment option is most likely to achieve a best

result. Information that may be supplied by the pathologist has been discussed

in Chap. 6.

To make a final determination of tumour staging after tumour removal the

pathologist should also provide the dimensions of the cancer removed, and whether

the surgical margins are clear of the edge of the tumour. The pathologist will also

provide the oestrogen-receptor and progesterone-receptor findings. These may

indicate the likelihood of hormone sensitivity of the cancer.

Stage 1 breast cancer is a small lump that is confined to the breast and should

be eminently curable by removal of the breast or the part of the breast in which

it is located.

Stage 2 breast cancer is when the primary cancer is less than 5 cm in diameter

and has spread into adjacent lymph nodes that are still mobile but there is no

evidence of spread beyond.

Stage 3 breast cancer is when there is a large cancer in the breast and/or

involvement of overlying skin and/or involvement and adherence to underlying

muscle and/or axillary lymph nodes are adherent to surrounding tissues, but

there is no evidence of spread into more distant organs or tissues.

Stage 4 breast cancer is when there is metastatic spread into more distant

organs or tissues. These cancers are clearly not curable by treatment of the breast

alone (Fig. 12.3).

12.7

Treatments

Treatment of breast cancer will largely depend upon whether the cancer was

detected early and is likely to be cured by surgery or surgery with radiotherapy

and other local treatment, or whether it is so advanced that cure by treatment of

the breast alone is impossible.

2.8 Prevention

There is no known practical way of preventing breast cancer. However studies

of the use of the anti-oestrogen hormone compound Tamoxifen, given in small

doses over a prolonged period of years, will reduce the risk of breast cancer

developing in women at special risk. It may be recommended in women with a

high incidence of the disease in their immediate family or those who have already

had cancer in one breast. However the final results of such trials and any pos-

sible long-term risks of this treatment are not yet fully known. Long-term use of

12.8 Prevention

159

Fig. 12.3. An advanced and neglected

fungating breast cancer. The patient

was a 55-year-old woman who had

not previously sought medical help

due to fear of having confirmed

what she suspected but had been

trying to deny that she had a breast

cancer. Such seemingly irrational

behaviour is not uncommon even in

very intelligent people who might

appear to be well adjusted in every

other way

Tamoxifen has been shown to be associated with an increased development of

cancer in the uterus and also a possible risk of thrombosis. More recent studies

have shown that a new drug raloxifene, (Evista), has similar cancer prevention

properties apparently with less risk of these long-term side effects.

EX ERCISE

What local features of a breast might be suggestive of breast cancer?

(Fig. 12.4)

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12 B reast Cancer

Fig. 12.4. Diagrams illustrating the four “stages” of breast cancer

Treatment of

Further studies are based on the fact that women in Asian countries have a

breast cancer

lower incidence of breast cancer, other breast problems and post-menopausal

will largely

syndrome, than women in Western societies. As previously mentioned, Asian

depend upon

women have a diet high in certain leguminous plants that contain relatively

whether the

high quantities of phytoestrogens. Studies are underway to determine whether

cancer was

the phytoestrogens, and especially the isoflavones in phytoestrogens, reduce

detected early.

the risk of breast diseases including cancer (see Sect. 2.13 in Chaps. 2 and

Sect. 3.5 in 3).

Lycopene (Chaps. 2 and 3) is another “natural” agent being studied for pos-

sible anti-cancer or cancer-preventive potential. At the time of writing this book

it is too early to speculate whether this or other agents will develop a place in

cancer-prevention therapeutics but encouraging studies continue.

12.9

Pathology

There are two main types of breast cancer depending upon whether the cancer

developed in breast ducts (duct carcinoma), or in the breast lobules at the end

of the ducts (lobular carcinoma). Although either may present in a non-invasive

in situ stage before becoming invasive, lobular carcinoma is more likely to

become invasive at an earlier stage and is more likely to be bilateral, especially

in younger women.

12.10 Early Breast Cancer

161

Fig. 12.5. Diagram

showing phases of

development of breast

cancer

Duct carcinoma, which is more common, may remain in situ for a period

before it develops into invasive cancer (Fig. 12.5).

12.10

Early Breast Cancer

2.10.1 Surgery and/or Radiotherapy

There has been much controversy in deciding the best treatment for early breast

cancer. For years, surgeons believed that for stage 1 or a small stage 2 breast cancer,

the best chance of cure was by total removal of the breast and all draining axil-

lary lymph nodes. This operation, radical mastectomy, used for many years,

undoubtedly cured many women of breast cancer but it was probably unneces-

sarily radical for many women.

Later studies showed that for early breast cancer, results of treatment were just as

good if the breast only was removed and lymph nodes were treated by radiotherapy.

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A number of non-radical breast saving treatment options can now be offered

for treatment of early breast cancer (stage 1 and 2) with equally satisfactory

prospects of cure.

For small in situ breast cancers local removal of the lump with some surround-

ing tissue and followed by radiotherapy to the breast is good treatment.

If a breast cancer is showing early evidence of becoming invasive then either

removal of that segment of the breast or total breast removal will give equally

good results. Radiotherapy is given post-operatively in case there is further

cancer in the breast.

With invasive breast cancer, which shows no clinical evidence of lymph-node

involvement, it is important to investigate lymph nodes in case there is microscopic

cancer cell invasion, even though the nodes are not enlarged. This is now done by

removing one or more “samples” of the closest axillary nodes and having them

examined microscopically. If no cancer cells are found in the lymph nodes then

no further lymph-node treatment may be indicated. But if cancer cells are found

in the nodes then total removal of all axillary lymph nodes is recommended. The

cancer is then classified as a pathology stage 2 cancer and adjuvant treatment with

chemotherapy or hormone therapy is usually indicated (as discussed below).

More recently the technique of sentinel node biopsy is often used to detect

and examine the most likely lymph nodes to contain tumour cells. (This was

discussed in relation to melanoma Chap. 10, Sect 10.4.)

For treatment of possible or proven involvement of axillary lymph nodes, sur-

gical excision is now usually regarded as the preferred option. Although radio-

therapy is generally used as follow-up treatment to the breast area, radiotherapy

to the axilla is better avoided after surgery to the axilla because of the high

incidence of impairment of shoulder movement and of subsequent lymphoedema

of the arm that can follow.

Thus there are now different options for treatment without total mastectomy

that have been shown to have equally good prospects of cure in most patients.

Patients should be offered a choice of the treatment options.

In most cases long-term results are equally good if only that part of the breast,

which contains the lump, is removed and radiotherapy is administered following

the surgery.

It is important to learn of the woman’s personal attitude to her breasts and to

her cancer. Some women regard their breasts as being crucial to their self-image

and femininity. For such women, if equally satisfactory results can be offered

without removing the whole breast, this would be preferable. To other women, a

breast is not so important and if a breast has a cancer in it they would prefer to

have the breast totally removed. Because in most cases long-term results have

been equally satisfactory, the patient’s wishes should be discussed with her and

taken into consideration.

Most women do not wish to lose an entire breast unless the surgeon can assure

them that this is essential in order to achieve best prospect of cure. In most cases

no such assurance can be given. In fact, most women can be assured that their

prospects of cure would be just as good with partial breast removal provided

12.10 Early Breast Cancer

163

radiotherapy is administered to remaining breast tissue and all axillary draining

lymph nodes are removed if there is pathology evidence of node involvement.

2.10.2 Adjuvant Chemotherapy

Whatever the initial form of treatment given, in a number of women with breast

cancer apparently confined to the breast and possibly nearby lymph nodes, there

will also be early but undetectable spread of some cancer cells to other parts of

the body. Adjuvant chemotherapy will improve the outlook for these women.

The most common sites for such spread are the lungs, distant nodes, liver,

Radio-therapy

ovaries and bones but almost any tissue may be a site for a secondary cancer. If che-

to the axilla is

motherapy is given at this stage, the very small clumps of scattered cancer cells, if

better avoided

present, are more likely to be destroyed than if they are allowed to get bigger before

after surgery

any potentially effective treatment is given. In women who have had an early breast

to the axilla

cancer removed but the cancer has also been found in the axillary lymph nodes,

because of the

or the cancer is histologically anaplastic and high grade, or is greater than 2 cm

high incidence

diameter, especially in a young woman, or it is a hormone receptor negative poor

of impairment

prognosis cancer, there is a real chance that it has spread. Although there may be no

of shoulder

proof of spread, the risk that it may have spread is significant, therefore a program

movement and

of adjuvant chemotherapy is usually given after the operation just in case there are

of sub-sequent

still some cancer cells somewhere (see Sect. 8.3.4). Women given adjuvant treat-

lymphoedema

ment are up to 10% less likely to have future metastatic cancer and are therefore

of the arm that

more likely to be cured. Adjuvant chemotherapy, must be given skilfully and the

can follow.

effects watched closely as side effects are common.

2.10.3 Hormone Sensitivity Tests

Not all breast cancers will respond to hormone therapy. Nowadays, when a

breast biopsy is taken and found to be cancer, a small piece is usually tested for

hormone sensitivity (called the oestrogen and progesterone receptor or ER and

PR tests). These tests will give an indication as to whether the cancer is likely

to respond to hormone manipulation. If not then some other form of treatment,

as for example cytotoxic chemotherapy, may be more appropriate.

In general patients with ER^−ve tumours should be treated with adjuvant che-

motherapy as their cancers are unlikely to respond well to hormonal manage-

ment. Patients with ER^+ve tumours are likely to get a favourable response to hor-

monal management and are usually better treated with tamoxifen if their tumour

is of intermediate or high risk. Adjuvant chemotherapy is also better tolerated by

younger rather than older women. In older age groups tamoxifen is unlikely to be

toxic and is better tolerated so that for elderly and frail women tamoxifen may be

the preferred adjuvant treatment regardless of hormone receptor findings.

Recent trials have indicated that another group of agents, called aromatase

inhibitors (anastrozole, arimidex, letrozole, exemestane) are even more effective

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12 B reast Cancer

than tamoxifen for postmenopausal women with metastatic cancer or women

who have had their ovaries removed as treatment for metastatic breast cancer.

12.10.4 Options in Management of Early Breast Cancer

There is no one best management of early breast cancer. Depending on circum-

stances the options for integrated management are as follows:

• Removal of the breast or that part of the breast containing the cancer.

• This to be followed by irradiation of the remaining breast tissue or chest region

from which the breast was removed.

• Sentinel node biopsy.

• Total excision of axillary nodes if tumour was found in any lymph node or if

the primary cancer was large and/or infiltrating and aggressive.

• Adjuvant chemotherapy if there was cancer in any lymph node, or if the pri-

mary cancer was infiltrating and aggressive or greater than 2 cm diameter, or

if ER/PR^−ve (especially in younger women).

• Hormone management (usually with Tamoxifen) if the cancer was ER/PR^+ve.

Studies continue to determine more precisely which combinations of therapy should

be recommended for treatment of a particular cancer in a particular patient.

12.11

Locally Advanced and Metastatic Breast Cancers

For women who present for treatment with advanced breast cancer, such as cancer

fungating (ulcerating) through the skin or cancer adherent to underlying muscles

or cancer with distant metastatic spread to other tissues or organs, cure cannot be

achieved by standard local surgery alone. Sometimes chemotherapy or radiotherapy

or both may be given first to reduce the tumour size. Sometimes this may be

followed by surgical removal of the breast to prevent further local growth or funga-

tion. (Chemotherapy given before planned surgery and/or radiotherapy is a form of

induction or neoadjuvant chemotherapy. See Chap. 8.) If the cancer was clinically

a stage 3 cancer without evidence of metastatic spread sometimes a cure can result

from this form of combined, integrated treatment. But in case there is undetected

metastatic spread further follow-up adjuvant chemotherapy is also given.

However for such advanced local cancers with distant metastases in other

tissues, the best palliation may often be achieved by some form of hormonal

treatment or by chemotherapy alone or with radiotherapy (as discussed in

Chap. 8). In many cases metastases will respond well to localised radiotherapy

giving at least temporary pain relief. This is especially appropriate for isolated

painful metastases in bones.

12.12 Physical and Emotional Needs

165

Two further treatments may be helpful for pain relief from bone metastases.

These are bisphosphonates or with radio-isotopes strontium 89 or samarium 153

(see Sect. 8.6.2 Treatment of Complications).

Strontium 89 is a beta-emitting radioisotope that becomes incorporated in

bone metastases causing local tumour cell destruction and pain relief. Being

poorly penetrating irradiation it is unlikely to cause damage to other tissues other

than nearby bone marrow. Before the treatment can be safely repeated care must

be taken to ensure that any blood count depression, and especially platelet depres-

sion, has fully recovered. Samarium 153 is used similarly to Strontium 89.

In addition to pain relief, treatment of other complications may be required.

Such treatment may include using a syringe to aspirate fluid from the chest (pleu-

ral cavity) blood transfusions to relieve symptoms of anaemia and always psy-

chological or spiritual support.

Real progress is being made in three new approaches in breast cancer treat-

ment, including development of various anti-enzymes involved in cancer-cell

development. These include enzymes called signal-transduction inhibitors,

related to relevant breast cancer growth factors.

Herceptin (Trastuzumab) is a prototype of successful development of thera-

peutic monoclonal antibodies (See Sect. 8.4.2 in Chap. 8). Herceptin has already

been shown to improve survival, possibly by 30%, when given in combination

with chemotherapy. It is now under study as adjuvant therapy. Other treatments

under investigation are the tyrosine-kinase inhibitors such as Gleevec, Iressa,

OSI 774; farnesyl transferase inhibitors; and angiogenesis inhibitors.

Another new approach is with gene therapy in which abnormal genetic mate-

rial in cancer cells is replaced with non-malignant genetic material. At the time

of writing techniques being developed to make gene therapy clinically effective

are causing a great deal of research interest.

12.12

Physical and Emotional Needs

12.12.1 Breast Prostheses and Breast Reconstruction

After loss of a breast, many women feel quite depressed and even humiliated and

require sympathetic help and understanding. Emotional depression to a greater

or lesser degree is almost inevitable after breast cancer treatment and further

depression following radiotherapy is common. Fortunately the most severe stage

of depression is usually temporary and improvement is usual after treatment has

been completed but it may take longer.

One obvious aid is the provision of a breast prosthetic padding to wear in a brassiere

or in a swimming costume. Many good appliances are now available that allow normal

activity, even swimming, without detection. This is good for the woman’s morale.

In other cases, reconstructive surgery may be considered to form a new breast.

In the past these procedures were usually not advised until at least a couple of

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12 B reast Cancer

years after mastectomy, in order to be as sure as possible that no further local

tumour recurrence was likely, but more recent studies suggest that immediate

reconstruction does not present any long term disadvantage. Some surgeons are

now offering immediate reconstructive surgery to replace the breast immediately

after its removal, with equally satisfactory results.

Some women do not choose to have any further surgery but to others breast

reconstructive procedures offer considerable emotional support and very good

cosmetic results can now be achieved (see Figs. 12.6a, b).

Fig. 12.6. Photographs (a) before and (b) after breast reconstruction surgery. The recon-

structed breast can be of very good appearance and will give the patient considerable

mental, physical and emotional support

12.12 Physical and Emotional Needs

167

2.12.2 Breast Clinics

Because of the high incidence of breast cancer in Western Societies and the broad

range of skills needed to best detect, manage and follow up patients often needing

integrated treatments for both clinical, emotional and supportive care, specialised

“Breast Clinics” have become widespread throughout most Western countries. These

involve not only diagnostic facilities and clinical medical specialists but also special

breast care nurses, physiotherapists and social workers in a team approach.

12.12.3 Cancer Societies and Breast Cancer Support Groups

Emotional support and understanding of family and friends is essential for most

women who have had a breast cancer especially after a mastectomy. As breast

cancer is one of the most common cancers in Western Societies many cities will

have a breast cancer support club (previously called a mastectomy club). Women

who have lost a breast are welcome to join. The companionship and advice from

fellow club members or from experienced professionals of a Cancer Society can

be of great help in coping with both physical and emotional needs of patients

(Sects. 8.6.3-8.6.5 and Chap. 9).

CASE REPORT

Early breast cancer

Sylvia is a 52-year-old lady who has had three children. She breast-fed all

three. She is otherwise fit and well and went through the change of life

at 46 years of age. She was placed on hormone replacement therapy for

post-menopausal symptoms and has been attending the Breast Screen Unit

annually from the age of 50. She regularly self-examines herself and there

is no family history of breast cancer. She is on no regular medications.

She attended the Breast Screen Assessment Unit, where a screening

mammogram with two views showed an area of spiculation in the upper

outer quadrant of the left breast at the 2 o’clock position, 4 cm from the

nipple. When she was examined by the surgeon in the breast-screening

unit she was found to have some thickening of the breast in the left upper

outer quadrant. The rest of the left breast was normal to examination with

no tethering or peau d’orange. Her right breast was normal to examination.

She had no evidence of axillary or supraclavicular lymphadenopathy and

no bony tenderness. An ultrasound was performed of both breasts espe-

cially concentrating on the area in the left upper outer quadrant and

(continued)

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12 B reast Cancer

(continued)

she was noted to have a hypo-echoic (solid) lesion with an irregular margin.

Clinically and radiologically, she had a lesion that was graded most likely

to be breast cancer so she underwent core biopsy. The core biopsy returned

a grade 2 invasive ductal carcinoma, which was ER and PR+ve.

The surgeon discussed management options for her disease. He recom-

mended wide local excision followed by 6 weeks of adjuvant radiotherapy.

To stage the axilla, he recommended a sentinel lymph node biopsy. Adjuvant

hormone therapy and chemotherapy would be considered once the surgery

had been performed.

A bone scan showed no evidence of any bone metastases. She was

booked in for her surgery and had a wide excision and sentinel lymph

node biopsy. The margins of excision were clear and the sentinel lymph node

was negative for any micro-metastases and negative for cytokeratin stain-

ing for epithelial cells. The final tumour pathology was a 21 mm, grade 2,

invasive ductal tumour that was ER/PR+ve and HER 2−ve (see Chap. 6).

She was seen at the Multidisciplinary Clinic by the radiation oncologist

and medical oncologist, where there was discussion of the use of adjuvant

chemotherapy, in addition to Tamoxifen. In view of her young age, the

infiltrating nature of the ductal cancer, the cancer was more than 2 cm in

diameter and her expressed wish to have any treatment that might help her

outcome she underwent 6 weeks of radiotherapy and this was followed by

four cycles of adriamycin and cyclophosphamide chemotherapy over 3

months. Following this, Tamoxifen was commenced for the next 5 years.

Sylvia will be followed-up in the first instance every 3 months to

exclude local recurrence and then 6 monthly for 2 years. Thereafter an

annual examination will be recommended for the rest of her life.

12.12 Physical and Emotional Needs

169

CASE REPORT

Breast cancer

Asha is a 40-year-old woman who was admitted to hospital after finding

a lump in her left breast. She is the mother of two children. Her menarche

was at 13 years. Her personal and family histories were unremarkable

but she had used oral contraceptives for several years. Mammography

revealed a 2.5 cm speculated lesion of left breast and the ultrasound con-

firmed the presence of an irregular solid lesion. A needle biopsy confirmed

the presence of malignancy.

She underwent a surgical excision as recommended. This consisted of

excision of the quadrant of breast containing the cancer (quadrantectomy)

and axillary node dissection. The final histology showed an infiltrating

ductal carcinoma, measuring 2.6 cm. Hormone receptive studies showed

the tumour to be oestrogen positive (ER+) and progesterone receptor

negative (PR−). Tumour margins were clear She was given radiation therapy

to the left breast followed by six cycles of chemotherapy (anthracycline-

based) with good tolerance.

An adjuvant chemotherapy program was decided because axillary

lymph nodes were found to be positive for malignancy, Radiotherapy to

the axilla was avoided because of the high risk of impaired shoulder move-

ment and of subsequent lymphoedema of the arm that can follow.

As the ER test was positive, she was given hormone therapy consisting

of tamoxifen for 5 years, after completion of radiation therapy.

She is kept under close and regular surveillance, which will be a life-

long recommendation.

EX ERCISE

Why is it so important to “follow up” breast cancer patients for virtually

as long as they live?

Cancers of the Digestive System

(Alimentary Tract)

•

In this chapter you will learn about:

› Cancer of the oesophagus

› Stomach cancer

› Cancers of the liver

› Primary liver cancer (hepatoma or hepatocellular carcinoma)

› Secondary (metastatic) liver cancer

› Cancer of the gall bladder and bile ducts

› Cancer of the pancreas

› Cancers of the small intestine

› Cancer of the large bowel (colon and rectum)

› Cancer of the anus

13.1

Cancer of the Oesophagus

Cancer of the oesophagus is a comparatively common disease in Eastern Asia,

especially China, and some African countries, particularly Southern African

countries, including South Africa. It also has a relatively high incidence in males

in France and Eastern Europe, especially Hungary (see Appendix). Although less

common in Britain, America, Canada, Australia, New Zealand and the white

population of South Africa the incidence is rising in some of these countries,

particularly in Britain. The reasons for this difference in incidence are not fully

understood although consumption of alcohol and perhaps different diets play a

part. In those parts of China and Africa that have a high incidence, a fungus that

grows on stored food may be at least partly responsible. Oesophageal cancer is

more common in men than in women especially in the middle and lower thirds of

the oesophagus but in the upper end, it is more common in women. Oesophageal

cancer, like cancers in the mouth and throat, is more common in smokers and

especially in smokers who are heavy drinkers.

Cancer of the lower end of the oesophagus is most often seen in people who

have a history of inflammation or degeneration (metaplasia) or an ulcer in the

lower oesophagus caused by long standing regurgitation of stomach contents.

Such an inflammatory degeneration with metaplasia in the lower oesophagus is

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_13, © Springer-Verlag Berlin Heidelberg 2009

171

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13 Cancers of the Digestive System (Alimentary Tract)

now called a Barret’s oesophagus but if an ulcer develops it is known as a Barret’s

ulcer. The conditions were first described by Dr Barret, an Australian surgeon

working in London. Barret’s ulcer is becoming more common in Western coun-

tries, so too is cancer of the lower oesophagus.

13.1.1 Pathology

Most cancers of the upper and middle regions of the oesophagus are of the flat

pavement or squamous-cell type, having developed in the squamous mucosal

lining. At the lower end of the oesophagus, where there may be glandular mucosa

similar to that of the stomach, increasing numbers of cancers are of glandular-

type cells. That is, adenocarcinoma is more common and increasingly so in

association with long-standing Barret’s ulcer.

13.1.2 Symptoms

Cancer of the

Unfortunately, cancer of the oesophagus is usually well established before it is

oesophagus

diagnosed. The most common symptom is dysphagia (difficulty with swallowing).

is usually well

First, there is difficulty in swallowing solid foods that seem to get caught in the

established

throat or chest. Later, there is difficulty in swallowing liquids. A person with

before it is

cancer of the oesophagus thus soon loses weight and may become quite wasted

diagnosed.

and even dehydrated.

13.1.3 Signs

The earliest sign of oesophageal cancer is for the doctor to observe the patient

having difficulty with swallowing. A later sign will be evidence of weight loss

and even dehydration.

13.1.4 Investigations

Barium swallow or barium meal X-rays (described in Sects. 7.3.2-7.3.3) will

usually show an obstruction to swallowing in the oesophagus. An irregular,

“apple-core” shaped, narrowing is a common feature at the site of this cancer.

Oesophagoscopy is carried out (described in Sect. 7.4.6) and, through the

oesophagoscope, the doctor can usually see an irregular tumour mass or an ulcer-

ated tumour. A biopsy will establish the diagnosis microscopically.

Cancers of the oesophagus have usually spread up and down and under the

mucous membrane lining of the oesophagus and into lymph nodes and other

13.1 Cancer of the Oesophagus

173

structures in the chest before the patient notices much in the way of symptoms.

Thus they are very often incurable when first diagnosed.

13.1.5 Treatment

Very early intramucosal adenocarcinoma in Barret’s oesophagus can some-

times be treated effectively by endoscopic resection. However, long-term

cure of well-established or invasive oesophageal cancer is all too infrequent

but the best hope of cure is by operation. The oesophagus is removed and

either the stomach or a section of bowel is used to make a new oesophagus

for passage of food.

Radiotherapy is also used to treat this cancer. Although it often makes a can-

cer smaller for a period, and relieves symptoms temporarily, it does not often

cure the cancer.

Even when radiotherapy and surgery are used together results have been

disappointing.

Chemotherapy alone has also been disappointing in treating this cancer.

The earliest attempts to improve results by using chemotherapy first to reduce

the cancer and then surgery to remove the remaining cancer did not improve

patient outcomes. However, more recently some encouraging results have been

reported using different drug combinations in integrated treatment programs in

which chemotherapy has been integrated and synchronised with radiotherapy

and possibly followed by surgery. Further studies are needed before a change in

standard practice can be recommended with confidence.

Sometimes attempts at removing an oesophageal cancer are not possible and

the most helpful treatment is for the surgeon to pass a plastic tube through the

oesophagus and past the cancer into the stomach, to allow the patient to swallow

food through the tube. Otherwise, some alternative food passage, possibly by

putting a feeding tube directly into the stomach or another method of feeding,

like intravenous nutrition may be required.

Screening. Because of the increased risk of cancer of lower oesophagus and

upper stomach associated with Barret’s metaplasia or Barret’s ulcer, it is

recommended that people with persistent or uncontrolled reflux or a known

Barret’s oesphagus be regularly screened by oesophagoscopy or endoscopy for

early detection of any malignant change.

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13 Cancers of the Digestive System (Alimentary Tract)

CASE REPORT

Lower oesophageal cancer

Michelle is a 63-year-old nurse.

She was 59-years old when she first complained of reflux and “burn-

ing” in her lower oesophagus. It had been troubling her for some months

or possibly a year when she first consulted her family doctor. Her doctor

arranged oesophagoscopy that confirmed gastric reflux and some mucosal

irritation suggestive of Barret’s oesophagus. The doctor advised Michelle

to avoid bending, to lose some weight, to elevate the head-end of her bed

and sleep with extra pillows under her head. He also prescribed an antacid

medication. He asked Michelle to return for consultation in 3 months.

Michelle explained that she was committed to working in an African mission

for 2 years. The doctor then proscribed a “proton pump” medication for

Michelle to take with her in case her symptoms were not distinctly better

in 3 months. He advised Michelle to return to Brussels or another major

centre for reassessment in no longer than 6 months.

Initially Michelle got some relief from the antacid medication but symp-

toms returned so she took a course of the “proton pump” medication. It too

gave her initial relief but symptoms returned and worsened. She continued

with her work but eventually had trouble swallowing and lost a great deal of

weight. After 13 months she returned to Brussels where her doctor arranged

a further gastroscopy. An ulcer with raised edges was seen in the gastro-

oesophageal junction. Biopsies showed it to be an adenocarcinoma. Chest

X-rays and CT scans did not show any evidence of tumour spread.

Possible treatments were discussed with Michelle. She was advised that

surgery alone would offer her no more than a 20% chance of cure. Radio-

therapy alone would probably give her temporary relief with but an even less

chance of cure. The specialist involved advised that his oncology group was

taking part in a clinical trial using either pre-operative (induction) chemo-

therapy followed by radiotherapy or preoperative chemotherapy followed by

surgery to determine whether better results could be achieved.

Michelle agreed to take part in the study. After five treatments with

chemotherapy at weekly intervals her cancer had become significantly

smaller. Surgical resection of lower oesophagus and proximal stomach

with draining lymph nodes was then performed and the residual oesopha-

gus was anastomosed to the remaining stomach in the chest.

After initial trouble with eating and some anaemia, Michelle is now

taking smaller nutritious meals more frequently, some treatment for anae-

mia and is beginning to gain some weight. To date, 6 months post-opera-

tively, she feels relatively well but has reduced energy. So far there is no

evidence of cancer recurrence.

13.2 Cancer of the Stomach

175

13.2 Cancer of the Stomach

Stomach cancer is uncommon before the age of 40 but thereafter the incidence

increases with age, reaching a peak between the ages of 60 and 65. For some

unknown reason, in most countries males are affected about two or three times

more commonly than females.

In the past, cancer of the lower or middle stomach was one of the more serious

and more common cancers affecting mankind but fortunately, over recent years,

it has become less common.

Stomach cancer has distinct racial, geographic and dietary associations. It is

about seven times more common in Japan and Korea and three or four times more

common in Eastern Europe than in the US (see Appendix).

Epidemiological studies suggest it has a direct close and relationship to diet.

People who have a diet that is high in animal fats, (especially chemically preserved

meats) and low in fresh fruit and vegetables have a greater risk of developing stom-

ach cancer. It may be related to a high intake of chemical food preservatives and

other methods of food preparation, curing, storage and preservation. For example

the high intake of smoked fish in Japan has been incriminated. There is also a

high incidence among people of northern Iceland who eat large amounts of crude

smoked fish as opposed to a lower incidence in the people of southern Iceland who

have a different diet. In Korea, the custom of eating a great deal of red pepper and

possibly other irritating spices in food is thought to be significant.

It has been suggested that a reason for the decreasing incidence of stomach

cancer in modern industrialised societies is the greater availability of fresh fruit

and vegetables due to modern transport and the greater use of refrigeration to

store foods rather than chemical preservatives and additives.

Medical conditions that increase a person’s risk of developing stomach cancer

are pernicious anaemia (six times the normal risk), chronic gastritis, polyps in

the stomach and gastric ulcers that may be due to Helicobacter pylori infection.

Smokers also have an increased risk and the risk is greater in smokers who are

also heavy consumers of alcohol.

3.2.1 Pathology

Having developed in gastric mucosa, most gastric cancers are glandular type

(adenocarcinoma). In the past, gastric cancer was much more common in the

lower stomach but the pattern is now changing. It is now becoming less common

in the lower stomach and increasingly more common in the upper end, especially

about the gastro-oesophageal junction. This change in pattern is at least partly

due to effective treatment of the Helicobacter pylori bacillus that commonly

caused ulceration and other mucosal changes in the lower stomach. Effective

treatment of this infection appears to have reduced the incidence of cancer in

the lower stomach.

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13 Cancers of the Digestive System (Alimentary Tract)

3.2.2 Symptoms

Like cancer of the oesophagus, cancer of the stomach is usually quite advanced

before pain or other symptoms cause most patients to seek medical attention. The

earliest symptom is usually vague indigestion that gradually becomes worse and

more persistent. Persistent indigestion occurring for the first time in someone

over the age of 40 must always be considered with suspicion. Sometimes an

early feature is loss of appetite especially for certain foods. Loss of appetite for

meat is common. Other symptoms may be of fullness or even feeling “blown

up” in the stomach after eating small amounts of food, or vomiting after food.

Vomiting may become frequent, regular or blood-stained. If a cancer has blocked

the stomach, vomiting becomes persistent. Pain is sometimes the first symptom

noticed but when pain is persistent the cancer is often quite advanced. Sometimes

a patient has not been aware of any symptoms but has found a lump in the upper

abdomen. Other patients feel weak and tired due to anaemia, or have experi-

enced recent unexplained weight loss that may be the reason they seek medi-

cal attention, rather than any particular indigestion or abdominal complaints.

Occasionally the first evidence of trouble is due to the cancer having spread to

other organs or tissues, for example an enlarged liver or jaundice or back pain

from the pancreas or other tissues behind the stomach.

13.2.3 Signs

Clinical examination may detect one or more of the following features: a swell-

ing or lump in the upper abdomen; evidence of enlarged liver or lymph nodes;

evidence of spread into the pelvis or onto an ovary (felt on vaginal or rectal

examination); or evidence of fluid in the abdominal cavity (ascites). Evidence of

anaemia or weight loss should also be checked. A palpable involved lymph node

just above the medial end of the clavicle, and usually on the left side, is called

a Virchow’s node and is often a feature of advanced intra-abdominal cancer,

especially stomach cancer, because these nodes drain lymph from around the

thoracic duct which comes up from the abdomen.

13.2.4 Investigations

Blood tests for anaemia or other abnormalities and examination for blood in the

faeces are standard investigations for possible cancer of stomach or bowel.

Endoscopy (or gastroscopy as described in Sect. 7.4) is a very useful test.

Endoscopy may allow a cancer to be seen (as an ulcer with raised edges, a

cauliflower-like mass or rigid abnormal distortion of the stomach wall) and

a biopsy to be taken. Present-day endoscopy is now so readily practised

and without stress to the patient that it is usually performed before barium meal

X-ray studies.

13.2 Cancer of the Stomach

177

A CT scan may be useful to determine the size and exact position of a cancer.

It may show, for example, that the cancer has spread into the pancreas or liver or

enlarged adjacent lymph nodes.

Barium meal X-rays (Sect. 7.3.2) may show an ulcer (usually with raised,

rounded edges), or they may show a lump on the stomach wall looking something

like a small cauliflower. The X-rays and screening may show a blocked stomach,

a change in its shape or size (bigger, or shrunken and smaller), or a more rigid

and stiff-walled stomach.

13.2.5 Treatment

The only present curative treatment of cancer of the stomach is surgery: to

The only

remove all of the stomach (total gastrectomy), most of the stomach (sub-total

present curative

gastrectomy), or part of the stomach (partial gastrectomy). Because of the high

treatment

risk of lymph-node involvement, draining lymph nodes are removed with the

of cancer of

gastric resection.

the stomach

If a cancer has already spread beyond the stomach region surgical cure may

is surgery.

not be possible but it may still be possible to relieve symptoms for example a

gastro-enterostomy to relieve stomach obstruction.

After total gastrectomy the small intestine is anastomosed (joined) to the

oesophagus or, in the case of a sub-total or partial gastrectomy, the small intes-

tine may be anastomosed to the small remaining part of the stomach to allow

food to pass through normally. After surgery the patient can eat only small meals

and therefore needs to eat frequently to avoid too much weight loss. Without a

stomach, the patient will also be given treatment to prevent anaemia. Anaemia

may be a macrocytic anaemia due to loss of gastric intrinsic factor or a micro-

cytic iron-deficiency anaemia due to inadequate iron absorption or, possibly,

blood loss.

In the past results of surgery alone in treating apparently resectable stom-

ach cancers have been disappointing (about 25-30% cures) but in general, the

smaller a cancer is at surgery the better the chance of cure. For this reason,

endoscopy and other diagnostic tests may be used to look for evidence of

cancer as soon as a patient complains of early symptoms. If the patient is a

male over the age of 40 years there is a greater risk that persistent symptoms

of indigestion, lack of appetite and local epigastric pain and discomfort are

due to a cancer. In some countries, and especially Japan, screening tests are

often carried out in people at risk even though they may have no symptoms.

When stomach cancers are found whilst they are small and in the early stages

of the disease (as is now often the case in Japan), surgery results are good with

a high rate of cure (more than 80% cure rates have been reported). However

this is not often the case in Western countries where stomach cancer is less

common and is not often diagnosed until troublesome symptoms have devel-

oped, by which time the cancers are more advanced and less likely to be cured

by surgery alone.

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13 Cancers of the Digestive System (Alimentary Tract)

Presently available anti-cancer drugs do not cure this cancer but they may

be useful in treating people whose cancers cannot be cured by operation. The

drugs will often make the cancers smaller and may give the patients good but

temporary relief.

More recently, anti-cancer drugs have been given to some patients before the

operation is carried out (see Sect. 8.3.4). Some reports have shown that if the

cancers are made smaller by the drugs and then the operation (gastrectomy) is

carried out, the results will be better and the chances of cure improved. The most

effective way of giving the anti-cancer chemotherapy before operation may be by

giving drugs directly into the coeliac axis artery that supplies blood to the stom-

ach. After 5 or 6 weeks of this therapy, the cancer is usually smaller and, with

following surgery, better results have been reported. These studies continue but

as yet there has been no agreement about the most effective plan for integrated

treatment.

More studies of these techniques are needed but there is some hope of better

results with treatment of stomach cancer in the future. Firstly, by earlier diag-

nostic tests to detect cancers at an earlier and more curable stage and secondly,

by the use of induction or neoadjuvant chemotherapy followed by surgery for

those people who present for treatment with established, invasive, but removable

cancers.

Studies in the use of postoperative adjuvant chemotherapy are in progress but

at the time of writing, although some positive results have been reported there is

no agreement on the benefits of adjuvant chemotherapy.

After gastrectomy it is important to carefully follow-up these patients not

only for possible tumour recurrence but for general nutrition and to avoid both

microcytic anaemia (possibly a feature of poor nutrition and iron deficiency)

and macrocytic anaemia (due to loss of gastric intrinsic factor).

EX ERCISE

List predisposing factors that may be associated with cancers of the stomach

and the oesophagus.

13.3 Cancer of the Liver

179

13.3

Cancers of the Liver

Cancers in the liver are either cancers that began in the liver cells (primary) or

cancers that have spread to the liver from another primary site (secondary or

metastatic).

13.3.1 Primary Liver Cancer (Hepatoma or Hepatocellular Carcinoma)

Cancer starting in liver cells (primary cancer) is uncommon in European races

but is common in Africans, South-East Asians, Chinese and Japanese (see Appendix).

It ranges as high as half of all cancers in African Bantu men. The reasons for

this difference in incidence are not completely understood although differences

in diet and food storage and preparation are probably important. Long-standing

liver infection with hepatitis B and hepatitis C and parasitic infestation, particu-

larly by the liver fluke, are responsible for much of the increased incidence in

some Asian countries. Certain fungi that commonly contaminate food in parts

of Africa and Asia may also play a part whereas food stored by refrigeration in

Westernised societies should be free from fungus contamination.

In Western Countries primary liver cancer is more likely in people with long-

standing cirrhosis of the liver, whether the cirrhosis is the result of excessive

alcohol consumption, post hepatitis or other causes.

13.3.1.1 Features o f P rimary L iver Cancer

The first evidence of primary liver cancer may be deterioration in general health

(loss of appetite, lassitude, malaise, weight loss, weakness and debility) or features

of liver enlargement with pain in the upper abdomen, swelling, jaundice or fluid

in the abdominal cavity (ascites).

13.3.1.2 Investigations

Investigations that may help include CT scans, MRI scans, ultrasound, sometimes

arteriography, but especially liver biopsy (see Sect. 7.3). Also, blood tests for liver

function, anaemia and biochemical changes are often helpful. The tumour marker

alpha-foeto-protein is usually raised in people with this cancer and should fall

to normal levels if the cancer has been successfully treated. Progressive alpha-

foeto-protein tests may give a useful indication of the effectiveness of treatment.

Other serological tests for hepatitis B surface antigens (HBsAg) or antibodies

for hepatitis C (anti-HCV) may also be positive in liver cancer.

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13 Cancers of the Digestive System (Alimentary Tract)

13.3.1.3 Treatment

Treatment of primary liver cancer is successful only if the disease is detected

whilst it is confined to a part of the liver that can be surgically resected. Because

the cancer has usually spread widely in the liver when first detected, cure is

usually not possible.

Chemo-embolisation can sometimes reduce tumour size and achieve pallia-

tion of symptoms. This treatment, in which anti-cancer agents are combined with

a clotting agent and injected into the hepatic artery feeding the cancer mass, is

commonly used in Japan. Another form of treatment now widely practised in

Japan and other Eastern countries is to infuse chemotherapy into the hepatic

artery together with different materials (often Lipiodol or microspheres) that

slow the rate of the anti-cancer agents in their flow through the liver. The slower

liver circulation increases the uptake of anti-cancer drugs by keeping the liver

and cancer cells exposed to them for longer periods. Several reports of improved

results are now well documented. In some trials immunological agents have also

been incorporated to make the chemo-embolic materials or other liver circulation

slowing agents even more effective.

Another treatment in suitable patients is cryosurgery (Sect. 8.5) or percutane-

ous alcohol injections to destroy all visible cancer. Some patients have repeated

treatments and some gain long-term relief.

Tamoxifen is sometimes used in patients with poor performance status who

wish some form of active treatment. This may give temporary relief and is unlikely

to cause toxicity.

Meanwhile the most hopeful way of dealing with the high incidence of pri-

mary liver cancer is by more intense and widespread hepatitis B immunisation

programs to prevent this cancer-prone liver disease. Although much needed there

is, at the time of writing, no effective hepatitis C vaccine.

13.3 Cancer of the Liver

181

CASE REPORT

Hepatoma (primary liver cancer)

Henri was a 70-year-old retired winemaker who had become a heavy

consumer of his wine product for many years. He had not felt well for

some months with loss of appetite for food, weight-loss and loss of energy

but unfortunately no loss of appetite for his wine.

He had developed abdominal discomfort and pain, especially pain in

his right shoulder, when he consulted his family doctor.

His doctor found him to be a thin, wasted man with slight jaundice, some

abdominal swelling with some ascites. Some petechial spots were noticed

on the skin of Henri’s abdomen. He felt an enlarged liver, with a distinct

mass protruding downwards from the right liver lobe. When he put his

stethoscope over the mass he could hear a vascular bruit.

Ultrasound, angiography and CT scans confirmed the appearance of

a vascular liver mass consistent with a primary liver cancer. Blood count

showed the presence of anaemia with a reduction in platelets. There was

no evidence of a stomach, bowel or lung cancer that might have suggested

the liver mass could be a secondary cancer so that a primary liver cancer

was assumed without a biopsy. Biopsy was not performed due to the risk

of haemorrhage.

Henri was given a transfusion of whole blood but was otherwise treated

symptomatically only. He died 1 month later and autopsy confirmed a

primary liver cancer (hepatoma) in a cirrhotic liver.

Comment

In Henri’s state of health there would have been no question of resecting

this cancer even though it appeared to be confined to the right lobe of the

liver and was not involving the vena-cava. There was also no possibility

of improving his outlook by systemic chemotherapy alone. However had

Henri been well enough, consideration might have been given to treating

his liver cancer by chemotherapeutic embolisation. In such treatment a

chemotherapeutic agent together with a “blocking agent” (such as lipiodol

or microspheres), is infused into the hepatic artery. The blocking agent

slows the arterial blood flow in the liver thus allowing a longer period of

exposure of the cancer cells to the chemotherapy. Such treatment is often

worthwhile in younger, fitter patients with liver cancer.

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13 Cancers of the Digestive System (Alimentary Tract)

13.3.2 Secondary (Metastatic) Liver Cancer

The liver is one

The liver is one of the most common sites of secondary cancer in Western races.

of the most

Cancers of the digestive tract, especially the stomach, pancreas, colon and

common sites

rectum commonly spread via the bloodstream to the liver. Cancers of almost

of secondary

any other tissue may also metastasise to liver, especially breast cancer, lung

cancer in

cancer and melanoma.

Western races.

Once involved with metastases, the liver enlarges. It may become uncomfort-

able or even painful. Jaundice often develops and ascitic fluid may accumulate

in the abdominal cavity. A person with secondary liver cancer sooner or later

usually notices a general malaise, loss of appetite, loss of weight and loss of

energy. Breathlessness may also develop.

13.3.2.1 Investigations

The most helpful investigations are usually the CT or MRI scan, ultrasound,

sometimes arteriography and laparoscopy. Liver isotope scans, once a standard

investigation, have largely been replaced by more helpful MRI scans. If needed,

a liver biopsy may be required to confirm the diagnosis but very often the diag-

nosis is obvious from the known previous history of a cancer.

Liver biopsy can be carried out under local anaesthesia with a special needle

through the lower chest or abdominal wall. Alternatively it may be carried out at

laparoscopy or open operation.

If the site of a primary cancer that has spread to the liver is not known, inves-

tigations may be required to discover where the metastatic cancer in the liver

originated (i.e. the primary cancer site) (Fig. 13.1 and 13.2).

Fig. 13.1. CT of liver showing a metastasis from a colon cancer

13.3 Cancer of the Liver

183

Fig. 13.2. Photograph of abdomen of a 63-year-old jaundiced woman with a big liver and

ascites. The liver contained many metastatic lumps from a primary breast cancer treated

6 years previously

13.3.2.2 Treatments

Metastatic cancer in the liver is usually incurable. The best hope of cure is

when there are only one to four metastases that are in a part of the liver that

can be removed by surgical operation. However provided all metastases are in

one resectable section, surgical removal may be worthwhile even if more than

four metastases have been identified. This is uncommon. In most people, the

secondary cancers are spread throughout both sides of the liver.

Although there is no cure for most patients, some metastatic cancers are sensi-

tive to anti-cancer drugs, especially those that have come from primary cancer of

the colon or rectum, stomach or breast.

Although the drugs do not totally cure them, metastases may be reduced

sometimes giving the patient good relief for some months.

The simplest method of giving such anti-cancer drugs is either by mouth or

intravenous injection. However, a more effective method is by direct chemo-

therapy infusion into the hepatic artery either intermittently through a catheter

placed into the hepatic artery or by a continuous infusion using a continuous

infusion pump.

Intermittent intra-arterial infusion chemotherapy can usually be given only

in a hospital and the patient returns for treatment at intervals as necessary.

There is now evidence that a larger dose and more effective treatment (using

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13 Cancers of the Digestive System (Alimentary Tract)

5FU) is better tolerated if systemic protection with low dose folinic acid is first

administered.

Some years ago a small pump was developed in America to continuously

pump anti-cancer drugs into the hepatic artery. A surgeon implants this pump

under the skin of the anterior abdominal wall where it stays without discomfort.

It allows patients who are having continuous intra-arterial infusion chemother-

apy to go home and lead relatively normal lives, returning for re-filling of the

pump once every week or two. Although such pumps are expensive and suit-

able only for certain patients using certain drugs, most patients with pumps live

comfortably for several months or even 2 years or more. For many of these

patients, their survival time has been increased with good quality of life. Other

studies are aimed at developing less expensive and more easily available methods

of giving similar relief to greater numbers of patients using the principle of intra-

arterial chemotherapy.

Implantable infusion pumps are expensive but can often be used with good

effect. All methods have shown encouraging results as far as improving the

patient’s quality of life and possibly life expectancy are concerned but, as yet,

with few exceptions, infusion chemotherapy is unlikely to achieve long-term sur-

vival or cure. Studies of each technique continue.

Different combinations of anti-cancer drugs given in different treatment

schedules with or without infusion pumps are under study in many world cancer

centres. Although good results can be achieved when the drugs are given into the

hepatic artery, as yet there are a number of difficulties and problems to be solved

before this form of treatment can be recommended for general use other than in

specialised cancer clinics.

Destruction of obvious liver metastatic masses by cryosurgery or by alcohol

injection under laparoscopic control is used in some specialised centres, usually

with good effect. Some patients obtain considerable benefit, and in some the treat-

ment can be repeated with reasonably good long-term control. In some highly

specialised clinics this treatment is sometimes combined with hepatic-artery infusion

chemotherapy with good long-term control in suitable patients. Over 70% long-

term survivors have been reported from some clinics. Such studies are continuing

but this sort of treatment does require a dedicated team of specialists.

Some encouraging results are also being reported from implantation of radio-

active “seeds” into liver cancers.

Radio-frequency ablation (RFA) is another new approach under study for

treating some cancers in the liver.

13.3 Cancer of the Liver

185

CASE REPORT

Metastatic liver cancer

Kiri was a 62-year-old Maori woman who attended her doctor for her

regular follow-up having had a bowel cancer resected 3 years previously.

Over the last 6 months, since her last attendance she had had a reduced

appetite and lost some weight. She said that she had little energy.

The surgeon could feel a lump protruding from her liver edge below

the right costal margin. He arranged CT scans and three distinct masses

were seen in the liver, three in the right lobe and a smaller lump in the

left lobe. A needle biopsy confirmed the presence of metastatic cancer of

large bowel origin.

Resection of these tumours was out of the question so that Kiri was

offered the option of systemic chemotherapy, chemotherapy infusions into

her hepatic artery on a monthly basis or cryosurgical injections into the

liver metastases. Although more complex to administer she was advised

that hepatic arterial chemotherapy would be more likely to achieve a

tumour response than systemic chemotherapy. She chose this treatment as

her preferred first line of therapy. She was treated on a monthly basis with

chemotherapy (5-FU infused over 8 h into the hepatic artery). On each oc-

casion a vascular radiologist inserted a cannula into the hepatic artery via

one of her femoral arteries.

Over the next 7 months the tumour masses were first reduced in size but

they then began to increase in size so that the surgeon proposed treatment

by cryotherapy to which Kiri agreed.

Under a general anaesthetic, with laparoscopic visual control, the sur-

geon inserted a probe into each tumour mass and injected a measured

amount of liquid nitrogen into each mass.

In subsequent weeks the tumour masses reduced in size but after 5

months further masses had developed in the liver.

The cryosurgery was repeated on one more occasion and although there

was an initial good response for 3 months further masses developed in the

liver. With this Kiri’s general health had deteriorated with development of

jaundice and ascites. Kiri was thereafter treated symptomatically.

Comment

Life expectancy after first diagnosis of colon cancer metastases in the liver

is about seven or 8 months. Kiri and her family were grateful that she

had survived to attend her granddaughter’s wedding 1 year after the liver

metastases were first treated and she survived 19 months in all.

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13 Cancers of the Digestive System (Alimentary Tract)

EX ERCISE

List the reasons why in Eastern and developing countries primary cancers in

the liver are more common than metastatic cancers but metastatic cancers

in the liver are much more common in Western and developed countries.

13.4

Cancer of the Gall Bladder and Bile Ducts

These are uncommon cancers in Western countries although quite common in

some countries such as South India. In Western countries, cancer of the gall

bladder is usually associated with gallstones that have been present for many

years. It is most common in older women. Cancer of the bile ducts, on the other

hand, is rather more common in men.

A cancer

One reason for advising removal of gall bladders with gallstones, especially

may develop

in young women, is that there is a risk that over the years a cancer may develop

as a result

as a result of years of irritation with gallstones.

of years of

Early cancer may occasionally be found unexpectedly and incidentally on

irritation with

examination of the gall bladder after it has been removed for other reasons. In

gall-stones.

such cases, cure of the cancer may have been achieved simply by the operation

of cholecystectomy.

13.4.1 Symptoms

If not diagnosed early, cancer of the gall bladder may cause persistent pain in

the upper right side of the abdomen, with inflammation of the gall bladder. It

may cause a swelling or lump felt in the upper abdomen under the ribs on the

right side.

13.4.2 Signs

Cancer of the gall bladder and more especially cancer of the bile ducts may

present with jaundice due to obstruction of the flow of bile from the liver. The

jaundice is often accompanied by a severe itch of the patient’s skin.

13.5 Cancer of the Pancreas

187

3.4.3 Pathology and Treatment

Cancer of the gall bladder tends to invade the liver as well as nearby lymph

nodes. Once this has happened it is virtually incurable by surgery and does not

respond well to radiotherapy. It also does not respond well to chemotherapy

although good response to more concentrated intra-arterial chemotherapy (see

Sect. 8.3.4.6) and cure with subsequent surgery has been reported. In advanced

cases jaundice and itch if present, can usually be relieved by a surgical opera-

tion in which the obstruction to bile flow is bypassed allowing the bile to flow

into the bowel by another route. Alternatively a rigid stent is sometimes inserted

surgically through the obstruction in the bile duct to allow passage of bile and

so relieve the jaundice.

13.5

Cancer of the Pancreas

Cancer of the pancreas has become increasingly common in Western Countries

over recent years. It is now the fourth leading cause of cancer death in middle-

aged males in the US. It is more common in males than females (see Appendix),

but the reason for this is unknown. It is becoming increasingly common in smok-

ers and is also more common in heavy drinkers of alcohol. Diabetics and people

with a history of chronic pancreatitis also have an increased risk of pancreatic

cancer. Questionable associations of pancreatic cancer with consumption of

coffee have been reported but not confirmed however tea drinking may even be

protective (possibly due to anti-oxidants in tea).

3.5.1 Presentation

Cancer of the pancreas often involves the common bile duct causing bile duct

obstruction and often first presents as obstructive jaundice As the obstruction

continues, the jaundice becomes a deeper yellow. The jaundice may be pain-

less although there is often pain felt deep in the upper abdomen and passing

through to the back. The jaundice may cause the patient’s skin to become

very itchy ( pruritus). As obstructive jaundice develops, the gall bladder and

the liver may become enlarged and palpable. Sometimes a pancreatic tumour

mass can be felt.

Most patients with cancer of the pancreas have vague malaise, anorexia and

weight loss, in fact these may be the first features of the disease. Diarrhoea may

also be a feature. Sometimes patients first present with a painless jaundice with

no otherwise obvious cause.

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13 Cancers of the Digestive System (Alimentary Tract)

3.5.2 Investigations

Because the pancreas lies across the back of the upper abdomen, behind the

stomach and other organs, it has been one of the more difficult organs to feel or

to investigate. With the improved methods of investigation now available, abnor-

malities including cancer are now more often diagnosed in earlier stages.

Ultrasound and CT scans have been of some help in detecting earlier cancers

although early detection of the smallest cancers at a potentially curable stage is

still difficult.

A tumour marker, CA19-9, is often elevated in patients with pancreas cancer.

A low level might suggest a resectable cancer but a level of more than 2,000

usually indicates a non-resectable cancer.

Endoscopic retrograde cholangio-pancreatoscopy (ERCP discussed in Sect.

7.4.10), has allowed pancreatic secretions to be examined for cancer cells and

X-rays to be taken of the duct. These may be helpful in detecting evidence of

some pancreatic cancers at an early stage.

An isotope material suitable and specific for scanning the pancreas has not

been found but work continues in the search for such a substance. When PET

scans become more readily available (see Sect. 7.3.12) this is one area where it

is hoped they will help significantly in early detection as well as diagnosis and

monitoring response to treatments.

Needle biopsy of any lump in the pancreas is the most useful method of estab-

lishing a diagnosis but this procedure is not always reliable and does have risks. It

depends very much on getting the needle into exactly the right part of the pancreas.

A significant risk is that the needle tract might cause pancreatic juices to leak into the

peritoneal cavity and possibly establish a fistula that will cause further problems.

13.5.3 Treatment

When first detected, cancer of the pancreas has usually spread to lymph nodes and

the liver and cure by surgery is usually not possible. However, some small early

cancers can be resected by a major surgical operation with fair prospects of cure.

The operation is known as a Whipple’s operation.

To date, treatment by radiotherapy or chemotherapy has been disappointing

although more effective anti-cancer drugs and combination therapies are con-

stantly being investigated. Downgrading some cancers by radio/chemotherapy

prior to surgical resection has been successful in some studies with some long-

term cures reported but further studies are needed before such treatment can be

more widely accepted.

Present studies include more effective use of intra-arterial chemotherapy

as the first measure of an integrated treatment program with radiotherapy and

surgery but a number of difficulties need to be solved and further studies are

needed before this can be recommended as safe or effective treatment.

13.5 Cancer of the Pancreas

189

For most pancreatic cancers, some hope of temporary palliation of symptoms

is usually the best that can be achieved.

Relief of jaundice due to pancreatic cancer obstructing the bile duct can

usually be achieved by surgery to bi-pass the obstruction. Alternatively, a rigid

stent passed through the lumen of the bile duct at the site of obstruction might

give temporary relief of bile-duct obstruction.

CASE REPORT

Advanced cancer of pancreas

Boris was a 54-year-old Russian factory worker. He had been a smoker

for more than 30 years.

His wife had noticed a change in colour of his skin for 3 or 4 weeks and

that he had not been eating well and seemed to be losing weight, when she

convinced him to consult a doctor. By the time he saw his doctor an obvi-

ous jaundice was present. He confessed to his doctor that he had had some

upper abdominal and back pain and discomfort for 5 or 6 weeks.

On examination the doctor felt the liver was enlarged below the right

costal margin. No abdominal mass could be felt but a CT showed a mass, in

the region of the head of his pancreas. He explained that this was likely to

be a cancer and that a laparoscopy was recommended to confirm this.

At laparoscopy a cancer in the head of the pancreas was confirmed and

the presence of a dilated gallbladder was noted.

A laparotomy was recommended. It was explained to Boris that the

fixed cancer mass was unlikely to be resectable but his jaundice could be

relieved by anastomosing his gall bladder to his small bowel, so bypassing

the obstructing mass in the head of his pancreas.

Boris agreed to surgery and the presence of a cancer fixed to the poste-

rior abdominal wall with several firm enlarged adjacent lymph nodes was

confirmed. The gallbladder and common bile duct were dilated.

The cancer was clearly not resectable so the surgeon anastomosed the

dilated gall bladder to small bowel to bypass the obstruction.

Over the next 2 or 3 weeks the jaundice resolved. Boris was then com-

menced on a course of chemotherapy (5-FU) given by intravenous infusion.

After 6 weeks when CT examination showed the mass to be a little

larger and his white cell and platelet count had fallen to dangerous levels

the chemotherapy was stopped.

Thereafter all but palliative treatment was withdrawn. Boris required

increasing doses of morphine and eventually a morphine drip to get pain relief.

Boris failed to eat, lost weight and his condition deteriorated until she

died 10 weeks after his operation.

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13 Cancers of the Digestive System (Alimentary Tract)

EX ERCISE

Using as examples case reports in this chapter and other chapters of this

book, construct a case report of a typical patient presenting with and being

investigated and managed for an operable cancer of pancreas.

13.6

Cancers of the Small Intestine

Metastatic cancers, especially melanoma, sometimes involve the small intes-

tine and the small intestine is sometimes involved from cancers of other nearby

organs, especially colon and ovary, but primary cancer of the small intestine

is rare.

The most common of the rare primary malignant tumours of small intestine

are adenocarcinoma (a glandular cancer), a lymphoma (as described in Chap.

19) and a tumour called a carcinoid (cancer-like) tumour. These are rare causes

of abdominal pain, bowel bleeding or small bowel obstruction. They are usually

treated by a surgical resection.

3.6.1 Carcinoid Tumour

Carcinoid tumours may occur anywhere in the alimentary tract between the

mouth and anus. The most common site is in the appendix. Most carcinoids in

the appendix, and in fact most small carcinoids, are benign. Sometimes when

an appendix has been taken out for appendicitis, a small carcinoid tumour may

be found in it. In most such cases the tumour has been cured by removal of the

appendix. Further treatment is usually not necessary.

When a carcinoid tumour is found in the small intestine, rather than the

appendix, it is more likely to be larger (2 cm diameter or more) and more likely

to be malignant.

Treatment is by resection of the section of bowel and draining mesenteric

lymph nodes but it may have already metastasised to the liver. Carcinoid metasta-

ses in the liver may release certain biochemical substances that can cause wheezing,

bouts of diarrhoea, flushing of the skin of the face. Treatment can be given to

control these episodes but once this tumour has spread into the liver, complete

cure is unlikely.

13.7 Cancer of the Large Bowel (Colon and Rectum)

191

13.7 Cancer of the Large Bowel (Colon and Rectum)

In most Western societies the large bowel is the third or fourth most common

Polyps in

site of primary cancer although in the Australian and New Zealand popula-

the large

tions, in both sexes combined, large bowel cancer is the most common after

bowel often

skin cancer. In the adult population of the US lung cancer is by far the most

predispose

common cause of cancer death followed by colorectal cancer then breast cancer

to cancer and

and prostate cancer.

should be

Bowel cancer is a glandular cancer (adenocarcinoma). Although occasionally

removed to

seen in young adults (and even in children) it is not commonly seen until after

avoid the risk

the age of 40. Thereafter the incidence rises with age, reaching a peak between

of malignant

60 and 75 years.

change.

Cancer of the large bowel is most common in Western societies where the food

intake is relatively high in meat and animal fats, relatively high in refined foods and

relatively low in fibre such as in wholemeal grains, nuts, legumes, fruit and vegeta-

bles (as discussed in Chaps. 2 and 3). It is a relatively uncommon cancer in Asian

countries except Japan and Singapore where “Western” diets are now widespread.

Colo-rectal cancer is uncommon in developing countries and in vegetarians.

Polyps in the large bowel often predispose to cancer and should be removed to

avoid the risk of malignant change. People who have had polyps removed should

be kept under regular observation in case further polyps develop.

The most useful screening tests for bowel polyps and bowel cancer are chemi-

cal tests for occult blood in the faeces and regular colonoscopy, particularly for

people in higher risk groups. The higher risk groups include anyone who has

previously had a bowel cancer, anyone with a strong family history of bowel cancer

and in fact anyone over 55 who has been living on a traditional Western diet.

Colorectal cancers in total are more common in males (especially rectal can-

cers) but cancers in the right side of colon are rather more common in females.

Smoking, obesity and a sedentary occupation are risk factors.

A highly pre-malignant condition is the uncommon hereditary condition

familial polyposis coli, in which about half of the members of an affected family

are likely to develop multiple polyps. Those who have these polyps should have

all large bowel surgically removed otherwise they will develop bowel cancer

usually before the age of 40. All close blood relatives in an affected family should

be kept under regular observation. If polyps are found, these people too should

have a total colectomy.

A villous papilloma, less common than polyps, sometimes occurs in the

rectum. It has considerable propensity to become malignant in its base and

should be surgically removed when detected (Figs. 13.3 and 13.4).

Other conditions with an increased risk of large bowel cancer are the inflam-

matory bowel disease ulcerative colitis and to a lesser extent granulomatous

(Crohn’s) colitis. The longer ulcerative colitis has been present and the greater

the severity of the disease and length of bowel affected, the greater is the risk

of cancer developing. About 10% of people with continuing ulcerative colitis

13.7 Cancer of the Large Bowel (Colon and Rectum)

193

will develop colon cancer after about 10 years. People with long-standing and

extensive ulcerative colitis must be kept under close and regular observation and

in some circumstances may be well advised to have the colon removed as a

precautionary measure.

Apart from familial polyposis coli, close relatives of a patient with any large

bowel cancer have a slightly increased risk of developing a similar cancer.

Whether this is mainly a genetic factor or due to similar diet and other habits is

uncertain. Although the majority of patients successfully treated for bowel can-

cer do not develop a second tumour they do have an increased risk so that regular

“follow-up” checks are important.

13.7.1 Clinical Features

The most common symptoms of large bowel cancer are a change in bowel habits

(constipation or diarrhoea or sometimes alternating constipation and diarrhoea),

bleeding from the bowel, and a feeling of incomplete evacuation after going to

the toilet. In some cases patients are not aware of any symptoms until the can-

cer has caused partial or complete bowel obstruction. The first symptoms may

thus be of bowel obstruction with intermittent griping abdominal pain (colic),

constipation and abdominal distension.

Other features of large bowel cancer may be of general debility, weight loss,

tiredness and lassitude (sometimes due to anaemia) or features of liver enlarge-

ment or jaundice due to liver metastases.

It may be possible to feel an abdominal lump or localised swelling or on anal

examination with a gloved finger, a mass in the anus or lower rectum can some-

times be felt. There may be evidence of blood in the faeces. In obstructive bowel

cancer, colic with abdominal distension or swelling is likely.

13.7.2 Investigations

Investigations include sigmoidoscopic or colonoscopic examinations (described

Colonoscopy

in Sect. 7.4.2). About half of large bowel cancers are in the rectum or lower

will allow the

sigmoid colon. These can be seen and biopsied through a sigmoidoscope.

whole length of

Barium (or Baryum) enema screening and X-rays may reveal a cancer, espe-

the large bowel

cially if an air-contrast barium study is used (see Sect. 7.3.2).

to be examined

If there is no evidence of bowel obstruction and especially if a cancer is

visually and

suspected in the first part of the large bowel (the caecum or ascending colon),

for biopsies

barium meal studies and X-rays may help outline a tumour mass but colonoscopy

to be taken

with biopsy is still the most helpful method of diagnosis.

Sigmoidoscopic examination, barium enema and barium meal studies can

all be done on an outpatient basis without anaesthesia but colonoscopy requires

good sedation or in some cases a general anaesthetic. Colonoscopy will allow the

194

13 Cancers of the Digestive System (Alimentary Tract)

whole length of the large bowel to be examined visually and for biopsies to be

taken from any part of the length of the colon.

A day in hospital is sometimes required for this examination although increas-

ing numbers are now performed on a short stay basis of half a day or so. In some

modern clinics the procedure can be carried out with the patient being mildly

sedated and even able to watch the procedure on a TV monitor.

Blood studies are used to detect anaemia or changes in biochemistry of the

blood or impaired liver function. Carcino-embryonic antigen (Sect. 7.5.5) is a

tumour marker that is usually strongly positive in people with large bowel cancer

and becomes negative after successful treatment. If it becomes positive again at a

later stage after treatment this suggests a recurrence of the cancer.

CT scans are used in detecting evidence of liver metastases.

13.7.3 Treatment

In good hands an

The only way of curing a large bowel cancer is by a surgical operation in which

early operation

the part of the bowel containing the cancer is excised together with its draining

will cure about

lymph nodes, into which the cancer may have spread. In most cases, cut ends

half the patients

of bowel are joined (anastomosed), so the patient can return to normal life. The

with large

place of chemotherapy or radiation therapy as adjuvant treatment before or after

bowel cancer.

surgical resection is still under study. Some studies have suggested that there may

be a place for pre-operative radiation for some advanced rectal cancers but the

use of radiotherapy is somewhat controversial. Several studies have shown some

improvement in long-term results using adjuvant chemotherapy after surgical

resection of more advanced colo-rectal cancers with or without radiotherapy.

Adjuvant chemotherapy (often with 5-FU and leucovorin) is now standard prac-

tice in many modern clinics when the cancer has involved local lymph nodes.

Recent studies using an angiotoxic substance “Avastin” are showing encouraging

results in enhancing the cytotoxic properties of chemotherapy for bowel cancer.

When the cancer is in the lower rectum it may be necessary to remove the anus

as well as the rectum and a colostomy bowel opening is made in the abdominal

wall for passage of faeces. The patient learns to wear a bag over the colostomy

and the bowel empties at regular intervals into the bag. The patient learns to

empty the bag at convenient times and gradually learns to live an active and

virtually normal life.

A colostomy club has been established with branches in many large cities.

Membership is open to all people who have a colostomy. This club is a meeting

ground for people with similar problems and has been a great help in assisting

many patients to adjust to the new circumstances of living with a colostomy.

Mutual support and advice help people to learn to live with a colostomy and to

cope with necessary social adjustments.

13.8 Cancer of the Anus

195

In good hands an early operation will cure about half the patients with large

bowel cancer. With adjuvant chemotherapy in appropriate patients, even better

results are reported. With or without a colostomy, most people then return to

normal life. The cure rate depends on the degree of penetration of the cancer into

the bowel wall and the involvement of nearby or more distant lymph nodes.

If a cancer first presents with bowel obstruction it may be necessary to make

a temporary colostomy to relieve the obstruction. Usually the cancer is resected

3 or 4 weeks later and the colostomy is subsequently closed, resulting in a return

to normal passage of bowel actions.

13.7.4 Follow-Up Care

As for all patients who have had a cancer treated, regular “follow up” consulta-

tions and care are required for patients who have had a bowel cancer resected.

There is always a risk of metastatic cancer showing up in the liver or elsewhere

and there may be a risk of another bowel cancer developing that can be effectively

treated if detected while still small. In the case of bowel cancer any metastatic

cancer usually shows up within 2 years. It is uncommon for recurrence to first

show up after 5 years.

Treatment for patients with metastatic cancer in the liver using surgical resec-

tion, intra-arterial chemotherapy, cryotherapy or alcohol injections has already

been discussed in this chapter (liver cancer).

13.8

Cancer of the Anus

3.8.1 Presentation and Pathology

Cancer of the anus is not common but may present as a lump, an ulcer, bleeding,

or pain in the anal region. Sometimes it may develop in a pre-existing lesion

such as a papilloma (possibly caused by the human papilloma virus (HPV)), a

patch of leukoplakia (white patch) or in a long-standing anal fissure (a crack in

the wall of the opening of the anus).

Most cancers of the anus are similar in type to squamous cell cancer of skin

but behave more aggressively. A minority of anal cancers are adenocarcinomas

of the glandular mucosa of the upper anal canal.

Most anal cancers tend to spread to lymph nodes in the groins or in the pelvis

at an early stage and often require radical treatment to achieve the best chance

of cure.

196

13 Cancers of the Digestive System (Alimentary Tract)

CASE REPORT

Colon cancer

Bruce was a 59-year-old former smoker and a little overweight. He had had

coronary bypass surgery 4 months previously when he mentioned to his

cardiologist that he had noticed a little fresh blood in his bowel motions

on three or four occasions recently. He had no other bowel symptoms and

had made a good recovery from his cardiac surgery.

The cardiologist could not detect any mass or other abnormality on either

abdominal or anal examination. She referred Bruce to a gastroenterologist

who did not detect any significant abnormality but arranged a colonoscopy

examination. Blood and liver biochemistry tests were normal.

At colonoscopy the doctor found a polypoid lesion with a 2 cm diam-

eter ulcer with raised edges in the sigmoid colon. Biopsy showed it to be

an adenocarcinoma.

CT scans of abdomen, liver and chest did not show any evidence of

cancer spread.

Bruce was advised to have a surgical resection of left colon including

descending colon, sigmoid colon and upper rectum. The draining lymph

nodes were also resected with the specimen.

No tumour involvement of lymph nodes was detected.

Bruce enquired as to whether he needed to have adjuvant chemother-

apy but it was explained to Bruce that there appeared to be no need for him

to be given adjuvant chemotherapy because no lymph nodes were found

to have cancer involvement, the liver was not involved and the cancer had

not penetrated the bowel wall.

Regular follow-up examinations were carried out, including annual

colonoscopies for 5 years but no residual tumour and nor any polyps were

detected.

After being relatively well for 8 years further cardiac problems resulted

in Bruce’s death 11 years after colon surgery. His bowel function had been

normal with no evidence of any residual bowel or cancer problem.

13.8 Cancer of the Anus

197

Fig. 13.5. An advanced cancer of the anus of a 67-year-old man

An increased risk of anal cancer has been correlated in people who prac-

tice anal sex. This increase may be associated with the HPV or HIV infection

(Fig. 13.5).

13.8.2 Treatment

First a biopsy is taken to confirm the presence and type of cancer.

Treatment may then be by local surgery or radiotherapy for small early

cancers with the objective of preserving the anal sphincter. Radical surgery,

including excision of the rectum and anus was standard practice for rather more

advanced cancers until reports of good results from combined use of integrated

chemotherapy and radiotherapy, and this has now become standard practice in

most modern centres. Radical surgery may still be required for cancers that have

not responded to chemo/radiotherapy. Radical excision of draining lymph nodes

from the groin will be required if these nodes appear to be involved.

Head and Neck Cancers

In this chapter you will learn about:

› Cancers of the lips

› Cancers of the mouth, anterior tongue and buccal mucosa

› Cancers of the posterior tongue, tonsillar region and pharynx

› Cancers of the post-nasal space

› Cancer of the larynx

› Salivary gland cancers

› Cancers of the thyroid gland

Cancers of the lips, mouth, tongue, nasal cavity, the paranasal air sinuses, throat,

The further the

larynx and pharynx constitute about 5% of all cancers recorded in the US and

cancers are away

the incidence is similar in most developed and developing countries. Most of

from the lips, the

these cancers are of squamous cells lining the mucosal epithelium. They are

more aggressively

similar in type to squamous cell carcinoma (SCC) of the skin. However they

they behave.

tend to behave in a more malignant and more aggressive fashion than SCCs of

skin. As a rule the further the cancers are away from the lips, the more aggres-

sively they behave. Cancers of the lips are more aggressive than skin cancers.

That is, they tend to grow more rapidly locally and have a greater tendency to

spread to draining lymph nodes at an earlier stage. Cancers of the floor of the

mouth, the anterior two-thirds of the tongue, and palate are more aggressive

than cancers of the lips. Cancers of the back of the tongue, in the region of the

tonsils and pharynx and upper air passages are the most aggressive. Cancers of

the vocal cords of the larynx are an exception to this rule. Possibly because the

vocal cords are poorly vascularized, these cancers tend to remain localised to

the vocal cords with no evidence of spread when they first cause symptoms. The

majority are readily curable at that stage.

These cancers are all much more common in smokers than non-smokers and

are most common in males over 50. It has been estimated that cancers in the

mouth and throat are about six times more common in smokers than in non-

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_14, © Springer-Verlag Berlin Heidelberg 2009

199

200

14 Head and Neck Cancers

smokers and this is increased to about 15 times if the smokers are also heavy

drinkers of alcohol. Other pre-malignant conditions that predispose to cancer in

the mouth include leukoplakia, papillomata, and chronic irritation from such

causes as ill-fitting dentures or jagged teeth (see Chap. 1).

14.1

Cancers of the Lips

Cancers of the lips being more obvious than cancers further back in the mouth

or throat are usually diagnosed at an earlier and more curable stage. They may

develop as a thickening in an area of hyperkeratosis (sun damage) - most com-

monly on the lower lip. They tend to ulcerate and possibly bleed or may form a

lump. They may then metastasise to lymph nodes under the jaw and in the sides

of the neck that may be felt as enlarged and usually firm or hard lymph nodes.

A biopsy is taken to confirm the diagnosis and thereafter treatment is usually

by surgical excision. Good results, both cosmetically and clinically are usually

achieved. Radiotherapy can also be used with good results.

For larger cancers of the lips, either radical surgery, (removing a large part of

the lip with some form of plastic or reconstructive surgery to fashion a new lip),

or radiotherapy may be used, and the chances of cure are still good.

If hard, enlarged lymph nodes are present either when the patient is first seen

or at a later follow-up visit to the doctor, these are best treated by surgical block

dissection to remove all local lymph nodes.

Occasionally, a patient first consults a doctor when the cancer is very large.

Possibly the whole of the lip is involved with cancer. In these patients, consider-

able success can be achieved with induction (neoadjuvant) chemotherapy to first

reduce the cancer then following this treatment with radiotherapy or surgery

or both. If special facilities for intra-arterial chemotherapy are available, the

chemotherapy may be best given regionally by infusion into the arteries that

supply blood to the cancer region but such treatment should be done only in specialist

clinics with special experience, equipment and skills. It is not necessary to use

this more complicated combined treatment for smaller cancers that can be readily

cured by operation or by radiotherapy (Figs. 14.1–14.2).

14.2 Cancers of the Floor of the Mouth (Under the Tongue), Anterior

Two-Thirds of the Tongue, and Buccal Mucosa (Inside the Cheek)

These cancers are more aggressive than lip cancers. Lymph nodes are involved

in about 30% of cases.

These cancers are usually first noticed as an ulcer or a lump either by the

patient or sometimes by their dentist before symptoms develop. Other common

features are bleeding or localised soreness. These cancers tend to be on the

14.2 Cancers of the Floor of the Mouth (Under the Tongue), Anterior Two-Thirds of the Tongue, and Buccal Mucosa

201

Fig. 14.1. A squamous cell carcinoma developing in sun induced hyperkeratosis of the

lower lip

Fig. 14.2. A localised SCC of lower lip

surface at first but soon invade locally with firm induration surrounding the lump

or ulcer. They usually become quite tender. Diagnosis is confirmed by taking a

small biopsy for microscopic examination.

Cancers in the buccal mucosa of the cheek pouch are most common in India,

Pakistan, New Guinea and The Solomon Islands due to the common practice

of chewing betel nut. After initial chewing, the nut is often stored in the cheek

pouch where its carcinogenic properties take effect.

Most cancers are well treated by surgical excision or radiotherapy. Involved

lymph nodes are best treated by block dissection of all lymph nodes in the region.

Sometimes reconstructive surgery may be required to replace resected tissue.

202

14 Head and Neck Cancers

Fig. 14.3 (a, b). Anteroposterior and lateral photographs of a man who first presented with

this very advanced SCC of his lower lip. The swelling under the jaw was a mass of meta-

static cancer in lymph nodes. (c) Photograph of the same lip after treatment with che-

motherapy (given over 5 weeks by continuous intra-arterial infusion). Three weeks after

completion of chemotherapy “follow-up” treatment with radiotherapy was started. Right

sided cervical nodes and submental nodes were resected 4 weeks after completion of radio-

therapy. They included a small residual node mass containing some cancer cells. (d) The

end result. This photograph was taken 2 years after completion of treatment. (e) Lateral

view of the end result. This man was well and without evidence of cancer when last seen

12 years after treatment

14.2 Cancers of the Floor of the Mouth (Under the Tongue), Anterior Two-Thirds of the Tongue, and Buccal Mucosa

203

For larger cancers in the floor of the mouth, anterior two-thirds of tongue,

or the cheek, treatment by prior induction chemotherapy followed by radio-

therapy or surgery, may give the best results. In some specialised clinics such

induction chemotherapy is given by intra-arterial infusion more directly to the

tumour site.

By these combined treatment methods, cures can now be achieved in patients

with advanced cancers, which, until recently, were considered incurable or pos-

sibly only curable by the most radical surgery. Such treatments do require special

skills, equipment and experience and should be carried out only in experienced

cancer centres (Chap. 8) (Fig. 14.4–14.6).

Fig. 14.4. Photographs showing (a) leukoplakia in the buccal mucosa of a 54-year-old

heavy smoker and heavy alcohol drinker; (b) the same mucosa 2 years later. It had

developed into a papillary squamous carcinoma

14.2 Cancers of the Floor of the Mouth (Under the Tongue), Anterior Two-Thirds of the Tongue, and Buccal Mucosa

205

CASE REPORT

Squamous cancer of the tongue

Tony was a 70-year-old Italian migrant enjoying his retirement in Sydney,

Australia. He had generally good health despite a smoking history of 40

years duration. He had rolled his own cigarettes (ten daily for 40 years)

but had stopped smoking 5 years before his first consultation. After

stopping smoking he continued to enjoy beer and wine, having up to five

alcoholic drinks daily.

Two months prior to presentation, Tony had noticed a small lump on the

side of his tongue. This was initially painless, so he ignored it thinking he

must have bitten his tongue in his sleep. However the lump progressively

enlarged. After a few weeks, he felt pain in his tongue, jaw and left ear.

Eventually the lump came to interfere with his speech and swallowing.

He reported the problem to his family doctor

His doctor recognised a large cauliflower-like tumour on the left side of his

tongue. He was promptly referred to a Head and Neck Surgeon. Tony was

then advised that he had developed a cancer of the side of his tongue

A small biopsy was performed in the surgeon’s office under local anaes-

thesia. Within 24 h it confirmed an invasive SCC.

Neither his family doctor nor the surgeon could feel any involvement of

lymph nodes in the neck. For confirmation, Tony underwent a CT scan.

There was no evidence of nodal metastasis. A chest X-ray showed some

emphysema, but no sign of spread to the lungs.

The tongue cancer was defined as Stage II (T2N0M0). However, because

of the tumour’s size and depth of invasion, there was still a 25% chance

of spread to the neck. He was advised to have surgical excision of both

the primary tumour and the lymph nodes at risk in the left neck.

Tony underwent excision of the left side of his anterior tongue. His tongue

was repaired primarily. A total of 45 cervical lymph nodes were removed.

Of these, one proved to contain metastatic cancer. As a result, he also

required post-operative radiation therapy to the mouth and neck.

The treatment for his tongue cancer took almost 3 months. Swallowing

was particularly difficult during the radiation therapy He lost a total of

18 kg in weight. His speech remained surprisingly good. After 1 year, he

continues to gradually recover from his ordeal. His mouth is very dry due

to irradiation involving his salivary glands but some taste has returned and

he has managed to regain some weight. He will remain under surveillance

for head and neck cancer for several years to come.

206

14 Head and Neck Cancers

14.3

Cancer in the Posterior Third of Tongue, Tonsillar Region and Pharynx

These cancers may present as an ulcer, a lump in the throat or tongue or some-

times a constant sore throat that has not responded to conservative treatment

including antibiotics. Sometimes patients will first notice a lump in the side of the

neck that is, in fact, an enlarged, hard lymph node containing metastatic cancer.

Diagnosis may appear to be obvious but must be confirmed by biopsy.

Except for small cancers in this region, most cannot be cured by surgery other

than extensive radical surgery and tissue reconstruction and even then long term

results have all too often been disappointing. Radiotherapy too is likely to cure

only small cancers although it may offer good temporary palliation to people

with large cancers.

Unfortunately, most people with these cancers do not attend a doctor or clinic

until the cancer is advanced and the chances of cure by surgery or radiotherapy

are not good. Most of these patients are heavy smokers and many are alcoholics

EX ERCISE

What are the most significant causes or predisposing features of cancers in

the lips, mouth and throat?

EX ERCISE

Using as examples case reports in this and other chapters of this book,

construct a case report of a typical patient presenting with and being

investigated and managed for a cancer of the floor of mouth.

14.4 Cancers of the Post-Nasal Space (The Air Passage at the Back of the Nose)

207

Fig. 14.7. A SCC of palate and oropharynx

and often do not notice symptoms until the tumours are advanced. In any case,

these cancers are aggressive and tend to grow and invade locally and metastasise

into lymph nodes in one or both sides of the neck at a relatively early stage. There

is a greater than 50% risk of lymph-node involvement.

Although radical surgery will cure some of these patients and radiotherapy

may cure some and offer palliation to the majority, combined treatment using

chemotherapy (preferably given by regional intra-arterial infusion) followed

by radiotherapy with or without surgery, may offer the best prospect of success

(Fig. 14.7).

14.4

Cancers of the Post-Nasal Space

(The Air Passage at the Back of the Nose)

These cancers are most common in adult Chinese people, especially those from the

Quantong province of China, Hong-Kong and Singapore (see Appendix). Sons and

daughters of people from Quantong and Hong-Kong regions also have an increased

incidence of this cancer even though they may have never lived in China.

Blood tests show that this cancer is most common in people who have been

infected with the Epstein-Barr virus. Their blood usually has a high level of

Epstein-Barr virus antibodies. If the Epstein-Barr virus titre is high before treat-

ment and returns to normal after treatment, it does indicate that treatment has

been effective and the patient has probably been cured.

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14 Head and Neck Cancers

4.4.1 Presentation

People with

People with post-nasal space cancer may present with persistent symptoms of a

post-nasal

blocked nose, nasal or post-nasal discharge of mucus, pus or bloodstained mate-

space cancer

rial or, alternatively, they sometimes first notice a lump in the side of the neck.

may present

The lump is due to metastatic cancer in a lymph node. Sometimes lymph nodes

with symptoms

on both sides of the neck are involved.

of a blocked

The cancer may sometimes be seen with a mirror in the back of the throat, but

nose.

diagnosis is made by taking a biopsy from the back of the nose or sometimes by

biopsy of an enlarged lymph node in the neck.

Occasionally the cancer invades bones at the base of the skull or the cranial

nerves that pass from the brain through the base of the skull and into the neck.

Special X-rays (tomograms) or CT scans may be taken to look for evidence of

bone involvement.

14.4.2 Treatment

Cancer in the back of the nose is not accessible to surgery. It is usually treated

by radiotherapy. With small cancers and no lymph node involvement 80% are

cured by radiotherapy. For larger cancers with involved lymph nodes in the

neck, the prospects of cure by radiotherapy alone are not good. The possibility

of improving results by first giving induction (neo-adjuvant) chemotherapy

(usually three courses) by intravenous injections prior to radiotherapy has now

been proven. Such combined integrated chemotherapy and radiotherapy is now

achieving better results in the treatment of advanced cancers even when lymph

nodes are involved (see Sect. 8.3.4.8-8.3.4.9, Treating Cancers).

If bone at the base of the skull is invaded by cancer, the chance of cure by any

means is poor.

14.5

Cancer of the Larynx

Laryngeal

This, too, is a cancer most common in smokers and especially in smokers who

cancer is also

are also heavy drinkers. It is more common in men than women. The most com-

a cancer most

mon site for cancer in the larynx is on a vocal cord. Cancers of the vocal cord

common in

usually cause a hoarseness or change in the voice when they are quite small and

smokers and

are therefore usually diagnosed early. They can be seen and biopsied through a

especially in

laryngoscope and if treated early either by radiotherapy or by surgery (in which

smokers who

the cord is removed), the results of treatment are good. Approximately 90% are

are also heavy

cured either by radiotherapy or by surgery.

drinkers.

If neglected until the cancer has spread from the vocal cord into surrounding

tissues, the chances of cure by simple surgery or radiotherapy are much reduced.

In some cases, partial removal of the larynx can be curative. However for more

14.5 Cancer of the Larynx

209

advanced laryngeal cancers that have spread onto the walls of the larynx or

metastasised into lymph nodes in the neck, or cancers that have recurred after

previous radiotherapy, the best chance of cure is by radical surgery. In radical

surgery the larynx is totally removed, possibly together with removal of all

draining lymph nodes (an operation called a radical laryngectomy).

Cancers in the larynx that develop above or below the vocal cords (supra-

glottic or sub-glottic respectively) are usually more advanced when they are first

diagnosed than cancers on a vocal cord. They also tend to be more aggressive

and for this reason are often treated by combined radiotherapy and laryngectomy.

Treatment using combinations of chemotherapy and/or radiation therapy and/or

surgery are also under study to try to produce better results. By using chemo-

therapy with radiotherapy it seems that equally good long-term results can be

achieved without surgical removal of the larynx.

If laryngectomy is necessary and is expertly performed the chance of cure

is reasonably good but the patient (usually a male) is left with an opening of

his trachea in the lower neck (tracheostomy). Without a larynx he cannot speak

normally but most patients learn a form of oesophageal speech. By this method

they can be taught to swallow air and use regurgitated air from the stomach to

CASE REPORT

Cancer of larynx

Alex is a 67-year-old man who first consulted with his family doctor about

increasing hoarseness of his voice for 3 months.

He was a heavy smoker (20 cigarettes/day for 50 years) but was other-

wise healthy. No enlarged cervical nodes were detected.

Consultation with an ENT surgeon was arranged. A thorough exami-

nation was carried out including examination of the larynx with an en-

doscope.

Under general anaesthetic an endoscopic examination revealed an ir-

regular wart-like lesion on the right vocal cord. Biopsy showed this to be a

squamous carcinoma that appeared to be confined to the right vocal cord.

He was referred for radiotherapy. External beam radiation therapy was

given and 3 months after treatment there was no evidence of residual tu-

mour.

Now 6 months after treatment he has now stopped smoking but has

some minor residual hoarseness of his voice. He will be kept under regular

observation but has been advised that this cancer is unlikely to recur.

210

14 Head and Neck Cancers

make sounds and words. Alternatively, a mechanical vibrator powered by a small

battery can be applied to the throat muscles to make speech that sounds rather

like the artificial voice of a robot or computer.

14.5.1 The Lost Cords Club

The Lost Cords Club is a club of people who have lost their larynx by surgery

and support each other in learning to speak as well as their endeavours to cope

with other social, health and mechanical problems. Like the Colostomy Club (for

patients with a colostomy) and breast cancer support groups, there are branches

in many big cities. The mutual social support offered to members is a great help

for people who have had a laryngectomy and need to re-adjust to their changed

circumstances and learn to live a relatively normal life again.

14.6

Salivary Gland Cancers

The salivary glands are located about the mouth and secrete saliva into the mouth

especially during eating to prepare food for digestion. Most salivary gland cancers

are adenocarcinomas but some that develop in the duct lining are SCCs. There

are three major and many minor salivary glands on each side of the face.

The largest salivary gland is the parotid gland, which is situated partly in front

of and below the ear and behind the jaw. This is the salivary gland in which both

benign and malignant tumours most commonly develop. Cancers in the parotid

gland are usually first noticed as a lump just in front of or below the ear. As the

cancer grows it commonly invades and destroys the facial nerve passing through

it, causing facial nerve palsy. Facial nerve palsy causes weakness of the muscles

of that side of the face resulting in inability to close the eye or to properly move

the corner of the mouth. There may be obvious loss of facial expression due to

paralysis of the muscles on that side of the face. These cancers usually develop in

middle-aged or older adults. They enlarge locally and tend to spread to local lymph

nodes in front of the ear and in the upper part of the neck. Occasionally cancers

develop from a pre-existing benign tumour in the parotid gland (a pleomorphic

adenoma or mixed parotid tumour) that may have been present for years.

Treatment of cancers of the parotid gland is usually by surgical resection.

With small cancers it may be possible to save the facial nerve but with larger

cancers it is likely that the facial nerve will be involved and will need to be sacri-

ficed. If lymph nodes are enlarged they are usually removed in the same block of

tissue with the parotid gland. Post-operative radiotherapy is often given because

of the risk of local recurrence of these cancers.

14.6 Salivary Gland Cancers

211

Cancers in the second largest salivary gland, the sub-mandibular gland under

the jaw, and the third major salivary gland, the sublingual gland in the floor of

the mouth under the tongue, are less common. However when present they tend

to spread early to lymph nodes and are best treated by surgical excision of the

whole of the gland together with any likely involved lymph nodes.

Salivary gland tumours occasionally occur in minor salivary glands either in the

tongue, in the cheeks, lips or elsewhere. Wide surgical excision is required for treat-

ment otherwise the chances of local recurrence are high. If there is any doubt that the

cancer has been totally removed, post-operative radiotherapy is usually given.

The use of chemotherapy in the treatment of salivary gland cancers is not yet

established. It has been used with limited success in the treatment of cancers

that have recurred after surgery. The use of induction (or neo-adjuvant) chemo-

therapy prior to surgical excision of salivary gland tumours is under investiga-

tion. This is one site where preoperative induction chemotherapy can be more

concentrated given by infusion into the external carotid artery but although some

success has been experienced as yet it is uncertain whether results will be consis-

tently improved by this combined, integrated technique (Fig. 14.8–14.10).

Fig. 14.8. Photograph showing

a large pleomorphic adenoma

(benign mixed parotid tumour) of

a parotid gland of an elderly man

14.7 Cancers of the Thyroid Gland

213

14.7

Cancers of the Thyroid Gland

The thyroid gland lies across the lower part of the neck with one lobe on either

side of the trachea on the lower part of the larynx. The thyroid gland uses iodine

to make the hormone thyroxine, which is essential for basic metabolism.

4.7.1 Causes and Presentation

Cancer of the thyroid gland is usually first noticed as a single lump in the gland.

Cancer of the

The lump is most often just to one or other side of the midline in the lower anterior

thyroid gland

part of the neck but cancer may occasionally develop as one lump that enlarges and

is usually first

becomes more obvious and harder in a multinodular goitre. Lumps in the thyroid

noticed as a

move up and down when the patient swallows due to movement of the tongue that

single lump

elevates the hyoid bone and the larynx, to which the thyroid gland is attached.

in the gland.

General enlargement of the thyroid gland is called a goitre, and multiple cysts

and other lumps may develop in some goitres. This process is usually due to a

shortage of iodine in the food. A lumpy goitre is known as a multinodular goitre.

CASE REPORT

Cancer of parotid gland

Akira, a 63-year-old retired Japanese businessman, first presented to his

doctor with a 3-month history of a lump just in front of his left ear. He

thought the lump had been slowly increasing in size.

The doctor found a 3 cm subcutaneous lump anterior to the left ear but

no other lumps or other abnormality was detected. Facial nerve function

was normal. The doctor referred Akira to a Head and Neck Surgeon who

performed a needle biopsy of the lump.

Biopsy showed the lump to be a pleomorphic adenoma (mixed parotid

tumour).

Parotidectomy was performed with care to preserve the facial nerve.

Final pathology examination showed the presence of an area of malignant

cells in the tumour.

Although apparently completely excised the tumour margin had been

close to the facial nerve. In order to reduce the risk of recurrence, post-

operative external radiation therapy was given.

Twelve months after treatment there is no evidence of residual disease.

He remains well, his facial nerve function is normal and his voice is nor-

mal but he still has dryness in his mouth.

Akira has been advised that his prognosis is good but it is still impor-

tant for him to be kept under regular observation.

214

14 Head and Neck Cancers

Occasionally one of the lumps in a multinodular goitre will become malignant

and develop into a cancer although more often when a cancer develops in the

thyroid gland it begins as a single lump in an otherwise apparently normal thyroid

gland. Most thyroid cancers, especially those that occur in young people, are

generally characterised by slow growth with a relatively good long-term outlook

compared to other cancers.

4.7.2 Accidental Irradiation

Increased numbers of people with thyroid cancer have been one of the most

serious long-term consequences of atomic irradiation as seen in survivors of

Hiroshima and Nagasaki atomic bombs and again after the Chernobyl atomic

energy plant disaster.

14.7.3 Investigations

An isotope scan is a useful investigation for thyroid cancer. In this procedure a

scan of the thyroid is taken after injection of a very small dose of radioactive

iodine into a vein (as described in Sect. 7.3.8). The cancer will usually show as

a “cold nodule”, that is, part of the thyroid gland that is replaced by cancer, does

not concentrate the iodine and appears non-functional and clear on the scan. Most

cold nodules are benign cysts or benign adenomas but about 10% of solitary cold

nodules are cancer. However as cysts and some other lumps also show up as “cold

nodules”, to make a diagnosis the lump should be biopsied. This is usually done

by needle aspiration of fluid or cells from the lump. Alternatively the diagnosis

is more certain if the lump is surgically excised and examined microscopically.

Frozen section examination (described in Sect. 7.6.5) may then allow the surgeon

to proceed with further surgery if the lump proves to be a cancer. Occasionally a

“hot nodule”, that is a functioning thyroid lump, may be found to be a cancer.

14.7.4 Types of Thyroid Cancer

There are four broad types of thyroid cancer.

4.7.5 Papillary Cancer

Papillary carcinoma constitutes about 60% of thyroid cancers and is three times

more common in women than men. It is more common in young adults, occa-

sionally in teenagers or even children but fortunately it is the least malignant

of thyroid cancers.

Papillary cancer may be present in different parts of the thyroid gland at the same

time and may spread to nearby draining lymph nodes, but usually does not spread

14.7 Cancers of the Thyroid Gland

215

further until very late in the disease. For this reason, removal of the whole of the

thyroid gland together with any enlarged lymph nodes will usually cure the patient.

After total removal of the thyroid gland the patient thereafter must take thyroid or

thyroxine tablets by mouth because thyroxine is essential for normal body function.

4.7.6 Follicular Cancer

The second most common type of thyroid cancer more commonly affects adults

of middle age and is called follicular carcinoma. It too, usually presents as a

lump in the thyroid gland and is usually not diagnosed with certainty until the

lump has been removed surgically and examined microscopically.

These cancers tend to be present in one lobe of the thyroid gland only and have

a greater tendency to spread by the bloodstream to bone, lungs or liver rather

than by lymphatics to lymph nodes. These cancers often more closely resemble

normal thyroid tissue than do the other thyroid cancers and although they usu-

ally appear as “cold nodules” in radio-iodine scans, they may sometimes scan as

normal thyroid tissue or even rarely as hyperactive “hot nodules”.

Because of their tendency to involve one lobe of the thyroid gland only they

are usually treated by removal of the involved half of the thyroid gland, leaving

the other half to carry out normal thyroid function and production of thyroxine.

Metastases may be treated by surgical excision (if in lymph nodes) by radio-

therapy or by radio-active iodine being injected intravenously so that it becomes

concentrated in thyroid tissue where it irradiates and destroys cells, including the

cancer cells wherever they are. Again thyroxine tablets must be taken thereafter

to maintain normal endocrine body function. Chemotherapy is also sometimes

effective in the treatment of metastases.

14.7.7 Medullary Cancer

This type of thyroid cancer arises from the calcitonin-producing cells in the

thyroid gland. It may be familial and it may be associated with other endocrine

disturbances or with an adrenal gland tumour called pheochromocytoma. Calci-

tonin levels can be elevated with this cancer and will fall to normal if treatment

has been successful. Total removal of the thyroid gland usually results in cure.

14.7.8 Anaplastic Cancer

The fourth broad type of thyroid cancer is anaplastic cancer. This is the most danger-

ous form of thyroid cancer and is usually rapidly growing. It is fortunate that it is also

the least common. It tends to affect older people and may grow rapidly presenting

as an enlarging lump or enlarging swelling of the whole of the thyroid gland. It may

press on the trachea and make breathing difficult. This cancer is virtually incurable

by surgery and is best palliated by radiotherapy or sometimes by chemotherapy.

216

14 Head and Neck Cancers

14.7.9 Other Types

The thyroid gland is occasionally the site of other primary malignant tumours

such as lymphoma, sarcoma or even secondary cancers from a primary cancer

elsewhere, but these are uncommon.

CASE REPORT

Metastatic thyroid cancer

James was a 43-year-old schoolteacher when he first consulted his family

doctor about a lump in his right upper neck that he had first noticed 6

months ago. His doctor did not find any other significant abnormality so

James was referred to a Head and Neck Surgeon.

A needle biopsy showed the lesion to be metastatic papillary cancer of

the thyroid in a lymph node.

James had previously been well with no history of thyroid disease and

no other palpable lumps or nodes were detected but a thyroid ultrasound

showed the presence of multiple small nodules throughout both lobes of

the thyroid gland. The largest nodules were one measuring 17 mm in the

right lobe and one measuring 15 mm in the left lobe.

When his larynx was examined his vocal cords were symmetric with

normal mobility.

James was advised that although he had a thyroid cancer and that a

lymph node was involved most such cancers were eminently curable by

surgery. Total thyroidectomy (surgical resection of his thyroid both lobes

and isthmus) together with all nearby lymph nodes in the right side of his

neck was advised and carried out without any complication. James made

an uneventful recovery.

A total of 23 lymph nodes were found in the resected tissue but no other

nodes were found to contain cancer. Pathology examination of the thyroid

gland showed it to contain multi-focal papillary thyroid cancer within the

right lobe.

James was commenced on thyroid hormone replacement therapy (thy-

roxin by mouth) and was advised that he would need to take thyroxin for

the rest of his life.

After 3 months James is well and has returned to his school-teaching

profession. He will be kept under regular observation but a long-term cure

is expected.

Cancers of Female Genital Organs

In this chapter you will learn about:

› Cancers of the uterus

› Cancer of the ovary

› Cancer of the vagina

› Cancer of the vulva

15.1

Cancers of the Uterus

There are two distinct types of cancer of the uterus. Squamous cell carcinoma

(SCC) of the cervix or opening of the uterus is the more common. The other

type is an endometrial or glandular cancer (adenocarcinoma) of the lining of

the cavity of the uterus (the body of the uterus).

15.2

Cancer of the Cervix

15.2.1 Presentation and Risk Factors

Cervical cancer can occur in any woman especially over the age of 40 but there

An annual

are particular risk factors in some groups of women, for example it is more

routine cervical

common in smokers and erosions and inflammation of the cervix are predispos-

smear test

ing factors Infection with a sexually transmitted virus, the human papilloma

(the Pap test)

virus (HPV), has become a very significant factor. The HPV, being sexually

will usually

transmitted, is more common in women who have had multiple sexual partners,

detect these

particularly if sexual activity started early in life. Prostitutes are at particular

cancers early

risk. Cervical cancer is significantly more common in women in lower socio-

and at a very

economic groups and in recent years has been seen to be one of the cancers that

curable stage.

more commonly develops in women with HIV infection or AIDS.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_15, © Springer-Verlag Berlin Heidelberg 2009

217

218 1

5 Cancers of Female Genital Organs

The earliest changes associated with this cancer are most often present in

women between the ages of 30 and 40. Usually at this age there are no symptoms

but there may be a little blood staining from the vagina between periods, espe-

cially after intercourse, or there may be a watery discharge.

Cancers of the cervix tend to develop slowly but can usually be detected by

routine cervical screening examination (the Papanicolaou or cervical smear test

described in Sect. 7.2.1) in which abnormal (dysplastic) or frankly malignant

cells may be found. An annual routine cervical smear test (the Pap test) will usu-

ally detect these cancers early and at a very curable stage.

5.2.2 Investigations

Sometimes the cancers cannot be seen on visual examination of the cervix but

at other times a cancer may be seen as a reddish, eroded ulcerated or possibly

bleeding lesion. Modern colposcopes are now often used to better visualise the

inner lining of the cervix and uterus. In any case a biopsy is taken for pathological

examination to confirm the diagnosis.

15.2.3 Treatment

Very small early cancers may be treated by surgical removal of the lining of the

cervix only, especially in women who wish to have more babies. Larger invasive

cancers are best treated by removal of the uterus (total hysterectomy). Cancers

that have begun to spread from the cervix onto the adjacent vagina present more

of a problem. They often respond well when initially treated with a combina-

tion of chemotherapy/radiotherapy given together as concomitant treatment and

sometimes followed by hysterectomy.

If cancer of the cervix has not been diagnosed until it is quite advanced, there

is a risk of metastatic spread to lymph nodes, especially lymph nodes in the

pelvis. This situation is more likely in women of more than 40 years of age who

have not had regular Pap tests. These women often complain of some bleeding

and discharge between menstrual periods or after intercourse. If an advanced,

ulcerating or fungating cancer is present it should be obvious on examination of

the cervix. Surrounding tissues such as the ureters or the rectum may become

involved as well as the local draining lymph nodes in the pelvis. CT scans will

help detect the extent of the cancer. Such advanced cancers are usually treated by

radical surgery or by radiotherapy or both or by radiotherapy and chemotherapy

concomitantly followed by radical surgery.

Early use of chemotherapy alone was disappointing with this cancer. It has

been given as induction treatment both systemically and by regional infusion as

part of an integrated treatment program and although early results were disap-

pointing studies have been continued in some centres using different treatment

schedules in different combinations with more encouraging results. However

15.2 Cancer of the Cervix

219

programs of chemotherapy (using the anti-cancer agent cisplatin) and radiother-

apy, given together as concomitant treatment, have given best results in several

studies. Chemotherapy is also sometimes given as palliative treatment for wide-

spread cancer but substantial prolonged benefit is not common.

5.2.4 Prevention

In recent years the association of the HPV with cancer of the cervix has been

more intensely investigated with a view to introducing more effective preventive

measures. Types 16 and 18 of this virus are considered to be the most pathogenic

and attempts at developing a vaccine against the virus are more than encourag-

ing. A successful preventive vaccination trial in a large study group has recently

been reported. National vaccination programmes are now being established in

several countries to 12-13-year-old girls.

CASE REPORT

Cervical cancer

When she first presented Dianne was 46 years of age and had previously been

in good health. She was married with three children. She had not had regular

Pap smears, the last possibly some 5 years previously. On presentation she

had recently experienced some menstrual cycle irregularity and post-coital

bleeding. Her general practitioner initially treated her with progesterone

agents to control what was thought to be dysfunctional bleeding.

She returned some 3 weeks later with reduced but ongoing irregular

bleeding. She was then referred to a gynaecologist who on vaginal pelvic

examination confirmed an obvious malignant growth involving her cervix.

A biopsy in the clinic confirmed an invasive SCC.

Dianne was then referred to a specialist gynaecological oncologist.

An examination under anaesthesia (EUA) was arranged, meanwhile an

abdominal and pelvic CT scan confirmed a large cervical lesion measuring

5 cm in diameter without obvious extension and no radiological evidence

of involvement of lymph nodes. The EUA, which included a cystoscopy,

sigmoidoscopy, vaginal speculum examination and bimanual recto-vaginal

pelvic examination, confirmed a large “barrel-shaped” cervical tumour

approximately 5 cm in diameter without para-metrial or vaginal exten-

sion. She was then staged (officially according to the international system)

as a stage 1b2 cervical cancer, meaning a large locally invasive cancer but

apparently limited to the cervix).

(continued)

220 1

5 Cancers of Female Genital Organs

(continued)

At the post-operative consultation, the gynaecological oncologist discussed

with Dianne and her husband the options for management. The first option was

for an abdominal radical hysterectomy and pelvic lymph node dissection.

Advantages of such an approach is the removal of the tumour and a formal assess-

ment of the pelvic lymph nodes rather than relying on radiological evidence of

apparent disease spread. Disadvantages of such an approach is that the majority

of patients with large barrel shaped tumours have pelvic lymph node metasta-

ses and the majority of patients also then need to undergo additional treatment

comprising concurrent chemo-irradiation treatment. The second and largely

favoured option was to treat with definitive chemo-irradiation therapy and avoid

surgery. Advantages of such an approach would be an identical survival rate but

significantly reduced morbidity, as surgery has not been undertaken.

Dianne considered her options and opted for the latter approach. She un-

derwent 6 weeks of external pelvic irradiation therapy with weekly chemo-

therapy (using low dose cisplatin). Towards the end of her external beam treat-

ment she was given additional treatment by internal or brachytherapy.

Now 3 years post treatment Dianne remains well without clinical evidence

of disease. She has undergone menopause, probably related to the effects of

therapy on her ovaries. Her only ongoing morbidity is narrowing of the vagina

requiring regular vaginal dilator treatment.

EXERCISE

Consider the reasons why there has been an increased incidence of cancer

of the cervix over the latter part of the twentieth century and why this

pattern is now likely to be reversed.

15.3 Cancer of the Body of the Uterus (Endometrial Cancer)

221

15.3

Cancer of the Body of the Uterus (Endometrial Cancer)

5.3.1 Presentation

These cancers are most commonly seen in older women. It is believed that change

in female sex hormones, and especially an imbalance of hormones, may contri-

bute to development of this cancer, which is becoming rather more common,

because more women are living longer. It is now recognised that endometrial

cancer is sometimes associated with long-term post-menopausal oestrogen therapy

or long-term use of tamoxifen to treat or prevent of breast cancer.

The most common feature of endometrial cancer is bleeding and bloodstained

discharge after the menopause but sometimes a watery discharge is the only

feature.

15.3.2 Investigations

The uterus is usually enlarged and, to establish a diagnosis, curettage is performed.

The scrapings from the curette are sent for pathology examination.

5.3.3 Treatment

Treatment of cancer of the body of the uterus is usually by radical surgery.

The surgeon performs a total hysterectomy as well as removal of ovaries,

fallopian tubes and removal of draining lymph nodes. For advanced cancers,

radiotherapy is sometimes given before or after hysterectomy.

Like most cancers, treatment at an early stage can achieve good results but for

more advanced cancers, results of treatment are often disappointing.

If endometrial cancer has spread to other tissues or organs it will often respond to

hormone treatment (for example large-dose progesterone therapy) but a long-term

cure is unlikely. Studies are being made of combined integrated treatment using

intra-arterial chemotherapy first as “induction” treatment followed by radiotherapy

and/or surgery (see Sects. 8.3.4.8-8.3.4.9). Chemotherapy and radiotherapy are

sometimes given concomitantly as induction treatment. Whether these programs

of treatment will achieve significantly better results is as yet uncertain.

222 1

5 Cancers of Female Genital Organs

CASE REPORT

Corpus cancer

On presentation Lynne was a 63-year-old obese woman with multiple medi-

cal complaints. She had been constantly in attendance at her general prac-

titioner’s surgery with various complaints. Apart from her obesity, she was

also diabetic and hypertensive. She had undergone menopause at age 51 and

although she had subsequently been on combined oestrogen replacement

therapy for 5 years, she was not on any hormonal treatment when she pre-

sented. Lynne had experienced 2-3 episodes of bright vaginal spotting over

the preceding 3 months. Her general practitioner performed a speculum and

vaginal pelvic examination and a Pap test. The cervix appeared normal and

the Pap test was subsequently also reported as normal. A trans-abdominal

and trans-vaginal ultrasound was arranged confirming a bulky uterus and

an endometrial lesion measuring 13-mm in thickness. She was referred to

a gynaecologist and subsequently underwent a hysteroscopy and dilation

and curettage (D&C). A fundal polypoid tumour was seen at hysteroscopy

and curettage confirmed a carcinoma (classified as grade 2 endometrioid

adenocarcinoma).

Lynne was referred to a specialist gynaecological oncologist. Manage-

ment options were discussed with Lynne and her husband including radiation

therapy and surgery. As the survival of patients treated with pelvic irradiation

is inferior to those treated with definitive surgery, the latter was chosen as the

preferable treatment option. Through a vertical midline incision an abdominal

hysterectomy and bila-teral salpingo-oophorectomy was performed. There

was no apparent extra-uterine spread. As frozen section histology confirmed

evidence of myometrial invasion a pelvic lymph node dissection was then

performed to define the extent of disease.

Lynne recovered from surgery without major morbidity. There was no

evidence of lymph node invasion in any of the 22 pelvic nodes examined.

Likewise pelvic cytology was negative for malignant cells and no malig-

nancy was found in an omental biopsy. Lynne was not given further treat-

ment as her disease had been confirmed surgically to be confined to the

uterus.

Her post treatment surveillance comprised regular attendances to her

gynaecological oncologist, pelvic examination, and vaginal vaults smears. Now

5 years post treatment Lynne remains without clinical evidence of disease.

15.5 Cancer of the Ovary

223

5.4

Choriocarcinoma

Although a choriocarcinoma starts and grows in the uterus, it is strictly not a

This is one of

cancer of the uterus. A choriocarcinoma is best considered as a cancer of an

the success

abnormal pregnancy.

stories of

After conception, very occasionally an abnormal growth of tissue devel-

chemotherapy.

ops instead of a normal foetus and placenta. If the foetus does not develop and

the placenta grows as a group of cyst-like structures something like a bunch of

grapes, this is called a hydatidiform mole.

Sometimes cells of an hydatidiform mole develop into an invasive cancer

called a choriocarcinoma. Occasionally choriocarcinoma will develop in associa-

tion with a foetus, usually an abnormal foetus, which is aborted spontaneously,

or rarely even with an otherwise normal pregnancy. However, most in fact are

in association with a hydatidiform mole with no foetus, usually in women over

40 years of age.

In the past, choriocarcinoma spread widely and rapidly through the mother’s

body and was a fatal form of cancer. Nowadays the condition is treated by empty-

ing the uterus of its contents, (curettage), and giving cytotoxic chemotherapeutic

drugs. This is one of the success stories of chemotherapy as choriocarcinoma has

been changed from a cancer approaching 100% fatality 30 or 35 years ago to a

cancer that is curable in 80% or more cases with modern chemotherapy.

15.5

Cancer of the Ovary

The ovaries are the source of a greater variety of tumours, both benign and

The ovaries are

malignant, than any other body organ. This is probably because of the multicel-

the source of a

lular and changing nature of the ovaries, as organs with a function of undergo-

greater variety

ing monthly cyclic changes to prepare one of the eggs (ova) in the ovaries for

of tumours,

potential development into new tissues, i.e. a foetus. Not only does the ovary

both benign

produce a variety of tumours ranging from benign (the majority) to low-grade

and malignant,

malignancy and to highly malignant cancers, they may also produce tumours that

than any other

excrete hormones that may affect body development and function. Some ovarian

body organ.

cancers are germ-cell cancers not unlike some cancers of the testis.

Cancers of the ovary may be solid or cystic or they may contain a mixture of

solid and cystic elements. They tend to cause no symptoms early in their develop-

ment and so they are often advanced when first diagnosed.

There is no known cause of ovarian cancers but there are some genetic asso-

ciations. The BRCA1 and BRCA2 tumour suppressor genes are known risk factors

and there is sometimes a strong family history of ovarian cancer (see Sect. 2.4).

These same genes are more commonly recognised as risk factors in premeno-

pausal breast cancer and there is an increased risk of women who have had a

breast cancer before menopause to later develop ovarian cancer.

224 1

5 Cancers of Female Genital Organs

5.5.1 Presentation

Cancers of the

Cancers of the ovary develop insidiously. They usually cause a gradually increasing

ovary develop

swelling in the pelvis and lower abdomen. The swelling may have been noticed by

insidiously.

the patient or may be found on examination by a doctor who may sometimes find

a symptomless pelvic mass during a general examination. They may sometimes

cause a “heavy feeling” or local discomfort or pain. Some produce hormones, in

which case the first evidence may be due to hormonal changes such as premature

menopause and the woman may notice loss of feminine features and the develop-

ment of male characteristics such as growth of hair on the face or deepening of

the voice. Sometimes too, generalised abdominal swelling may be noticed due

either to a huge tumour or to fluid in the abdominal cavity (ascites).

Any rapidly enlarging swelling on an ovary, especially if it is solid or contains

a mixture of cystic and solid elements, must be regarded with suspicion as likely

to be malignant.

5.5.2 Investigations

Examination of the pelvis and pelvic structures by abdominal, vaginal or rectal

examination without anaesthetic may not be adequate and EUA may be required.

Abdominal X-rays or CT scans may help but ultrasound examination is the

least harmful examination, especially in young women, and is often the most

helpful because cystic changes in the ovary and cystic tumours are best detected

by ultrasound.

Laparoscopy or culdoscopy (Sects. 7.4.12-7.4.13) may allow the surgeon or

gynaecologist to see the contents of the pelvis, especially the ovaries.

A tumour marker, CA125, can be useful in assessing not only the presence

of cancer but response to treatment and risk of recurrence after treatment. Simi-

larly germ-cell tumours, like germ-cell tumours of the testis, usually produce the

tumour markers alpha-foeto-protein (AFT), human chorionic hormone (HCG)

and lactate dehydrogenase (LDH). Measuring the levels of these may give a good

indication of the presence of this cancer and its response to treatment.

Usually a diagnosis of cancer cannot be established with certainty until an

operation (laparoscopy or laparotomy) has been carried out and a biopsy speci-

men of any suspicious lesion has been examined microscopically.

15.5.3 Treatment

The best treatment of ovarian cancer, especially if not advanced, is by total

surgical removal of the ovaries and fallopian tubes. Because the other ovary

and other pelvic organs may also be the site of cancer, it is usual to remove both

ovaries as well as the uterus and tubes and any other involved tissue. However

in a young woman with early and localised ovarian cancer, sometimes one ovary

can be spared. The operation is sometimes followed by radiotherapy to the pelvis

15.5 Cancer of the Ovary

225

or chemotherapy. If the cancer is advanced chemotherapy and radiotherapy

may be used together with good effect. Even if the cancer cannot be removed,

results are better if the tumour is “debulked”, that is, as much of the cancer as

possible is removed. The patient is often then treated by radiotherapy. Adjuvant

chemotherapy after surgical removal also improves survival rates.

Chemotherapy is often effective in controlling widespread metastases for a

worthwhile period (possibly some years) but long-term cure is unlikely.

Combinations of local chemotherapy (intra-arterial infusion and/or intra-

peritoneal) with radiotherapy and/or surgery, are presently under study in some

special clinics but it is not yet certain whether these techniques of integrated

treatment will achieve significantly better results with safety.

Studies are also being carried out on the use of pre-operative chemotherapy

given as induction treatment to reduce locally advanced cancers. The surgery

that follows is then hopefully more likely to be curative but even if it is not cura-

tive “debulking” the cancer mass by removing most of the residual cancer does

improve the patient’s quality of life for a longer period. In some clinics, where

appropriate and facilities are available, pre-operative induction chemotherapy

is given by intra-arterial infusion with a greater concentration and apparently

greater local tumour impact. To date results have been encouraging but long-

term results of clinical trials are awaited with interest (see Chap. 8).

5.5.4 Prevention

Because cancers sometimes develop from benign tumours of the ovary it is usu-

ally advisable to remove both ovaries in treating any woman over 40 years for a

benign ovarian tumour. In some women whose families have strong associations

with breast and/or ovarian cancer or women known to have BRCA1 or BRCA2

genes, oophorectomy should be considered as an effective cancer prevention

measure. Also, gynaecologists often advise removal of ovaries as a preventive

measure when they perform hysterectomy in women over 40.

A slightly lower incidence of ovarian cancer in women who use modern oral

contraceptives has been reported.

15.5.5 Metastatic Cancer of the Ovary

The ovaries are commonly a site of secondary metastatic cancer from a primary

The ovaries

cancer elsewhere. Advanced cancer of the breast, stomach, bowel and melanoma

are commonly

frequently metastasise to ovaries. Sometimes a cancer of the ovary that appears

a site of

to be a primary ovarian cancer has come from an unknown and symptomless

secondary

primary cancer in another organ or tissue. When stomach cancer was much

metastatic

more common that it is today, it was not uncommon to find an apparently pri-

cancer from a

mary cancer of the ovary was composed of gastric cancer cells and was in fact

primary cancer

a secondary gastric cancer. This was first described by a Dr Krukenberg and

elsewhere.

became known as a Krukenberg tumour.

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5 Cancers of Female Genital Organs

CASE REPORT

Oarian cancer

Mary was a 63 year-old woman who had been unwell for 3 months when she

noticed increasing non-specific gastrointestinal upsets and abdominal swelling.

While her complaints were initially attributed to a minor gastrointestinal

upset, she returned to her GP with progression of symptoms. On physical

examination shifting dullness confirmed clinical ascites. A CT scan of the

abdomen and pelvis confirmed a large complex pelvic mass, gross ascites

and thickening in the omentum, consistent with an ovarian cancer.

She was referred directly to a specialist gynaecological oncologist.

(A CA125 tumour marker test was ordered and noted to be grossly elevated

at 1,200 U/mL; the normal being < 35 U/mL). A pelvic examination con-

firmed a large fixed pelvic mass.

The options for management discussed with Mary were for initial in-

duction (neoadjuvant) chemotherapy for three cycles to assess the chemo-

sensitivity of the tumour followed by debulking or cytoreductive surgery.

This would be followed by another three cycles of chemotherapy. The sec-

ond and more commonly employed management of patients with suspected

ovarian cancer was for initial surgery, again to confirm the diagnosis,

secondly to debulk or remove as much tumour load as possible and then

follow this with six cycles of combination chemotherapy.

Mary subsequently underwent exploratory surgery via a midline abdo-

minal incision. Three litres of clear ascites fluid was drained. Operative

findings included a large pelvic mass arising from the left ovary and

involving the recto-sigmoid colon. There was also a large omental tumour

mass, (sometimes referred to as “cake”), replacing both the infra and

supra-colic omentum. Successful tumour de-bulking was accomplished

but this required resection of the pelvic mass en bloc including the uterus

and recto-sigmoid. A primary end-to-end anastomosis was performed to

restore functional integrity of the bowel.

Final pathology confirmed a high-grade serous ovarian cancer.

Mary completed six cycles of combination chemotherapy (comprising

Carboplatin and Taxol) and was in clinical, biochemical and radiological

remission for 22 months. At one of her surveillance visits her CA125 level,

which had become normal with treatment, was again rising from a baseline

of 20-120 U/mL. She remained asymptomatic and no disease was initially

seen on CT scanning but she was given Tamoxifen for 3 months. However

a PET scan 3 months later confirmed widespread recurrence of cancer. Her

CA125 level had risen to 400 U/mL and she was now developing further

non-specific gastrointestinal symptoms.

(continued)

15.4 Cancer of the Ovary

227

(continued)

She was again treated with chemotherapy but despite having initial

improvement in her symptoms and her CA125 level, she suffered another fur-

ther relapse some 9 months later and was commenced on second line palliative

chemotherapy. Further response was not achieved despite receiving a number

of other chemotherapy agents. Lynne died of disease causing further bowel

obstruction 42 months after her initial surgery.

C AS E R E P O R T

Oarian cancer

A 55-year-old woman was admitted to hospital with abdominal pain and

vomiting. She had surgery 10 years previously for a right ovarian cyst. She

was the mother of one child and had been menopausal for 5 years. Since

menopause she had been taking hormone replacement therapy.

Her family history included breast cancers in her mother and a maternal

aunt and a colon cancer in her father. Rapidly, Investigations were imme-

diately arranged, including abdominal CT scan and tumour marker tests.

The CT scans showed a right ovarian tumour with ascites and enlarged

retroperitoneal lymph nodes. Tumour markers were CEA (carcinoembri-

onic antigen) with a high level of 50 ng/mL and most significantly a CA125

of 1,200 U/mL.

A laparotomy was carried out both to establish a diagnosis and to remove

as much of the tumour as possible. This is called “de-bulking surgery”. It

included removal of both ovaries and fallopian tubes, the uterus and most

of the omentum, as well as pelvic lymph nodes.

The tumour was an undifferentiated adenocarcinoma of the ovary, with

bilateral ovarian, peritoneal and lymph nodes involvement. Cancer cells

were also in the ascitic fluid.

After surgery, the CA125 level fell to 500 U/mL and the CEA to 20 ng/mL.

Adjuvant chemotherapy has been shown to improve survival rates with

metastatic ovarian cancer so the oncologist arranged six cycles of a taxane-

based chemotherapy. After completing the six cycles of chemotherapy a

CT-scan showed no evidence of a residual cancer and the tumour markers

were normal. No further surgery was performed but the patient was kept

under regular surveillance.

Less than 2 years later, the patient faced an increasing swelling in the

pelvis and lower abdomen and the diagnosis of local recurrent disease was

(continued)

228 1

5 Cancers of Female Genital Organs

(continued)

made (ascites and peritoneal carcinomatosis). Another combination of cyto-

toxic agents was administered over 6 months without success. Abdominal

pain and discomfort developed so that a program palliative care commenced

first by her oncologist and subsequently by a specialist palliative care team.

Much needed symptomatic, physical, psychological and emotional support

and care were achieved until the patient’s final death.

As the history of breast cancer in her family and her personal ovarian cancer,

the oncologist proposed to investigate the status of the patient’s daughter for

genetic mutations in BRCA1 and BRCA2 genes was advised as a possible

preventive measure. Some women with mutations in these genes elect to have

a double mastectomy to prevent risk of cancer.

EXERCISE

Consider why cancers of the ovary are of so many and varied types

and why cancers of the ovary are so often not diagnosed

until the later stages of the disease.

Metastatic cancers in an ovary are best treated by removal of the ovaries if

there is no apparent cancer anywhere else, otherwise the treatment will depend

upon the best treatment for the type of cancer concerned wherever else it may be

and from where it originated.

15.6 Cancer of the Vagina

The vagina is occasionally the site of a cancer. Most are squamous cell cancers

in middle aged or older women. However some cases of adenocarcinomas of the

vagina have been reported in adolescent girls and young women. Some of these

have been associated with stilboestrol which was once given to their mothers, in

the early stages of the mother’s pregnancy, to prevent spontaneous abortion.

15.7 Cancer of the Vulva

229

Cancers of the vagina usually present as bleeding and discharge. Pain on passing

urine and pain with intercourse (dyspareunia) are often features that most trouble

the patients.

Most small cancers can be cured by surgical excision but larger cancers are

treated with radiotherapy with about a 50% cure rate. Care must be taken to treat

groin lymph nodes if they show evidence of involvement either at the time of

treatment of the primary cancer or in the follow-up period.

15.7 Cancer of the Vulva

Like cancer of the anus, cancer of the vulva is a rare but rather aggressive form

Cancer of the

of skin cancer usually of the squamous cell type. Most occur in women of

vulva is often

post-menopausal age. Cancer of the vulva is often preceded by a long history

preceded by

of irritation, discomfort or inflammation of the vulva and possibly with a local

a long history

bloodstained discharge. There may be a pre-malignant condition of leukopla-

of irritation,

kia or a chronic rash. Previous infection with the sexually transmitted HPV is

discomfort or

responsible for some cases.

inflammation

In the more advanced stages there may be an ulcer, a lump or a cauliflower-

of the vulva.

like growth. Metastatic spread to lymph nodes in one or both groins is likely in

about half of the patients at the time of diagnosis.

Diagnosis is established by biopsy and treatment is usually by wide and radical

surgical excision, and most patients are cured. Pre-malignant papillomas or a

localised patch of leukoplakia are best treated by surgical excision as a cancer

preventive measure.

For very advanced cases, radiotherapy offers palliative relief but integrated

treatment using chemotherapy and radiotherapy or intra-arterial induction che-

motherapy followed by radiotherapy and/or surgery, are presently under study in

specialised centres. As yet it is not established whether better long-term results

will be achieved by these techniques.

Cancers of the Male Genital Organs

In this chapter you will learn about:

› Cancer of the penis

› Cancer of the testis

› Cancer of the prostate gland

16.1

Cancer of the Penis

Penile cancer is uncommon, particularly in Western societies. It is almost unknown

in Jewish males who are circumcised soon after birth but is a little more common

in Muslim males who are circumcised at about 10 or 12 years. Most that are seen

are in uncircumcised men. Lack of genital hygiene and cleanliness may be a factor

or sometimes this cancer is associated with the sexually transmitted human papil-

loma virus.

It is essentially a squamous cell cancer similar to the common skin cancers

but somewhat more aggressive. It tends to spread rather more readily to draining

lymph nodes in the groins than is usual for other squamous cancers of skin.

Most cases are first seen when a small crusty, papillomatous or small ulcer-

ated skin lesion is present and these can usually be well treated by surgical

removal of the lesion, keeping a close watch on draining groin lymph nodes

thereafter. Occasionally very advanced cases are seen, usually in men living in

remote places or undeveloped communities. These usually respond well to induc-

tion chemotherapy especially if given by intra-arterial infusion. Involved lymph

nodes should be surgically resected. A series of quite spectacular responses of

very advanced cancers on the penis have been reported from Taiwan using intra-

arterial infusion chemotherapy, followed by surgery or radiotherapy. A high inci-

dence of cure was reported.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_16, © Springer-Verlag Berlin Heidelberg 2009

231

232

16 Cancers of the Male Genital Organs

16.2

Cancer of the Testis

Testicular tumours are not common but when they do occur they are almost

always malignant. Most occur in young adult males between the ages of 18

and 40. They are almost all classified as “germ cell” tumours. Germ cells are

embryonic type cells capable of developing into different cell types. Germ cell

cancers are uncommon, but they occur most often in a testis. Occasionally they

occur in midline structures like the mediastinum or retro-peritoneum or pineal

gland usually in children or young adults. Some cancers of the ovary are also

germ cell cancers.

There are no known causes of testicular cancer. They are more common in

developed than developing countries but the reason for this is not known. They

are distinctly more likely to occur in undescended testes. Cryptorchidism is a

condition in which the testes have not descended from the abdomen, where they

develop, into the scrotum where they should be present at birth. If one or

both testes are not present in the scrotum of infant boys, they are retained in the

abdomen or the inguinal canal or somewhere nearby. Surgical operation (orchi-

dopexy) should be performed before the age of 8 or 10 to place the testes into their

normal position. This will reduce the risk of development of testicular cancer

sometime later in life, after puberty. It is postulated that the warmer temperature

of the testes in the abdomen may be responsible for the increased risk of testicular

cancer in undescended testes.

Similarly there is an increased risk in men with Klinefelter’s syndrome. This

is an abnormal genetic condition in which rather than having XX or XY sex

chromosomes, the affected individuals have three chromosomes, XXY. This

gives some female characteristics in otherwise apparently tall, thin underdevel-

oped males with small underdeveloped testes that are more prone to malignant

change.

6.2.1 Presentation

Cancer of the

Cancer of the testis is usually found as a painless and non-tender swelling of a

testis is usually

testis although occasionally the swelling is tender and possibly painful. Occa-

found as a

sionally no swelling is noticed in the testis until there is evidence of metastatic

painless and

spread of a cancer. Metastases may be noticed as a mass of enlarged and some-

non-tender

times tender lymph nodes in the abdomen, enlarged lymph nodes in the neck,

swelling of

usually the left side known as Virchow’s nodes (Sect. 5.4) or as metastases in

a testis.

lungs seen in chest X-rays. Occasionally the first evidence of a testicular cancer

may be swelling of a man’s breasts due to hormonal changes. In other patients

the first evidence may be of general debility, anorexia (loss of appetite) and

weight loss.

16.2 Cancer of the Testis

233

6.2.2 Investigations

If a swelling is detected in a testis, ultrasound of the testis will help confirm if

a solid tumour is present. If found it is almost always a cancer. In such cases

investigations are carried out to look for evidence of metastatic spread. CT scans

and excretory urograms (IVP X-rays described in Sect. 7.3.2) and these may be

helpful in detecting any enlarged lymph nodes in the abdomen. Chest X-rays

may help detect metastases in lungs or in lymph nodes in the chest (mediastinal

lymph nodes).

An operation is recommended to confirm the diagnosis and allow the testis to

be examined and removed if a tumour is clearly present.

6.2.3 Pathology

There are two broad types of testicular cancer, of about equal incidence, seminomas

A number

and non-seminomas most of which are teratomas. Seminomas tend to occur in

of tumour

slightly older age groups (mean 35 years) and are very sensitive to radiotherapy.

markers in

Non-seminomas, or non-seminoma germ cell tumours (NSGCT), often contain a

the blood will

mixture of histologies including embryonal, yolk sac, choriocarcinoma, teratomas

help detect

and seminomas. They are most often in younger age groups (mean 25 years) and

and classify

are less sensitive to radiotherapy but are highly responsive to chemotherapy.

testicular

A number of tumour markers in the blood will help detect and classify testicu-

cancers.

lar cancers and so indicate most appropriate treatment and help assess response

to treatment. Alpha-feto-protein (AFP), human chorionic gonadotropin (HCG)

and lactate dehydrogenase (LDH) can all be useful testicular cancer markers. If

the level of a tumour marker is elevated, it helps establish a diagnosis of tumour

type and if the level falls to normal after treatment it indicates a good response

to treatment and probably a cure.

16.2.4 Treatment

Cancer of a testis is treated by surgical removal of the testis (through an inguinal

approach) and radiotherapy is given to draining lymph nodes in the abdomen

or to any other lymph nodes likely to be involved, especially if seminoma was

diagnosed.

In the case of teratoma even if the cancer is widespread into the lungs or

elsewhere, good results, with a high proportion of long-term cures, are achieved

with chemotherapy.

From being among the cancers with a poor prognosis a few years ago, with present-

day integrated and combined treatment programs using surgery, radiotherapy and

chemotherapy, testicular cancers are now among the most curable cancers.

Patients should be advised that it is still possible to lead a normal sex life and

to father children with only one testis.

234

16 Cancers of the Male Genital Organs

EX ERCISE

Drawing on case reports in this chapter and other chapters of this book,

construct a case report of a typical patient presenting with and being

investigated and managed for a testicular cancer.

16.3

Cancer of the Prostate Gland

Cancer of the prostate is uncommon before the age of 45 but in Western countries,

other than skin cancer, it is the most common cancer in men over the age of 65

and became increasingly common during the twentieth century, especially in

the latter part of the twentieth century.

This rapid rise in recorded incidence is due in part to the use of the prostate

specific antigens (PSA) test for detecting early subclinical prostate cancers or

“latent” prostate cancers that might not have otherwise progressed to a clinical

stage. The rise in apparent incidence of prostate cancer after the common use of

PSA as a screening test is somewhat similar the increased numbers of early breast

cancers in the 1980s and 1990s after common use of mammography as a screen-

ing test. However the PSA test is much less specific for prostate cancer, a raised

index simply indicates increased prostate cell activity that may be due to benign

prostate disease, latent prostate cancer or established prostate cancer. Evidence

suggests that early breast cancers are unlikely to remain “latent” for any length of

time but “latent” prostate cancer may well remain non-invasive indefinitely.

Almost all

The cause of prostate cancer is largely unknown but its association with old

men over the

age is illustrated by the fact that in Western countries almost all men over the age

age of 90 have

of 90 have microscopic evidence of at least early prostate cancer.

microscopic

There is a familial association of prostate cancer especially in younger men

evidence of

(below 55 years) and some of these are linked to mutations of the BRCA2 gene

at least early

(see Sects. 2.4 and 2.5). The increased familial association is greater if male rela-

prostate cancer.

tives have had prostate cancer but there is also some increase in families with a

high incidence in men on the mothers’ side of the family.

There is also an increased risk in men with a history of prostatitis.

Prostate cancer is now the second most common cancer in males in Western

countries, after skin cancers, and it is second only to lung cancer as a cause of

cancer death in men. In stark contrast epidemiological studies show that Asians,

16.3 Cancer of the Prostate Gland

235

Africans and native-Americans living in their traditional lifestyles have a low

incidence of prostate cancer (see Appendix and Table 1).

The highest incidence is in black males in the USA followed by white males

in the USA, Europe, and other Western countries. The lowest incidence of pros-

tate cancer is in men in India and South East Asia and also in black males living

in Africa. Men of Asian or African ethnicity who have lived all their lives in

Western Countries have a high risk, and in Afro-Americans an even higher risk,

than in white males of those countries. This suggests that causes are more closely

related to environmental factors rather than racial or genetic factors. It is likely

that differences in diet may play a part because prostate cancer is less common

in communities that have predominantly vegetarian diets.

Recent studies have indicated that diets with a high content of legumes, such

as soybeans, may be protective and it could be that the high content of phytoe-

strogens is at least partly responsible. Results of studies of the possible preventive

or clinical use of lycopene are similarly being awaited with considerable interest.

Laboratory studies with lycopene indicate that its apparent anti-cancer protec-

tive activity is synergistically enhanced if used together with beta-carotenes or

vitamin D (Sects. 2.8, 2.13 and 3.5.1). Each of these alone has been shown to have

some cancer protective activity but used together the total anti-cancer activity is

greater than the sum of the activity of each used alone. Whether a similar sym-

biotic activity might result from phytoestrogens used with lycopene is presently

under study.

There have also been reports of a protective factor in tea, possibly by virtue

of anti-oxidants in tea, but this is as yet unconfirmed. Other anti-oxidants that

may have some protective effect are selenium, and vitamin E as well as lycopene,

possibly by interfering with the pathway towards cellular mutation. It has also

been reported that men taking Statins (used for lowering blood cholesterol) have

been incidentally found to have a reduced incidence of aggressive metastasis-

ing prostate cancers. Fish and fish oils in diet also give some protection against

prostate cancer.

Oboesity with lack of exercise and a high animal fat intake are increased risk

factors.

6.3.1 Presentation

The most common presentation of prostate cancer is frequency, hesitancy and

other difficulties in passing urine. Non-malignant enlargement of the prostate

(prostate hyperplasia) is very common in late middle-aged and older men and is

most often the cause of urinary difficulty, but prostate cancer is also a common

cause of this trouble, especially in older men.

Occasionally the first evidence of cancer of the prostate is due to metasta-

ses either in bone (causing bone pain or fractures) or in the liver (causing liver

enlargement). Metastases in the lower vertebral column or pelvis may cause

pressure on a sciatic nerve before it passes into the leg, but causing severe pain

236

16 Cancers of the Male Genital Organs

in the back and leg called sciatica. Sciatica is sometimes the first evidence

of prostate cancer but more often there is another physical cause such as a

“slipped vertebral disc”.

16.3.2 Investigations

The prostate gland can be felt by an examining finger in the rectum. This is

called a digital rectal examination (DRE). With a gloved finger passed through

the anus into the rectum the prostate gland can be felt in front of the finger.

Cancer in the prostate usually feels like a hard lump or lumps in the prostate

or sometimes the whole of the prostate gland may feel hard and rigid. A biopsy

may be taken with a needle passed via the anus through the anterior rectal wall

or it may also be taken with a needle passed through the skin in front of the

anus and guided by a finger in the rectum.

Ultrasound is now used with special equipment that is passed through the

anus into the rectum. Ultrasound will show any lumps in the prostate and any

general prostate enlargement. Biopsies are usually now best taken with a special

punch or needle during ultrasound examination to discover whether any of the

lumps are cancer.

X-rays will be taken for evidence of metastatic spread into bones. These may

show as dark eroded areas in bone or as sclerotic (dense white) areas in the bone if,

as is often the case, they contain calcium. Chest X-rays may show metastases in the

lungs, in lymph nodes in the chest, or even in the ribs. Isotope bone scans are also

valuable in showing evidence of bone metastases (Sect. 7.3.8) (Fig. 16.1).

Blood studies may show anaemia if bone metastases have developed and are

destroying the blood-forming cells in bone marrow. Cancer of the prostate may

also cause an elevation of a serum enzyme, acid phosphatase, and, if bone is

destroyed by metastatic cancer, an enzyme released from the bone called alkaline

phosphatase may also be elevated.

Obstruction by the cancer to the flow of urine may result in infection in the

bladder and possibly in the kidneys. The urine and blood are examined for

evidence of infection in urine or damage to the kidneys.

16.3.3 Screening Tests: The PSA (Prostate-Specific Antigens) and the DRE

(Digital Rectal Examination)

Nowhere in the

In recent years the PSA blood test has been developed which indicates whether

field of cancer

there is likely to be an abnormality in the prostate. PSA is a special tumour

treatment is

marker that is now commonly used as a screening test in men over the age of

there more

55 to help find those with early prostate cancer that might be effectively

controversy and

treated. A raised PSA does not necessarily indicate cancer is present but it may

confusion than

indicate the need for further investigations, possibly including ultrasound study

is the case with

and biopsies. However DRE is a very helpful prostate cancer detection test that

prostate cancer.

16.3 Cancer of the Prostate Gland

237

MALE PELVIS

SHOWING POSITION OF THE PROSTATE GLAND

WITH A CANCER IN ITS POSTERIOR ASPECT

RECTUM

BLADDER

SACRUM

PUBIC BONE

(end of backbone)

COCCYX

(tail bone)

URETHRA

(urine passage)

PENIS

CANCER

ANUS

PROSTATE

SCROTUM

Fig. 16.1. Diagram showing a common site for cancer in the prostate gland

can be easily and safely carried out in a doctor’s rooms. If a prostate is found to

be hard or lumpy then biopsies should be taken to determine whether a cancer is

responsible. A raised PSA must certainly indicate the need for a DRE if a DRE has

not already been carried out. If the PSA is significantly raised and a DRE indicates

a hard or lumpy prostate, the chance of prostate cancer is high.

16.3.4 Controversies in Management of Men with Prostate Cancer

Nowhere in the field of cancer treatment is there more controversy and confusion

than is the case with prostate cancer.

Some bias is inevitable in trying to compare survival statistics in men with

prostate cancer. Elective screening will usually detect this cancer before it becomes

symptomatic. It is therefore inevitable that men with prostate cancer detected before

it is symptomatic will generally live longer than men whose cancer was causing

symptoms before being detected. This is called “lead-time bias”.

Similarly more slowly developing cancers are more likely to be detected at an

earlier phase by routine screening than rapidly growing cancers so giving a bias

so that post treatment survival time will be biased in favour of those detected by

PSA screening. This is called “length-time bias”.

Another inbuilt bias in comparing treatments is known as “selection bias”.

Radical surgery will not proceed if a patient is found to have extensive cancer

whereas radiotherapy is more likely to have been given to a proportion of patients

238

16 Cancers of the Male Genital Organs

who already have extensive cancer. Thus these potentials for inbuilt bias make it

difficult to compare management protocols.

However the PSA screening test has led to investigation and diagnosis of

prostate cancer in increasing numbers of middle aged and elderly males. Yet

even if a biopsy diagnosis of cancer is confirmed it is estimated that only about

one in four or five prostate cancers will grow in a malignant fashion to become

life threatening by spreading to tissues beyond the prostate during the patient’s

otherwise expected lifespan. There is as yet no way of determining those cancers

that are likely to spread. Most prostate cancers are slow growing and even after

some years may show no evidence of spread beyond the prostate, but some will

spread to such places as lungs, liver and especially to bones where they are likely

to form painful metastases and lead to the death of the patient. Appropriate treat-

ment of early cancers will cure most patients but all treatments have serious side

effects and it is not possible at this stage to determine which patients will benefit

from treatment and who might be better left untreated. A PSA found to be rapidly

rising is more likely to be associated with metastasising prostate cancer.

A most common and distressing side effect of treatment is erectile dysfunc-

tion causing impotence. This occurs in the majority of patients whether treated

by surgical removal of the whole prostate gland or by radiotherapy. Other side

effects can be prolonged incontinence or occasional stress incontinence, espe-

cially after radical surgery, or some damage to the bladder or rectum after

radiotherapy. Irradiation damage to bladder or rectum can leave the man with

long-term urinary scalding or frequency or with precipitous diarrhoea. When

hormones are used to treat metastases, either by giving feminising hormones or

anti-male hormones or by castration or a combination of treatments, loss of libido

and impotence are also usual (see Sect. 8.4.1).

Whether or not to use the PSA or any other attempt at screening for prostate

cancer in asymptomatic men in the age group most at risk remains controversial.

If cancer is detected, especially a small area of “latent” or “in situ” cancer, it

is often impossible to know whether the cancer is likely to cause the man any

significant problem during his otherwise expected lifespan. Thus it is a matter

of controversy as to whether anxieties should be raised about a cancer being

detected that may never cause him any serious trouble. Yet if left undetected or

untreated one in four or five will advance to an incurable stage likely to cause a

painful and miserable death but for some, who opt for treatment (and its inevi-

table side effects), life expectancy will not have changed.

Whether to treat or not to treat will depend on many factors. These will

include whether there is evidence of progressive disease (e.g. rising PSA or

enlarging cancer or increasing biopsy changes), the family history, the family

circumstances and social circumstances of the patient, the age and general health

of the patient, his otherwise life expectancy, and especially his personal priori-

ties in life. For example. he may not think life would be worth living if he were

impotent or alternatively sexual activity may no longer be of any interest to him

but he has a lot of other interests in life. It should always be explained to these

men that in most cases there is now effective treatment for impotence be it with

16.3 Cancer of the Prostate Gland

239

prostaglandin penile injections, Viagra or similar medications, a special vacuum

pump device to engorge the penis or other techniques.

One of the greatest needs in medical research is a test to determine whether

low-grade prostate cancer cells detected by biopsy are likely to become aggres-

sive. The pathologist can help in this by indicating the relative aggressiveness and

local invasion of cancer cells in the prostate by estimating a “Gleason score”. The

Gleason score, ranges from 1 to 10; Gleason 1, being very early evidence of local

(in situ) malignant cells, and Gleason 10 indicating highly anaplastic invasive

cancer likely to have spread beyond the prostate.

16.3.5 Treatments

Although at present controversial and uncertain as to whether treatment should

be recommended, the following are standard treatments that should be consid-

ered and discussed between a patient and his medical advisers.

For small cancers apparently confined to the prostate, total surgical removal

of the prostate gland, possibly with removal of adjacent lymph nodes, should

result in cure. Radical prostatectomy (total removal of the prostate gland and

adjacent lymph nodes) is most-often performed by an open surgical operation

but like several other abdominal operations it can now be performed by a robot

assisted laproscopic technique.

Alternatively, obstruction to the flow of urine may be relieved by a TUR (trans-

urethral resection) in which an instrument (resectoscope) is passed into the urethra

through the penis and some of the enlarged prostate is cut away to relieve obstruction.

Specimens of the resected tissue are sent for microscopic examination to look for the

presence of cancer.

Cancer of the prostate will respond to radiotherapy that is often used to

treat both the primary prostate cancer and a limited number of painful meta-

static deposits in bone. In suitable patients local external radiotherapy and/or

brachytherapy with radioactive “seeds” implanted into the prostate and the can-

cer, can now give results virtually matching results of radical surgery (Sect. 8.3.3).

Although there are still risks of similar side effects, they are less likely than after

radical prostatectomy. More locally advanced cancers are often better treated

by radiotherapy as the field of irradiation can extend beyond the local prostate

region. Sometimes after radical surgery for locally advanced cancer, when there

is doubt as to whether all the cancer-involved tissues were removed, follow-up

radiotherapy is also recommended.

High Intensity Focused Ultrasound (HIFU) is a more recently studied treatment

for some cancers not extending outside the prostate gland. From different sources

high-energy ultrasound waves are directed into the prostate tissue by means of a

rectal probe. The whole prostate tissue is destroyed by the heat created, leaving a

small remnant of scarred remnant. Advantages of this treatment are that it can be

repeated and it is less likely to cause troublesome side-effects. However more studies

are needed before the most appropriate use of this treatment will be known.

240

16 Cancers of the Male Genital Organs

When American doctors, Charles Huggins and Clarence Hodges, discov-

ered that prostate cancers would often respond to stilboestrol, stilboestrol then

became standard treatment for prostate cancer. Most patients had some benefit

with symptom relief and some increased life expectancy but not a cure in the long

term. Stilboestrol is no longer the preferred hormone therapy but other forms of

hormone therapy are now used.

Prostate cancer is androgen (testosterone) dependent; that is, without any

androgen the cancer cells will not grow although eventually some aggressive

prostate cancers will continue to grow in the absence of androgens. Most but not

all androgen in men comes from the testes but the testes can produce testosterone

only if they are stimulated by gonadotrophic hormone. One way of reducing the

growth of prostate cancer therefore is by castration - a treatment not at all popu-

lar with most men. Another way of reducing the effects of androgen is to use an

anti-hormone, either an anti-testosterone or an anti-gonadotrophin.

The modern alternatives to stilboestrol, Lutenising Hormone Releasing

Hormone (LH-RH) analogues have long been used in treatment for advanced

prostate cancer when cure by surgery or radiotherapy has not been possible. More

recently anti-androgens have been used but (LH-RH agonists) are now becoming

more commonly used because they are equally effective and less likely to have

troublesome side effects. With stilboestrol and some other agents, some patients

reported feeling nauseated, many developed some enlargement and tenderness

of the breasts and there was an increased risk of deep-vein thrombosis. Desire

for sexual activity was reduced and there may have been complete impotence.

With modern hormone treatments these side effects are still often a problem but

less common and less severe. Eventually aggressive prostate cancers will become

androgen resistant and will grow in the absence of androgens.

There have been few studies of the use of cytotoxic chemotherapy in treat-

ment of prostate cancer. In general, early cancers can be well treated by opera-

tion, slightly bigger localised cancers are often well treated by radiotherapy, and

metastatic cancer usually responds well, possibly for some years, to hormone

treatment. Radiotherapy can be given to a limited number of bone secondaries.

Prostate cancers are slowly growing so that palliative chemotherapy, with all its

side effects (more toxic than hormone therapy), is usually not advised, as first

treatment in these older age group men.

Prostate cancer will respond to treatment with some cytotoxic agents but

these are generally used only in patients whose cancer no longer responds to

hormones. Hormones are usually more reliable, more effective and less toxic

than cytotoxic agents in treating prostate cancer. Studies are now being made,

especially in Germany, to determine whether better results can be expected from

using regional cytotoxic chemotherapy before surgery in treating patients with

locally advanced prostate cancers or whether regional chemotherapy used before

radiotherapy might make the operation unnecessary in some patients. In the past

most clinicians found responses to cytotoxic chemotherapy to be disappoint-

ing no matter how it was given but an anti-cancer agent called Mitoxantrone

gave encouraging responses, especially with relief of symptoms but no convinc-

16.3 Cancer of the Prostate Gland

241

ing evidence of improved survival. A newer anti-cancer agent called Docetaxel

(Taxotare) given at 3 weekly intervals is now giving even better symptomatic

relief with some improvement in long-term survival for those men with hormone

refractory prostate cancer.

16.3.6 Treatment of Bone Metastases

If bone scans show “hot spots” of metastatic prostate cancer in bones that are

painless, a decision must be made as to whether or not treatment is needed. For

an elderly man with small painless lesions it may be better not to treat actively

but to keep under observation in case they change. If a large bone metastasis

is seen, especially in a weight-bearing bone that could easily fracture, local

radiotherapy might be advisable.

In most men with bone metastases who are not already having treatment, a

program of hormone treatment is usually recommended.

For men having bone pain that has not been well controlled by standard

treatment with hormones and/or local radiotherapy and/or standard pain-relief

measures, treatment with bisphosphonates or strontium-89 will often give

good pain relief. There is also evidence that these treatments might sometimes

help prevent further bone metastases from developing (Sects. 8.6.2 and 12.11)

(Fig. 16.2).

Fig. 16.2. Widespread

metastatic prostate

carcinoma in bones

of pelvis, vertebrae

and ribs

242

16 Cancers of the Male Genital Organs

EX ERCISE

Why is there controversy about most appropriate management of men

with prostate cancer?

CASE REPORT

Prostate cancer

Karl is a 76-year-old businessman who, at the age of 69, when he had a

routine health check, was found to have a PSA of 6.1 ng/mL. At the time

he had been well and was a keen golfer. With a digito-rectal-examination

(DRE) his doctor felt a slightly enlarged prostate but no other abnormality.

Concerned about the raised PSA, the family doctor arranged a consulta-

tion with a specialist urologist.

The urologist did not feel anything abnormal except that as well as

being slightly enlarged the prostate gland was a little harder than normal.

No lumps were felt. The urologist arranged ultrasound studies of the pros-

tate. No lumps were seen but three biopsies were taken from each side of

the prostate gland. The biopsies were all negative for cancer.

One year later the tests were all repeated. The PSA had risen to 8.3 and

ultrasound revealed a small nodular area in the right lobe of the prostate

gland. Biopsy of this showed a small collection of low-grade malignant

cells (Gleason 1) in one of the three right lobe specimens.

The urologist explained to Karl that the few positive cells might repre-

sent low-grade “latent” cancer that may or may not progress into a serious

cancer problem during his lifetime. The urologist explained that any sur-

gical or other “curative” procedure would risk complications (especially

erectile dysfunction with impotence and possibly some incontinence) and

may not change his life expectancy. After discussion between Karl and

the urologist it was decided to repeat all tests in 4 months.

(continued)

16.3 Cancer of the Prostate Gland

243

(continued)

In 4 months the PSA had risen to 9.3 and biopsies showed positive

cancer cells in two specimens with a slightly higher-grade in one speci-

men (Gleason 4).

Karl was otherwise still fit and well with an otherwise good life expec-

tancy. In view of the apparent progress of the disease, which still appeared to

be contained within the prostate gland and therefore was eminently resect-

able, Karl and his wife decided that they would accept the option of radical

prostatectomy with all the risks rather than further “wait and see”.

The operation was performed without a major problem and the surgeon

tried to preserve the erectile nerve on the left side. There was no evidence

of lymph-node involvement. Six weeks after discharge Karl’s urinary

function was good, except for occasional stress incontinence, but he was

unable to achieve an erection in spite of his urge to have intercourse.

The options of management of erectile dysfunction were discussed be-

tween Karl, his wife, the family doctor and the urologist. For some months

the tablet Viagra was used but not always with reliable success so that penile

injection of prostaglandins has since been used with reliable success.

Karl is now alive and well 6 years postoperatively and plays golf regu-

larly. Since operation his PSA has been less than 0.1. Apart from needing

help to achieve an erection, and occasionally a little stress incontinence of

urine, he has no significant health problem.

Comment

Karl has heard that improvements in radiotherapy and especially

brachytherapy with radioactive implants into the prostate gland, if avail-

able, may have been a preferred treatment option with equally good

long-term results and fewer side-effects, especially with erectile dysfunc-

tion. The urologist explained that this may be so with presently available

radiotherapy facilities but when he was first treated there was no proof

that his long-term cure would be the same. As more cases of early, limited

prostate cancer have been treated by brachytherapy it does appear that in

suitable patients long-term results can match results of surgery with the

advantage of less fewer side-effects.

Cancers of Bladder and Kidneys

In this chapter you will learn about:

› Bladder cancer

› Kidney cancers

› Wilm’s tumour (nephroblastoma)

› Adenocarcinoma (Grawitz tumour or hypernephroma)

› Carcinoma of the renal pelvis or ureter

17.1

Bladder Cancer

Many years ago bladder cancer was found to be increased in industrial workers

who were exposed to aniline dyes and certain other chemical compounds. It has

since been found to be more common in smokers and in people who abuse the

use of analgesics. Cancer may also develop in a papilloma, a small benign fern-

like or cauliflower-like tumour of the bladder. Some patients have several small

papillomas in the lining of the bladder wall and any one of these can change to

become a cancer if not treated. In some countries, including Egypt and some

other North African countries, infestation with the fluke parasite, Schistosoma

or Bilharzia, is common. If these flukes infest the bladder they can cause inflam-

mation and erosions of the mucosa and penetrate into the bladder wall. In those

countries this is a well-recognised cause of bladder cancer.

Most bladder cancers develop in the transitional cells that line the bladder

cavity. They are about twice as common in males as in females and in both sexes

are more common in developed than developing countries. They most commonly

present in men between 50 and 70 years. The most common symptom of bladder

cancer is blood in the urine (haematuria). The blood may be intermittent at first

but becomes more constant as the tumour grows and invades the bladder wall.

At a later stage there may be discomfort in passing urine (dysuria) and symptoms

of bladder infection (cystitis) such as frequency, burning and pain when passing

urine. Sometimes a ureter may become obstructed by the growth and pain may

be felt in the loin due to backpressure on the kidney.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_17, © Springer-Verlag Berlin Heidelberg 2009

245

246

17 Cancers of Bladder and Kidneys

After losing blood in the urine for some time, anaemia may develop and

symptoms of anaemia (pallor, tiredness, palpitations, etc.) may be noticed.

17.1.1 Investigations

The urine is examined for blood and may also be centrifuged and examined for

cancer cells. Excretory urograms, (IVP X-rays as described in Sect. 7.4) may

show a filling defect or lump in the bladder. They may also show evidence of

obstruction to a ureter if present.

CT scans may reveal a lump in the bladder wall but the ultimate investigation

is with a cystoscope. The cystoscope (described in Sect. 7.4) is passed into the

bladder through the urethra usually under general anaesthesia, and the inside of

the bladder is examined. A section of any suspected cancer together with a small

piece of adjacent bladder wall is taken as a biopsy for microscopic examination.

17.1.2 Types of Bladder Cancer (Pathology)

There are

There are various degrees of bladder tumours ranging from a single benign

various degrees

cauliflower-like papilloma to an invasive ulcerated thickened cancer. Between

of bladder

these extremes there may be several papillomata, one or more of which may

tumours

show signs of early malignancy, or there may be a malignant lump or malignant

ranging from a

ulcer in the bladder wall. Superficial non-penetrating bladder cancers tend to

single benign

remain confined to the bladder-wall for a long time before they spread but more

cauliflower-like

penetrating bladder cancers often metastasise at an early stage. After a time,

papilloma to

bladder cancers may involve the whole thickness of the bladder-wall and even

an invasive

invade the rectum or other organs nearby. Penetrating cancers often spread to

ulcerated

nearby lymph nodes but they do not commonly metastasise more widely.

thickened

cancer.

17.1.3 Treatment

Small papillomata of the bladder are usually treated by burning them off with

an electro-cautery. The electro-cautery instrument is used through a cystoscope.

The patient is cystoscoped regularly thereafter in case the tumour recurs.

For larger papillomas or early invasive cancers, treatment by radiotherapy

or surgical excision or a combination of both radiotherapy and surgical excision

may offer good prospects of cure.

Early non-invasive bladder cancer will often respond to Bacillus Camille

Guerin (BCG) irrigation. BCG is a harmless bacterium that seems to stimulate

an immune healing response. This treatment is repeated at intervals as necessary

to control the cancer. However if the cancer becomes invasive surgical resection

or radiotherapy will be needed.

17.2 Kidney Cancers

247

For more advanced cancers, surgery to remove the whole of the bladder (cys-

tectomy), may be necessary. A new type of bladder is then usually surgically

constructed from a part of the bowel.

When cure by surgery is impossible, palliative radiotherapy may give relief.

Chemotherapy has a limited place in the treatment of bladder cancer, although

studies are being carried out in the hope of improving prospects of cure or worth-

while palliation with the use of newer agents and newer techniques of giving che-

motherapy. Systemic chemotherapy is used with some benefit in treating bladder

cancer if it does become widespread or metastatic.

17.2 Kidney Cancers

Kidney cancers are not common but there are three well recognised types. The

Wilm’s tumour (nephroblastoma) occurs in infants or young children. In adults

kidney cancers are either adenocarcinoma (sometimes called hypernephroma or

Grawitz tumour), or carcinoma of renal pelvis (usually squamous or transitional

cell type).

7.2.1 Wilm’s Tumour (Nephroblastoma)

The Wilm’s tumour usually is found in children of less than 4 years. It can even

The Wilm’s

be present at birth. Whilst in most cases only one kidney is affected, occasionally

tumour usually

there is a cancer in both kidneys.

is found in

This cancer is most commonly found as a lump in the loin of an infant. It may

children of less

present by causing the child to be in poor general health with a fever, anaemia,

than 4 years.

or sometimes blood is seen in the urine. It may spread to nearby lymph nodes or

It can even

into the large veins. From these veins cancer cells may be carried by the blood to

be present

the lungs where metastases may develop.

at birth.

17.2.2 Adenocarcinoma (Hypernephroma or Grawitz Tumour)

This is the most common type of kidney cancer and is usually seen in adults

The first

of middle age or older. It is about twice as common in men than women and is

symptom

more common in smokers of either sex. The first symptom is usually passing

is usually

blood in the urine, most often painlessly. (Passing blood in the urine with severe

passing blood

pain in the loin is more likely to be caused by a kidney stone.) There may be

in the urine,

a fever or a lump may be felt in the loin or sometimes there is local pain. This

most often

cancer may spread into nearby lymph nodes but commonly grows into the large

painlessly.

renal vein and may spread by the bloodstream into the lungs, liver or bones.

Occasionally the first evidence of this cancer is the presence of metastases in a

lung or in one or more bones.

248

17 Cancers of Bladder and Kidneys

17.2.3 Carcinoma of the Renal Pelvis Or Ureter (Transitional Cell Carcinoma)

This cancer is rather like cancer of the bladder and behaves in a similar way.

The first sign of this cancer is also usually blood in the urine. Smoking and

analgesic abuse are commonly associated with development of these cancers.

They also sometimes develop as a reaction from a stone present in the kidney

for a long time.

17.2.4 Investigations

X-rays of the abdomen may show an enlarged kidney. Excretory urograms

(intra-venous pyelograms or IVP), CT scans, ultrasound, and arteriography

(as described in Sect. 7.3) are all useful investigations to help diagnose a tumour

in a kidney and to help determine whether a kidney lump is solid and likely to

be cancer, or a fluid-filled cyst and probably benign.

Other investigations include examination of the urine for blood or malignant

cells and X-rays of lungs for evidence of metastatic cancer, or bone scans or

X-rays to show evidence of metastases if there are any swelling or painful areas

in bones.

17.2.5 Treatment

Cancer of a kidney is best treated by an operation to remove the kidney (nephre-

ctomy). For Wilm’s tumour (nephroblastoma) in children, results are much better

if radiotherapy and chemotherapy are used in combination with nephrectomy.

For adenocarcinoma nephrectomy is the only likely cure for a patient. Radio-

therapy and chemotherapy may be used as palliative treatment in advanced cases

but results other than by complete surgical removal have been disappointing.

Sometimes these cancers will show a temporary response to male or female hor-

mones and some studies have reported responses in patients with metastases

treated with the immunological agents interferon or interleukin 2. Adenocarci-

noma of a kidney is one cancer that sometimes spreads to a lung as one single

metastatic lump, resembling a “cannon ball”, and this can sometimes be cured by

an operation removing the part of the lung containing the lump.

For cancer of the renal pelvis, the best results are achieved if the kidney is

removed together with the whole of the ureter and a small part of the bladder

because seedlings of this cancer sometimes grow in the ureter between the

kidney and the bladder.

17.2 Kidney Cancers

249

CASE REPORT

Wilms’ tumour

Andrew is a 4-year-old boy who was brought to the Emergency Room of

the Children’s Hospital after his parents noticed he was passing heavily

blood-stained urine. On examination in the Emergency Room, he looked

well, with normal male genitalia, and no evidence of penile ulceration or

excoriation. A firm non-tender mass was palpable below the liver on the

right side of his abdomen. His blood pressure was 140/90. A specimen

of urine was frankly blood-stained.

An abdominal ultrasound revealed a right-sided renal mass consistent

with a right-sided renal tumour. Examination of the inferior vena cava by

ultrasound revealed a patent vessel with no evidence of tumour thrombus

in the cava. CT scan of chest, abdomen and pelvis revealed no evidence of

metastatic disease and no other abnormalities.

A needle biopsy of the renal tumour was performed under general

anaesthesia guided by image intensification in the Medical Imaging

department. Histopathology confirmed a Wilms’ tumour (nephroblastoma),

with the histology being of the usual (“favourable”) type. No evidence of

anaplasia was seen. A central venous catheter was inserted in the operat-

ing theatre under a separate general anaesthetic. A low dose of an oral

anti-hypertensive agent was administered for a few weeks after diagnosis

to control the hypertension.

Andrew received 7 weeks of outpatient chemotherapy (using vincris-

tine, and actinomycin-D and doxorubicin). This was associated with in-

termittent fever, episodes of abdominal discomfort, and constipation, and

mild inflammation of the oral mucous membranes and temporary mild

bone marrow depression following each of two pulses of actinomycin-D

and doxorubicin. The renal mass was noted to be somewhat smaller by

the seventh week.

Eight weeks after diagnosis, Andrew underwent a right radical nephrec-

tomy, from which he recovered uneventfully. Histopathologic examination

of the excised kidney indicated a significant degree of tumour cell destruction

from the initial chemotherapy and no visible spread of the tumour beyond

the renal capsule. He is currently continuing adjuvant chemotherapy (with

vincristine, actinomycin-D and doxorubicin), which will be continued

for 12 months. Blood pressure fell to normal levels immediately after

the nephrectomy.

(continued)

250

17 Cancers of Bladder and Kidneys

(continued)

Andrew has an excellent prognosis. The definitive surgery is typically

delayed a few weeks after diagnosis to allow shrinkage of the tumour to

occur with the initial induction chemotherapy, to lessen the likelihood of

intraoperative haemorrhage, facilitate early ligation of the renal vein, and

improve the safety of the procedure.

Around 90% of children with localised Wilms’ tumour with the usual

histology will be cured permanently using this combination of induction

chemotherapy, surgery and adjuvant chemotherapy.

Comment

Survival historically with surgery alone was no better than 20%. Radia-

tion therapy to the renal fossa and rear of abdomen is reserved for those

patients where regional spread has occurred at diagnosis, and where loca-

lised residual disease is considered likely after nephrectomy. Preservation

of unaffected kidney tissue in the diseased organ may be attempted in

patients whose tumour is confined to one or other poles of the affected

kidney.

Cancers of the Brain and Nervous System

In this chapter you will learn about:

› Brain cancers

› Clinial features

› General features

› Focal features

› Investigations

› Treatment

› Secondary cancers in the brain

› Nerve cell cancers

18.1

Brain Cancers

Although most brain cancers occur in people over the age of 45, with a peak

incidence between 60 and 70 years, in fact the brain is also one of the more

common sites for primary cancer in children and young adults. Brain cancers

are more common in developed than developing countries (see Appendix), but

the reason for this is not known.

There are two groups of cells in the brain that may form tumours. The glial

cells (true brain cells) from which most of the malignant tumours develop, and

the non-glial cells or supporting cells (such as cells of the meninges or cells of the

nerve sheaths) from which develop the majority of benign tumours.

Cancers that arise from true brain cells or glial cells are called gliomas.

There are a number of different types of gliomas ranging from the more slowly

growing types called astrocytoma or oligodendroglioma to more rapidly and

highly malignant types called medulloblastoma (usually in children) or glio-

blastoma multiforme (more often in adults). These different types of glioma

tend to occur in different parts of the brain in children and adults. They also

have other differences for example medulloblastomas are usually highly radio-

sensitive and are sometimes cured by radiotherapy but other types are less

radiosensitive (if at all).

There are no known causes of cerebral tumours. The commonly held belief

that electromagnetic fields, (including the use of mobile telephones), may play

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18 Cancers of the Brain and Nervous System

a part has not as yet been substantiated with statistical evidence. However the

possibility remains and anecdotal evidence justifies further study.

18.1.1 Clinical Features (Symptoms and Signs)

Brain cancers tend to cause two types of clinical features:

(a) General features due to generalised pressure on the brain

(b) Focal or local features due to pressure or interference by the tumour on

parts of the brain or nerves near the tumour.

18.1.1.1 General Features

The common general features of cancer in the brain are due to pressure and

swelling on the brain as a whole. This causes headache, nausea, vomiting and

disturbances of vision due to swelling of the optic nerve at the back of the eye (seen

as papilloedema). The most significant single feature is persistent headache.

Other features may be listlessness, tiredness and mood or personality change.

The sufferer may progressively withdraw from social contacts and gradually

become confused and stuporous and may lapse into coma. In young children the

increased pressure may cause the head to enlarge and hydrocephalus (so-called

“water on the brain”) may develop.

Fitting alone is

It should be noted that in children, convulsions or fitting are most often caused

rarely caused

by a fever or other less serious problem. Fitting alone is rarely caused by cancer

by cancer in

in children. In an adult, however, with no previous history of epilepsy, injury or

children.

fitting from another known cause, the sudden onset of a fitting attack may be the

first sign of a brain tumour.

18.1.1.2 Focal Features

Focal features are due to interference of function of a local region of the brain.

These features will depend upon the site of the tumour. In one place it may be

interference with speech, in another it may be loss of movement of an arm or leg,

or elsewhere or loss of sensation in a part of the body. Tumours elsewhere might

cause local twitching or focal fitting with different sensations such as olfactory

or visual hallucinations like the flickering of lights. There may be disorders of

balance, or clumsy movement or interference with a cranial nerve such as the

optic nerves for vision, the nerves that move the eyeball or the facial nerves that

move the muscles of the side of the face. In the frontal lobes, the earliest features

might be mood or personality change.

18.1 Brain Cancers

253

8.1.2 Pathology Types

Astrocytomas can range from relatively low-grade to anaplastic high-grade

cancers called glioblastoma multiforme. Low-grade astrocytomas develop more

slowly with more prolonged symptoms and a longer life-expectancy but the

majority of primary brain cancers, especially in adults, are glioblastoma multi-

forme with a more rapid onset of headache and other symptoms.

Medulloblastomas are malignant tumours in the cerebellum and are the most

common brain cancers in children causing headaches and problems of balance

and loss of co-ordination, possibly with fitting.

18.1.3 Investigations

CT scans and MRI scans have revolutionised investigations for brain tumours.

Before these scans were invented, cerebral angiography (arteriography after

injecting a radio-opaque iodine compound into one of the internal carotid arter-

ies), radio-isotope scans, and air encephalograms (described in Sect. 7.3) were

used almost routinely together with a number of other investigations such as

the electroencephalogram (EEG), which records brainwave activity. Nowadays,

however, the CT scan or the MRI scan, usually supplies most of the informa-

tion of other investigations and even more precisely. Angiography may still give

added information particularly concerning the vascularity of a tumour. Surgeons

often use angiograms to plan operations. The surgeons then know exactly where

the tumour is in relation to nearby blood vessels. The angiograms also indicate

which vessels are supplying blood to the tumour.

18.1.4 Treatment

Whilst the majority of benign cerebral tumours, like meningiomas, can be cured

by surgical removal, malignant tumours, other than radiosensitive medulloblas-

tomas, are not often curable. For this reason, it is vital to determine - often at

operation - whether a tumour in the brain is benign or malignant. If malignant,

it is also important to determine the type of malignancy because the outlook

for some is better than others and some, such as medulloblastomas, may be

curable.

Whilst the majority are not curable, most patients with brain cancer can be

given considerable relief of symptoms by a number of means. First, corticoster-

oids can be used to reduce swelling and so reduce pressure on the brain, which

will relieve headaches and other pressure symptoms. Then surgical operation

can be carried out to remove at least most of the cancer, giving further and more

prolonged relief of symptoms. Following surgery, radiotherapy alone will usually

further improve the immediate outlook but not in the long term.

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18 Cancers of the Brain and Nervous System

Recent studies have shown that post-operative chemotherapy with radiotherapy

has given added benefit and some apparent cures have been reported, particu-

larly in the case of medulloblastomas but also in some cases of other cerebral

malignancies.

CASE REPORT

Glioblastoma multiforme

Elsie is a 60-year-old retired teacher who does not smoke and seldom

drinks alcohol. She had enjoyed good health. She is right-handed.

Elsie gave a very short history. About 7 days before consulting her

doctor she had experienced a visual disturbance, which lasted for less

than 2 h. She was reading but could not interpret the words.

For 3 days she had had some unusual visual sensations. On one occasion

she thought she saw something in the peripheral right visual field, like a

street sign, but there was no such sign. In speech there were some errors of

word selection. She knew what she wanted to say but sometimes the wrong

word “came out”. For example on one occasion she told someone that she

had three wolves at home when she was meaning to say three dogs.

On examination there were no abnormalities on visual field testing. The

fundi and optic discs were normal. The lower cranial nerves were intact.

No abnormality was found on neurological examination of the limbs.

A CT scan of the brain demonstrated a spherical lesion 1.5 cm in

diameter in the inferior and medial aspect of the left temporal lobe with

swelling and oedema around it.

The differential diagnosis of such lesions includes a primary brain

tumour or a solitary metastasis. Blood tumour markers were negative for

the most common undiagnosed cancers likely to metastasise to brain in

a woman of her age, breast cancer and bowel cancer (CA 15-3 and CEA

both normal).

A mammogram and breast ultrasound showed no abnormality. A CT

scan of the chest, abdomen and pelvis was clear. A PET scan of the brain

was consistent with a high-grade tumour.

Anticonvulsants and corticosteroids were commenced.

A neurosurgical operation was done. The tumour was biopsied, and

frozen sections indicated a high-grade glioma, glioblastoma multiforme,

(a malignant primary brain tumour). Most of the tumour was then removed.

She woke with no new deficits. After recovering from the surgery a course

of radiotherapy was commenced but her outlook must be very guarded.

18.1 Brain Cancers

255

CASE REPORT

A large benign cerebral tumour (meningioma)

Gur is a 47-year-old successful businessman who had smoked for many

years. He drank little alcohol, and was being treated for hypertension. His

brother had been treated for a cerebral meningioma some years before.

For some months Gur had been aware of cognitive problems, with insidi-

ous onset and progression. He misplaced things continuously. This had been

noticed by his family and golf partners. His handwriting had altered greatly.

Normal tasks required great effort. Although very experienced he

dithered and dawdled in running his business, and in organising the purchase

of a new house.

He often woke up at night because of a throbbing pain in the head. He

had lost some weight recently but was not aware of a change in appetite. He

was aware that he had become quite moody. He was left-handed and his wife

would chasten him because of a tendency to carry things around in his left

hand unknowingly. He took the flag out appropriately at one of the holes when

his golf-playing partner was putting, but then continued to carry the flag in his

left hand while attempting to shape up for his next stroke.

On examination he was slow in responding. His writing was shaky and

difficult. When asked to undress for physical examination he undressed in

a very odd fashion. He was holding his wallet in his left hand. He did not

put the wallet down. For the whole period while he took off his shoes and

socks the wallet stayed where it was and he removed his shoes and socks

one-handed with his right hand. Neither arm swung when he walked.

There was an increase in left upper limb tone, the limb appeared stiff but

power was normal. Coordination was slightly less in the left upper limb

but sensory examination was normal. Stance and heel-toe walking was

good. The reflexes were brisker for the left biceps, knee and ankle jerks

and the left plantar response was equivocal.

A CT scan indicated an unusual tumour with a large cystic component.

An urgent MRI scan showed a very significant tumour in the right medial

frontal lobe, abutting the sagittal sinus and probably arising from the falx,

uniformly enhancing with contrast. Around the tumour and cyst there was

some brain oedema.

Dexamethasone (a corticosteroid) was given to relieve the cerebral

pressure and oedema and anticonvulsants were commenced.

At operation a giant meningioma (a usually benign tumour of the

meninges) was diagnosed. Even though it was so large and odd, the his-

tology was benign. The tumour was entirely removed, and his cognitive

functions improved rapidly over the next 3 months.

He is now back to normal and has a good prognosis.

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18 Cancers of the Brain and Nervous System

CASE REPORT

Malignantastrocytoma

Mr P is a 59-year-old barrister who at the age of 56 years first noticed

that he was beginning to feel “old and tired”. During a stormy court case

he had occasionally lost the word he was trying to express. He concluded

that he had been working too hard and arranged to take a holiday in a

month’s time.

Unfortunately before his holiday period he began to have headaches

that he felt “all through” his head. Sometimes the headaches were more

pronounced in the left temporal region just above his ear. He took some

proprietary headache tablets with only limited relief. One morning

the right side of his face began to spasm in a most alarming fashion. He was

unable to speak and a few minutes later the spasm moved into his right

shoulder and arm.

Terrified of this symptom (as most people are with their first seizure)

he sat on the edge of his bed until he was able to call his wife who drove

him to the nearest Hospital Emergency Department.

On examination he was found to be a middle-aged man who had a

partial weakness of the right side of his face and right arm and shoul-

der although he appeared otherwise fit. His tendon reflexes were much

increased on the right side and papilloedema (swelling of the optic nerve)

could be seen when his eye was examined with an ophthalmoscope.

MRI studies showed a moderate sized tumour within the brain in the left

temporo-parietal region.

Mr P was referred to a neurosurgeon who informed him that this was

almost certainly a malignant brain tumour but that he would not recom-

mend surgery because it would not be possible to remove the tumour with-

out damaging the part of his brain controlling speech and movement of the

right side of his body. He advised, and carried out, a needle biopsy of the

tumour to establish its exact nature.

Biopsy showed it to be a high grade malignant astrocytoma.

Mr P was advised that his tumour might respond to combined therapy

using a new agent called temozolomide and radiotherapy. After consulta-

tion with a neuro-oncologist and radiotherapist he was treated with this

drug and radiotherapy synchronously.

Over the next 12 months MRI studies showed that the tumour gradu-

ally regressed. Three years later, at the age of 59, Mr P has returned to his

practice as previously. He remains well but continues to have 6-monthly

courses of temozolomide and 6 monthly MRI studies.

(continued)

18.2 Secondary Cancers in the Brain

257

(continued)

Comment

In the past results of treatment of aggressive brain cancers, especially in

adults, have been so negative that it is very encouraging to see results of

the combined treatment as given to Mr P. Whilst several similar results

have now been reported it is too early in this clinical study to speculate

what percentage of patients so treated will have similar responses or for

how long such responses will be maintained. This is an example of the

cutting edge of clinical studies in cancer treatment. Such studies are

practiced in all areas of cancer treatment, especially where there is no

established successful alternative.

EX ERCISE

Drawing on case reports in this and other chapters of this book, construct

a case report of a typical patient presenting with and being investigated and

managed for a medulloblastoma.

18.2

Secondary Cancers in the Brain

The brain is sometimes the site of a metastatic cancer. Cancers of lung, breast

and melanomas are the most common primary cancers that metastasise to brain

but occasionally the brain may harbour secondary cancer from almost any other

primary site or from leukaemia.

Cure by any means is unlikely for metastatic cerebral tumours but consider-

able, although temporary, relief is often gained by surgical removal, radiotherapy

or even sometimes chemotherapy. A combination of these treatment modalities

is often more effective.

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18 Cancers of the Brain and Nervous System

18.3

Nerve Cell Cancers

8.3.1 Neuroblastoma

Neuroblastoma is a malignancy of primitive nerve cells. After acute lymphoblastic

leukaemia and brain tumours, it is the most common malignancy of childhood, about

10% of childhood cancers. About 80% of cases occur in infants less than 4 years.

Neuroblastomas can occur anywhere in the sympathetic nervous system from

the neck to pelvis and including the adrenal glands.

8.3.2 Presentation

The child is usually failing to thrive, often irritable and may have lost bladder

or bowel control.

There may be an abdominal mass but symptoms and signs will depend upon

which site in the sympathetic nervous system the tumour started and which tis-

sues are involved in tumour invasion (e.g. the neural canals), or metastases (bone,

subcutaneous tissue or liver are common).

Occasionally, especially in infants less than 1 year, the tumour may resolve

spontaneously but treatment usually requires a combination of surgery, chemo-

therapy and radiation therapy, sometimes to a degree requiring bone-marrow

transplantation to restore blood-forming tissues. Local tumours are often con-

trolled by treatment but widespread metastases are rarely controlled.

18.4

Retinoblastoma

A retinoblastoma is an uncommon childhood cancer in the eye of infants and

children up to 4 years. In about 25% of patients it is bilateral and in almost half

of the cases there is a genetic factor with a family history of a similar tumour,

and invariably both eyes are enucleated to prevent the development of cancer.

Retinoblastoma is an anaplastic malignancy of the retina. It can spread from

the eye to involve brain and meninges, and cause premature death in infancy.

8.4.1 Presentation

The first sign is often a white reflex through the child’s pupil (leukocoria) noticed

by the parents. a squint may have developed in the eye.

Treatment often involves cryosurgery, radiotherapy and chemotherapy (both

induction and adjuvant chemotherapy), with or without enucleation of the eye.

If diagnosed early (before local spread or metastases) a high incidence of cure

is achieved. Neurosarcomas are discussed in Chap. 20.1.5

TheLeukaemias and Lymphomas

In this chapter you will learn about:

› The leukaemias

› The acute leukaemias

› Chronic lymphocytic (lymphatic) leukaemia

› Chronic myeloid (granulocytic) leukaemia

› The lymphomas

› Hodgkin lymphoma (previously called Hodgkin disease)

› Non-Hodgkin lymphomas

› Multiple myeloma

19.1

The Leukaemias

Leukaemia is a cancer of blood-forming cells. Leukaemias are classified into

two broad groups according to the type of blood-forming cell that has become

malignant. These are called lymphatic leukaemia and myeloid (or non-lymphatic)

leukaemia.

In lymphatic leukaemia the cells that have become malignant are the bone

marrow cells that normally make lymphocytes. Lymph nodes and lymphoid tissue

are usually involved and some nodes become enlarged. In myeloid leukaemia the

cells that have become malignant are cells in the bone marrow that normally make

the other types of white blood cells (that is myeloid cells that make polymorphs

and other white cell types). The spleen usually becomes involved and enlarged.

Leukaemias may be acute or chronic according to whether the disease would

tend to run a rapid and rapidly fatal course (acute leukaemia) or whether the

disease would progress more slowly (chronic leukaemia).

Thus there are four main types of leukaemia:

• Acute lymphocytic (lymphatic) leukaemia (ALL)

• Acute myeloid (non-lymphatic or granulocytic) leukaemia (AML or ANLL.)

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19 The Leukaemias and Lymphomas

• Chronic lymphocytic leukaemia (CLL)

• Chronic myeloid (non-lymphocytic or granulocytic) leukaemia (CML or

CNLL or CGL)

It is important to distinguish between the major types of leukaemia because they

tend to run different courses and respond differently to different treatments.

19.1.1 Incidence and Prevalence of Leukaemias

Leukaemias occur throughout the world but the incidence varies in different

countries and in different races. All types of leukaemia are slightly more

common in males. The Scandinavian countries and Israel have the highest

incidence and the lowest reported incidence is in Chile and Japan but in general

they are more common in developed countries (see Appendix). In the USA the

highest incidence is in Jews and the lowest is in African Americans.

Acute leukaemia

The overall incidence of ALL and AML is about equal but there is a distinct

accounts for about

age difference. Acute leukaemia accounts for about half of all cancers in children

half of all cancers

and acute lymphocytic leukaemia is the most common of all cancers in young

in children

children, with a peak incidence of between 2 and 4 years. The incidence of AML

is low in children but increases with age.

The causes of leukaemia are unknown although some predisposing factors

are recognised. Leukaemias, especially myeloid leukaemias, have been linked

with ionising radiation. There is also evidence that exposure of a foetus to X-rays

during its mother’s pregnancy is associated with a slightly increased risk of

leukaemia developing later in childhood. However, there is no evidence that

normal use of diagnostic X-rays in adults is associated with leukaemia. Myelofi-

brosis (myeloplastic disease) is a disorder of bone marrow cell proliferation that

sometimes presents in adults as anaemia of no obvious cause and commonly

degenerates into an acute leukaemia.

Excessive exposure to some chemical agents such as benzene is associated

with a slightly increased risk of leukaemia. AML will occasionally develop in

patients who have had some other form of cancer including Hodgkin lymphoma,

or cancer of the ovary, that has been treated with chemotherapy.

Use of anti-cancer cytotoxic drugs for other cancers, and especially their

pronged use with radiotherapy, also slightly increases the risk of later develop-

ment of leukaemia.

Familial leukaemia is rare although some families with multiple cases of

leukaemia have been reported. In general, siblings of a child with leukaemia have

only a slightly higher risk of developing leukaemia although if one identical twin

develops acute leukaemia the other twin has about a 20% chance of developing

the disease.

People with Down’s Syndrome have a twenty times greater risk of developing

acute leukaemia than other people. Women who become mothers at an advanced

19.2 The Acute Leukaemias

261

age not only have an increased risk of producing children with Down’s syndrome

but otherwise normal children born of older age group mothers have a slightly

greater risk of developing acute leukaemia.

Genetic mutations and complex gene rearrangements are of basic importance

in the pathogenesis of leukaemias and lymphomas. There is presently a great

deal of study of these chromosome changes. Studies indicate that the chromo-

somal and genetic changes not only show different patterns in different forms of

leukaemias but genetic patterns may also indicate likely responses to different

treatments and an indication of likely progress.

There were increased numbers of people with leukaemias after the atomic

bomb explosions at Hiroshima and Nagasaki and after the Chernobyl atomic

energy plant disaster in Russia, CML was the most prevalent.

Viruses are known to cause leukaemia in some animal species but only one

type of leukaemia in humans has been linked to a virus. Adult T-cell leukae-

mia/lymphoma, prevalent in the Carribbean, Japan and New Guinea, is probably

caused by a Human virus designated “T-cell leukaemia virus” (HTLV-1). The

Epstein-Barr virus has been implicated in Burkitt’s Lymphoma/leukaemia.

19.2

The Acute Leukaemias

9.2.1 Clinical Presentation

19.2.1.1 Acute Lymphatic (Lymphoblastic) Leukaemia (ALL)

This is the most common form of leukaemia in children with an age peak of

about 5 years. Symptoms are caused by replacement of normal blood-forming

cells of bone marrow by malignant leukaemic cells and infiltration (invasion) of

other tissues such as spleen, lymph nodes, tonsils and sometimes liver, kidneys,

lungs and brain.

Fever, weakness, anorexia (loss of appetite), pallor, and infection are com-

mon. Infection is especially common in the region of the tonsils or anus and the

lungs may also become infected causing pneumonia. There may be pain in bones

or joints.

Lymph nodes, tonsils and spleen are commonly enlarged. Sometimes the liver

and kidneys are enlarged.

Platelets may be deficient and there may be petechial spots or bruising or signs

of bleeding from any site especially from the gums, the digestive tract or anus.

Bleeding in the brain or from the lungs may also occur. Thrombosis (clots) may

also develop in veins.

Meningitis due to leukaemic cell spread into the meninges frequently occurs

in patients with ALL unless prevented by radiotherapy or chemotherapy.

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19 The Leukaemias and Lymphomas

9.2.1.2 Acute Myeloid Leukaemia

AML more commonly affects adults. Anaemia, bleeding or bruising and infec-

tion are the likely presenting features. But as with ALL, general ill health with

fever, lassitude, loss of appetite and involvement of other tissues or organs with

septicaemic infection is likely.

9.2.2 Investigations

The diagnosis of leukaemia can be made only after careful examination of blood

and bone marrow. Blood is taken by a needle from a vein in the arm and bone

marrow is usually taken with a small instrument that is used to puncture a bone

of the pelvis (the iliac crest). Bone puncture is painful so it is done under local

or even general anaesthesia. A pathologist then examines the blood and bone

marrow for leukaemic cells and for other features of leukaemia. These may

include anaemia (with a reduction in numbers of red blood cells), reduction in

number of normal white blood cells, and reduction in the number of platelets.

About one third of patients with acute leukaemia will have an elevated white

blood count, one third will have a low white blood count and in one third the

white cell count is about normal.

Patients with AML are usually found to have abnormalities of chromosomes.

There may also be changes in blood chemistry, including increased uric acid, that

may be associated with features of gout.

Cytogenetic studies on bone marrow are now part of a full investigation of

leukaemia patients. These studies identify specific molecular genetic syndromes

and help in selecting the best therapy. They also give a good indication of the

likely prognosis.

19.2.3 Treatment

Encouraging

Encouraging progress has been made in recent years in the treatment of the

progress has

acute leukaemias.

been made in

The best opportunity to achieve the maximum cure of leukaemia is when the

recent years in the

disease is first diagnosed. Cells that remain after the first treatment tend to develop

treatment of the

resistance to drugs. It is therefore important that patients with acute leukaemia

acute leukaemias.

should immediately be referred to a readily available specialist clinic so that the

most effective treatment can be given under expert supervision without delay.

Chemotherapy using cytotoxic drugs and cortisone forms the basis of

modern treatment. Combinations of effective cytotoxic drugs have produced

best results.

19.2 The Acute Leukaemias

263

With the best current treatment methods, more than 90% of children and about

80% of adults with ALL now achieve complete remission (that is, the disease

apparently disappears and the patient feels and looks well again).

Because after a time most ALL patients will develop the disease in the meninges,

the lining around the brain, and because anti-cancer drugs do not pass in high

concentration into the nervous system, injections of cytotoxic drugs are given

into the meningeal space around the brain and the brain is also treated by radio-

therapy. In the case of AML, nervous system involvement does not occur so often

but this treatment is also given immediately there is any sign that there may be

brain or central nervous system involvement.

With AML, good results of chemotherapy have not been as reliable as with

ALL. Recently, in attempts to further improve results, bone marrow transplan-

tation has been used effectively, especially in younger people (aged under 50).

In marrow transplantation the leukaemic cells are destroyed by big doses of

chemotherapy and radiotherapy (total body irradiation). This is a dangerous

procedure and is carried out only in highly expert units within specialised hospi-

tals. The patient is then given an infusion of bone marrow taken from a matched

donor (that is, a donor with similar body cells unlikely to cause a rejection reac-

tion). The best donor is often a sibling or other family member. Bone marrow

transplantation involves a number of risks and should therefore be carried out

only by appropriately trained experts, in specially equipped hospitals. Results

have been most encouraging in this otherwise fatal illness. An alternative

source of haemopoietic stem cells for transplantation is to use peripheral blood

stem cells or umbilical cord stem cells Blood stem cells are collected from the

blood after stimulation by colony stimulating factors (like G-CSF). Although

controversial from an ethical and moral point of view embryonal stem cells may

have the ability to respond in the bone marrow in a similar way to bone marrow

derived cells.

In recent years, treatment with immunotherapy has been further investigated.

Although major success has not as yet been achieved there have been interesting

results that give hope for better treatments in the future.

Transplantation of matched unrelated bone marrow (bone marrow from a

matched donor person not related to the patient) is used to elicit graft vs. leukaemia

effect. The immunological effect of the graft might be as important or even more

important than chemotherapy. In recent years mini-allogeneic transplants have

been used (allogeneic stem cells are used without myelo-ablative chemotherapy).

Studies are proceeding to determine whether such interventions might be safer

and equally effective.

During the acute illness there may be special problems of anaemia, lowered

resistance to infection, bleeding or even clotting. These may require blood trans-

fusion or platelet transfusion and antibiotics or other treatment for infection.

Aspirin should be strictly avoided because it interferes with blood clotting.

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19 The Leukaemias and Lymphomas

C AS E R E P O R T

Acute lymphoblastic leukaemia

Elizabeth is a 5-year-old girl whose mother took her to their family doctor

with a 4-week history of increasing lethargy, loss of appetite, pallor, and

low grade intermittent fevers. The doctor noted that Elizabeth was pale,

had a pulse rate of 140 per minute with a systolic flow heart murmur. She

had scattered petechiae (little red spots) on the lower limbs, and a moder-

ately enlarged but non-tender liver. Blood count revealed low haemoglobin

(56 g/L), a raised white cell count (9 × 10⁹/L), differential predominately

blasts cells, and a low platelet count (15 × 10⁹/L).

Elizabeth was admitted immediately to the Children’s Hospital, where

compatible platelets and packed red blood cells were administered to

correct the thrombocytopenia and anaemia. Under general anaesthesia, a

bone marrow aspirate was performed, confirming the diagnosis of ALL.

A lumbar puncture contained no white cells (suggesting that cerebral involve-

ment was unlikely). An indwelling central venous catheter was inserted.

Elizabeth commenced chemotherapy treatment (a national childhood

ALL protocol, was used. This is an international program based on a very

effective German protocol) in which a steroid (prednisolone) is given first.

Her peripheral blast, white cell, count fell (to less than 0.1 × 10⁹/L) after the

first week of oral prednisolone. She continued induction therapy (receiving

intra-venous vincristine, daunorubicin, and asparaginase), in addition to

the oral prednisolone. A repeat bone marrow aspirate at the completion

of the first 5 weeks of therapy indicated haematologic remission with no

detectable blast cells (primitive white cells). Chemotherapy continued

on an outpatient basis, followed by four doses of high-dose methotrexate

intravenously over 8 weeks, and a final extended phase (using mercap-

topurine daily and methotrexate weekly) for a total of 2 years of therapy.

Minimum residual disease (MRD) assays performed on marrow obtained

at the completion of both the first (induction) phase and completion of the

second (consolidation) phase were both negative for disease.

Comment

Elizabeth has as good an outlook as is possible to have for childhood

ALL. Her gender, age at diagnosis, and peripheral white cell count at

diagnosis are all long-recognised indicators of a favourable prognosis. The

favourable response to prednisolone as a single agent is a highly reliable

indicator of responsiveness established by German studies in the late

1980s as a key determinant of required intensity of therapy. The negative

MRD assays at day 33 and day 72 are, in 2005, the most advanced and

sensitive indicators of an optimal response to therapy. Elizabeth has a

better than 90% chance of being cured.

19.3 Chronic Lymphocytic (Lymphatic ) Leukaemia

265

19.3

Chronic Lymphocytic (Lymphatic) Leukaemia

CLL tends to occur in older people with an average age of about 60 years and is

usually a very slowly progressive disease. In this disease there is an overproduc-

tion of mature and relatively normal looking lymphocytes resulting in increased

numbers of lymphocytes in the blood.

9.3.1 Clinical Presentation

The most obvious feature is lymph-node enlargement. Enlarged lymph nodes

may be felt as lumps in the sides of the neck, in the axillae or groins. Enlarged

lymph nodes in the abdomen are more difficult to feel but enlarged lymph nodes

in the chest may be detected in a chest X-ray. The spleen and sometimes the liver

may also be enlarged. The normal bone marrow may be replaced by malignant

lymphocytes and the patient may become anaemic and deficient in platelets. This

may lead to bleeding and clotting problems. Due to the replacement of normal

white cells by abnormal white cells the patient has decreased ability to combat

infection and may also have immunologic abnormalities.

19.3.2 Investigations

Blood count, bone marrow biopsy and tests of immune function will establish

the diagnosis.

9.3.3 Treatment

CLL may be present for years without causing troublesome symptoms. Many

patients may not need treatment for months or years. The median age is about 60

years and there is an increased family incidence. There is no evidence that chronic

lymphatic leukaemia can be cured by early treatment, so treatment is usually

reserved for episodes of the disease that are causing the patient to feel ill or causing

other problems. Eventually fatigue, malaise, weight loss, bleeding and symptoms

of anaemia will develop. In its early stages treatment of symptoms only may be all

that is needed but eventually more aggressive treatment may be necessary.

Treatment should be initiated for CLL only when anaemia, thrombocytopenia

or other disease-related symptoms appear.

Large and conspicuous lymph nodes and a large spleen can be reduced by

radiotherapy. If the patient’s general health is poor, treatment with anti-cancer

cytotoxic drugs, often with cortisone, will usually cause reduction of enlarged

lymph nodes and spleen, improve the bone marrow and make the patient feel better.

Two cytotoxic anti-cancer drugs are commonly used - these are chlorambucil

and cyclophosphamide. Both are given by mouth. More recently the development of

266

19 The Leukaemias and Lymphomas

new purine analogues (fludarabine phosphatee or Fludara, 2CdA and Pen-

tostatin) is rapidly changing the treatment of this disease. Many experts advise

that fludarabine phosphate should now be the initial treatment of choice. There

is also interest in the development of monoclonal antibodies to CD20 and CD52

(Rituxan and Campath-1H respectively). These agents are now undergoing trials

in association with cytotoxic chemotherapy. Rapid changes and advanced trials

are proceeding into treatments of these leukaemias.

Unlike CML, CLL only very rarely changes into an acute type of leukaemia but

in about 10% of cases it will change into a high-grade B-cell lymphoma-like disease

as described in the following pages. This is known as Richter’s transformation.

19.4

Chronic Myeloid Leukaemia (CML)

CML can occur at any age but the median age of people affected is about 50

years. Males are affected more often than females. There is an association with

a specific chromosomal abnormality called the “Philadelphia” chromosome,

which produces an enzyme called tyrosine kinase that is involved in the cellular

changes of CML. Although there is no known specific cause in most cases, it

was found that in Japan there was an increase in both acute and CML 5-8 years

after the atomic bomb explosions.

In CML there is a marked increase in the number of white cells in the blood.

This is associated with a big increase in the number of cells in bone marrow.

There may also be a considerable increase in the numbers of blood platelets. Bone

marrow occupation by non red-cell precursors leads to gradual but progressive

anaemia.

9.4.1 Clinical Presentation

One of the more common symptoms is a pain in the left upper abdomen due to

an enlarged spleen. Usually the spleen is felt easily in patients with this disease

(a normal spleen cannot be felt with examining fingers). There may also be

features of anaemia, tiredness, weight loss or fever. Sometimes, abnormal bruising,

bleeding or clotting problems may be the first evidence of the disease.

19.4.2 Investigations

Blood count and bone marrow biopsy will usually establish the diagnosis. As

for the other forms of leukaemia and the lymphomas, genetic arrangements

and genetic mutations are not only associated with CML but may indicate

19.4 Chronic Myeloid Leukaemia (CML)

267

likely patterns of progress of the disease, most appropriate treatments and

likely outcomes.

19.4.3 Treatment

There are two phases of CML. The chronic phase is the least dangerous and

with modern treatment may last for many months or years before the dangerous

acute phase takes over.

During the chronic phase, the disease can usually be kept under good control

with cytotoxic chemotherapy. The drug most commonly used with good effect

has been hydroxyurea, although other drugs are now found to give equally good

or possibly better disease control. With these treatments the blood count may

return to normal and the spleen may be reduced considerably in size.

The immunological agent “interferon” is proving to be effective in producing

remission but because in most cases it does not eliminate the “Philadelphia chro-

mosome”, it is unlikely to cure the disease. Interferon alpha with hydroxyurea

significantly prolong survival (by about 20 months) of patients with chronic-phase

CML compared to previously standard treatment with busulfan. For patients who

do not tolerate interferon, hydroxyurea alone has also been shown to give better

results than busulfan.

For younger patients in good health, allogenic bone marrow transplanta-

tion (BMT) appears to be a preferred option. Bone marrow transplantation is

more likely to be successful in the chronic phase than in the acute phase. If the

spleen remains large and causes pain or other problems due to its large size and

over-activity it may sometimes be necessary to have the spleen removed by a

surgeon.

Sooner or later, a more acute and more dangerous episode of this disease will

develop resembling acute leukaemia. This phase of the disease is more difficult

to control. Sometimes other cytotoxic chemotherapy with cortisone might give

control for a period. Studies are also being made to control this acute phase of the

disease with intensive radiotherapy and bone marrow transplantation. Although

a number of problems still need to be overcome, results have been encouraging

especially in younger people.

The most exciting new addition to the treatment of CML is the tyrosine-kinase

The most

inhibitor STI 571 (Glivec or Gleevec) which is a newly discovered agent. STI 571

exciting new

inhibits intracellular tyrosine kinase. Tyrosine kinase is targeted because it is a

addition to

growth promoting enzyme involved in the cellular changes of CML.

the treatment

Recent studies have shown a remarkable high response rate. STI 571 coun-

of CML is the

teracts tyrosine kinase. Further studies are needed but responses to date appear

tyrosine-kinase

to be dramatic. In a third of cases there is a complete cytogenic remission with

inhibitor STI

apparent elimination of the Philadelphia chromosome. Studies are now being

571 (Glivec

conducted on the possible potential of tyrosine kinase inhibitors being effective

or Gleevec).

in treating other cancers.

268

19 The Leukaemias and Lymphomas

EX ERCISE

Consider why recent results of treatment of CML has caused such intense

interest in possible new treatments of other cancers.

9.4.4 Hairy Cell Leukaemia

This uncommon form of chronic leukaemia is so named because of the unusual

features of its cells, which appear to have fine hair-like projections from the

surface. It is of special interest because it is a leukaemia that usually responds

well to immunological treatment with interferon (see Sect. 8.4.2). Treatment with

interferon and purine analogues (2CdA and Pentostatin), has been very effective.

Previous treatment by splenectomy as first-line treatment is no longer indicated.

C AS E R E P O R T

Acute myeloid leukaemia

Brett is a 34-year-old swimming instructor at a private school. He had

noticed that over the last few weeks his energy levels were not as good

as usual and in the last week a few little “blood spots” had appeared

on his lower legs round the ankles. He hadn’t taken much notice of this

until he had a bad nose-bleed which he could not stop, so he went to the

Emergency Department of his local hospital clutching a handkerchief

around his bleeding nose.

The Emergency doctor noticed that he was pale and that he had the

blood spots about his ankles. After he had packed his nose the doctor

ordered some blood tests.

Within an hour the laboratory had phoned to say that the blood test was

very abnormal and that Brett was very anaemic with a haemoglobin level

of 60 g/L, a low platelet count, and a very high white cell count.

(continued)

19.4 Chronic Myeloid Leukaemia (CML)

269

(continued)

It became clear that Brett had had a serious bleeding episode and that

this was probably caused by the low platelet count. Brett was admitted to

the hospital for a blood and platelet transfusion, and a specialist haema-

tologist was consulted. The specialist advised Brett of the abnormal blood

result and recommended a bone marrow biopsy. (The bone marrow acts

like a factory for blood cell production.)

The bone marrow test confirmed a diagnosis of AML. This was based

on the appearance of the leukaemic cells in the bone marrow but also on

some special tests that determine the genetic make-up of the cells and

what chemicals are present on their surface.

Naturally Brett was very upset to hear the diagnosis as was his wife

and family of two young children. After the transfusions the bleeding

stopped and Brett felt much better. The haematologist explained that he

would require anti-leukaemia treatment with powerful cytotoxic drugs

and that this would mean hospitalization for probably 4-6 weeks. While

the leukaemia drugs are usually given for about 7 days the drugs are very

powerful and cause the blood counts to become very low so that blood and

platelet transfusions are very commonly needed during and after the treat-

ment until the bone marrow and blood recovers. In addition intravenous

antibiotics may be needed to protect against infection.

After storing some sperm samples in case his fertility was affected,

Brett agreed to start treatment and appears to be doing well after the first

2 weeks. Although it is still early days, plans are underway to test his two

brothers to see if they could donate stem cells for a stem cell transplant

after the initial chemotherapy. This determination can be done by simple

blood tests.

CASE REPORT

Chronic myeloid leukaemia

Richard is a 48-year-old publisher with an English publishing group. He

has enjoyed good health except for a soccer related knee injury when he

was 17.

He presented to his general practitioner with left upper quadrant

abdominal pain and a feeling of early satiety after eating meals. He looked

reasonably well but on examination his GP had found an enlarged spleen,

8 cm below the left costal margin. The spleen was not tender to palpation

and the liver edge was not palpable.

(continued)

270

19 The Leukaemias and Lymphomas

(continued)

His GP arranged for some routine blood tests and was telephoned

later that day by the local pathologist to indicate that the white cell count

was grossly elevated at 112 × 10⁹/L. The haemoglobin level was slightly

reduced at 127 g/L and the platelet count was slightly elevated at

521 × 10⁹/L.

Richard was referred to a haematologist who, other than the spleno-

megaly, found little else of note. Review of the blood film confirmed the

grossly elevated white cell count, which showed a spectrum of myeloid

cells, ranging from a few myeloblasts through promyelocytes, myelocytes,

metamyelocytes and mature neutrophils.

A bone marrow examination was arranged and showed a hypercellular

marrow with active proliferation of myeloid cells. A cytogenetic (chromo-

some) analysis of these bone marrow cells revealed the presence of the

Philadelphia chromosome in 100% of the cells examined, confirming the

diagnosis of CML.

[The Philadelphia chromosome is a small chromosome derived by the

reciprocal translocation of genetic material (DNA) between chromosomes

9 and 22 leading to the juxtaposition of DNA and the creation of a so-

called new “fusion gene” that can lead to the production of new protein. In

this particular case the new protein, which has tyrosine kinase activity, is

called BCR-ABL protein because of its origins from the genetic material

on chromosome 22 (bcr) and chromosome 9 (abl).]

In Richard’s case, a sample of his blood and bone marrow cells were

sent to a specialized laboratory to analyse the cells for the presence and

quantification of the bcr-abl gene transcripts, by the polymerase chain

reaction (PCR), to allow for future disease monitoring.

The nature of the disease was explained to Richard and he was com-

menced on a new oral drug Imatinib, (400 mg/day), a specific tyrosine

kinase inhibitor which has specificity for the bcr-abl gene transcripts.

Imatinib is also known by its proprietary names Gleevec or Glivec.

Richard’s blood counts quickly reverted to normal within 2 months,

his spleen became impalpable and at 6 months from starting Imatinib, the

Philadelphia chromosome had disappeared from his blood and marrow,

although the bcr-abl gene transcripts could still be detected by PCR.

Comment

Although, at the time of writing, this drug, imatinib, has only been avail-

able for treating CML for a few years there is good reason to believe that

it will herald a new era in the treatment of this disease and it also has

potential in treating other cancers, especially gastro-intestinal stromal

cancers.

19.5 The Lymphomas

271

19.5

The Lymphomas

The lymphomas are a group of cancers of the body tissues that constitute the

The lymphomas

body defence system known as the reticuloendothelial (immune system). The

are a group of

majority of lymphomas arise from lymph nodes but they may arise from B and

cancers of the

T cells in extra nodal sites such as in lymphoid tissue elsewhere for example the

body tissues

tonsils, spleen, stomach or bowel lining, liver, lung, kidneys or skin.

that constitute

There are two main types of lymphoma called Hodgkin lymphoma (or

the body

Hodgkin disease, HD) and the so-called Non-Hodgkin lymphomas (NHL).

defence system

NHLs are the more common. They tend to affect a rather older age group than

known as the

Hodgkin lymphoma. Both types are more common in developed countries

reticulo-

(see Appendix).

endothelial

About 15% of cases of lymphoma are Hodgkin lymphoma, which predomi-

(immune

nantly originates in lymph nodes. NHLs are predominantly of the “B” cell type.

system).

“B” cells are especially concerned with humoral immunity i.e. the circulating

immune system, including manufacture of immune antibodies.

The NHLs may also develop in lymph nodes but they develop almost as com-

monly in lymphoid tissue in other organs.

Lymphoma is predominantly a disease of adults and other than common skin

cancers in the US it is the fifth most common cancer in men (after prostate, lung,

colo-rectal, and bladder). In women other than skin cancers, it is also the fifth

most common (after breast, lung, colo-rectal and uterus). The average age is

about 32 years for Hodgkin lymphoma and somewhat older, about 42 years, for

NHL.

9.5.1 Causes of Lymphoma

The causes of most lymphomas are not known. Viruses are known to cause

lymphomas in some animals but, with one exception, have not been found to be

a significant factor in lymphoma in humans. A lymphoma called Burkitt’s lym-

phoma which is uncommon in most countries but is more common in children in

tropical Africa and New Guinea, has been found to be associated with infection

by the Epstein-Barr virus. This same virus causes glandular fever and in Western

societies people who have had glandular fever have a slightly increased risk of

developing a lymphoma later in life. On the other hand, doctors and nurses who

specialise in caring for people with lymphoma have not been found to have any

increased risk of developing the disease.

It is well recognised that people with a deficiency of their immune systems, do

have an increased risk of developing a lymphoma. This is especially seen in AIDS

patients but also in people who have had an organ transplant and are given drugs

to suppress the rejection of the transplanted organ. In Western countries between

3 and 4% of patients with AIDS develop lymphomas. This represents more than

272

19 The Leukaemias and Lymphomas

100 times the incidence in the general population. It is uncertain whether this is a

direct effect of the HIV virus or a general deregulation of the immune system.

There is also a slightly increased tendency to develop lymphomas in some

families but this may be due to an hereditary tendency towards immune defi-

ciency in these families or possibly there is an, as yet unknown, environmental

factor.

19.6

Hodgkin Lymphoma

9.6.1 Presentation

Hodgkin lymphoma is more common in upper socio-economic groups and espe-

cially in males (about 2:1 ratio males/females). The most common presentation,

especially in young people, is of enlarged lymph nodes usually in one side of

the neck. The nodes are rubbery and movable and usually feel distinctly dif-

ferent to the hard, enlarged nodes that may result from metastatic spread from

other cancers.

Sometimes, other symptoms are a general feeling of ill health, lassitude, fever,

weight loss and/or night sweats. An unusual feature sometimes complained of, is

pain in swollen lymph nodes after drinking alcohol.

The disease usually progresses from the site of origin (most commonly the

lymph nodes in the neck) to other lymph nodes nearby - then to lymph nodes in

the chest or abdomen - to the spleen - and eventually to the liver and bone nar-

row. The earlier the disease is detected before it has spread widely, the greater the

likelihood of cure by modern treatment (Fig. 19.1).

19.6.2 Investigations

In order to decide what is the best treatment it is important to find out as accu-

rately as possible exactly which lymph nodes and organs are involved. A thorough

examination of the patient is needed including all lymph node areas, spleen, liver

and chest. X-rays are taken of the lungs, especially, to look for enlarged lymph

nodes between the lungs (mediastintal lymph nodes).

To establish a diagnosis the most obvious and easily removed lymph node is

removed surgically and to have it examined microscopically. In fact any lymph

node of diameter greater than 1 or 1.5 cm that remains enlarged for more than

about a month without an obvious cause, may need to be removed and examined

in case it is an early indication of a serious disease like Hodgkin disease. The

pathology microscopic hallmark of Hodgkin disease is a large multinucleated

cell, called the Dorothy Reed-Sternberg cell.

If a positive diagnosis of Hodgkin disease is established, a number of other

tests should be done, including a blood count, because anaemia may develop.

19.6 Hodgkin Lymphoma

273

Fig. 19.1. Photograph of a 20-year-old man

with enlarged rubbery lymph nodes in

his neck. This was his first evidence of

a Hodgkin lymphoma

Other features of Hodgkin disease may also be found in immuno-histochemical

studies. CT scans and ultrasound help in discovering if there are any enlarged

abdominal lymph nodes as well as any enlargement of the liver or spleen.

Gallium isotope scans (see Sect. 7.3.8) may now be used to show abnormal or

enlarged lymph nodes.

A liver biopsy and bone narrow biopsy may indicate spread of the disease

to these tissues. Likewise, studies of kidney function or a kidney biopsy may

indicate involvement of the kidneys.

19.6.3 Staging and the Staging Laparotomy

Some patients who had Hodgkin lymphoma a few years ago (then called Hodgkin

disease) will remember that an operation was done by a surgeon to find out what

organs and tissues in the abdomen were involved. This operation is rarely needed

nowadays because of the accuracy of CT scans, ultrasound, isotope scans, gal-

lium scans and by lymphoscintigram studies. These may even be replaced one

day by PET scans which have shown promising results in studies but are very

expensive and are not available in most places. In any case, it is still uncertain

whether PET scans will add anything to the combined information from the

other tests.

274

19 The Leukaemias and Lymphomas

19.6.4 Treatment

Treatment of Hodgkin lymphoma is either by radiotherapy or chemotherapy or

both. In experienced hands well-delivered treatment can now improve greatly

the outlook for this once lethal illness. It is now possible to cure most patients,

especially those who do not have extensive disease.

In general, limited areas of disease are best treated by radiotherapy (a modern

linear accelerator is the most appropriate equipment) but the exact doses, tech-

niques of delivery and fields of irradiation must be expertly arranged.

For widespread disease (in which tissue other than lymph nodes and spleen

are involved), treatment is usually with chemotherapy, using appropriate com-

binations of cytotoxic drugs. Present-day lymphoma specialists are now able to

achieve very good results and keep toxic side effects (see Sect. 8.3.4) to a mini-

mum. For advanced cases chemotherapy and radiotherapy may both be required

in an integrated treatment program.

CASE REPORT

Hodgkin lymphoma

Julie is a 22-year-old law student coming up to her final exams. She was

under a lot of stress and studying hard. She was often up late at night

and was also having difficulty sleeping. Like a lot of girls in this situa-

tion she was probably not eating regular meals and noticed that she was

losing weight. She had woken up a couple of times in the last week with

bad sweats and on the last occasion she had been drenched with sweat, so

much so that she had to change her pyjamas. She also noticed a swelling

in the area above her left clavicle although there had been no pain, but she

was persuaded by her flatmate to go to her local family doctor.

The doctor saw Julie and confirmed that there was a swelling above her

left clavicle but could not find any other abnormal findings. She arranged

for some blood tests and a chest X-ray. When the results came back she

arranged for Julie to attend for follow up consultation.

The blood tests showed that Julie was mildly anaemic with a haemoglo-

bin level of 98 g/L, and her kidneys and liver function tests were normal.

Her chest X-ray showed a mass of lymph nodes between her lungs. After

discussing the results, Julie was referred to a surgeon who arranged a

biopsy of the mass above the clavicle. Within 2 days the result confirmed

that the biopsy had shown Hodgkin lymphoma.

(continued)

19.7 Non-Hodgkin Lymphomas

275

(continued)

The surgeon explained that this was a type of cancer of the lymph

nodes and referred Julie to a specialist as, with appropriate treatment, this

type of cancer can often be cured. Julie saw a specialist within a few days.

The specialist explained that it was important to “stage” the disease, i.e.

find out where else the disease might be. Julie had a CT scan (to assess if

there were any other enlarged lymph nodes or other organs), a PET scan

to assess if there were any areas of increased metabolic activity and a bone

marrow biopsy to see if the disease had spread to the bone marrow. After

these tests, Julie was said to have Stage IIB Hodgkin lymphoma. This

meant that she had disease in two sites (the neck and chest) (II), and she

had night sweats (B symptoms).

Julie has now started a course of cytotoxic chemotherapy called ABVD,

(after the initials of the drugs used). She has treatment every 2 weeks at

the hospital’s out-patient cytotoxic unit, and after two courses she noticed

that her sweats had disappeared. She has deferred her final exams until

after her chemotherapy is finished and spoke to a gynaecologist about

her fertility before starting treatment. At Julie’s age and with this type of

chemotherapy the gynaecologist felt that there was a good chance that her

fertility should be retained.

Comment

Julie has a very good chance that her disease will be eradicated by the

treatment but will require further blood tests and scans to be sure.

19.7

Non-Hodgkin Lymphomas

NHL is not just one disease. It is a range of diseases of the reticuloendothelial

NHL is not just

system grouped together and called the NHLs. The particular type of lymphoma

one disease.

depends upon the predominant type of malignant cell in the tissue in which it

It is a range of

arose. One uncommon form of NHL is a “T” (tissue) cell lymphoma that pre-

diseases of the

dominantly involves skin. It is called mycosis fungoides (Fig. 19.2).

reticuloendo-

thelial system.

9.7.1 Presentation

Like Hodgkin lymphoma, this group of diseases begins in reticulo-endothe-

lial tissues (the “immune” body defence system) and may first be noticed in

lymph nodes. However, the first indication of NHLs may be enlargements of

the spleen, tonsils or lymph nodes, or lumps in other organs such as stomach,

276

19 The Leukaemias and Lymphomas

Fig. 19.2. Photograph showing advanced mycosis fungoides (a rare form of lymphoma

that predominantly develops in skin). This patient was a 63-year-old woman

bowel, lung, bone or skin. NHL is more common than Hodgkin lymphoma in

older age groups. The gender ratio is about 2:1 males/females. The incidence

increased over the last two decades of the twentieth century and is still increasing.

About 3-4% of Aids patients will develop NHL. Treatment is somewhat

controversial and complex. It depends on the tissues involved and the stage of the

disease. For early disease, radiotherapy is used while for more advanced disease,

chemotherapy using an alkylating agent. High-dose chemotherapy with rescue

may be indicated for very advanced disease.

The purine analogues (as mentioned early under treatments for chronic

lymphocytic anaemia, CLL) and monoclonal antibody therapy (Rituxan and

Campath 1H) have become important in treating some lymphomas (Fig. 19.2).

19.7.2 Investigations

Diagnosis is usually made by surgical removal of an enlarged lymph node or biopsy

of a lump in another tissue with microscopic examination and also by immuno-

histochemical features in blood, especially LDH (lactodehydrogenase).

The disease tends to involve a number of tissues other than lymph nodes and

the best form of treatment will depend upon the predominant type of malignant

cell rather than the organs or tissues involved. However, similar investigations as

for Hodgkin disease are usually required including full blood count, chest X-ray,

CT scan, bone marrow biopsies and liver biopsy. PET scans may be of additional

diagnostic help when these become more readily available. Surgery to determine

the stage of the cancer is now rarely needed.

19.7 Non-Hodgkin Lymphomas

277

19.7.3 Treatment

Just as for Hodgkin lymphoma, treatment of the NHLs is by radiotherapy,

chemotherapy or both. However, depending on the type of lymphoma, different

plans of radiotherapy or different programs of chemotherapy are used. With

this information lymphoma therapy teams can arrange the most appropriate

treatment plan.

In general, radiotherapy is best used for localised disease. Because NHL are

likely to involve more than one site treatment by general body chemotherapy

(systemic chemotherapy) is usually required. Sometimes, in some types of lym-

phoma, the use of a single anti-cancer cytotoxic agent will achieve good results

but, in general, best results are achieved when a combination of two or more

cytotoxic drugs is used.

Over recent years, results of treatment of most NHLs have improved signifi-

cantly with modern treatment regimens. This is especially so in some specific

types of lymphoma. For some patients, especially younger ones, very high dose

toxic treatment followed by a bone marrow transplant may be used for advanced

disease. Results to date have been encouraging especially in young people.

CASE REPORT

Non-Hodgkin lymphoma

Arthur is a 67-year-old farmer who was still working on his farm but for

a few weeks he had noticed that his energy had not been as good as usual.

He had lost his appetite and he had noticed his clothing, particularly his

trousers, had become a bit looser than normal. One day while taking a

shower he noticed a swelling in his left groin. The swelling was not pain-

ful and he wondered if it was a hernia. He mentioned this to his wife who

suggested he get things checked by the local doctor.

Next day the doctor confirmed that Arthur had a swelling in his groin

but it was firm and was not reducible and did not feel like a hernia. There

was also a vague sensation of a mass in the abdomen. His doctor referred

him to a surgeon at the local hospital who agreed that the mass in the groin

was worrying and recommended a biopsy to see what the problem was.

Within a week Arthur was in the Day-surgery area having a biopsy and it

showed that the mass was a collection of enlarged lymph nodes affected

by NHL.

(continued)

278

19 The Leukaemias and Lymphomas

(continued)

The surgeon explained that this is a type of cancer of the lymph nodes

and that in broad terms these types of cancer can be divided into two

main types depending on microscopic findings. The more common type

is called NHL and the less common type is Hodgkin lymphoma. It is

important to differentiate, as the treatments for the two diseases are

different.

Even within these two broad categories there are many different sub-

types which the pathologist can identify and aid treatment strategies.

In Arthur’s case the diagnosis was diffuse large cell lymphoma, which

is one of the common types of NHL. Arthur was seen by a specialist who

arranged some blood tests and staging procedures (CT scan, PET Scan,

Bone marrow biopsy) to identify where else the disease was present. In

addition, as Arthur had been on treatment for blood pressure, a gated heart

pool scan was arranged to ensure his heart would tolerate treatment. The

scans showed that Arthur did indeed have a mass of lymph nodes in his

abdomen (about 4 × 3 cm in diameter) and an enlarged lymph node (2 cm)

in his left axilla. Arthur was thus classified as Stage III (having lymph

nodes enlarged above and below the diaphragm). The bone marrow test

was clear.

After these tests were completed, Arthur was started on a program of

intravenous chemotherapy called R-CHOP (after the initials of the drugs

used). This contains a new product (R) called a monoclonal antibody

(Rituximab) in addition to standard chemotherapeutic agents and has

been shown to be of benefit in patients with diffuse large-cell lymphoma.

The monoclonal antibody directs the chemotherapy directly to the target

tumour cells. This treatment is given as an outpatient every 3 weeks.

Comment

In Arthur’s case the specialist indicated that the treatment had a reason-

able chance of success and that the aim of treatment was to eradicate the

disease. If this could be done the chances of being alive in 5 years was

about 30-40%.

A major improvement in treatment outcome has been the development of a

genetically engineered antibody directed against the lymphoma cells. This is

produced using biotechnology industrial processes using mouse cells to pro-

duce a humanized antibody. The antibody is named Mabthera (Ritiximab) and

is used in combination with chemotherapy. The results of treatment for some of

the early stage lymphomas can be excellent with a high cure rate, particularly

for the so-called diffuse large B cell lymphomas.

19.8 Multiple Myeloma

279

19.8

Multiple Myeloma

This tumour occurs in bone but is not truly a tumour of bone. It is in fact a

malignant tumour of plasma cells in bone (plasmocytoma). Plasma cells are

cells responsible for making antibodies or immunoglobulin molecules, they are

a type of blood forming cell in bone. Plasmocytoma shows in X-rays as a “hole”

or “holes” in one or more bones. Usually there are many lesions in a number of

bones although occasionally a single “hole” only is present. A single lesion is

called a solitary plasmocytoma.

Multiple myeloma most often affects adults over 40 or 50 years and is more

common in “developed” countries. It causes local pain and swelling and some-

times fractures in affected bones. Back pain is sometimes associated with col-

lapse of a vertebral body.

19.8.1 Investigations

X-rays may show typical “punched out” areas in bones. A blood count is taken

because patients usually have anaemia. Other changes in the blood proteins

may confirm the diagnosis. The lesions and pain are often in vertebrae or near

the ends of long bones so that pain is often felt in the back or limbs. There may

be hypercalcaemia and kidney failure and sometimes, unexplained fevers or

infections.

The urine is also examined for a particular type of protein (Bence-Jones pro-

tein) which, if present, is diagnostic for multiple myeloma.

19.8.2 Treatment

Because this tumour is usually widespread, it cannot be eradicated by sur-

gery. Treatment by chemotherapy with local radiotherapy of painful lumps

offers the best relief of symptoms and sometimes long-term control. As yet

there is no known cure but interferon has been found to increase duration of

chemotherapy and has induced remissions and thalidomide (and especially the

thalidomide analogue lenalomide) has demonstrated efficacy, probably because

of its anti-angiogenic effects. (That is it prevents the tumour developing new

capillaries on which all tumours depend for nourishment and further growth.)

Treatment of anaemia may require blood transfusion. Bisphosphonates are used

to reduce pain and help stabilise diseased areas of bone.

Autologous stem cell transplantation using blood-derived stem cells has been

shown to be beneficial in patients fit enough to undergo the procedure. Combina-

tions of lenalomide with high dose chemotherapy and stem cell transplantation

is now regarded as most appropriate treatment for most patients, especially for

patients under 65 years.

Soft-Tissue Sarcomas

•

In this chapter you will learn about:

› Fibrosarcoma

› Liposarcoma

› Rhabdomyosarcoma

› Leiomyosarcoma

› Neurosarcoma

› Malignant fibrous histiosarcoma (MFH)

› Angiosarcoma

› Synovial sarcoma (synoviosarcoma or malignant synovioma)

A sarcoma is a cancer of connective tissue such as muscle, bone, cartilage,

fat, nerves, fascia, tendons, and blood and lymph vessels. Hence sarcomas can

develop in any part of the body although they are not as common as carcino-

mas that develop from epithelial tissues such as skin and other lining cells and

glands. This is probably because there is not such a constant turnover of cells

in connective tissues as in epithelial tissues.

Sarcomas are classified into two groups, soft-tissue sarcomas and hard sar-

comas of bone or cartilage (osteosarcomas and chondrosarcomas). There are no

known causes.

The soft tissues are those connective tissues that surround the bones of the

body and include muscles, fat, fascia, nerves, tendons, blood vessels and lym-

phatic vessels. The majority of soft-tissue tumours are not malignant - it is only

when they are malignant that the term sarcoma applies. Thus most tumours of

fatty tissue are lipomas - it is only when one of these is malignant that it is called

a liposarcoma. Similarly, most tumours of fibrous tissue are benign and are called

fibromas, and most tumours of nerves are benign and are called neuromas. Most

tumours of blood or lymph vessels are benign and are called angiomas, either

haemangiomas composed of primitive blood vessels, or lymphangiomas com-

posed of primitive lymphatic vessels (Fig. 20.1).

Soft-tissue sarcomas are classified according to the type of tissue from which

they arise and the type of tissue they most resemble.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

DOI: 10.1007/978-3-540-92925-3_20, © Springer-Verlag Berlin Heidelberg 2009

281

282

20 S oft-Tissue Sarcomas

Fig. 20.1. Photograph of a large

benign haemangioma of tongue

in a young woman

The following is a list of tissues from which soft-tissue sarcomas develop:

Fibrous tissue - fibrosarcoma

Fatty tissue - liposarcoma

Nerve tissue - neurosarcoma

Histiocytes (protective cells - malignant fibrous histiocytoma (MFH)

Synovial membrane lining a joint or tendon sheath - synovial sarcoma (synovioma)

Blood vessels - haemangiosarcoma

Lymphatic vessels - lymphangiosarcoma

Muscle - myosarcoma

Myosarcomas may be further classified as rhabdomyosarcoma and leiomyo-

sarcoma. A rhabdomyosarcoma is a malignant tumour of a voluntary muscle

(that is, one of the muscles of the body over which we have control in moving

arms, legs, abdomen, back, head and neck or the muscles used in breathing).

A leiomyosarcoma is a malignant tumour of involuntary muscle, that is, one of

the muscles over which we have no conscious control such as the muscle in the

wall of the stomach or bowel, or the muscles in the wall of the uterus or the wall

of large blood vessels.

Soft-tissue sarcomas make up only about 2% of malignant tumours. They can

occur in people of all ages from birth to old age and are relatively more common

20.1 Classification: Pathological Types

283

in children and young adults than are most carcinomas. Unless radically excised

sarcomas have a tendency to recur locally. Whilst most cancers tend to metas-

tasise via the lymph vessels, to lymph nodes first, most sarcomas have a greater

tendency to metastasise via blood vessels to lungs rather than to lymph nodes.

201

Classification: Pathological Types

20.1.1 Fibrosarcoma

These tumours develop in fascia or fibrous tissue that covers and surrounds mus-

cles, nerves and other tissues and is distributed widely throughout the body. Thus

a fibrosarcoma may develop almost anywhere in the body especially in a limb or in

the tissues of the trunk. One very fibrous and slowly growing type of fibrosarcoma,

called a desmoid tumour, has a tendency to grow into nearby tissues and to recur

locally after surgical excision but rarely metastasises to other organs. Other more

cellular and less fibrous types have a greater tendency to metastasise.

20.1.2 Liposarcoma

These tumours develop from fatty tissue and may arise in any tissue or organ where

fat is present. They tend to vary from a low-grade malignancy likely to recur locally

after excision but unlikely to metastasise, to a high-grade malignancy in which

both local recurrence and metastatic spread to lungs is common. As a rule the

deeper they are (sometimes they are deep in muscle tissue) and the larger they have

become, the more likely they are to be a higher grade of malignancy (Fig. 20.2).

Fig. 20.2. A large liposarcoma of shoulder

region in a 73-year-old man

284

20 S oft-Tissue Sarcomas

0.1.3 Rhabdomyosarcoma

This tumour presents most commonly in infants and young children as a swelling

in voluntary muscle, especially in muscles of the head and neck, genitourinary

tract, thorax and limbs. It is the sarcoma most likely to metastasise to lymph

nodes although it does metastasise to lungs (Fig. 20.3).

20.1.4 Leiomyosarcoma

This tumour may occur at any site where there is smooth muscle, including the

wall of the stomach or bowel or the uterus or the wall of large blood vessels.

20.1.5 Neurosarcoma

This tumour may develop on any nerve. Sometimes it is purely a tumour of nerve

cells, and sometimes it is a mixture of fibrous tissue and nerve tissue and it may

then be called a neurofibrosarcoma.

Fig. 20.3. The swelling in the jaw in this

4-year-old boy proved to be a rhab-

domyosarcoma

20.1 Classification: Pathological Types

285

20.1.6 Malignant Fibrous Histiocytoma (MFH)

These tumours most commonly develop in muscles, fascia or fatty tissues in

limbs. They are firm rounded tumours rather like liposarcomas or fibrosarcomas.

If deep in muscle, they may become quite large before they are noticed as they

cause few if any symptoms until a lump is felt (Fig. 20.4).

20.1.7 Angiosarcoma

These tumours may develop from endothelial cells of blood vessels or lymph ves-

sels. They develop as enlarging vascular masses (clumps containing partly formed

blood vessels). They are softish tumours and may contain either blood or lymphatic

fluid and thus may be called haemangiosarcoma or lymphangiosarcoma.

Angiosarcoma is a poor prognosis neoplasm because of the high propensity

of blood-born metastases.

20.1.8 Synovial Sarcoma (Synoviosarcoma or Malignant Synovioma)

This tumour of synovial membrane is often a highly aggressive malignant

tumour and occurs most commonly in limbs near joints or in association with

the sheaths around tendons.

Fig. 20.4. A large malignant fibrous histiocytoma caused this swelling in the thigh of a

77-year-old woman

286

20 S oft-Tissue Sarcomas

0.1.9 Presentation

Sarcomas

Sarcomas occasionally develop from previously benign tumours of a similar

occasionally

type. For example, a previously benign lipoma may begin to enlarge, showing

develop from

evidence of malignant change to become a liposarcoma. More often, however,

previously

these tumours arise as a local swelling from no apparent pre-existing abnormality.

benign

Usually, though not always, the lump is painless. Occasionally the swelling

tumours of a

develops at a site of recent injury and the possibility of a sarcoma developing as

similar type.

a result of injury cannot altogether be dismissed. It is more likely, however, that

More often,

in most cases the injury drew attention to a lump that was already present.

however,

Rarely the first evidence of a soft-tissue sarcoma is found on a chest X-ray

these tumours

showing lung metastases.

arise as a local

swelling from

no apparent

20.1.10 Investigations

pre-existing

Like all health problems the first requirement is to take a history of the presenta-

abnormality.

tion of the problem from the patient’s point of view. In the case of a sarcoma it

will usually include a history of the lump and how and when it was first noticed;

the presence, or absence of pain or other possible associated symptoms and if,

when and how rapidly it started to enlarge or otherwise change; then the general

health of the patient and any relevant previous or family history. The lump is

measured, the local draining lymph nodes and other lymph nodes are examined

and a chest X-ray and full blood count are performed. CT scans or MRI scans,

ultrasound and angiography (as discussed in Chap. 7) may also give more infor-

mation about the tumour (Fig. 20.5). MRI scans are now used preferentially in

most centres. Microscopic examination of a biopsy specimen of the lump will

establish the diagnosis.

More recently,

Whether further information of value can be learned from PET scans is pres-

induction, or

ently being investigated.

neo-adjuvant,

chemo-therapy

has been

20.1.11 Treatment

used before

operation to

The standard treatment of soft-tissue sarcomas is excision at a surgical operation.

reduce the

Because the risk of local recurrence of sarcoma is high, the surgeon must remove

size, extent

a great deal of apparently normal tissue around the tumour to be as sure possible

and viability

that all of the malignant cells have been removed. For large sarcomas in a limb,

of large or

sometimes amputation of the limb may offer the best chance of surgical cure.

aggressive

Because of the high risk of local recurrence amputation was the preferred choice

primary

of treatment for most large sarcomas in limbs and even moderate sized sarcomas,

sarcomas

until the mid or late 1970s until it became appreciated that whilst these tumours

before surgery.

are usually not particularly sensitive to radiotherapy, sometimes radiotherapy

before or after local surgery could achieve better results than surgery alone.

20.1 Classification: Pathological Types

287

Fig. 20.5. Angiogram showing vascularity of a large synoviosarcoma in the popliteal

fossa of a 43-year-old woman

Many of these tumours respond to cytotoxic chemotherapy. Early medical

experience with chemotherapy to treat metastatic sarcoma, especially in the

lungs, achieved some regression, with improved length of survival for some

patients, but dramatic improvement in results was rare. More recently, induction,

(or neoadjuvant), chemotherapy has been used before operation to reduce the

size, extent and viability of large or aggressive primary sarcomas before surgery.

This chemotherapy (see Sect. 8.3.4.9), will be more concentrated if given by

regional infusion into a supplying artery and good results have been reported

when this procedure is followed by surgery.

Another form of combined therapy proving to be effective in many cases is

concomitant chemotherapy and radiotherapy. In experienced hands this is proving

very effective in treating a number of locally advanced cancers, however it is

potentially considerably more toxic to local tissues than serial use (i.e regional

chemotherapy followed by surgery).

Combined treatments with chemotherapy and surgery with or without radio-

therapy have often avoided the need for amputation and should now be consid-

ered by experts experienced in these techniques before a decision to amputate is

made. Liposarcomas and malignant fibrous histiocytomas are the most common

of the soft-tissue sarcomas and even when very large they usually respond well

to chemotherapy, especially when given directly to the tumour site by regional

infusion before surgery. This will often reduce them to smaller, less aggressive

288

20 S oft-Tissue Sarcomas

and locally resectable tumours, making follow-up surgical resection possible and

successful in most cases without the need for amputation.

Another effective technique being studied in treatment of large or aggres-

sive sarcomas in limbs is by closed circuit infusion with chemotherapy and TNF

(tumour necrosis factor) (Sect. 8.4.2.4). Good results that avoid amputation have

also been reported.

With some sarcomas, the risk of metastatic spread to lungs is considerable and

there may be virtue in also giving a post-operative course of systemic adjuvant

chemotherapy (Sect. 8.3.4.5) to reduce this risk. Studies are being carried out to

determine whether routine use of adjuvant treatment is worthwhile for patients

with aggressive sarcoma.

Sometimes after successful treatment of a soft-tissue sarcoma one solitary

metastatic deposit will be seen in a follow-up chest X-ray. This may have the

appearance of a small round “cannon-ball” and is referred to as a “cannon ball

metastasis”. Occasionally such a lesion can be resected and if it truly is a solitary

metastasis the patient may be cured.

Angiosarcoma being of and in blood or lymph vessels metastasises early and

although surgery, radiotherapy and chemotherapy are the mainstays of treat-

ment, because of the poor outlook, biotherapy treatments are now being closely

investigated.

CASE REPORT

Rhabdomyosarcoma

John is a 3-year-old Turkish boy whose mother took him to their family

doctor after noticing a swelling of the muscles in the posterior aspect of

his left leg. The family doctor found a firm, non-tender, slightly mobile,

mass, that was attached to the muscles below and behind the left knee.

Physical examination was otherwise unremarkable, and plain X-ray of the

lower legs detected no abnormality. An MRI scan of the legs detected a

localised lesion in the left soleus muscle measuring 5.6 cm (superior to

inferior) by 2 cm (anterior to posterior) by 4 cm (left to right). The mass

had a slightly increased density compared to muscle. Multiple septa-

tions (lobules) were identified within the mass. No fat-like component

or haemorrhage was identified. The appearances were reported as be-

ing suggestive of a sarcoma or fibrosarcoma in the left soleus muscle.

John was admitted urgently to the Children’s Hospital. A biopsy of the

lesion performed under general anaesthesia revealed rhabdomyosarcoma

(continued)

20.1 Classification: Pathological Types

289

(continued)

(of the aggressive alveolar type). Staging investigations, including a CT

scan of chest, abdomen and pelvis, bone scan, gallium scan, bone mar-

row aspirate, and PET scan, detected no distant metastases. However a

discrete PET-enhancing scan suggested a lesion in the left popliteal fossa,

remote to and above the primary tumour, consistent with an infiltrated

regional lymph node. A central venous catheter was inserted under the

same anaesthetic for the biopsy. Cardiac, liver function, and glomerular

filtration tests were all normal.

John commenced intensive systemic chemotherapy (using a combina-

tion of vincristine, actinomycin-D, doxorubicin, and cyclophosphamide,

given in pulses every 3-4 weeks for three courses. G-CSF, a bone-marrow

cell stimulating factor, was administered subcutaneously daily between

courses to hasten bone marrow recovery. Each chemotherapy course

caused severe mucositis, severe bone marrow depression, fever and pre-

sumed sepsis requiring broad-spectrum IV antibiotics, and anaemia and

thrombocytopenia, requiring transfusion support. John remained hospi-

talised for the first 2 months of therapy to receive either planned chemo-

therapy or supportive care while recovering.

Progress MRI and PET scans performed 2 months after the initial scans

revealed some reduction in size of the primary tumour, and persistence of

the regional abnormal lymph node.

John is currently recovering from the third course of chemotherapy and

is under consideration for a surgical procedure, which would remove the

muscles from the rear compartment of his left leg along with the regional

lymph node. This is considered an effective method of gaining control of

the visible component of the disease, with an acceptable level of conse-

quent orthopaedic disability. The alternative is radiation therapy to the left

lower leg, which would cause sufficiently severe long-term effects to require

probable late amputation of the lower leg. Adjuvant chemotherapy is to be

continued following a stem-cell harvest, collected to permit a high dose

marrow-ablating chemotherapy treatment with stem-cell rescue to be given

to complete planned chemotherapy around 9 months from diagnosis.

Comment

Sadly this boy has a poor prognosis despite the intensity of treatment

given. The alveolar subtype of histology documented in the primary tu-

mour and the detectable regional node involvement at the time of diagnosis

are poor prognosis features.

Malignant Tumours of Bone and Cartilage

In this chapter you will learn about:

› Osteosarcoma

› Osteoclastoma (central giant cell tumour of bone)

› Ewing’s tumour

› Chondrosarcoma

21.1

Osteosarcoma

A malignant tumour of bone-forming cells is called an osteosarcoma. This is a

highly malignant cancer and tends to affect children and young adults, with the

highest incidence between 10 and 25 years. The cause of osteosarcoma in young

people is not known although it does occur most often in the growing parts of

bone near the bone ends while the patient is still growing and developing.

A rare and virtually incurable osteosarcoma sometimes develops in old people

but in these people the sarcoma has almost always occurred in a bone with a long-

standing bone disease called osteitis deformans or Paget’s disease of bone.

21.1.1 Presentation

Osteosarcoma in young people usually first develops as a painful lump near

Osteosarcoma

the end of a long bone. There may be an obvious swelling occasionally with

in young people

overlying redness and sometimes a fever. The swelling may be tender and may

usually first

at first look like an acute infection in bone. This sarcoma tends to metastasise

develops as a painful

to lungs early in its course so that best results are achieved if it is diagnosed

lump near the end

and treated very early.

of a long bone.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

291

292

21 Malignant Tumours of Bone and Cartilage

21.1.2 Investigations

Bone X-rays showing a diseased area with “sunray” appearance is typical of

osteosarcoma. There is evidence of bone destruction and irregular new bone

formation in the same area of bone. More precise information can be learned

from CT studies or MRI studies. PET scans if available may give even more

information about the tumour. However, the ultimate deciding test is a biopsy in

which a small piece of the tumour is taken for microscopic examination. Chest

X-rays will also be taken to look for evidence of spread to the lungs although

there is commonly micro-metastatic spread to the lungs before becoming visible

in chest X-rays.

21.1.3 Treatment

In the pre-chemotherapy days, osteosarcoma could rarely be cured. Treatment was

by early amputation of an affected limb, sometimes in combination with radio-

therapy, but death usually resulted due to development of lung metastases.

The outlook has been greatly improved with modern chemotherapy given

before and after surgery (Sect. 8.3.4.8).

The outlook has

At first, amputation was commonly used to eradicate the primary sarcoma

been greatly

and the chemotherapy was used to eradicate any small microscopic metastases in

improved

the lungs before they could grow into larger incurable metastases. From almost

with modern

no cures previously the cure rate was improved to about 50% but in virtually all

chemotherapy

cured patients a limb was amputated.

given before

The use of chemotherapy has now been taken even further. Rather than ampu-

and after

tation of the limb induction chemotherapy is given first. The chemotherapy will

surgery.

affect the primary sarcoma in the bone making it smaller and less aggressive. At

the same time the circulating chemotherapy helps eradicate any micro-metastatic

deposits of sarcoma in lungs or elsewhere. In some specialised treatment centres

the primary cancer can be exposed to an even greater concentration of chemo-

therapy if given by intra-arterial infusion. Having passed through the limb, the

chemotherapy then flows into the general circulation as systemic chemotherapy

and affects micro-metastatic deposits in lung or elsewhere. Although attractive as

a potentially more effective method of exposing the primary cancer to more con-

centrated chemotherapy, the technique requires close nursing attention and expert

management and as yet studies have not been carried out to determine whether the

advantage gained justifies the more complex and more expensive technique.

Reports of cures without amputation in 80% of cases in which intra-arterial

chemotherapy was given first as induction treatment have now been matched

by reports of equally successful results with treatment by intense high-dose

chemotherapy given systemically pre-operatively. In both cases post-operative

systemic “adjuvant” chemotherapy is given to deal with any residual cancer cells

wherever they might be, most likely in the lungs.

21.1 Osteosarcoma

293

After reduction of the size and aggressiveness of the primary tumour, either

by systemic or regional chemotherapy, the section of bone containing the residual

primary sarcoma must be excised and replaced by a metal or plastic prosthesis

to reconstruct the bone. An experienced orthopaedic surgeon is needed to carry

out this operation. If there is any remaining doubt about any malignant cells still

being present, radiotherapy might also be given after the surgery (Fig. 21.1).

Fig. 21.1. On the left is an angiogram showing vascularity of a large osteosarcoma of

lower femur of a 22-year-old man. On the right is a repeat angiogram of the same

leg showing the response to chemotherapy. In this case the pre-operative “induction”

chemotherapy was give by infusion into the femoral artery. The lower femur still with

residual but much reduced sarcoma was then resected and the bone reconstructed with

a metal prosthesis. The patient was then given adjuvant chemotherapy by intravenous

infusions at monthly intervals for 6 months. When last seen 8 years later he was well

and walking well with no evidence of residual sarcoma

EX ERCISE

What investigations are helpful in diagnosing the presence, size, blood

supply and extent of sarcomas?

294

21 Malignant Tumours of Bone and Cartilage

CASE REPORT

Osteosarcoma

Mohammed was a 12-year-old boy who had complained of pain in the right

knee region. The pain had been first noticed 5 weeks previously and had

been gradually increasing, causing him to limp. For 2 weeks his mother

noticed swelling just below the knee. The swelling had been slowly in-

creasing. His mother also said that Mohammed had appeared feverish.

His family doctor arranged X-rays of his knee. The X-rays showed an

area of mixed destruction and increased calcification in the upper end of

the tibia with slightly raised periosteum. There were small spicules of

bone protruding at right angles from the lesion in the bone.

Mohammed was referred to an orthopaedic specialist who arranged an

MRI scan of the knee and a chest X-ray.

No abnormality was seen in the chest X-rays but the presence of a de-

structive lesion consistent with osteosarcoma was confirmed in the MRI.

A core biopsy of the lesion, CT scans of lungs and radio-isotope bone

scans were arranged. The biopsy confirmed the presence of osteosarcoma.

No lesion was seen in the lung CTs and other than the lesion in the upper

tibia no other bone lesion was detected.

Mohammed was treated with three cycles of chemotherapy (cisplatin

and adriamycin were used by systemic infusion).

The pain and swelling decreased and after completion of chemotherapy

the lesion had regressed significantly but blood counts showed reduced

white cells requiring antibiotic cover.

Four weeks later when the blood count had returned to normal the

lower femur and upper tibia were excised and a joint prosthesis inserted.

Histopathology confirmed almost total destruction of the sarcoma.

Four cycles of post operative adjuvant chemotherapy was administered

using the same chemotherapeutic agents.

Five years later Mohammed remains well with no evidence of disease.

21.1.4 Intra-Operative Irradiation

A recent study in treatment of osteosarcoma is for the surgeon to excise the

section of bone containing the tumour, and have that section heavily irradiated

(with a certain tumouricidal irradiation dose) and re-implanted into its original

site. The irradiated bone forms as a strut around which new tumour-free bone

develops so acting as a graft. Encouraging results are being reported.

21.2 Osteoclastoma (Central Giant Cell Tumour of Bone)

295

EX ERCISE

Consider why amputation of a limb for advanced soft tissue sarcoma

or osteosarcoma is now a relatively rare event.

21.2

Osteoclastoma (Central Giant Cell Tumour of Bone)

This tumour occurs most commonly in the ends of long bones of middle-aged

adults, most often around the knee joint. It is a tumour of low-grade malignancy

in that it does not often metastasise to other organs or tissues but does tend to

develop locally, and commonly recurs locally after attempts at removal. Some-

times recurrent osteoclastomas develop malignant changes.

1.2.1 Presentation

The first evidence of this tumour is usually swelling near a joint, such as the

knee joint, often with pain. It may be first noticed due to a fracture of the

weakened bone.

1.2.2 Investigations

X-rays, CT or MRI will usually show a typical cystic appearance of this tumour.

A pathologist will establish the diagnosis after microscopic examination of a

biopsy specimen.

21.2.3 Treatment

Recurrent

osteoclastoma

If possible, the tumour is removed surgically. If inadequately removed, radio-

tends to be more

therapy may be given post-operatively.

malignant and

Recurrent osteoclastoma tends to be more malignant and treatment by ampu-

treatment by

tation may then be required.

amputation may

be required.

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21 Malignant Tumours of Bone and Cartilage

21.3

Ewing’s Tumour

This is an uncommon highly malignant tumour that occurs most often in the

shafts of long bones of children and adolescents from 5 to 15 years. Although it

occurs in bones, it is not truly a tumour of bone cells but is a tumour of undif-

ferentiated connective tissue or neurogenic tissue in bone.

1.3.1 Presentation

Pain, swelling, fever and anaemia are common features of Ewing’s tumour, so

much so that a diagnosis of infection (osteomyelitis) may be thought to be pres-

ent. Sometimes lesions are present in more than one bone. Metastases to lungs

or other bones are common.

21.3.2 Investigations

An increased erythrocyte sedimentation rate (ESR), increased white cell count

and a degree of anaemia are usual features. X-rays of the bone typically show a

laminated “onion peel” appearance due to periosteal reaction. Further informa-

tion may be gained from CT or MRI studies or from isotope scans. Biopsy and

microscopic examination will establish the diagnosis.

This is a tumour where, if available, PET scans may be especially helpful to

detect any focus of tumour in bones at other sites and to evaluate response to

chemotherapy and radiotherapy.

1.3.3 Treatment

In the past, standard treatment was by surgery (usually amputation), but was gen-

erally unsuccessful. Fortunately Ewing’s tumour is radiosensitive and chemo-

sensitive.

With modern treatment using induction chemotherapy, radiotherapy and

possibly local surgical excision of the affected piece of bone, and further post

irradiation or post-operative adjuvant chemotherapy, significantly better results

are now being achieved. Recently myelo-ablative chemotherapy followed by

autologous bone marrow transplantion for poor prognosis patients has given

good results.

From being a malignancy considered almost universally incurable a few years

ago most of these patients are now cured.

21.4 Chondrosarcoma

297

21.4

Chondrosarcoma

1.4.1 Presentation

Chondrosarcoma is a malignant tumour of cartilage and most often affects

middle-aged adults. It varies from low-grade (the majority) to high-grade malig-

nancy. This tumour may develop on any bone, especially at the ends of long

bones or in bones of the pelvis, shoulder or ribs. It usually presents as a slowly

growing painful lump on a bone, often near a large joint.

21.4.2 Investigations

X-rays will often show typical appearance of a chondrosarcoma: a cartilage-like

swelling. Biopsy will establish the diagnosis. CT or MRI studies will help show

the exact position, nature and extent of the tumour.

21.4.3 Treatment

If possible, radical surgical excision of the tumour with adjacent bone is carried

out. This may require amputation of a limb.

These sarcomas are not sensitive to standard radiotherapy or chemotherapy

but, because they are slowly growing and usually do not metastasise until late

in the disease most can be cured as long as the primary tumour can be widely

excised before the sarcoma is very advanced.

Encouraging responses with high percentage of apparent cures of chondrosar-

comas in inaccessible surgical sites, especially the base of skull, are now reported

from Boston , USA and other clinics with proton-beam radiotherapy facilities.

Metastatic (Secondary) Cancer

In this chapter you will learn about:

› The most likely sites of metastatic spread from primary cancers

A metastatic (secondary) cancer is the term used to describe a cancer that is

growing in an organ or tissue some distance away from the tissue or organ in

which it originated. The most important differences between benign tumours

and malignant tumours are that benign tumours tend to be slowly growing and

remain localised to the tissue in which they arose. Malignant tumours tend to

grow more rapidly, grow into surrounding structures and spread and establish

secondary growths in tissues or organs away from their primary site of develop-

ment. To spread to distant sites, malignant cells usually grow into blood vessels

or lymph vessels. Individual cells or clumps of cells break off and are carried by

the bloodstream or the lymphatic vessels to a distant organ or tissue or to lymph

nodes where they may grow as secondary or metastatic tumours. It is somewhat

akin to the spreading cancer cells acting like “seeds” and being transported

along blood or lymph vessels to a new “soil” where they may take root and grow.

Malignant cells may also sometimes spread along nerve sheaths, or, across body

cavities such as the abdominal cavity or a pleural cavity.

The most common site for metastatic spread of carcinomas as opposed to

sarcomas, is via lymph vessels into lymph nodes. First, they grow in lymph

nodes near the original cancer and then spread into lymph nodes further away

(Fig. 22.1). The next most common sites of spread are by the bloodstream to

the lungs or liver.

Other common sites of metastatic spread are to bones, the brain, under the

skin, or to the ovaries. No tissue is exempt from developing a metastasis, including

the adrenal glands and the kidneys. However, some organs and tissues tend to

have a relatively low incidence of metastatic growth of most cancers for no

obvious reason. These include the spleen and muscles.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

299

300

22 Metastatic (Secondary) Cancer

EX ERCISE

What primary sites are likely to have resulted in metastatic involvement of

cervical (neck) lymph nodes?

Fig. 22.1. This elderly woman had met-

astatic cancer in enlarged, hard cer-

vical lymph nodes from a squamous

cancer under the right side of her

tongue. She had not been aware of

any trouble in her mouth

The likelihood

The likelihood of a tumour metastasising to a particular site depends to a consid-

of a tumour

erable degree on the type of tumour and its place of origin. Stomach, pancreas and

metastasising

bowel cancers, for example, tend to spread first to abdominal lymph nodes and by

to a particular

portal vein to the liver. Breast cancer tends to spread first to nearby lymph nodes and

site depends to

later to the lungs, liver and bone. Prostate cancer tends to spread local lymph nodes

a considerable

and to bone. Skin cancer and cancers in the mouth and throat tend to spread to nearby

degree on the

lymph nodes with the exception of basal cell cancer which rarely spreads anywhere

type of tumour

other than into surrounding tissues. Lung cancers, on the other hand, tend to spread

and its place

early not only to lymph nodes but to almost any other organ or tissue in the body

of origin.

including bone and brain. Like lung cancer melanoma tends to spread not only to

lymph nodes, lung, liver, lung, bowel and brain but also to the spleen.

22 Metastatic (Secondary) Cancer

301

Sarcomas are more likely to first spread via the bloodstream to the lungs rather than

Primary

Common sites for metastases

Chap.

BCC of skin

Very rarely metastasises

SCC of skin

Regional lymph nodes; the next group of lymph

nodes; lungs very late in disease spread

Melanoma

Regional lymph nodes; next group of lymph

nodes; lung; liver; brain; remote lymph nodes;

small intestine; subcutaneous tissues; spleen; bone;

adrenal glands

Lung

Mediastinal lymph nodes; remote lymph nodes;

bone; brain; liver; subcutaneous tissue; adrenal

glands

Breast

Axillary lymph nodes; supraclavicular lymph

nodes; chest lymph nodes; lung; liver; subcutane-

ous tissues; brain

Oesophagus

Adjacent mediastinal lymph nodes; other intra-

thoracic lymph nodes; supraclavicular lymph nodes

sometimes liver and sub-diaphragm lymph nodes

Stomach

Peri-gastric lymph nodes; para-gastric lymph

nodes; coeliac lymph nodes; small omentum lymph

nodes; supra clavicular lymph nodes; (usually left

side); liver; omentum; peritoneum; ovary

Liver

Other sites in liver, lungs, regional lymph nodes,

rarely to bone

Gall bladder and bile

Small omentum lymph nodes; liver; peritoneum

duct

Pancreas

Adjacent lymph nodes; coeliac lymph nodes; small

omentum; liver; peritoneum; lungs

Small intestine

Mesenteric lymph nodes; para-aortic lymph nodes;

liver

Colon and rectum

Para-colic lymph nodes; next group of lymph

nodes; para-aortic lymph nodes; liver;

peritoneum

Anus - upper anal

Pelvic lymph nodes; para-aortic lymph nodes;

canal Lower anal

liver; inguinal lymph nodes

canal

Lips

Submental and submandibular lymph nodes; cervi-

cal lymph nodes; parotid lymph nodes

Tongue, floor of

Submental lymph nodes; submandibular lymph

mouth, buccal

nodes; cervical lymph nodes; supra clavicular

mucosa

lymph nodes

Posterior tongue,

Tonsillar lymph node; cervical lymph nodes;

tonsillar region and

supra-clavicular lymph nodes; lung

pharynx

(continued)

302

22 Metastatic (Secondary) Cancer

Table 22.1 (continued)

Primary

Common sites for metastases

Chap.

Salivary glands

Adjacent lymph nodes; cervical lymph nodes;

supra-clavicular lymph nodes

Thyroid gland fol-

Adjacent lymph nodes; more distant lymph nodes;

licular cancers

also bones; lungs; liver

Uterus

Adjacent lymph nodes; pelvic lymph nodes; ova-

ries; peritoneum

Ovaries

Adjacent lymph nodes; pelvic lymph nodes; the

other ovary; fallopian tubes; abdominal lymph

nodes; small intestine; peritoneum; liver

Vagina

Adjacent lymph nodes; pelvic lymph nodes;

inguinal lymph nodes

Vulva

Inguinal lymph nodes; more distant lymph nodes

Penis

Inguinal lymph nodes; more distant lymph nodes

Testis

Para-aortic lymph nodes; more distant lymph

nodes; lungs

Prostate

Adjacent lymph nodes; pelvic lymph nodes; bone;

lung; liver

Bladder

Adjacent lymph nodes; pelvic lymph nodes;

peritoneum

Kidney renal pelvis

Hilar lymph nodes; para-aortic lymph nodes; lung

(sometimes a solitary metastasis); also ureter

Brain

Rarely metastasises before causing death from

primary tumour

Leukaemia and lym-

These are systemic diseases

phomas

Soft tissue sarcomas

Predominantly lung (sometimes a solitary metas-

tasis)

Osteosarcoma

Lung (multiple and early)

Osteoclastama

Rarely metastasises unless it degenerates then to

lungs

Ewings tumour

Lung; bone

Chondrosarcoma

Lung, other bones but rarely metastasises until

large, painful and degenerate

This table provides a summary of most primary tumours, their most likely sites of

cancer metastatic spread and reference to the relevant chapters in this book where

further details of each type of cancer is discussed

Techniques and Evidence of Progress

In this chapter you will learn about:

› Evidence-based medicine

› Clinical trials

23.1

Evidence-Based Medicine

It would be good to think that doctors would always know just what was the

Nowhere in the

right thing to do about every health problem in different people under different

field of medical

circumstances but the reality is that this is not the case. The evidence is not

practice is the

always available for deciding just what is best for each individual patient.

situation more

Nowhere in the field of medical practice is the situation more uncertain than

uncertain

in some aspects of treating cancer.

than in some

The objective of all doctors has always been to get best evidence of most

aspects of

effective management. However, the advent of computerised information with

treating cancer.

a variety of approaches in statistical and mathematical analysis and randomised

studies, made it appropriate to link new scientifically studied and mathemati-

cally confirmed clinical information under the group umbrella known as

“evidence-based medicine”. This label distinguishes such evidence from infor-

mation based on a “one-off” experience, a collection of anecdotes, traditionally

accepted beliefs, medical folklore, wishful thinking or grandmothers’ tales.

Nowadays most acceptable evidence is based on randomised trials.

23.1.1 Randomised Trials

In a randomised trial all patients referred to a specialised clinic with a problem

that needs to be studied to discover best method of care are invited to take part.

There are strict ethical standards that must be observed in conducting randomised

trials. Approval must be obtained, not only from the patients involved, but from

independent ethics committees.

F. O. Stephens and K. R. Aigner, Basics of Oncology,

307

308

23 Techniques and Evidence of Progress

The nature of the trial is fully explained to patients considered appropriate

for the study and if they agree they are allocated randomly to one of two “test

groups” over which the researchers have no control. In some special studies there

may be more than two test groups. The researchers have no control over which

patients are allocated to each group. Patients in one of the two groups are treated

by the best known available standard treatment and patients in the other group

are treated by the new technique under study that is believed may be a better

method of treatment. Ideally results are recorded “blind” that is by a third party

who does not know what treatment each patient was given. Results of the two

groups are compared, usually by an appropriate form of statistical analysis, to

discover which was the better form of treatment. Such studies are known as

randomised controlled studies and are stopped as soon as there is enough

evidence that one method is better than the other. The better method is then usually

recommended for all patients.

Although this is not the only way of finding convincing “evidence” of best

practice, it is usually regarded as the most persuasive.

23.1.2 Other Historic Methods of Gathering Evidence

Much evidence accumulated over many years of medical practice has not been

evaluated scientifically or statistically proven to give best clinical information.

In the past, doctors had to make decisions and introduce practices and concepts

based on best available evidence but this was usually gathered from historical

evidence or evidence learned by “trial and error”. Trial and error is based on the

principle of trying not to repeat mistakes, or making least mistakes. This often

masquerades as experience, but one way or another, inevitably by making some

mistakes, new information was produced and progress was made.

Often

Often traditional or historically accepted practices just “grew” and became

traditional or

accepted without close analysis or criticism. The dominant medical or surgical

historically

teacher may have been skilled in practice but unskilled in critical analysis. Each

accepted

practitioner’s own personal experience was often taken as convincing evidence

practices

without proper analysis or fair comparison with other evidence or under different

just “grew”

circumstances. This type of a teacher’s belief, or of personal experience in a

and became

limited practice, is often referred to as “anecdotal evidence”. Although anecdotal

accepted

evidence may well be true, there is no proof that the outcome will be consistent

without close

when used by different practitioners, in different circumstances, and for differ-

analysis or

ent patients.

criticism

However there are some notable exceptions to the value of a “one off”

experience.

Edward Jenner was so convinced that “immunisation” with the mild disease

cowpox would give protection against the deadly and virulent small pox disease,

that he tested his belief on himself. He injected himself with cowpox and had a

mild reaction. He later injected himself with small pox and did not get the dis-

ease. His belief was based on “anecdotal” observations and historic evidence.

23.1 Evidence-Based Medicine

309

There was no scientifically proven information or randomised trial yet vital

medical progress was made. In fact Jenner’s discovery of 1796 has still not been

proven by randomised trials.

Alexander Fleming, working in London in 1928, noticed a mould growing

on a culture stopped the growth of bacteria. Later, in 1940, an Australian,

Dr Howard Florey, also working in Britain, showed that an extract of Fleming’s

mould, called penicillin, could be used effectively and safely in people to kill

bacteria causing infection in humans. So penicillin was discovered and the era

of present-day antibiotic treatment of bacterial infections began. Success of treat-

ment of pneumonia and other infections with penicillin was so obvious that no

randomised trial was ever initiated.

The approach of Edward Jenner, in using himself as a test case, is still occa-

sionally used in testing strongly held beliefs in other areas of medicine.

In 1983 Dr Robin Warren and Dr Barry Marshal in Australia reported in

Lancet their finding of a bacterium called the Helicobacter pylori was present in

the gastric mucosa of patients with gastric ulcers. They believed that rather than

being a coincidental finding it would be found to be a cause of gastric ulcers.

To prove that this bacterium actually was a cause of gastric ulcers rather than an

incidental finding Dr Marshal and a friend swallowed cultures of the bacterium.

Both contracted gastritis with vomiting and abdominal pain and underwent gas-

troscopic examination. Biopsies showed the organism in the inflamed gastric

mucosa. This confirmed the association between H. pylori and gastritis and sub-

sequent epidemiological studies confirmed that without treatment, ulcers could

develop in the inflamed gastric mucosa.

Another report of this type of approach was published in The Medical Journal

of Australia in 1997 in relation to prostate cancer. A doctor was diagnosed by

biopsies as having prostate cancer. Because he believed that there was good evi-

dence that plant phytoestrogens could influence the growth of prostate cancer,

(as do human oestrogens), he gave himself 7 days of treatment with a moderate

dose of phytoestrogens before undergoing radical prostatectomy. After the radical

prostatectomy, the pathologist was asked to examine the prostate cancer cells and

compare their appearance with the appearance of the cancer cells taken in the

biopsies prior to any treatment.

The pathologist found clear evidence of apoptosis (inbuilt cell death) in the

cancer after the treatment without any evidence of apoptosis in the biopsy speci-

mens taken 3 weeks earlier. This of course was a “one off” study as were the stud-

ies of Edward Jenner and Barry Marshal. Although it did not prove anything as

convincingly as would a scientifically controlled “randomised study”, it certainly

indicated that further study would be justified.

An attempt to more scientifically determine the most likely outcome of different

medical practices or treatments has now evolved, especially over the last two

or three decades of the twentieth century. Led by medical scientists with a sta-

tistical frame of mind and epidemiologists’ aptitude, “randomised trials” have

now become the doctor’s basic “measuring stick” of new information and the

foundation upon which “new” and “old” practices are now compared and judged.

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23 Techniques and Evidence of Progress

This is a great leap forward in ability to make acceptable medical progress more

efficient. Where possible, progress in medical practice is best made in scientifi-

cally tested studies where the evidence can be tested and comparisons made and

measured against existing best practices.

However, it should not be forgotten that much of our present knowledge,

“know how” and effective practice is based on a broad range of skills in gath-

ering evidence and it is still true that not all relevant information can be mea-

sured or converted into a computerised model. There is still need for solutions

based on logic and close and personal relationships between practitioners and

their patients. These relationships and evidence gained must not be lost in the

momentum for mathematically based science. Such factors as warmth of rela-

tionship and personal understanding of priorities in social, domestic spiritual

and other circumstances between practitioners and their patients cannot be

measured but are important in decision making. Because they cannot be mea-

sured does not mean that they should be ignored or discarded. They do make

a difference to outcome as far as people are concerned and patients are special

people.

Historical evidence, clinical experience, patient belief systems, personal and

social priorities and needs and other considerations still must play an important

part in clinical decision making. The patient must always be a person first, a

person with a health problem, not primarily a health problem to be solved.

The relationship between the doctor and patient must be personal and sacrosanct,

based on many unmeasurable and intangible aspects of human emotion as well

as knowledge, and applied to the immediate health needs as worked out between

patient and doctor, not as dictated by “scientific data” alone.

Scientific limitations, variations and uncertainties are very evident in deter-

mining best treatment for women with breast cancer and men with prostate can-

cer. Outcomes of investigation and treatment are still unpredictable. Patients’

priorities are often quite different. What will be the right decision for one

patient will not necessarily be right for another patient. Individual judgement

and understanding must play important roles but these are difficult to measure

scientifically.

Some years ago from randomised controlled studies in women with breast

cancer it was learned that the standard operation of radical mastectomy with

removal of underlying muscles and all adjacent lymph nodes from the axilla did

not result in any more cures than a “modified” radical operation. In the modi-

fied operation, no muscle was removed. From further randomised trials it is now

known that for women with a relatively small cancer in the breast, cure is just as

likely by a “breast saving operation”. In a “breast saving operation” only that part

of the breast containing the cancer is removed together with any likely involved

axillary lymph nodes. This is followed by radiotherapy to the remaining breast

tissue. Yet some women who have a breast cancer are not comfortable unless the

whole breast is removed and they should be entitled to make this decision for

themselves if that is their wish. To these women the saving of the breast would

be more worry to them than the loss of the breast.

23.1 Evidence-Based Medicine

311

To other women, and especially to most younger women, the breast is emo-

tionally very important to them. If the whole breast must be removed they would

choose to have an artificially reconstructed breast operation immediately rather

than be left for a period without a breast. Until recently most surgeons were

reluctant to reconstruct an artificial breast for at least 2 years, by which time

recurrence of the cancer in the breast region was unlikely. Randomised studies

have now shown that this delay does not improve the outlook for the patient and

in most cases she should be allowed to choose immediate reconstruction if she

wishes. There are sometimes other variables in patients’ wishes that may need to

be considered such as whether or not to have adjuvant chemotherapy or hormone

therapy, or radiotherapy or chemotherapy for widespread asymptomatic disease.

Some women wish to have their other breast removed, especially if there is a high

incidence of breast cancer in their families. The ultimate decision on these and

other matters must be based on the patient’s special and personal priorities and

needs together with an understanding of the best evidence available of possible

outcomes of different courses of action as explained by the doctor and treatment

teams.

In the case of prostate cancer, a histological diagnosis of cancer does not mean

that the cancer will progress during the patient’s lifetime. In only about 1 in 4

patients is the prostate cancer potentially life threatening before he dies of other

causes yet there is no certain way of determining which cancers must be treated

as a life saving measure. Most men with prostate cancer are in the older age group

and side effects of treatment aimed at cure are likely to be severe. Decisions must

be made on best available evidence but modified by the patient’s lifestyle needs

and priorities.

There are so many variations in disease processes, environmental and social

situations, human needs, beliefs, emotions, priorities and interpersonal relation-

ships, as well as medical skills, facilities and practices that it is not always possible

to subject even basic information to scientifically designed statistical analysis.

The following truisms sums up the complexities involved.

Not all evidence can be justified by statistics and

“The absence

Not all statistics can be justified as evidence

of evidence” Is

not the same

It is also important to keep in mind that:

as “Evidence of

the absence.”

The absence of evidence

is not the same as

Evidence of the absence.

In other words because there is no statistical evidence to prove that something

is true does not, in itself, prove that it is untrue.

In those instances where anecdotal or historic evidence or information based

on a logically proposed hypothesis is still the best available evidence, it must

inevitably still play a part in medical thinking and gathering of knowledge.

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23 Techniques and Evidence of Progress

Evidence based on a logical hypothesis, but not yet ready for a “randomised

trial”, can still be put to the test under a label of scientific study sometimes called

“a pilot study”. The idea and study proposed is usually put to a group of “peers”

or well-informed colleagues for comment and approval before being “trialled” in

a small group of well-informed, consenting and interested patients. If the initial

“trial” is successful a further and larger group is studied. This allows new ideas

to be tested and new evidence gained but under well-organised, closely observed

and safe conditions.

An obvious example of important but uncomplicated information gathered

without scientific analysis is that there has been no randomised study to prove

that people who develop pneumonia will have a better outcome if they are treated

with antibiotics than with the treatment that was standard in the pre-antibiotic era.

Similarly anecdotal and historic evidence alone suggests that surgical removal of

an acutely inflamed appendix is likely to achieve a better outcome than the treat-

ment that was used in pre-anaesthetic days without the intervention of surgery.

There has been no randomised trial to prove this.

In a more recent context the traditional and most effective known treatment

for people with an advanced cancer (usually a sarcoma) in a limb that was too

big for successful local surgical removal, was amputation. Anything less was

known to result in a high risk of local cancer recurrence. Experience in some

clinics now indicates that, rather than amputation, in most cases equally satisfac-

tory results can be achieved by first “reducing” the cancer with chemotherapy,

followed by local surgical removal of the remaining cancer (Chap. 8). This has

never been proven in a strictly randomised controlled study and, in fact, in some

clinics amputation is still regarded as the treatment of choice. Ideally it should be

studied in a properly organised trial but who would be prepared to ask patients to

enter a study in which the amputation of a limb depended on the luck of the draw?

Even if such co-operative patients could be found would this not be a rather select

group of people who would seem to be different to the rest of us?

23.2

Clinical Trials

With so many different ways of treating cancers in general it is important for

major treatment teams to continue to discover which method or methods of treat-

ment are most likely to achieve best results. This will depend on many variable

factors such as the age and place of living and home circumstances of the patient,

the type of cancer and its degree of advancement, the range of treatments avail-

able, any potential side effects of treatment and the acceptance by the patient of

treatment options. In order to compare different treatments of different cancers

in different patients and different circumstances it is important for studies to be

continued in well-conducted clinical trials. In such trials, when it is not known

which option of treatment is best for patients who have a particular problem,

studies are conducted by experts who agree to compare treatment options.

23.2 Clinical Trials

313

If more than two treatment options are being studied, the trial is said to have

“more than two arms”. Such studies must be well considered and planned by

teams of experts and well conducted in a closely supervised fashion. Usually

such trials are best conducted in major teaching hospitals. This is the way much

progress has been made and will continue to be made in improving treatment

for patients with all types of cancer.

Patients should have the conditions of the trial fully described to them. They

should know why the trial is needed, why they have been selected as good patients

for the trial, what potential benefits may result, what are the potential problems,

if any, and the advantages or disadvantages of taking part in the trial (especially

any potential side effects). If patients are invited to take part in a clinical trial, it

is because the specialists cannot be sure that one treatment to be used is better

than another. However in taking part in a study to try to find the answer, patients

will certainly be given closely supervised and highly skilled care. They must be

reassured that their entry into the trial is completely voluntary and they can with-

draw at any time but their participation should help the expert teams discover just

which treatment achieves best results. This information will be important for the

future care of patients perhaps including members of their own family or friends

or even themselves.

Clinical trials of drugs under study are carried out in three phases:

Phase I is planned to determine the maximum well tolerated dose of a drug

that can be safely given. Usually beginning with small doses in a small number

of patients (usually two or three) and gradually increasing the dose in succes-

sive small groups of patients until a maximal well tolerated dose is apparent.

Phase II is planned to determine how effective the safe maximum dose deter-

mined is in treating a number of patients.

Phase III is a randomised trial of sufficient numbers of patients to compare

results of treatment with the new agent under study compared to results of treat-

ment by standard best practice.

23.2.1 Ethics Approval

In medical practice and research there are different types of clinical trials but

all require informed consent from patients and approval of independent ethics

committees. To achieve best information, especially when dealing with rela-

tively uncommon health problems, it is often necessary to organise multi-centre

studies. Multi-centre studies involve patients in a number of different hospitals

or institutions under the care of a number of different practitioners. Such trials

require strict ethical standards of data collection and privacy, approved by inde-

pendent ethics committees as well as agreed methods of gathering, analysing

and publishing results.

Future Directions

In this chapter you will learn about:

› Preention

› Improved cancer screening and diagnostic techniques

› MRS (magnetic resonance spectroscopy)

› Combined imaging using PET and CT or PET and MRI

› Magnetic resonance-guided focused ultrasound surgery

› Vaccines

› Impoved treatment agents

› New agents

› Therapeutic viruses

› argeted therapies

› Impovements in radiotherapy

› More effective integrated treatments with chemotherapy, radiotherapy

and surgery

› Preention of metastases

› Heat therapy

› Other physical treatments - cryosurgery, electrolysis

› Immunoherapy

› Stem cell research

› Genetic engineering and gene therapy

› Studies in cell mediated anticancer activity

› Molecular characterisation in future cancer treatment

› Learning from “alternative” and “naturopathic” practices

› Improved palliative care and supportive care

› Hope for the future

The future for cancer sufferers is a mixture of hope and caution. Certainly there

is much that can be done by application of present knowledge. There is also great

expectation of future improvements in prevention, diagnosis and care. However,

just as there will be great advances in management of cancer in the future, so

too there will be new challenges. AIDS in Western countries is most prevalent

in promiscuous male homosexuals and intravenous illicit drug users who share

needles but in some parts of Africa and Asia it is widespread and increasing in

F. O. Stephens and K. R. Aigner, Basics of Oncology,

315

316

24 F uture Directions

both sexes. Affected people have increased susceptibility to infections and to

developing malignant tumours. As yet no cure is in sight.

People who have undergone organ transplantation and are dependent upon

immune-suppressive drugs to prevent rejection of the transplanted organ, also

have an increased risk of developing a cancer and the sexual revolution has

exposed young women to an increased risk of developing cancer of the cervix.

Lastly it is quite unknown what potential other modern drugs, especially the

illicit drugs, might have in regard to increasing the risk of some cancers. It took

many years before the dangers of tobacco smoking became manifest.

24.1

Prevention (See Chap. 3)

The most obvious measure in reducing the incidence of cancer is to avoid

smoking. This has been known for years, but human nature being what it is,

this precaution has been widely disregarded. While ever there are large profits

to be made from the sale of tobacco products, there will be resistance to the

introduction of more severe statutory measures aimed at reducing smoking.

Tobacco smoking is related to a greater incidence of cancers of lung, mouth,

throat, larynx, oesophagus, stomach, pancreas, large bowel, kidneys, bladder

and even breast cancer.

Another useful active measure is to encourage fair-skinned people to take

greater protection against exposure to the sun and ultraviolet irradiation and

especially for young people to avoid sunburn.

More attention can be paid to removal of pre-malignant conditions such as

hyperkeratoses, leukoplakia, stomach and bowel polyps and papillomas and to

avoid and prevent such infections as hepatitis and AIDS.

Some changes in lifestyle should be encouraged, including a reduction of

animal fats, and artificial additives and chemical preservatives and other con-

taminants in the diet. A greater intake of fibre, nuts, grains, fresh fruits and

vegetables including legumes should also be encouraged as should moderation

in the use of alcohol, although the possibility of some cancer protective value of

a little red wine cannot be denied. There will continue to be advances based on

epidemiological information such as a better understanding of protective quali-

ties of high fibre diets and apparent protective qualities of diets high in other

possible protective agents such as phytoestrogens and lycopene.

Slim, fit, active

General physical fitness with absence of obesity is desirable from every point

people have a

of view. Slim, fit, active people have a lower risk of several cancers including

lower risk of

lung, breast, colon and rectum, prostate and pancreas, as well as better ability to

several cancers

tolerate treatment programs.

Reduction of atmospheric pollutants, vigilant observation of protective indus-

trial laws and protection against radioactive sources are also important preventive

factors.

24.2 Improved Cancer-Screening and Diagnostic Techniques

317

24.2

Improved Cancer-Screening and Diagnostic Techniques (See Chap. 7)

Another measure of increasing importance is regular screening of people

at special risk for certain kinds of cancer so that any early lesion may be

treated before an advanced cancer develops. This may be most appropriate to

detect early breast cancer, cancer of the cervix, cancer of the stomach in some

communities and large bowel cancer. Screening for prostate cancer can often give

a valuable guide but is not universally practiced. It will be more widely accepted

if a method can be developed for determining which prostate cancers are likely

to become aggressive during the patient’s otherwise expected lifetime.

A newer technique of “digital mammography” is showing promise of

improving the accuracy of diagnostic screening of breast cancer in women

younger than 50.

It is anticipated that improved, more accurate and simpler screening measures

for increasing numbers of different cancer types will become available. These

may include simple blood screening tests for cancer antibodies or other tumour

markers to indicate the presence of early cancer at a more curable stage and

before symptoms have developed.

Improved diagnostic measures will also allow more certain and more accurate

diagnosis at an earlier stage. Already improvements in CT scanning and other

organ imaging techniques have made considerable progress and further advances

are assured. Magnetic resonance imaging (MRI) has added to these improved

diagnostic and imaging methods and it is anticipated that positron emission

tomography (PET) scanning might make an even greater impact than CT and

MRI scanning within a few years (Chap. 7). PET gives information about activity,

composition and survival of tumour cells as well as detection of metastatic cells

at an earlier stage than has been possible in the past.

Fine-needle aspiration cytology, frozen section techniques and other improved

Studies are

pathology techniques have allowed major progress in establishing early detection

being made in

and the nature of early tumours. Improvements in the ability to examine body

a number of

cavities with the use of flexible fibre-scopes and endoscopes have allowed con-

laboratories to

siderable progress in detecting and assessing early cancers in recent years. Such

develop tumour

instruments and their application will undoubtedly continue to be improved.

markers that

Studies are being made in a number of laboratories to develop tumour markers

will detect

that will detect cancers in their earliest stages. One such study with encouraging

cancers in their

potential is a test for a molecule present when cells are abnormally dividing.

earliest stages.

Studies of bowel cancer are showing this molecule is a possible indicator of the

presence of a bowel cancer in its preclinical stages. A future screening test for

bowel cancer may result. Studies are also being made in relation to other cancers

including breast, bladder, cervix, mouth and lung.

318

24 F uture Directions

24.2.1 MRS (Magnetic Resonance Spectroscopy)

MRS is an application of MRI. It is evolving technology that has potential to

diagnose many tumours and characterise their metastatic potential. It is a non-

invasive diagnostic test that uses strong magnetic fields to measure and analyse

the chemical composition of human tissues.

New laboratory testing methods will also give information as to which treat-

ment methods and which anti-cancer agents are likely to be of greatest benefit in

treating each individual cancer; for example a tumour cell scanning technique

under study known as magnetic resonance scanning is investigating better methods

of screening for and determining more specific anti-cancer chemotherapy for

different cancers, and trying to match each individual cancer with the agent or

combination of agents to which it is most sensitive.

Experience with MRS of primary breast cancers indicates that it may also

have a valuable application in other cancers. For example it may be possible to

predict the metastatic potential of melanoma by spectroscopic analysis of the

primary tumour and to distinguish naevi from melanomas, thus better selecting

patients for surgery.

24.2.2 Combined Imaging Using PET and CT or PET and MRI

Early imaging studies combining PET and CT or PET and MRI have shown pros-

pects of demonstrating both functional and anatomical information of primary

and metastatic cancers. Such combined imaging has considerable advantage in

diagnosis and assessing response of cancers to treatment. Such techniques are

sure to be further developed in the very near future.

24.2.3 Magnetic Resonance-Guided Focused Ultrasound Surgery

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is a non-

invasive technique that can coagulate tumours, both benign and malignant.

It has been used in some clinical studies and has been shown for example to

have potential as a non-invasive replacement for some open operative procedures

such as lumpectomy of breast lumps. Undoubtedly it will become more widely

used to remove other tumours in the future.

24.3

Vaccines

An effective vaccine traded as “Gardasil” (Merk) against the human papilloma

virus has now been developed and successfully trailed for clinical use against

cancer in humans. It is now used in several countries to vaccinate teenage girls.

24.5 Self Rescuing Concept (SRC)

319

Progress is also being reported in developing vaccines against breast, colo-rectal,

ovarian and kidney cancers and melanomas.

24.4

Improved Treatment Agents

Improved treatment with more effective and more specific anti-cancer drugs is

proceeding and there is constant progress in how best to use anti-cancer drugs

in appropriate combinations and treatment schedules. New and more effective

anti-cancer agents like the Taxanes (derived from a plant) are adding to the

range of available anti-cancer drugs and many drugs are being made safer and

more effective by increasing availability of agents that protect bone marrow and

other body tissues.

Solving many of the problems of bone marrow transplantation has also

allowed stronger and more effective anti-cancer treatment to be given with

improved safety. It is anticipated that heavy-dose chemotherapy with life-saving

bone marrow transplantation may be used effectively in treating patients with

more types of widespread cancer. At present only limited numbers of tumour

types, mostly lymphomas and leukaemias, can be effectively treated this way

with relative safety.

A new class of agents, Cox-2-inhibitors, is being tested in both prevention and

clinical trials. Epidemiological studies have shown that people who regularly take

non-steroidal anti-inflammatory drugs, such as aspirin, for arthritis, have lower

rates of colorectal polyps and colorectal cancers. These block certain enzymes

(cyclogenase enzymes) that are produced in the body when there is inflammation

and are also produced by precancerous tissues. Inhibition of Cox-2 enzymes may

help treat and prevent cancer. Clinical trials of new Cox-2 inhibitors (one is called

celecoxib), in cancer prevention and cancer treatment are under study.

24.5

Self Rescuing Concept (SRC)

S-1 is an active oral flourouracil anti-tumour drug, which is called a “self-

rescuing” drug. The first of a new concept of combining an anti-cancer agent

(5-FU) with a protective or self regulating agent to give dual actions that is

enhancement of pharmacological actions of 5-FU and reduction of its adverse

reactions. By making use of the biochemical and enzymological properties of

5-FU in combination with FT, which is gradually converted to 5-FU in the body,

with a 5-FU’s adverse reaction reducing substance.

It seems that the combined regimen of S-1 with other anti-cancer agents and

with other therapeutic modalities will contribute to the routine medical practice

of cancer treatment in the future.

320

24 F uture Directions

S-1 based combination therapies with other promising drugs like cisplatin,

irinotecan and taxanes, are expected to yield good results. Above all, S-1 plus

CDDO therapy showed a high efficacy and is expected to become a standard

therapy for advanced gastric cancer.

24.6

New Agents

A whole range of new anti-cancer agents is presently undergoing trials in cancer

treatment and some are proving to be very effective. Some under study have

been mentioned in this book in treating different cancers (Chaps 8 and 19).

The most significant of these new agents are gemcitabine, vinorelbine, topoi-

somerase I inhibitors (topotecan, irinotecan), liposomal anthracyclines, new

fluoroprimidines and tyrosine kinase inhibitors but as progress is made more

agents will be added to this list and some older agents will no longer be used.

24.7

Therapeutic Viruses

A new approach in anti-cancer treatment is to find a virus that will specifi-

cally damage cancer cells without damaging normal cells. In some laboratories,

genetically engineered anti-cancer viruses are being designed. Present labora-

tory studies in relation to breast cancer cells have been encouraging although

the anti-cancer potency has been shown to become less effective with prolonged

use. An adenovirus (OnyxO15) has been developed which specifically kills head

and neck cancer cells with p53 mutations, though not as simply as originally

thought. A variant of this has been licensed in China, though its approval and

use remains controversial At the time of writing, safety and effectiveness in

clinical studies has rarely yet been demonstrated.

24.8

Targeted Therapies

Recently, a new avenue of cancer chemotherapy began to show promise with the

discovery of an antagonist to the enzyme involved in myeloid leukaemia, tyrosine

kinase, STI571 (Gleevec or Glivec) The discovery of this agent has stimulated

further research to discover more inhibitors of possible enzymes involved in

production of other cancers (see Sect. 19.4). Future enzyme treatment of prostate

cancer and certain gastro-intestinal cancers appears promising.

A great number of new targeted therapies are under consideration at the clinical

level and the use of multi-target tyrosine kinase inhibitors is increasing for solid

24.9 Improvements in Radiotherapy

321

tumours. Focusing on EGFR-tyrosine inhibitors (gefitinib or erlotinib) some

positive clinical results for lung cancer patients have been encouraging.

Other new studies of special interest in cancer treatment are those investigating

the use of “angiostatic” and “angiotoxic” agents. These drugs have potential to

eliminate cancers by destroying the new fragile blood vessels that cancers depend

upon for their survival. One such agent under investigation is Thalidomide (see

Sects. 8.5.2 and 19.8.2). Thalidomide taken by mothers to reduce morning sick-

ness in early pregnancy some years ago, was responsible for many birth defects.

The birth defects resulted from thalidomide damaging newly developing blood

vessels in the foetus. It is precisely this damaging property to developing capillaries

that may help destroy blood supply to developing cancers. Another new agent

called “Avastin” damages tumour capillaries and when used with chemotherapy

it magnifies the cancer destructive activities of the chemotherapy. Encouraging

results have been reported in treating bowel cancer and studies in treating a range

of other cancers are under investigation.

Lastly the search goes on for agents to promote apoptosis in cancer cells (see

Chap. 1). There is some evidence that it may be possible to restore the self-

destructive features of normal cells to at least some types of cancer cells, possibly

by administration of some biological agents. One of the more interesting studies

of this type is being made in relation to phytoestrogens or related compounds

that seem to have ability to restore apoptosis properties to prostate cancer cells.

Breast cancer cells are similarly under study.

24.9

Improvements in Radiotherapy

Radiotherapy is also being constantly improved with different types of radio-

emission and different treatment schedules integrated with anti-cancer drugs or

hormones for more effective treatment. Improved techniques of administration

include more effective doses of radiation delivered to the tumour volume with

reduced risk of damage to normal tissues. Because tissue sensitivity to radio-

therapy, including that of cancer cells, is dose-dependent, techniques of deliver-

ing increased doses of irradiation more precisely to cancer tissue and sparing

normal tissues are constantly under investigation. Such techniques will continue

to improve local tumour control. The combination of external radiotherapy and

brachytherapy in treatment of prostate cancer is one example (Sect. 16.3) and

further advances continue to be made in treating this and other cancers. The com-

bined synchronous use of radiotherapy with chemotherapy or sometimes more

precisely with regional chemotherapy is another avenue being studied. A further

study using reduced oxygenation with chemotherapy together with radiotherapy

is showing encouraging results in the treatment of advanced head and neck

cancers. Radiotherapy together with immunological agents is similarly under

study. Further treatment progress can be anticipated from of these studies.

322

24 F uture Directions

Implantation of radioactive “seeds” is now established treatment for some

prostate cancers but encouraging results are now being studied using more effec-

tive “seeds”, implanted more precisely into other types of cancer in different

situations. Cancers in the liver for example are now under study and encouraging

results have been reported.

Anticipated technical advances in radiotherapy include three-dimensional

planning techniques, radio-surgery and ionising magnetic radiotherapy (IMRT)

will increase the likelihood of delivering high doses to smaller well-delineated

tumour regions.

Photon therapy with more specific use of X-rays, gamma rays, proton rays and

neutron rays are under study for more specific therapy of some cancers.

24.9.1 Improvements in Focussing Radiotherapy

Treatment by radiotherapy is also being constantly improved with sophisticated

computer planning technology coupled with CT, MRI and PET scans that accu-

rately image tumour targets. The ability to combine radiotherapy with chemo-

therapy has improved treatment results. More effective use of chemotherapy and

radiotherapy integrated with surgery can be anticipated as cancer specialists

become better organized in multidisciplinary teams focusing on specific tumour

types. The best example of this has been in the treatment of breast cancer.

The combined effects of earlier diagnosis, less mutilating surgery combined with

either adjuvant chemotherapy and or hormonal therapy has seen the death rate

from this disease fall by over 20% in the last 15 years.

Newer forms of radiation therapy being tested in trials in a small number of world

specialist centres include a cyberknife, tomotherapy and proton beam therapy.

A cyberknife is basically an advanced linear accelerator technique that rotates

around the tumour region focusing the irradiation onto a limited central region.

At the time of writing this equipment and technique is being especially studied in

a small number of centres including Washington. Tomotherapy, now available in

a number of US centres, is also a technique of focusing irradiation onto a central

tumour with minimal irradiation of surrounding tissues. Proton beam therapy

directs irradiation to a deep especially targeted tumour region. At the time of writing

this equipment and technique is being especially studied in a small number

of centres including Boston.

24.10

More Effective Use of Chemotherapy

and Radiotherapy Integrated with Surgery

With a few possible exceptions such as organ replacement or the use of regional

tissue perfusion techniques, it does not seem that surgical measures for cancer

eradication will advance greatly over present techniques. However, there is need

24.13 Other Physical Treatments

323

for an increasing role for better-organised and better-planned combined, inte-

grated treatment schedules in which chemotherapy, radiotherapy, and surgical

modalities are used more effectively in planned combined approaches from the

outset to improve the treatment of advanced cancers. Further studies are seeking

to refine surgically and radiologically placed intra-arterial catheter techniques

to more selectively distribute anti-cancer agents in greater concentration to the

region of a tumour. Together with PET imaging, it is anticipated that future

treatments will be directed more selectively and more precisely to those parts

of the body where it is needed.

24.11

Prevention of Metastases

Recent reports that bisphosphonates appear to help prevent bone destruction by

secondary cancers have created much interest (Chap. 8). These substances seem

to have ability to protect bone from osteoclast activity and they possibly also

promote apoptosis in secondary cancer-forming cells in bone.

24.12 Heat Therapy

Heat is another treatment modality as yet not well exploited. Cancer cells have

increased susceptibility to destruction by heat. The application of heat to selec-

tively eradicate cancer cells, possibly in combination with anti-cancer drugs,

may in the future produce improved treatment techniques for certain types of

cancer (see Sect. 8.5.1).

24.13 Other Physical Treatments

New studies in progress include cryosurgery and electrolysis in cancer treatment.

Some cancers in liver are being treated and some cancers in lung and other

tissues are being investigated, but as yet, apart from very effective treatment

of liver metastases by cryosurgery, no new major clinical application has been

substantiated (see Chap. 8). Radio-frequency ablation therapy either alone or in

combination with other treatments is being widely investigated for treatment of

liver metastases, with a number of successes being reported.

Perhaps the greatest hopes for the future are in the fields of immunotherapy,

genetic engineering molecular biology and Nanotechnology. (Nanomedicines

and nanopharmaceuticals). This relates to small molecules 2-15 nm in size (simi-

lar to proteins) used for drug delivery or analysis.

324

24 F uture Directions

24.14

Immunotherapy

Perhaps the

Cancers are often thought to be due to a deficiency in the body’s immune

greatest hopes

defence system. Whereas abnormal cells are usually recognised and eradicated

for the future

by the immune defences, in cancer patients, the abnormal cells have continued

are in the fields

to survive and multiply. There is a great deal of supportive evidence for this

of immuno-

“immune surveillance theory”, including the fact that, very occasionally, a

therapy,

really advanced and aggressive type of cancer will suddenly and spontaneously

genetic

disappear without trace, for no apparent reason. This suggests that somehow the

engineering

body’s natural defence mechanisms have taken charge again and eradicated the

and molecular

abnormal cancer cells.

biology.

A great deal of work has been carried out in leading hospitals, cancer insti-

tutes and other institutions in search of greater knowledge about and better appli-

cation of the immunological defence mechanisms. There is hope that specific

immunological tumour markers will reveal evidence of more cancers very early,

and before they can otherwise be detected clinically. Related research indicates

that tumour antibodies may not only reveal early evidence of cancer but may

be used in treatment either in a direct attack upon cancer cells or by carrying

cytotoxic chemical agents specifically to the cancer cells. In time a more reliable

means of stimulating the immune defence system to eradicate cancer cells may

also emerge from these studies. Preparations of monoclonal antibodies are now

available for some tumours, and treatments based on their use are under study.

Studies with such products of the immune defence system as interferon and the

interleukins (see Chap. 8) have not yet had the impact originally hoped for but

more recent products, tumour necrosis factor (TNF) and Herceptin (a monoclo-

nal antibody product) have immediate valuable clinical application, especially

when used in combination with other anti-cancer agents (Chap. 12).

24.15

Stem-Cell Research

Stem cells are undifferentiated “immortal” cells capable of differentiating

into any type of cell and tissue. They have been extracted from bone marrow

of adults, they are present in umbilical cord blood or may be taken from very

early human embryos at the stage of little more than a fertilised ovum. They

are used in research in attempts to replace or to change special body tissues

or to restore normal tissues where needed. They are thus used to develop tis-

sues needed to solve many health problems such as diabetes, cystic fibrosis

and spinal cord injuries as well as tissues involved with cancer. Taking stem

cells from embryos for research purposes is the subject of much ethical and

moral controversy.

24.18 Development in Antibody Treatment

325

24.16

Studies in Cell-Mediated Anti-Cancer Activity

Further basic studies of dendritic cells are leading to a greater understanding of

cell-mediated anti-cancer activity.

Dendritic cells that develop from stem cells in bone marrow give rise to

immature dendritic cells in myeloid or lymphoid pathways and they develop into

mature dendritic cells under inflammatory microenvironments. They therefore

consist of heterogenous (different types) of myeloid or lymphoid cells at differ-

ent stages of maturity. They are widely distributed in both lymphoid and non-

lymphoid tissues.

Mature dendritic cells are major antigen-presenting cells capable of activating

T cells to different cell-mediated immune responses.

Immature dendritic cells play a crucial role in inducing tolerance by induction

of naïve T cells into accepting (anergic) regulatory cells.

In addition dendritic cells recognise various pathogens and can produce

cytokines that activate other immune cells. Thus dendritic cells are crucial for a

link between innate and adaptive immunity.

There is thus an increasing interest in development of immunotherapy with

dendritic cells in cancer treatment as well as other immunopathogenic diseases.

24.17

Genetic Engineering and Gene Therapy

New techniques of molecular DNA biology offer a different approach in combating

cancer. It may soon be possible to change the arrangement of genes in cells and

thus change the nature of actually or potentially malignant cells into cells without

the properties of malignant growth.

Present studies include replacement of abnormal genes with normal genes,

transfer of a gene that can induce tumour cells to die or that can enhance the envi-

ronment to generate a systemic immune response against the tumour. The former

strategy includes suicide gene therapies, tumour suppressor gene therapy and

oncolytic virus therapy. The latter adopts immunogene therapy. Other possible

gene therapies under study include therapies to control cell cycle or apoptosis and

therapies to promote antiangiogenesis.

24.18

Developments in Antibody Treatment

Developments in genetic engineering have promoted further activity in the use

of monoclonal antibody therapy in three major pathways.

326

24 F uture Directions

(a) Monoclonal toxicity (“killer” or cytotoxic antibodies) against the specific

cancer cells.

(b) Antibodies to focus delivery of radiation specifically to the cancer cells.

cancer cells.

24.19

Molecular Characterisation in Future Cancer Treatment

In addition to histological typing, molecular typing of cancer will increasingly be

necessary. For example, the Philadelphia chromosome (Ph), the hallmark of chronic

myeloid leukaemia, is formed by the reciprocal translocation of genetic material

between two chromosomes, designated chromosome 9 and chromosome 22. This

gives rise to the juxtaposition of DNA from chromosome 9, at the site of the another

gene, the ableson gene (abl), to sit beside DNA at the so-called breakpoint cluster

region (bcr) on chromosome 22, giving rise to a gene caused by fusion of the two

genes, called BCR-ABL This new gene will then produce new and different RNA

and new protein that has tyrosine kinase activity. This is thought to be important in

the pathogenesis of this type of leukaemia. This new RNA can be detected using

molecular techniques involving the polymerase chain reaction (PCR).

The enzyme STI-571 (Gleevec), active in treatment of chronic myeloid leu-

kaemia and some gastrointestinal stromal tumours, is the first clinical applica-

tion of such molecular biochemistry in treatment of cancer (see Sect. 19.4).

This kind of knowledge at a molecular level has now been put into therapeutic

practice with the design of molecules which can block the tyrosine kinase activity

associated with this new protein, leading to disease control and perhaps even cure.

This is just one example of the way in which molecular knowledge can give rise to

new and exciting ways to diagnose, monitor and even treat cancer in the future.

Similarly, mutation and polymorphism in the p53 gene, microsatellite-instability,

and up-regulation of enzymes such as thymidylate kinase, influence tumour

sensitivity to chemotherapy. In future, identification of molecular changes in

tumour cell DNA, RNA and proteins will influence estimation of prognosis and

decisions about management.

24.20

Gene Expression Profiling for Prediction of Response

to Chemotherapy

Numerous genes are involved in the development and progression of each cancer.

The expression of these genes is controlled by complex regulatory interaction

networks. The tumour characteristics of each tumour will be an end result of

these genetic inter-reactions.

24.23 Improved Pallative Care and Supportive Care

327

Recent studies of the DNA micro-array provides a potential opportunity to

assess detailed characterisation of tumour cells indicating clinical behaviour and

drug responsiveness. Thus individualised therapy with molecular targeted drugs

should become more widely available in the near future.

24.21

Molecular Heterogeneity

Clinical trials in the twentieth century were based on the assumption that there

was a uniformity of cancer cells and different agents affected different cancers

more-or-less randomly. Further understanding and acknowledgment of hetero-

geneity of cancer cells is vital for the development of individualised therapy in

malignancies. The twenty-first century will be the Era of pharmacogenomics-

based medicine obtained from personal genomic information. Already it has

been developed and started personalised (tailored) treatment based on the expres-

sion of the specific gene or change in drug metabolic enzyme as a biomarker.

24.22

Learning from Alternative and Naturopathic Practices

Finally the possibility that more will be learned from alternative medicine

and naturopathic practices as well as traditional practices from ancient and

“unsophisticated” communities must not be ignored. A number of important

medications and treatments have been developed from plants and practices of

other eras, cultures and civilizations. However care must be taken to properly

analyse such practices and not allow wishful thinking, emotion or “fashion” to

cloud scientific and clinical judgement (see Sect. 8.6.8).

24.23

Improved Palliative Care and Supportive Care

For those people with advanced cancer who are in great discomfort or pain,

methods of relieving suffering with understanding counsel and comfort are now

better understood and better practised. Such measures are more readily available

and palliative care has become a specialty in its own right. These specialists

can now offer very much needed support in patients’ physical, nutritional and

emotional care so that there is little need for patients to suffer greatly from pain

or other distressing symptoms of cancer. Palliative care now extends beyond

immediate hospital needs into domestic, social and long-term needs of patients

and their loved ones and communities (see Sects. 8.6.3 and 8.6.7).

Specialist “supportive care” teams are becoming more established to care

for those cancer patients with treatment complications or patients with a good

328

24 F uture Directions

long-term prognosis but needing active treatment other than traditional pallia-

tive care.

24.24

Hope for the Future

Oncology is an exciting but continuously evolving study with constant progress

in understanding, prevention, investigation and management. This includes a

constant search for better treatment agents and treatment methods. There is now

an increasing plethora of names of chemotherapeutic, hormonal, immunological,

and anti-enzyme anti-cancer agents and gene therapy. Some are of historic inter-

est, some are presently in clinical use, some are under study in clinical trials

and some are still confined to laboratory investigation. Students are advised that

agents and protocols for use of agents are constantly changing. Newer agents and

newer techniques inevitably replace older ones. With constant progress in cancer

research and treatment schedules some names, doses and treatment programs

of today will become outdated. What we have learned today may have to be

changed or added to tomorrow. We must never stop being students.

The Western medical model of health care and education is complex. Some

of its main areas of speciality include medicine, surgery, pathology, radiotherapy

and palliation with further specialisations within each of these. In a medical

system of such complexity it is not possible, nor indeed necessary, for individual

practitioners, researchers or teachers to keep abreast of all areas of progress.

However it is the responsibility of all of us, both those caring directly for patients

and those teaching future doctors and health professionals, to seek the optimum

treatment for our patients and we can do this by either working in or keeping in

contact with collaborative teams that provide the range of skills to offer best care

to our patients.

The probability or possibility of cure or prevention is now available for

increasing numbers of patients with cancer and for some currently considered

incurable, new prospects of cure may be around the corner.

Further Reading

Traditional detailed teaching of cancer for students includes study of each cancer

under sub-headings including introduction, incidence, causes, symptoms, signs,

pathology, clinical investigations, prevention, treatment, complications, prog-

nosis, follow-up or long-term care and record-keeping. Details of treatment

included could be surgical procedures, radiotherapy indications and techniques

and medical management involving drugs, hormones or other agents used, their

indications, doses, treatment schedules as well as special nursing, dietary, social

and community care requirements and facilities. To cover all known informa-

tion about each cancer recorded in one book this way would not be possible and

would require many volumes and indeed before it could be published much would

already be outdated.

In this book a limited number of drugs and techniques only can be mentioned

to help establish principles of cancer-care and understanding. Some likely future

directions are also suggested but practitioners will need to be constantly updated

as years pass.

Many books and multitudes of papers are available for further reading on dif-

ferent aspects of cancer, according to more specific needs or at a more advanced

level.

Some we recommend are:

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hepatic artery floxuridine infusion for colorectal liver metastases”. Lancet 1994;

344: 1255–1260.

Andersson I, “Mammographic screening under age 50: A review”. Breast 2000; 9:

125–129.

Bishop JF, “Cancer Facts”. Harwood Academic, Singapore, 1999.

Bismuth H, Adam R, “Resection of non-resectable liver metastases from colorec-

tal cancer after oxaliplatin chemotherapy”. Seminars in Oncology 1996; 224:

509–522.

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London, 1997.

Brennan MF, “Management of extremity soft tissue sarcoma”. European Journal Surgi-

cal Oncology 1989; 158: 71–77.

Buthiau D, Khayat, “Virtual endoscopy”. Springer, New York, 1999.

329

330

Further Reading

Buthiou D, Khayat D, “CT and MRI in oncology”. Springer, New York, 1998.

Casper ES, Gaynor JJ, Harrison LB, et al. “Preoperative and postoperative adjuvant

combination chemotherapy for adults with high-grade soft tissue sarcoma”. Cancer

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cancers of the liver biliary tract and pancreas”. British Journal of Cancer 1999; 79:

640–644.

Coates A, Rumpke P, Systemic chemotherapy - new strategies. In: “Malignant Mela-

noma”, Lejeune, Chaudhiri, DasGupta (eds.). McGraw-Hill, New York, 1994:

287–294.

Cox K, “Doctor and patient - exploring clinical thinking”, University of NSW Press,

Sydney, 1999.

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research - novel clinical approaches”. Nature Reviews 2002; 1: 415–426.

Dart DA, Picksley SM, Cooper PA, Double JA, Bibby MC, “The role of p53 in chemo-

therapeutic responses to cisplatin, doxorubicin and 5-flurouracil treatment” Inter-

national Journal of Oncology 2004; 24: 115–125.

Dawson AE, Mulford DK, Taylor AS, et al. “Breast carcinoma detection in women age

35 years and younger: Mammography and diagnosis by fine needle aspiration cytol-

ogy”. Cancer 1998; 84: 163–168.

DeVita V, Jr., Hellman S (eds.), “Principles and practice of oncology, 6th edn.” Lippincott

Williams and Wilkins, Philadelphia, PA, 2001.

Dowell SP, McGoogan E, Picksley SM, et al. “Expression of p21, WAF1/CIP1,MDM2

and p53 in vivo: Analysis of cytological specimens”. Cytopathology 1996; 7:

340–351.

Early Breast Cancer Trialists’ Collaborative Group, “Tamoxifen for early breast cancer.

An overview of the randomised trials”. Lancet 1998; 351: 1451–1467.

Eckardt A, “Intra-arterial chemotherapy in head and neck cancer”. Einhorn-Presse,

Reinbek, 1999.

Eggermont AM, Schraffordt Koops H, Leinard D, et al. “Isolated limb perfusion with

high dose tumour necrosis factor in combination with interferon-gamma and mel-

phalan for non-resectable extremity soft tissue sarcomas: a multicentre trial”. Jour-

nal of Clinical Oncology 1996; 14: 2653–2655.

Elting Linda S, Shih Ya-Chen Tina, “The economic burden of supportive care of cancer

patients”. Supportive Cancer Care 2004; 12: 219–226.

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tion chemotherapy of metastatic seminoma: Results of EORCT trial 30874”. British

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cancer.” Journal of Clinical Oncololgy 1996; 14: 2047–2053.

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with complete remission following combination chemotherapy for metastatic breast

cancer”. Journal of Clinical Oncololgy 1996; 14(8): 2197–2205.

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Hortobagyi GN, “Long-term results of combined modality therapy for metastases. The

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Ivan Damjanov, “Anderson’s Pathology, 10th edn”. Mosby, St Louis, 1996.

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with [18F] fluorodeoxyglucose in identifying operable colorectal cancer metastases

to the liver” Archives of Surgery 1996; 131: 703–707.

LeJeune, Chaudhuri, DasGupta, “New strategies in malignant melanoma”. McGraw-

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Harwood Academic, NJ, 1999.

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160 patients with Barrett’s oesophagus or Barrett’s adenocarcinoma”. The Austra-

lian and New Zealand Journal of Surgery 2000; 70: 26–33.

Marks R, Hill D, “Melanoma control” UICC, Geneva, 1992.

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www.cancerhelp.org.uk

Glossary

Acute

Having a sudden onset.

Adenoma

A benign (not malignant) tumour in which the cells

are derived from glands or from glandular epithe-

lium (such as the lining of the stomach).

Adenocarcinoma

A cancer of glandular cells.

Adjuvant Chemotherapy

Chemotherapy given after operative surgery to help

ensure complete eradication of all cancer cells.

Allele

One of two or more alternative forms of a gene.

Anaemia

A blood condition with a reduction in the amount of

haemoglobin carried in the blood.

Anaplasia

More extreme abnormality of cells. Cancer cells are

described as being anaplastic when they have lost the

special features of the cells from which they devel-

oped. Anaplastic cells tend to grow and invade more

aggressively. They more readily invade surrounding

tissues and more readily spread to other places to

form metastases.

Angiogram

An X-ray of blood vessels (see arteriogram).

Anorexia

A feeling of not wanting to eat (lack of hunger) or

early satiety.

Antibody

A type of protein produced by the immune system

that recognises invading organisms or other sub-

stances as foreign. The antibody attaches itself to

the foreign or invading substance in an attempt to

destroy it.

Apoptosis

An inbuilt ability of cells to undergo self-destruction

after they have served their function; part of the age-

ing process of death and replacement and turnover of

ageing cells during normal life. Cancer cells seem to

have lost this inbuilt self-limiting life process.

Arteriogram

A radiograph (X-ray photograph) of an artery taken

after injection of an iodine-based radio-opaque sub-

stance into an artery.

Aspiration

Act of sucking up or sucking out.

335

336

Glossary

Ascites

Accumulation of abnormal amounts of fluid in the

abdominal cavity.

Astrocytoma

A malignant tumour of connective tissue cells in

the brain.

Atrophic

Wasted; degenerate; having lost special qualities.

Atrophy

Wasting away; losing special qualities

(verb or

noun).

Axilla

Armpit.

Bacteria

Germs. Microscopic organisms usually consisting

of one cell only that normally occur in skin, mouth

and the alimentary tract of humans and all animal

species. Some bacteria are toxic and some tend to

invade body organs or tissues causing damage and

illness.

Barium Enema or

Similar to a barium (baryum) meal except that the

Baryum Enema

radiopaque/contrast material is introduced via a tube

(French)

through the anus to allow X-ray films and X-ray

screening of the rectum and large bowel.

Barium Meal or

A test that involves swallowing a liquid contain-

(Baryum French) Meal

ing the radio-opaque element - barium. This allows

radiographs (X-rays) to be taken to show the size and

shape of organs such as the stomach or duodenum.

Barium Swallow

Similar to a barium meal except that while the mate-

(Baryum Swollow)

rial is being swallowed, the shape and outline of the

oesophagus can be studied.

Basal

The lowest part of a structure forming its base. The

basal layer of the skin consists of the deep cells from

which the upper or more superficial cells grow.

BCC

Basal cell carcinoma. A slowly growing skin cancer

that has grown from the basal (deep) layer of skin

cells.

BCG

Bacillus Calmette-Guerin. A bacterial preparation

originally used as an active immunising agent against

tuberculosis. It consists of harmless living organisms

that promote a similar body defence action to that

of tuberculosis bacteria. It is also used in the blad-

der as an immune stimulating agent against benign

papillomata and non-invasive carcinoma.

Benign

Not malignant; favourable for recovery; unlikely to

be dangerous. A benign tumour is one that remains

localised and does not invade or destroy the tissue

in which it originates and does not spread to distant

sites in the body.

Glossary

337

Benign Mammary

A condition of the breasts that is likely to cause cysts

Dysplasia

and other benign lumps in the breasts. This condi-

tion is probably more widely known as fibro-cystic

disease, but other names are fibro-adenosis-cystica,

hormonal mastopathy or “chronic mastitis”. Cells

in dysplastic tissues are not themselves malignant

or pre-malignant but when a cancer develops in a

breast with lumpy dysplastic changes it may be more

difficult to identify. They do have a small but signifi-

cantly greater potential for malignant change.

Biopsy

The removal of a small sample of tissue for micro-

scopic examination.

Block Dissection

Total surgical excision of a whole group of lymph

nodes in one piece of tissue.

Brachytherapy

A method of applying radiotherapy by placement of

tiny radioactive pellets (seeds) or wires or needles

directly into a tumour to destroy it.

Buccal Mucosa

The lining of the cheek in the mouth.

Calcitonin

A hormone produced by certain cells (C cells) in the

thyroid gland. Calcitonin lowers the level of calcium

and phosphates in the blood.

Cancer

A malignant growth of cells. A continuous, pur-

poseless, unwanted and uncontrolled growth of cells

that actually or potentially has power to invade and

damage surrounding tissues and of metastasising to

distant tissues or organs.

Cachexia

The wasting condition often associated with termi-

nal cancer due to abnormal metabolism of glucose.

Capsule

The fibrous or membranous sac-like covering that

encloses a tissue or organ.

Carcinogen

A substance that causes cancer.

Carcinoma

Cancer. More specifically a cancer of epithelial lin-

ing cells or of glandular cells.

Cervix Uteri

The neck of the uterus; the entrance of the womb.

Chemotherapy

Treatment with chemical agents or drugs.

Chronic

Persisting for a long time; having a long or protracted

course.

Chronic Atrophic

A gradual and persistent degeneration of the lining

Gastritis

of the stomach.

Colostomy

An opening made surgically between the large bowel

(colon) and the abdominal wall to allow evacuation

of faeces when the lower bowel is blocked.

Congenital

Present from the time of birth.

338

Glossary

Corynebacterium

A harmless bacterium sometimes A bacterium used

parvum

to stimulate an immune reaction defence reactions.

Cryotherapy

The use of cold or freezing as treatment.

Crohn’s Disease

A chronic granular inflammatory condition that may

affect the small intestine, the large intestine or both.

It was first described by Dr Dalziel in Scotland and

thoroughly studied and reported by Dr Crohn in

America (see granulomatous colitis).

CT Scan

CAT scan or computerised axial tomography; a

method of visualising body tissues by using com-

puterised radiographic techniques. These give X-ray

“pictures” of sections of body tissues.

Cytokines

Protein molecules released by cells when activated

by an antigen. Cytokines are involved in cell-to-cell

communication as enhancing mediators for immune

responses through interaction with specific cell-surface

receptors on white blood cells. Interleukins are cytok-

ines produced by leukocytes. Interferons are cytokines

produced by lymphocytes. Lymphokines and tumour

necrosis factor (TNF) are also cytokines.

Cytotoxic

Having a toxic or harmful effect upon cells.

DNA

Deoxyribonucleic acid. The material from which the

genes and chromosomes in body cells are made.

Dysplasia

An abnormal development of tissues. Dysplastic tis-

sues are not in themselves malignant but have an

increased potential for malignant change.

Endocrine Gland

A gland that secretes its product into the blood stream

for wide distribution in the body. The thyroid, the

pituitary and adrenal glands are examples.

Endoscope

An instrument used for visual examination of the inte-

rior of hollow organs or the interior of body cavities.

Epidemiology

The branch of medicine that deals with the dis-

tribution of diseases, their causes and the ways in

which they appear and spread in different population

groups and at different periods of time.

Epidemiological

To do with epidemiology.

Erythropoietin

A hormone secreted by certain cells in the kidneys

to increase rate of red cell production.

ESR (erythrocyte

The rate at which red blood cells settle out of suspen-

sedimentation rate)

sion in plasma. In general the ESR is raised in poor

health conditions including cancer, inflammations,

arthritic conditions etc.

Exocrine Gland

A gland that secretes its product through a duct into

a body cavity. The parotid gland is an example.

Glossary

339

Faeces

Waste material passed as a bowel motion. Stool, poo

or shit (slang).

Familial Polyposis Coli

An inherited condition in which about half of the

members of a family will develop polyps (small glan-

dular tumours) in the wall of the large bowel. Eventu-

ally one or more of these will become malignant.

Fascia

A fibrous layer or covering.

Superficial Fascia

The fibro-fatty layer consisting mostly of fat under

the skin.

Deep Fascia

The fibrous or membranous layer of tissue that covers

muscles, nerves and blood vessels, or separates mus-

cles or other tissues into different compartments.

Fibroma

A benign tumour composed of fibrous tissue and

cells capable of forming fibrous tissue.

Floor of Mouth

The lower part of the mouth under the tongue.

Gastroscope

A long, thin, flexible instrument used for visual

examination of the interior of the stomach.

Genome

The total genetic material of an organism, containing

the genes in its chromosomes.

Germ Cells

Cells of embryonic tissue that have capacity to

develop into spermatozoa or ova.

Gland

A tissue or organ that manufactures and secretes

fluids and chemical substances necessary for main-

tenance of normal health and body function (e.g.

a salivary gland secretes saliva, an adrenal gland

secretes a number of hormones).

Glucan

A complex carbohydrate (type of sugar or starch)

that constitutes much of the fibre in common veg-

etable and grain foodstuffs and has also been found

to have immune stimulatory properties.

Goitre

Enlargement of the thyroid gland causing a swelling

in the front part of the lower neck.

Granulomatous Colitis

A chronic inflammatory condition of the large bowel

of no known cause (see Crohn’s disease).

Hormone

A chemical substance produced by an endocrine

gland and secreted directly into the bloodstream.

HRT

Hormone replacement therapy: Treatment with a low

dose of hormones to reduce menopausal and post

menopausal symptoms and other problems such as

loss of calcium from bones.

Hutchinson’s Freckle

A large freckle that develops slowly on the face or

other sun exposed skin of elderly people. Sometimes

it develops into a superficial melanoma.

340

Glossary

Hyperkeratosis

A thickening of the flat protective surface layer of

epithelium of skin or lip. The condition is usually

characterised by the formation of crusts or flakes

that drop off. There is a tendency for malignant

changes to appear gradually and thus a skin cancer

may develop.

Immunotherapy

The treatment of disease by giving immune sub-

stances or by stimulating the immune system of

body defences.

Induration

Hardening or thickening of a tissue or a part of the

body such as due to inflammation or infiltration

with cancer.

Induction

The process of starting a change or starting some-

thing to happen. The first step in a process that will

be developed.

Induction

Induction chemotherapy is the use of chemotherapy

Chemotherapy

to begin changes in a cancer as the first step in an

integrated cancer treatment program. The cancer is

usually made smaller and less aggressive by the

use of induction chemotherapy, hopefully making

it more curable by following treatment, usually sur-

gery or radiotherapy or both.

Inflammation

A reaction of tissues due to injury.

Isoflavones

Members of a class of plant hormones (phytoestrogens)

that are present in many plants but are especially plen-

tiful in legumes like soybeans. The greatest known

source is the red clover plant. The red clover is a

legume that contains all the phytoestrogens known to

be most active in human physiology.

Isotope

A different form of an element with the same chemi-

cal properties but different physical properties.

Radioactive isotopes are unstable and slowly emit

small amounts of irradiation and thus decay into

other isotopes.

Kaposi’s Sarcoma

A malignant tumour arising in blood vessels in the

skin.

Kinase

An agent that can convert the inactive form of an

enzyme (pro-enzyme) to the active form.

Langerhan’s Cells

Cells of the immune system in skin.

Lesion

An abnormal area of tissue.

Leukocyte

A white cell. The “white” or colourless type of cell

that circulates in the blood, has amoeboid movement,

and is chiefly concerned with defending the body

against invasion by foreign organisms.

Glossary

341

Leukoplakia

A white patch. A condition distinguished by the

presence of white thickened patches in mucous

membranes, commonly in the mouth. There may be

a tendency for malignant characteristics to appear

gradually and thus for a cancer to develop.

Lipoma

A benign tumour composed of fat cells.

Lycopene

A recently studied anti-oxidant found in tomatoes

and some other fruits that appears to have anti-

cancer or cancer preventative properties. It is the

red colouring component of tomatoes. Tissue culture

and animal experiments suggest potential especially

against prostate and breast cancer calls.

Lymphangiogram

A radiograph

(X-ray photograph) of lymphatic

vessels shown after injection of a radio-opaque

substance (dye) into the lymphatic vessels.

Lymphocyte

One of the types of white cells that circulate in

the blood and take part in immune reactions and

the body’s defence reactions. A mononuclear, non-

granular leukocyte produced by lymph nodes and

other lymphoid tissue.

Lymphoid

Resembling or pertaining to the tissue of the lym-

phatic system. Tissue that contains and produces

lymphocytes.

Lymphoma

A malignant disease or cancer of lymphoid tissue.

Lymph Nodes

Small masses of lymphatic tissue contained in a

bean shaped capsule measuring 1-25 mm. They

are scattered along the course of lymph vessels and

often grouped in clusters. They form an important

part of the body’s defence system. They function as

factories for the development of lymphocytes and

as filters for bacteria and foreign debris from tissue

fluid. They are not glands but are sometimes referred

to as lymph “glands”.

Lymph Vessels or

Small vessels that drain tissue fluid into lymph nodes

Lymphatics

and inter-connect groups of lymph nodes. Eventu-

ally the larger lymph vessels drain this fluid into the

blood stream.

Malaise

A general feeling of lassitude and ill-health; feeling

unwell.

Malignant

Life threatening. A condition that in the natural

course of events would become progressively worse

resulting in death. A malignant growth or cancer is

a growth of unwanted cells that tends to continue

growing and invading, thus destroying surrounding

tissues. It also tends to spread to other parts of the

body causing eventual destruction of other tissues.

342

Glossary

Malignant Fibrous

A malignant tumour of histiocytes which are protec-

Histiocytoma

tive (immune) cells in soft tissues (muscles, fat etc.)

or in bone.

Mediastinum

The central midline area within the chest and

between the lungs. That part of the chest between

the sternum (breast-bone) and the vertebrae (back-

bone), containing the heart, great blood vessels,

trachea and oesophagus.

Medulloblastoma

An uncommon malignant brain tumour that usually

develops from primitive brain cells in the cerebellar

part of the brain, most commonly in children and

young people.

Melanoma

A malignant tumour of pigment-producing cells

most commonly arising in the skin, sometimes in

the eye or occasionally elsewhere.

Menopause

The “change of life”; that time in the life of a woman

when menstruation stops due to reduced activity of the

ovaries and other glands. A number of other physical

and emotional changes are likely to be associated.

Metaplasia

An abnormal change in a tissue, a cell or cell genes.

Metastasis

Metastatic cancer - a secondary growth of malig-

nant cells that has spread from a primary cancer

elsewhere.

Mitosis

A process of cell division in which a single cell

including its nucleus and genes divide to form two

identical cells.

Mitotic Figures

The numbers of dividing cells in a tissue

MRI

Magnetic resonance imaging; a special test based

on certain laws of physics (electro-magnetic fields).

The test allows very detailed pictures to be taken of

cross sections of the trunk, head, neck or limbs. The

resulting pictures are rather like those of CT scans.

Mucus

A protective slimy material secreted by certain

glands and certain cells lining body cavities and

hollow organs.

Mucous Membrane or

The lining of most hollow organs and some body

Mucosa

cavities, such as the mouth, stomach, bowel or

vagina, all of which contain mucous glands and

secrete protective mucus onto the surface.

Myelodysplasia

An abnormal change in bone marrow blood form-

ing cells.

Naevus (or Nevus)

A localised collection of pigment-forming skin cells

forming a circumscribed malformation, usually light

or dark brown in colour, such as a mole or a birth-

mark.

Glossary

343

Neoplasm

“New growth”; an abnormal growth of body cells.

A neoplasm may be benign (innocent and usually

harmless) with limited growth, or malignant (cancer)

with continuing, unwanted and uncontrolled growth.

Neuroblastoma

A malignant tumour of primitive nerve-forming

cells that usually arises in the autonomic nervous

system.

Neuroma

A benign tumour composed of nerve cells.

Occult Blood

Hidden blood. Blood that cannot be seen with the

naked eye but is found to be present on chemical

testing.

Oesophagus

The gullet; the part of the digestive tract for pas-

sage of food from the mouth and pharynx above to

the stomach below. It is a muscular tube lined with

epithelium and extends from the neck, through the

chest and into the abdomen

Oncology

The study of tumours and of patients suffering from

tumours.

Osteomyelitis

Infection of bone. Acute osteomyelitis occurs

when bacteria enter the bone via the bloodstream

establishing a localised, painful swelling with

fever and sometimes septicaemia. It most often

occurs in children. Osteosarcoma in children can

sometimes resemble acute osteomyelitis in its

initial presentation.

Paget’s Disease of Bone

A degenerative bone disease in which bones become

thickened and disorganised.

Paget’s Disease of the

A malignant condition of the nipple in which the

Nipple

nipple appears to develop a rash or “abrasion-like”

appearance.

Palliative

Giving relief; relieving symptoms but not curing

the condition.

Palliation

Relief.

Pancreas

A pale fleshy gland that lies across the back of the

abdominal cavity behind the stomach. It is responsi-

ble for secreting digestive juices containing digestive

enzymes into the digestive tract and for secretion of

the hormone insulin into the bloodstream.

Papilloma

A benign wart like or fern like tumour derived from

epithelium and projecting from an epithelial surface

with a central core of small blood vessels.

PCR (Polymerase Chain

Simple laboratory technique that involves repeat

Reaction).

cycles of targeted replication of genes, to produce

copies that can easily be analysed.

344

Glossary

Petechiae

Small, often pinhead size, reddish or pink spots in

the skin caused by minute haemorrhages. They are

often associated with a deficiency of blood plate-

lets but are sometimes associated with other condi-

tions such as liver failure or some infections such

as typhoid.

Petechial

Having to do with petechiae.

Pernicious Anaemia

A type of anaemia resulting from a failure of gastric

mucosa (stomach lining) to produce a vital ingredient

for making blood. This is called intrinsic factor.

PET Scan

Positron emission tomography scan. A special imag-

ing technique that produces “pictures” of body tissues

based on glucose metabolism in the cells of those tissues

(cancer cells metabolise more glucose than do normal

cells).

Philladelphia

A chromosome detected in cells in patients with

Chromosome

chronic myeloid leukaemia.

Phytoestrogens

Natural occurring oestrogen-like hormones present

in all plants but in large quantities in certain legumi-

nous plants such as soy beans. Thought to be at least

partly responsible for the lower incidence of some

diseases (especially breast and prostate) in people

such as Asians living in Asia who have a high intake

of legumes in their diets.

Platelets

Small disc-shaped particles in the blood that are

essential for normal blood clotting.

Pleomorphic

Having a variety of appearances. Pleomorphic cells

in a cancer are cells of different sizes shapes and

other features in the cancer.

Pleura

The lining or membrane surrounding the lungs and

surrounding the cavity in which the lungs move dur-

ing respiration.

Polyposis Coli

A condition in which there are many polyps in the

colon mucous membrane lining.

Polyp

A tumour projecting on a stalk from the mucous

membrane lining the cavity of a hollow organ.

PMS

Post menopausal syndrome; symptoms of hot

flushes, depression, vaginal dryness, bone wasting

etc associated with menopausal changes.

PMT

Pre menstrual tension. Hormone produced emotional

changes that often occur in women over a few days

preceding menstruation.

Prosthesis

An artificial replacement for a missing body part.

Prosthetic

To do with a prosthesis.

Glossary

345

PSA

Prostate specific antigen. The PSA test is a blood

test to determine the amount of this special protein

enzyme in the circulation. Prostate gland cells pro-

duce this enzyme and when the number of these

cells is increased there is usually a raised level of

PSA in the blood. High PSA levels can be an indi-

cation of the presence of prostate cancer although

other non malignant conditions, especially prostate

hyperplasia and prostatitis, can also cause the PSA

level to be raised.

Radical

Extreme or very extensive. A radical mastectomy

is removal of the whole breast together with lymph

nodes in the axilla and other nearby tissues.

Radio-Opaque Material

A substance that does not allow penetration of

X-rays. It thus shows as a white area on an X-ray

film. It is commonly referred to as “dye”.

Radiotherapy

Treatment with X-rays or gamma rays.

Reticulo-Endothelial

Special defensive cells that form part of the immune

System

system. These cells protect the body against for-

eign materials and invading organisms. The cells

are predominantly found in bone marrow, spleen,

liver and lymph nodes but are also found in other

tissues such as skin and soft tissues and the wall of

stomach and bowel.

Retinoblastoma

A rare malignant tumour of the eye retina that occurs

in infants. Mono-lateral forms represent sporadic

tumours, and bilateral forms are familial.

Sarcoma

A cancer that arises and develops in connective tis-

sues such as muscle, fat, fascia or bone.

Science

The study of truth or fact; provable information.

Scientific Methods

Methods of determining what is truth as opposed to

what might be unproven beliefs, theories, assump-

tions or concepts. The most accepted form of scien-

tific method is to propose a hypothesis and then pres-

ent it for scrutiny or testing. Different methods are

used for testing hypotheses in different situations.

In medicine the most commonly used method of

scientific analysis is to propose a hypothesis and

subject it to scrutiny by making statistical compari-

son with one other, or several other, concepts in the

same field. The hypothesis is then further tested, by

determining whether information gained will reli-

ably give the same results when tested in different

circumstances

346

Glossary

Screening Test

A relatively simple, safe, inexpensive and easily per-

formed test that can be carried out on large numbers

of people to determine whether they are likely to

have a cancer or other serious disease.

Sentinel Node

The lymph node into which tissue fluid first drains

from a tissue via lymphatics.

Side Effect

An effect other than the effect wanted.

Sigmoidoscope

A sigmoidoscope may be a rigid, hollow metal tube

or a long flexible tube containing multiple fibre-optic

channels.

Sigmoidoscopy

Passage of a sigmoidoscope through the anus to

allow visual examination of the inside of the lower

bowel and biopsy of suspicious areas.

Squamous

Flat, like a scale or pavement. Squamous cells are flat

scale-like cells that cover the skin, the mouth, throat,

oesophagus, vagina and some other cavities.

Stem Cells

Cells that have the capacity to develop into all cells

within the organ and repair or replace organ tissue;

immortal, undifferentiated and uncommitted cells.

Most commonly used in reference to stem cells in

bone marrow.

STI 571

Code name for an agent that counteracts tyrosine-

kinase, an enzyme involved in cellular changes of

some cancer cells, especially chronic myeloid leu-

kaemia. Generit name, imatinib. Trade name, glivec

or gleevec.

Tamoxifen

A drug that combines with oestrogen receptors of

cells thus “blocking” the attachment of oestrogen

to the cells.

Telangectasia

A collection of distended capillaries in skin giving a

red lacework pattern or “spidery” localised appear-

ance to an area of skin.

Therapy

Treatment.

Tissue

A layer or group of cells of particular specialised

types that together perform a special function.

Toxic

Poisonous.

Transcription Factor

A protein transferred from DNA to RNA that is

responsible for the first step in manufacture of cel-

lular proteins.

Trauma

Injury (e.g. broken bones) or response to surgery

or sepsis.

Traumatised or

Injured.

Traumatized

Appendix

Table A.1 Worldwide incidence of more common cancers: male

Brain/

Non-

nervous

Hodgkin

Multiple

system

Thyroid

lymphoma

disease

Leukaemia

myeloma

World

3.6

1.2

6.1

1.3

5.2

1.5

More developed

5.9

1.8

10.3

2.3

7.9

2.7

countries

Less developed

2.8

1.0

4.3

1.0

3.9

0.9

countries

Eastern Africa

0.7

1.6

7.9

2.1

3.9

0.9

Middle Africa

0.1

1.1

4.4

0.8

1.2

1.5

Northern Africa

2.5

0.8

4.8

2.0

4.3

0.8

Southern Africa

1.5

0.9

4.8

0.9

3.7

1.6

South Africa

1.6

1.0

5.0

0.9

3.7

1.6

Western Africa

0.4

0.7

7.3

1.7

2.4

0.9

Caribbean

3.4

0.8

4.9

2.0

6.6

2.7

Central America

4.5

1.2

5.2

2.0

6.3

2.2

South America

4.8

1.8

6.9

1.4

5.8

1.9

Argentina

4.2

1.5

8.1

1.5

6.9

1.8

Brazil

6.0

2.1

6.6

1.3

5.5

1.7

USA

6.5

3.0

16.1

2.3

9.6

4.0

Canada

6.8

2.3

14.6

2.7

10.4

4.3

Eastern Asia

3.5

0.8

3.7

0.3

4.6

0.8

China

3.6

0.7

2.9

0.2

4.3

0.6

Hong Kong

4.4

2.1

8.7

0.6

6.7

1.7

Japan

2.7

1.4

7.4

0.4

5.9

1.8

Korea

3.7

1.4

6.6

0.8

5.2

0.8

S.E. Asia

1.6

1.4

5.2

0.7

4.3

0.8

Indonesia

1.4

1.2

6.0

0.7

4.4

1.3

Malaysia

2.1

1.9

7.7

1.1

6.1

2.0

Philippines

2.5

4.9

0.7

6.0

0.8

Singapore

2.5

1.9

7.5

0.7

6.2

1.3

Thailand

1.9

1.1

3.7

0.6

3.3

0.3

(continued)

349

350

Appendix

Table A.1

(continued)

Brain/

Non-

nervous

Hodgkin

Multiple

system

Thyroid

lymphoma

disease

Leukaemia

myeloma

South Central

Asia

2.4

1.0

3.4

1.3

3.0

0.9

India

2.6

1.0

3.2

1.1

3.1

1.0

Pakistan

3.4

1.2

5.1

2.8

3.4

0.9

Saudi Arabia

3.9

2.9

10.0

3.3

6.0

2.2

Turkey

3.8

0.8

5.7

1.3

6.5

0.9

United Arab

4.6

2.4

5.7

6.0

4.8

2.0

Emirates

Eastern Europe

5.8

1.5

6.6

2.9

6.6

1.5

Russian

5.7

1.5

6.0

2.7

6.1

1.4

Federation

Northern Europe

7.0

1.0

10.1

2.1

8.7

3.2

Denmark

7.0

1.3

9.7

2.1

8.6

3.6

Ireland

7.3

1.0

10.4

2.1

9.2

4.2

Norway

8.0

1.6

10.7

2.2

8.2

3.7

Sweden

11.1

1.7

10.6

2.0

10.5

3.5

6.4

0.7

10.4

2.0

8.8

3.2

Southern Europe

6.8

1.2

9.2

2.5

8.0

2.8

Italy

6.3

1.8

12.3

3.1

8.7

3.4

Greece

10.6

0.8

5.6

4.9

8.8

2.3

Spain

6.5

0.5

8.3

1.6

8.0

2.6

Western Europe

6.5

1.7

11.1

2.9

8.9

3.2

France

5.7

1.4

12.8

2.3

8.7

3.4

Germany

7.0

2.0

10.5

3.0

9.2

3.0

Netherlands

6.2

1.0

10.7

2.1

8.5

4.2

Australia

7.0

2.2

14.4

2.1

10.3

4.0

New Zealand

8.6

1.7

14.0

1.9

11.8

5.1

Melanesia

0.4

1.3

8.0

0.7

3.8

0.2

Polynesia

2.3

4.6

8.4

1.1

7.6

2.0

Appendix

351

Table A.1

(continued)

Oral

Naso-

Oro-

Oeso-

Colon/

cavity

pharynx pharynx

phagus

Stomach

rectum

World

6.4

1.7

3.8

10.8

21.5

19.1

More developed

7.6

0.7

4.8

6.7

24.6

37.3

countries

Less developed

6.0

2.0

3.5

12.8

19.9

9.9

countries

Eastern Africa

5.9

1.6

2.6

10.4

7.1

7.2

Middle Africa

4.8

0.7

1.3

1.9

17.0

2.0

Northern Africa

3.5

2.8

1.0

2.7

5.6

6.5

Southern Africa

12.4

1.6

1.5

17.6

8.6

12.7

South Africa

11.3

1.6

1.2

16.4

8.8

13.7

Western Africa

2.4

0.4

1.1

5.4

4.3

Caribbean

7.7

0.8

3.9

6.7

14.5

15.5

Central America

3.8

0.4

2.0

3.1

18.6

9.5

South America

7.4

0.4

4.7

8.3

23.1

15.6

Argentina

6.5

0.3

2.1

8.6

12.8

27.9

Brazil

10.5

0.6

7.9

10.8

21.6

13.6

USA

6.3

0.6

3.1

4.9

7.6

40.6

Canada

7.4

0.8

2.9

4.1

9.1

40.8

Eastern Asia

1.7

2.6

0.6

21.8

42.6

17.8

China

1.2

3.0

0.4

24.5

36.1

13.0

Hong Kong

4.8

25.2

2.6

14.2

19.4

35.0

Japan

4.0

0.5

1.8

10.0

69.2

43.2

Korea

3.3

0.5

1.1

10.1

70.0

14.9

S.E. Asia

3.6

5.8

2.3

3.1

8.7

12.6

Indonesia

1.5

5.7

0.7

0.6

3.5

11.9

Malaysia

2.4

9.7

1.5

3.0

12.1

25.7

Philippines

5.8

6.4

2.3

2.5

9.2

18.1

Singapore

3.7

15.0

2.5

5.9

21.4

37.9

Thailand

5.3

3.5

3.3

3.7

4.9

10.3

South Central

13.0

0.6

8.8

8.5

6.6

4.8

Asia

India

12.8

0.5

9.6

7.6

5.7

4.7

Pakistan

14.7

1.2

6.7

6.3

3.8

5.0

Western Asia

3.7

1.4

1.2

2.4

11.2

11.4

Saudi Arabia

3.7

3.4

1.2

3.9

6.6

7.7

Turkey

3.5

0.9

1.5

2.2

10.5

9.1

United Arab

2.9

2.8

1.0

2.8

6.1

9.4

Emirates

Eastern Europe

7.8

0.7

5.3

7.2

34.1

32.9

Russian

7.7

0.7

5.1

9.0

42.9

31.8

Federation

Northern Europe

5.0

0.4

2.2

7.4

12.7

34.7

Denmark

7.7

0.3

3.4

6.4

8.4

38.8

(continued)

352

Appendix

Table A.1

(continued)

Oral

Naso- Oro-

Oeso-

Colon/

cavity

pharynx pharynx

phagus Stomach

rectum

Ireland

5.9

0.6

2.8

8.6

12.9

44.2

Norway

5.8

0.3

2.2

3.2

11.6

40.0

Sweden

4.5

0.3

1.7

3.1

8.8

33.0

4.4

0.4

1.9

8.9

12.4

35.4

Southern Europe

9.2

0.9

4.9

4.7

19.5

32.9

Italy

6.7

0.9

3.8

4.0

19.9

35.3

Greece

3.0

0.5

1.7

1.6

11.6

17.4

Spain

13.8

1.0

6.1

17.9

32.0

Western Europe

12.6

0.8

10.6

7.7

13.8

42.1

France

14.9

0.7

19.2

11.9

11.1

39.8

Germany

13.2

1.0

7.7

5.8

16.2

45.0

Netherlands

5.8

0.5

3.0

6.4

12.9

41.6

Australia

13.6

0.6

3.2

5.2

9.6

49.9

New Zealand

4.6

0.7

2.0

5.4

10.9

55.3

Melanesia

36.3

0.2

1.5

3.1

5.9

9.2

Polynesia

5.2

2.8

4.9

3.9

13.0

14.3

Appendix

353

Table A.1

(continued)

Larynx

Lung

Melanoma

Prostate

Testis

Bladder

World

5.5

34.9

2.2

21.2

1.6

10.0

More developed

7.7

55.6

6.7

46.7

5.0

18.9

countries

Less developed

4.5

24.8

0.8

7.7

0.8

5.5

countries

Eastern Africa

3.4

3.1

1.8

14.8

0.5

4.9

Middle Africa

2.0

5.7

3.0

25.4

0.1

2.5

Northern Africa

5.2

15.4

0.9

7.2

0.7

25.3

Southern Africa

6.4

23.8

6.0

41.1

0.7

12.1

South Africa

5.7

25.5

6.4

42.8

0.7

13.4

Western Africa

0.7

2.2

1.2

17.8

0.5

3.2

Caribbean

7.0

28.8

0.9

38.6

0.8

7.5

Central America

5.1

22.7

2.1

26.9

1.5

5.2

South America

7.3

25.3

3.1

28.5

2.2

8.6

Argentina

8.5

40.8

4.1

29.4

4.3

14.7

Brazil

9.3

25.0

3.5

28.7

1.6

8.5

USA

5.3

58.7

13.3

104.3

4.0

23.4

Canada

5.0

55.1

8.2

83.9

3.9

17.9

Eastern Asia

2.3

39.4

0.3

3.4

0.5

5.0

China

1.7

38.5

0.2

1.7

0.4

3.9

Hong Kong

7.8

74.7

1.0

7.6

1.3

14.3

Japan

3.2

40.3

0.4

11.1

1.3

9.2

Korea

10.0

31.1

0.3

4.2

0.6

9.5

S.E. Asia

3.8

27.8

0.4

7.1

0.8

4.0

Indonesia

2.0

20.8

0.5

7.0

0.9

4.0

Malaysia

3.6

35.6

0.4

11.7

1.1

6.0

Philippines

5.8

51.6

0.8

18.8

0.8

4.1

Singapore

5.4

47.5

0.4

13.8

1.1

7.1

Thailand

3.3

26.0

0.4

4.4

0.4

5.2

South Central

7.1

11.6

0.4

4.3

0.7

4.2

Asia

India

6.2

9.0

0.3

4.6

0.6

3.2

Pakistan

8.5

20.1

0.2

5.6

0.7

8.8

Western Asia

8.1

31.2

1.3

9.1

1.6

12.7

Saudi Arabia

2.8

10.3

0.6

7.9

0.8

8.2

Turkey

10.2

40.1

1.0

6.9

1.9

11.6

United Arab

3.1

15.1

0.4

9.7

0.9

6.4

Emirates

Eastern Europe

12.1

69.7

5.2

19.4

6.4

17.7

Russian

13.0

74.9

5.4

15.9

6.4

16.4

Federation

Northern Europe

4.2

44.3

7.4

45.4

5.6

18.2

Denmark

5.6

46.8

10.6

31.2

10.4

13.6

Ireland

3.7

39.6

7.9

47.8

4.3

14.3

(continued)

354

Appendix

Table A.1

(continued)

Larynx Lung Melanoma Prostate Testis

Bladder

Norway

3.2

35.1

14.1

65.3

8.8

21.3

Sweden

2.1

21.4

12.6

70.0

6.2

17.9

4.2

47.6

6.1

40.2

5.6

19.2

Southern Europe

11.7

58.8

3.8

23.9

4.6

24.6

Italy

10.8

59.4

4.6

24.9

5.8

28.0

Greece

6.9

55.8

1.9

20.2

3.7

22.5

Spain

14.1

53.2

2.8

24.2

3.8

28.4

Western Europe

8.2

53.2

7.0

54.9

7.3

20.0

France

10.2

53.5

6.8

56.5

6.3

25.6

Germany

7.3

50.3

6.5

53.6

8.9

18.0

Netherlands

5.7

62.0

9.4

55.9

4.9

15.5

Australia

4.3

42.2

40.5

76.0

5.7

15.6

New Zealand

2.9

41.4

36.7

101.1

6.5

17.1

Melanesia

3.3

4.7

5.1

4.6

0.8

2.0

Polynesia

2.0

38.4

5.8

35.4

2.6

6.3

The table shows the incidence of the more common cancers in different parts of the

world and in major countries in these world regions. (Countries are italicised, regions

not italicised.) They show the incidence per 100,000 people per annum. These fig-

ures are not the absolute incidence but have been age standardised to give a truer

comparison because of different life expectancies of people in different parts of the

world and in different countries

The table has been compiled from Globocan website. Specific download reference as

follows: 09/01/2004, http://www-dep.iarc.fr/cgi-bin/exe/globom.exe

Index

angiography, 73, 74

abdominal lymph node, 56

angioma, 281

ableson gene, 326

angiosarcoma, 285, 288

acid phosphatase, 236

angiostatin, 113

acquired immune deficiency syndrome

anorexia, 51, 113

(AIDS), 18, 109, 217, 276, 315

anti-angiogenesis, 113

actinomycin D, 249, 289

anti-angiogenic effect, 279

acupuncture, 116

antibiotics, 206

acute

anti-cancer

lymphatic leukaemia (ALL), 260, 261

drug, 96, 97, 183, 184, 319

lymphoblastic leukaemia, 264

virus, 320

myeloid leukaemia, 262, 268

anti-enzyme anti-cancer agent, 328

trauma, 28

antigen-presenting cell (APC), 111

adenocarcinoma, 144, 172, 174, 191, 247

anti-melanoma vaccine, 139

adenoma, 15

antimetabolite, 96

adenovirus, 320

anti-oestrogen, 105

adjuvant chemotherapy, 98, 163

anti-oxidant, 31, 33

adriamycin, 294

apoptosis, 10, 20, 309, 321

age, 24

aromatase inhibitor, 105, 163

air

asbestos, 148

encephalogram, 72

ascites, 53, 224, 228

pollution, 35

asparaginase, 264

alcohol, 11, 37

aspiration cytology, 86

injection, 184

aspirin, 116, 319

alkaline phosphatase, 236

asthenia, 51

alkylating agent, 276

astrocytoma, 251, 253, 256

allogeneic stem cell, 263

atomic irradiation, 12, 214

alpha-foeto protein (AFP), 83, 179,

atrophic gastritis, 26

224, 233

atypical hyperplasia, 153

alternative medicine, 118

autologous stem cell transplantation, 279

amelanotic melanoma, 134

avastin, 321

ampulla of Vater, 81

axillary lymph node, 162, 163

anaemia, 56, 58, 114, 177, 194, 279

blood test, 176

anal

cancer, 195

Bacillus Camille Guerin (BCG)

treatment, 197

irrigation, 246

speculum, 80

bacteria, 15

analgesics, 116

barium meal, 70, 72, 172, 177, 193

anaplasia, 7, 59, 65

Barret’s

anaplastic cancer, 215

metaplasia, 173

androgen, 240

oesophagus, 172-174

anecdotal evidence, 308

ulcer, 26, 67, 172, 173

365

366

Index

basal cell carcinoma (BCC), 8, 34, 42,

breast

125, 126

biopsy tissue, 62

Bence-Jones protein, 279

cancer, 18, 21, 25, 30, 37, 38, 43, 92,

benign tumour, 7, 28

118, 121, 151, 152, 300

benzene, 260

development, 161

beta-carotene, 235

family history, 153

betel nut, 11, 12, 37, 201

fungation, 164

bilateral salpingo-oophorectomy, 222

hormone therapy, 104

bile duct obstruction, 187

in males, 156

bilharzia, 245

inflammatory, 156

biomarker, 327

metastases, 164

biopsy, 84

pathology, 160

tissue, 62

prevention, 158

bisphosphonate, 115, 165, 241, 279, 323

screening tests, 157

bladder

solitary lump, 154

cancer, 245

staging, 158

treatment, 246

support groups, 167

infection, 245

symptoms, 154

papillomata, 246

treatment, 158

stones, 27

cell, 24

bleeding, 51, 56

clinic, 167

bleomycin, 103

lump, 157

block dissection, 90

prosthesis, 165

blocking agent, 181

reconstruction, 165, 166

blood

screening, 67

loss, 56

trauma, 152

sedimentation, 83

breast-feeding, 43

stem cell, 263

breast-saving operation, 310

test, 82

bronchogenic carcinoma, 143

transfusion, 115

bronchoscopy, 80, 145

tumour marker, 254

buccal mucosa, 12

blood-forming cell, 259

Burkitt’s lymphoma, 14, 261, 271

blue dye test, 138

busulfan, 267

bone

marrow

bio psy, 86, 266, 269

dysplasia, 104

cachetin, 110

transplantation, 263, 267, 319

calcitonin, 215

metastasis, 53, 154, 235

cancer

treatment, 241

cachexia, 51, 90, 110

puncture, 262

cell, 5

bowel

enzyme inactivator, 96

cancer, 30, 32, 33, 191, 195

growth, 110

treatment, 194

clinico-pathology, 59

obstruction, 193

cultural and social custom, 37

papilloma, 192

debulking, 225

polyp, 191, 192

detecting, 65

Bowen’s disease, 129, 131, 132

diet, 29

brachytherapy, 94, 243

future directions, 315

brain cancer, 251

general effects, 49

treatment, 253

genetic factor, 34

branchial cyst, 28

grading, 60

BRCA, 20, 24

in the back of the nose, 208

breakpoint cluster region, 326

in the buccal mucosa, 201

Index

367

in the parotid gland, 210, 212

of the tonsillar region, 206

in the posterior third of the

of the ureter, 248

tongue, 206

of the uterus, 217

incidence, 17

of the vagina, 228

local effects, 49

of the vocal cord, 208

lump, 55

of the vulva, 229

metastasis, 301

oncogene, 19, 21

molecular characterisation, 113

physical signs, 55

molecular typing, 326

prevalence, 6

of parotid gland, 213

prevention, 41, 316

of the anus, 195

racial factor, 33

treatment, 197

registry, 39

of the bile duct, 186

risks, 28

of the bladder, 245

role of stress/emotion, 38

of the body of the uterus, 221

screening, 88, 317

treatment, 221

staging, 60, 61

of the brain, 251

symptoms, 49

treatment, 253

treatment, 87

of the cervix, 19, 38, 217, 218

of complications, 114

treatment, 218

typing, 60

of the colon, 32

cancer-associated gene, 113

of the floor of the mouth, 200

cannon ball metastasis, 288

of the gall bladder, 186

carbohydrate glucan, 29

of the kidney, 273

carcino-embryonic antigen (CEA), 83,

treatment, 248

194, 227

of the large bowel, 191

carcinogen, 10, 13, 36

of the larynx, 208, 209

carcinoid cancer, 190

of the lips, 200

carcinoma, 7

of the liver, 179

castration, 107

treatment, 180, 183

CAT. See computerized axial tomography

of the male breast, 156

cell

of the nervous system, 251

cycle

of the oesophagus, 26, 171

control system, 22

treatment, 173

regulation gene, 19, 20

of the ovary, 223, 226, 227

death, 10

treatment, 224

proliferation, 3, 4

of the pancreas, 187

cell-mediated anti-cancer activity, 107,

treatment, 188

110, 325

of the penis, 37, 231

cerebral meningioma, 255

of the pharynx, 206

cerebro-spinal fluid, 100

of the post-nasal space, 207

cervical

of the prostate gland, 234

cancer, 217, 219

treatment, 239

treatment, 218

of the rectum, 28, 57

smear, 66

of the renal pelvis, 248

test, 218

of the scrotum, 13

chemical carcinogen, 13

of the small intestine, 190

chemo-embolisation, 180

of the stomach, 175

chemotherapy, 89, 94

symptoms, 176

adjuvant, 98, 163

treatment, 177

induction, 101

of the testis, 232

infusion, 99

treatment, 233

intermittent intra-arterial infusion, 183

of the thyroid gland, 213

intraperitoneal, 101

of the tongue, 205

neoadjuvant, 164

368

Index

chemotherapy (cont.)

cryotherapy, 111, 128, 132, 180,

palliative, 98

185, 338

perfusion, 99

cryptorchidism, 232

regional, 99

CT. See computed tomography

side-effects, 98, 102

culdoscopy, 82, 224

systemic, 99

curative treatment, 89

chest X-ray, 73

cyberknife, 322

chlorambucil, 265

cyclin, 22

cholangiogram, 70

cyclogenase enzyme, 319

cholecystectomy, 186

cyclophosphamide, 265, 289

cholecystogram, 70

cystectomy, 247

chondrosarcoma, 281, 297

cystitis, 245

choriocarcinoma, 223

cystoscopy, 80

chronic

cytomegalovirus, 14

lymphocytic leukaemia, 260

cytoplasm, 5

treatment, 265

cytotoxic drug, 262, 263

myeloid leukaemia (CML), 266, 269

treatment, 94, 102

treatment, 267

cigarette smoking, 143

cirrhosis, 11, 179

cisplatin, 219, 220, 294

daunorubicin, 264

clinical

debulking surgery, 225, 226

staging, 62

deep-vein thrombosis, 240

trial, 312

dendritic cell, 110, 325

closed-circuit

depression, 93

infusion, 139

desmoid tumour, 283

perfusion, 139

dexamethasone, 255

cold nodule, 214, 215

diarrhoea, 193

colectomy, 191

diffuse large B cell lymphoma, 278

colon cancer, 21, 182, 196

digital

metastasis, 185

mammography, 317

colonoscopy, 66, 81, 193, 196

rectal examination (DRE), 69,

colo-rectal cancer, 191

236, 242

treatment, 194

dioxin, 43

colostomy, 194, 210

DNA

combined integrated treatment, 101

damage, 9, 22

common bile duct, 187

agents, 96

computed tomography (CT), 75-76

synthesis, 21

computerized axial tomography, 75

docetaxel, 241

constipation, 193

Dorothy Reed-Sternberg cell, 272

continuous infusion pump, 183

Down’s syndrome, 260, 261

contraceptive pill, 38

doxorubicin, 249, 289

contrast barium enema, 72

duct carcinoma, 160

Cori cycle, 51

dyspareunia, 229

corpus cancer, 222

dysuria, 245

corticosteroid, 255

cortisone, 106, 262

Corynebacterium parvum, 108

cowpox, 108, 308

echo-endoscopy, 81

cox-2 inhibitor, 319

Efudix, 132

cranial nerve, 252

electro-cautery, 246

Crohn’s

electroencephalography, 253

colitis, 191

electrolysis, 323

disease, 27

emotional distress, 117

Index

369

endocrine therapy, 169

gastric

endometrial cancer, 107, 221

cancer, 225

endoscopic

ulcer, 175, 309

examination, 79

gastritis, 175, 309

retrograde cholangio-pancreatoscopy

gastro-oesophageal screening, 67

(ERCP), 72, 188

gastroscopy, 81, 176

test, 65

gefitinib, 321

endoscopy, 81, 176

gene

epilepsy, 252

expression, 326-327

epirubicin, 104

therapy, 112-113, 325, 328

Epstein-Barr virus, 14, 207, 261, 271

general

erectile dysfunction, 238, 243

anaesthesia, 90

erlotinib, 321

health, 113-114

erythrocyte sedimentation rate (ESR),

genetic

83, 296

blueprint, 4, 20

erythropoietin, 114

engineering, 325

ethical standards, 313

molecular biology, 323

etoposide, 104

mutation, 4, 10

evidence-based medicine, 307

testing, 69

Ewing’s tumour, 296

genomic information, 327

treatment, 296

germ-cell cancer, 223, 232

excision biopsy, 59, 84, 135, 140

of the testis, 89

excretory urogram, 246, 248

giant cell tumour of bone, 295

external irradiation, 94

Gleason score, 239

glial cell, 251

glioblastoma multiforme, 251, 253, 254

glioma, 251

facial nerve palsy, 210, 212

gluconeogenesis, 51

familial polyposis coli, 23, 45,

glycolysis, 51

191, 193

goitre, 213

family doctor, 121

belt, 35-36

female sex hormone, 221

gonadotrophic hormone, 240

fertilisation, 103-104

grading, 60

fibro-cystic disease, 153

Grawitz tumour, 247

fibrosarcoma, 283, 285

fibrous histiosarcoma, 285

fine-needle aspiration cytology, 317

flexible scope, 81

haemangiosarcoma, 285

fludarabine phosphatase, 266

haematuria, 245

5-fluorouracil, 184, 194

haemoglobin, 82

folinic acid, 184

haemopoietic

follicular cancer, 215

growth factor, 115

follow-up care, 117-118

stem cell, 263

food habit, 15

haemoptysis, 144

frozen section biopsy, 86, 317

hairy cell leukaemia, 109, 268

head and neck cancer, 199

heat therapy, 111, 323

Helicobacter pylori, 15, 27, 175, 309

G1 phase, 21

helper T cell, 111

gallium isotope scan, 273

hepatitis

gallstone, 27, 186

B, 19, 107, 179

gamma ray, 77

immunisation program, 180

Gardasil, 318

surface antigen (HBsAg), 179

gastrectomy, 177, 178

vaccination, 42

370

Index

hepatitis (cont.)

induction chemotherapy, 101, 102

C, 19, 179

industrial

antibody (anti-HCV), 179

cancer, 44

vaccine, 180

irritant, 13

hepato-carcinoma, 34

infectious disease, 7

hepatocellular carcinoma, 179

inflammatory

hepatoma, 14, 34, 179, 181

breast cancer, 156

Herceptin, 62, 108, 109, 165, 324

condition, 89

herpes zoster, 58

infusion chemotherapy, 99

high-intensity focused ultrasound

inherited cancer gene, 23

(HIFU), 239

interferon, 109, 267, 268, 324

HIV infection, 18, 217

interleukin, 109, 110, 324

Hodgkin lymphoma, 260, 271, 272, 278

intestinal cancer, 190

staging, 273

intraperitoneal chemotherapy, 101

treatment, 274

intravenous pyelography (IVP),

hormone, 13

70, 248

replacement therapy (HRT), 13, 44,

inverted nipple, 155

106, 153, 167, 216, 227

iodine, 43

sensitivity test, 163

contrast X-ray, 70

side effect, 106

ionising

hot nodule, 214, 215

irradiation, 35, 44

human

magnetic radiotherapy (IMRT), 322

chorionic gonadotropin (HCG), 83,

irinotecan, 320

224, 233

irradiation

epithelial growth factor, 108

dose, 94

papilloma virus (HPV), 14, 19, 41,

field, 92

66, 107, 195, 217, 318

isoflavone phytoestrogen, 33

Hutchinson’s

isotope scan, 74, 214

freckle, 134, 136

malignant melanoma, 133, 134

hydatidiform mole, 223

hydrocephalus, 252

jaundice, 187, 189

hydroxyurea, 267

hypercalcaemia, 53, 279

hyperkeratosis, 26, 128,

200, 201

Kaposi’s sarcoma, 14, 19, 109

skin lesions, 132

kidney

hypernephroma, 247

biopsy, 273

hyperplasia, atypical, 153

cancer, 247

hypnotherapy, 116, 117

treatment, 248

hysterectomy, 218, 221, 222

stones, 247

hysteroscopy, 222

killer

antibody, 108

cell, 111

Klinefelter’s syndrome, 232

iliac crest, 262

Krukenberg tumour, 225

Imatinib, 270

imatinib mesylate, 110

immune surveillance theory, 324

immunisation, 308

lactate dehydrogenase (LDH), 83, 224,

immunotherapy, 107, 139, 323, 324

233, 276

implantable infusion pump, 184

Laetrile, 119

impotence, 238

Langerhans cell, 42, 126

incision biopsy, 59, 84

laparoscopy, 82

Index

371

laryngeal cancer, 209

lymphoma, 19, 57, 88, 108, 271

laryngectomy, 209, 210

lymphoscintigraphy, 138, 140

laryngoscopy, 80

lymphoedema, 162

laser surgery, 112

lead-time bias, 237

leiomyosarcoma, 282, 284

lenalomide, 279

Mabthera, 278

length-time bias, 237

macrocytic anaemia,178

lentigo maligna, 133

macrophage, 29, 109, 110

leucovorin, 194

magnetic resonance imaging (MRI),

leukaemia, 12, 25, 35, 57, 82, 88, 257,

78, 317

259, 260

magnetic resonance-guided focused

treatment, 262

ultrasound surgery, 318

leukocoria, 258

magnetic resonance spectroscopy

leukoplakia, 27, 195, 200, 203, 229

(MRS), 318

lifestyle changes, 316

malignancy, 3, 5

Li-Fraumeni syndrome, 23

malignant fibrous histiocytoma, 285

lipiodol, 180, 181

mammography, 39, 43, 67, 68, 72, 153,

liposarcoma, 281, 283, 285-287

234

liquid nitrogen, 132

mastectomy, 162, 166, 167, 310

liver

mediastinal lymph node, 233

biopsy, 179, 182

mediastinum, 73

blood tests, 179

meditation, 116

cancer, 11, 179

medullablastoma, 24, 251, 253, 254

treatment, 180, 183

medullary cancer, 215

cirrhosis, 179

melanoma, 25, 26, 34, 108, 111, 118, 125,

isotope scan, 182

133, 134, 138, 140

metastasis, 141

chemotherapy, 138

lobular carcinoma, 160

skin penetration,137

loss of appetite, 176

treatment,137

lost cords club, 210

melphalan,104

lump, 50, 55, 57

meningioma, 7, 253, 255

lumpy prostate, 237

meningitis, 261

lung cancer, 25, 29, 36, 143, 300

menopause, 152

chest X-ray, 145

menstruation, 152

diagnosis, 144

meperidine, 116

histological findings, 146

mesothelioma, 35, 36, 148

pathological subtypes, 144

metamyelocyte, 270

symptoms, 145

metaplasia, 171

treatments, 146

metastasis, 5, 9, 55

luteinising hormone releasing hormone

prevention, 323

(LH-RH), 105, 240

metastatic

lycopene, 31-33, 160, 235

brain cancer, 257

lymph node, 9, 62, 89, 131, 146, 162

breast cancer,164

dissection, 135

cancer

draining, 56, 129

of the lung,148

enlargement, 52, 56

of the ovary,225, 228

lymphangiography, 74

growth, 62

lymphangiosarcoma, 285

liver cancer,182, 185

lymphatic

melanoma,140

leukaemia, 259

sarcoma, 287

mapping, 138

secondary cancer, 299

lymphoblastic leukaemia, 25

spread, 52

lymphocyte, 61, 109, 259, 265

thyroid cancer, 216

372

Index

methadone, 116

microcytic anaemia,178

obstructive cancer of the prostate

micro-metastases, 98, 102

gland, 114

mini-allogeneic transplantation, 263

occult

mitosis inhibitor, 96

blood, 56

mitoxantrone, 240

test, 66

mole checks, 68

cancer, 58

molecular heterogeneity, 327

oesophageal cancer, 171

monoclonal antibody, 108, 266, 276

treatment, 173

morphine, 116

oesophagoscopy, 80, 172, 173

MRI. See magnetic resonance imaging

oestrogen, 105-107, 153

MRI. See magnetic resonance

contraceptive pill, 38

spectroscopy

receptor, 158, 163

mucositis, 289

oligodendroglioma, 251

multi-centre study, 313

omega-3 oil, 43

multinodular goitre, 213, 214

oncogene, 5, 24

multiple myeloma, 279

oncolytic virus therapy, 325

treatment, 279

oophorectomy, 94, 105

muscle weakness, 51

optic nerve, 252

mycosis fungoides, 275, 276

orchidopexy, 232

myeloblast, 270

organ imaging, 69

myelocyte, 270

oropharynx, 207

myelodysplastic syndrome, 104

osteitis deformans, 291

myelofibrosis, 260

osteoclastoma, 295

myelogram, 70

treatment, 295

myeloid leukaemia, 260, 320

osteomyelitis, 296

myeloplastic disease, 260

osteosarcoma, 13, 281, 291, 293, 294

myosarcoma, 282

treatment, 292

ova, 103

ovarian cancer, 223, 226, 227

treatment, 224

nanotechnology, 323

oxygen-free radicals, 21

narcotics, 116

needle aspiration, 85

neoadjuvant chemotherapy, 164

nephrectomy, 248

p53, 14

nephroblastoma, 24, 247-249

mutation, 320

nerve cell cancer, 258

gene, 20, 23

neuroblastoma, 258

protein, 20

neurofibrosarcoma, 284

Paget’s disease

neuroma, 281

of bone, 291

neuropathy, 58

of the nipple, 154, 155, 157

neurosarcoma, 258, 284

pain, 50

nitrogen spray, 128

relief, 115

nodular melanoma, 133

painless lump, 50

non-Hodgkin lymphoma, 14, 19,

palliative

271, 275

care, 118, 327-328

treatment, 277

chemotherapy, 98

non-seminoma, 233

pancreatic cancer, 187, 188

germ cell tumour, 233

treatment, 188-189

nuclear

Papanicolaou test, 66, 218

pleomorphism, 61

papillary

scintigraphy, 74

cancer, 214-215

nutritional deficiency, 15

squamous carcinoma, 203

Index

373

papilloedema, 252, 256

prostate, 13, 121

papilloma, 15, 28

biopsy, 69

papillomata, 200

cancer, 4, 30, 43, 88, 107,

of the bladder, 246

234-235, 237-239,

parotidectomy, 213

240, 300, 309-311

pathological

enzyme treatment, 320

fracture, 115

hyperplasia, 69, 235

staging, 62

prostatectomy, 239

peau d’orange, 157

prostate-specific antigen (PSA), 69,

penicillin, 309

234, 236-237

penile cancer, 231

screening test, 66, 238

perfusion

prostatitis, 234

chemotherapy, 99

prosthesis, 293

pump, 139

protease, 8

peritoneal carcinomatosis, 228

proton

peritoneoscopy, 82

beam therapy, 138, 322

pernicious anaemia, 26, 175

pump, 174

PET. See positron emission

proto-oncogene, 4, 9, 19-21

tomography

pruritus, 187

petechial spot, 51

PSA. See prostate-specific antigen

pethidine, 116

punch out biopsy, 85

pheochromocytoma, 215

purine analogue, 266, 268

Philadelphia chromosome, 96,

266, 267, 270, 326

phosphorus, 13

photodynamic therapy, 112

quacks, 118

photon therapy, 322

phytoestrogen, 30-33, 160,

235, 309

pigmentation, 134

radical

pilot study, 312

laryngectomy, 209

plasmacyte, 60

mastectomy, 92

plasmocytoma, 279

radioactive iodine, 74

pleomorphic

radio-frequency ablation,

adenoma, 210, 211, 213

184, 323

cell, 61

radiographic screening, 72

pleural effusion, 114, 148

radio-iodine scan, 215

pneumonia, 312

radio-isotope, 165

polymerase chain reaction (PCR),

radiotherapy, 89, 92, 116, 128, 131

270, 326

dose, 93

polyp, 15

improvement, 321-322

in the large bowel, 27, 191

Raloxifene, 159

positron emission tomography (PET),

randomised trial, 307-309, 312

78-79, 317

red cell count (RCC), 82

post-nasal space cancer, 208

reflux, 174

prednisolone, 264

regional chemotherapy, 99-100

pregnancy, 37, 103-104

resectoscope, 239

pre-malignant condition, 45

retinoblastoma, 14, 258

prevention, 41

protein, 23

proctoscopy, 80

rhabdomyosarcoma, 24, 282, 284,

progesterone, 106, 153

288-289

receptor, 158, 163, 169

Richter’s transformation, 266

promyelocyte, 270

rigid scope, 79

prostaglandin penile injection, 239

ritiximab, 278

374

Index

switch off mechanism, 5

salivary gland cancer, 210-211

synovial sarcoma, 285

salpingo-oophorectomy, 222

systemic chemotherapy, 99

samarium-153, 165

sandwich treatment, 104, 139

sarcoma, 7, 9, 92, 286, 288, 300

schistosomia, 245

tamoxifen, 105, 107, 158, 163, 168, 169,

sciatica, 236

180, 221

screening program, 66

targeted therapy, 320

seborrhoeic keratosis, 136

taxane, 319

selection bias, 237

T-cell leukaemia virus, 261

selenium, 33

telangiectasia, 93

self rescuing concept (SRC),

temozolomide, 256

319-320

temporary colostomy, 195

seminoma, 25, 233

teniposide, 104

sentinel node biopsy, 138, 162

teratoma, 25, 233

serum

testicular tumour, 232

biochemistry, 83

treatment, 233

test, 82

testosterone, 240

sex hormone, 105

thalidomide, 113, 279, 321

sexually transmitted virus, 217

therapeutic virus, 320

sigmoidoscopy, 79-80

thoracoscopy, 82

signal-transduction inhibitor, 165

thrombosis, 261

skeletal

thyroglossal cyst, 28

muscle loss, 51

thyroid cancer, 12, 34, 43, 214, 215

X-ray, 73

thyroidectomy, 216

skin cancer, 25, 26, 29, 34, 42, 125, 300

thyroxine, 213, 216

prevention, 125

tablet, 215

screening, 67

tissue biopsy, 84

slipped vertebral disc, 236

tobacco smoking, 10, 153, 316

small molecule target inhibitor, 110

tomography, 317

small pox disease, 308

topoisomerase II inhibitor doxorubicin,

smoking, 9, 10, 36-37, 41, 143, 316

104

soft-tissue

topotecan, 320

sarcoma

total

treatment, 286-288

body irradiation, 263

spermatozoa, 103, 104

mastectomy, 162

spontaneous genetic mutation, 20

tracheostomy, 209

squamous cell carcinoma, 14, 34, 42, 125,

transitional cell carcinoma, 248

128-129, 199, 201, 217, 228

transurethral resection (TUR), 239

staging, 60

trastuzumab, 108, 165

standard paraffin section biopsy, 86

treatment method, 89

stem cell research, 324

trial and error, 308

stilboestrol, 95, 240

Trousseau’s sign, 56

stomach cancer, 31-32, 175

Trucut needle, 85

symptoms, 176

tumour

treatment, 177-178

blush, 74

strontium-89, 165, 241

cell scanning technique, 318

suicide gene therapy, 325

marker, 83, 317

sunlight, 12, 26

necrosis factor (TNF), 109, 110,

superficial spreading melanoma, 133

139, 324

supportive care, 115, 327-328

suppressor gene, 4, 19-21, 153, 325

surgery, 90

tumouricidal irradiation dose, 294

swelling, 50, 57

typing, 60