Nutrition and Cancer [1 ed.] 9781444329292, 9781118788707

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NUTRITION AND CANCER EDITED BY CLARE SHAW Nutrition plays a crucial role in supporting patients receiving treatment for cancer. Carefully considered nutritional options can help to manage patients with weight loss and cachexia, support the patient’s ability to recover from surgery and cope with treatments such as chemotherapy and radiotherapy. Patients living with and beyond cancer can also benefit from advice on optimal nutrition and lifestyle changes. Edited by Dr Clare Shaw, Consultant Dietitian at The Royal Marsden NHS Foundation Trust, Nutrition and Cancer takes an unrivalled look at this prevalent disease, offering the reader: • • • •

An insight into the nutritional challenges faced for patients with cancer A practical guide to nutrition and dietetic practice in cancer care A detailed look at nutritional options for different diagnostic groups Contributions from a wide range of cancer specialists

An excellent resource for dietitians, clinical nutritionists, doctors, nurses and other health professionals working with cancer patients, this book is also a fascinating reference for students and researchers with an interest in the area.

Cover design by David Ollerhead

NUTRITION AND CANCER EDITED BY CLARE SHAW

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Nutrition and Cancer

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Nutrition and Cancer Edited by

Clare Shaw, PhD, RD

A John Wiley & Sons, Ltd., Publication

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This edition first published 2011
C 2011 Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing programme has been merged with Wiley’s global Scientific, Technical, and Medical business to form Wiley-Blackwell. Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 2121 State Avenue, Ames, Iowa 50014-8300, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell. The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Library of Congress Cataloging-in-Publication Data Nutrition and cancer / edited by Clare Shaw. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-9042-8 (pbk. : alk. paper) 1. Cancer–Nutritional aspects. I. Shaw, Clare, 1963[DNLM: 1. Neoplasms–diet therapy. 2. Nutrition Therapy–methods. 3. Nutritional Physiological Phenomena. QZ 266 N9757 2011] RC268.45 .N873011 616.99 40654–dc22 2010018328 A catalogue record for this book is available from the British Library. This book is published in the following electronic formats: ePDF 9781444329292; ePub: 9781444329308 R Set in 10/12.5 pt Times by Aptara
Inc., New Delhi, India Printed in

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2011

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Contents

Contributors Preface 1

2

3

Cancer in the twenty-first century Natalie Doyle and Clare Shaw

xi xiii 1

Introduction What is cancer and what causes it? Development and spread of cancer What is the global burden of cancer? Whom does cancer affect? Historical perspective on cancer treatment Cancer survivorship – living with and beyond cancer Nutrition and cancer References

1 1 2 4 5 6 9 10 11

Cancer and nutritional status Alessandro Laviano, Isabella Preziosa and Filippo Rossi Fanelli

13

Introduction Nutritional status and outcome in cancer patients Cancer cachexia Pathogenesis of anorexia and reduced energy intake Pathogenesis of wasting Cancer cachexia: a neurological disease? Summary References

13 13 14 16 20 23 24 24

Treatment of cancer Sanjay Popat

27

Introduction Treatment intent Treatment setting Treatment modalities Conclusion References

27 27 28 28 43 44

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4 Effect of malnutrition on cancer patients Louise Henry Introduction Prevalence of malnutrition amongst cancer patients Effect of malnutrition on outcome Mortality Type of cancer Nutritional status as a prognostic indicator Morbidity Quality of life References 5 Nutrition screening Sian Lewis Introduction Scored Patient-Generated Subjective Global Assessment Malnutrition Universal Screening Tool Mini Nutritional Assessment Nutritional Risk Screening Malnutrition Screening Tool Conclusion Summary References

45 45 46 61 68 69 69 70 71 75 83 83 85 89 90 91 91 93 93 94

6 Nutritional requirements of patients with cancer C. Elizabeth Weekes

97

Introduction Energy Methods used to estimate energy requirements Disease-specific requirements Staging and tumour burden Treatment Response to treatment Tumour recurrence Inflammatory response and cachexia Protein Micronutrients What should we do in clinical practice? Summary References

97 98 100 102 105 105 107 107 107 108 111 112 114 115

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8

9

10

vii

The psychosocial influences of food choices made by cancer patients Lucy Eldridge

121

Introduction Food and cancer Influences to food choices Other dietary approaches patients choose to take and the reasons why Sourcing information Summary References

121 121 122 125 126 127 128

Nutritional support for the cancer patient Clare Shaw and Jane Power

130

Introduction Food provision in a health care setting Symptom management Oral nutritional supplements Artificial nutrition support Summary References

130 130 136 141 142 153 154

Late effects of cancer treatment in adult patients Jervoise Andreyev

158

Cancer is a chronic disease What is survivorship? Who should the dietitian aim to help? The stocktaking interview at the end of the treatment The metabolic syndrome Management of the metabolic syndrome Malnutrition in the cancer survivor Summary References

158 160 160 161 163 164 164 170 170

Nutrition and palliative care Clare Shaw

173

Introduction The role of nutrition in palliative care Psychological aspects of food intake Nutrition support in palliative care Management of nutritional problems Artificial nutrition support in palliative care Summary References

173 175 177 179 180 182 185 185

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Head and neck cancer Bella Talwar

188

Introduction The impact of malnutrition Treatment in head and neck cancer Nutritional intervention and outcomes Immunonutrition Functional implications following surgery Nutrition effects in radiotherapy and chemoradiotherapy Nutritional management Nutritional screening Nutritional assessment Nutritional requirements Oral nutrition support Enteral nutrition support Nutrition monitoring and rehabilitation Summary References

188 189 189 192 195 196 201 204 204 206 207 208 209 212 214 215

Nutrition in upper gastrointestinal cancer Saira Chowdhury and Orla Hynes

221

Introduction Epidemiology and aetiology The upper gastrointestinal anatomy Clinical presentation Staging Treatment pathways and role of nutrition Advanced disease Summary References

221 221 223 224 226 227 242 244 245

Cancers of the lower gastrointestinal tract Jane Power

255

Introduction Nutritional management Symptom management in palliative care Summary References

255 261 267 267 267

Gynaecological cancer Mhairi Donald

270

Introduction Ovarian cancer Endometrial cancer

270 270 272

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Cervical cancer Vulval and vaginal cancers Nutritional issues Nutritional implications of treatment Medical problems Nutrition and survivorship Summary References

272 273 273 274 279 283 283 283

Haemato-oncology Gayle Black

287

Introduction Disease characteristics and nutritional implications at diagnosis Nutritional implications during induction and intensification treatment Stem cell transplantation (consolidation phase) Nutrition support post-transplantation Long-term implications following transplantation Summary References

287 287 289 289 299 304 305 305

Paediatric oncology Evelyn Ward

311

Introduction Types of childhood cancers Aetiology of malnutrition in children with cancer Identification of nutritional risk Nutritional support References

311 312 315 317 318 329

Nutrition and breast cancer Barbara Parry

334

Introduction The role of diet in breast cancer aetiology and survival Gestational nutrition and subsequent birth weight Breastfeeding Body fatness, body composition and weight management Alcohol Dietary fat Fruits and vegetables (including beans and pulses) Dairy foods Meat and meat products Specific nutrient associations and nutritional supplements Contaminants in foods Physical activity

334 336 336 341 342 343 345 347 351 352 353 353 354

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Benefits of physical activity to breast cancer survivors Nutritional problems during breast cancer treatment Summary References

355 356 358 358

Nutritional management in prostate cancer Kathryn Parr

363

Introduction Dietary factors that may reduce the risk of prostate cancer Factors that may increase risk of prostate cancer Dietary interventions and prostate cancer progression Obesity/weight management Nutritional issues during treatment for prostate cancer Nutrition-related side effects of medications used to treat prostate cancer Malnutrition in prostate cancer Palliative care in prostate cancer Summary References

363 364 367 368 371 371 372 373 373 373 375

Lung cancer Cherry Vickery

379

Introduction Diet and development of lung cancer Nutritional status at presentation Treatment of non-small cell lung cancer Treatment of small cell lung cancer Treatment of mesothelioma Palliative treatments Symptom management Summary References

379 380 381 382 383 384 384 386 388 388

Index

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Contributors

Jervoise Andreyev The Royal Marsden NHS Foundation Trust, London, UK Gayle Black The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK Saira Chowdhury Department of Nutrition and Dietetics, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, London, UK Mhairi Donald Sussex Cancer Centre, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK Natalie Doyle The Royal Marsden NHS Foundation Trust, London, UK Lucy Eldridge Barts and the London NHS Trust, London, UK Filippo Rossi Fanelli Sapienza University of Rome, Rome, Italy Louise Henry The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK

Orla Hynes Department of Nutrition and Dietetics, Guy’s and St. Thomas’ Hospital NHS Foundation Trust, London, UK Alessandro Laviano Sapienza University of Rome, Rome, Italy Sian Lewis Velindre Hospital, Cardiff, Wales, UK Kathryn Parr Clatterbridge Centre for Oncology NHS Foundation Trust, Wirral, UK Barbara Parry Winchester and Andover Breast Unit, Royal Hampshire County Hospital, Winchester, UK Sanjay Popat The Royal Marsden NHS Foundation Trust, London, UK Jane Power Betsi Cadwaladr University Health Board and Wrexham Maelor Hospital, Wrexham, Wales, UK Isabella Preziosa Sapienza University of Rome, Rome, Italy

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Contributors

Clare Shaw The Royal Marsden NHS Foundation Trust, London, UK

C. Elizabeth Weekes Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Bella Talwar Head and Neck Cancer Services, University College London Hospitals NHS Trust, London, UK

Cherry Vickery North Wales Cancer Treatment Centre, Betsi Cadwaladr University Health Board (Central), Wales, UK

Evelyn Ward The Leeds Children’s Hospital, The Leeds General Infirmary, Leeds, UK

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Preface

Good nutrition is essential for good health. However, maintaining a good nutritional status and adequate nutritional intake during illness is often difficult. Weight loss, reduced intake of food and fluid may be early presenting symptoms of disease, particularly cancer. These changes may proceed to profoundly influence body composition, functional ability and quality of life. After a diagnosis of cancer, the focus is on successfully treating the cancer and importantly managing symptoms that patients may experience. Treatment modalities such as surgery, chemotherapy, radiotherapy and novel treatments such as targeted therapies are often used in combination or sequentially. Increasingly, these treatments are successful, and there are now rising numbers of people living with and beyond cancer. When cancer is diagnosed, the patient embarks on investigations and a treatment pathway. Often, the issues relating to weight loss and nutritional risk are poorly addressed at this time. This is despite the fact that high levels of malnutrition in cancer patients have been documented for many years. Treatment modalities may cause a further deterioration in nutritional status which ultimately impacts on functional status, ability to tolerate treatment, quality of life and potentially survival. Not all cancer diagnoses and treatments will have the same effect on nutritional status, so individualised screening, assessment and appropriate advice and support are essential to address individual problems. Whilst it is known that poor nutritional status can impact on an individual’s ability to undergo cancer treatment, there is a paucity of nutrition intervention studies to demonstrate the best method of nutritional support, when more intensive nutritional support should be commenced, which clinical outcomes can be influenced and to what extent. Nutritional issues may contribute to health both during treatment and throughout the person’s life. Some patients may have no long-term nutritional problems, but for others their appetite, ability to eat, digest and absorb food may be altered irreversibly. Some may struggle with changes in body weight or function, whilst others consider how their future diet can influence their health and survival. This book aims to explore many of the nutritional issues that occur after a diagnosis of cancer. Although there is increasing evidence of the role of diet as a causative factor in the development of cancer, this aspect of diet is addressed in a number of excellent publications elsewhere. The first part of this book addresses a number of generic aspects of nutrition that apply across different diagnostic groups. It looks at the physiological changes that may occur in cancer and the impact these may have on clinical outcomes. It outlines current cancer treatments which ultimately influence nutritional management as screening, assessment

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Preface

and the provision of nutrition support must be tailored to patients’ needs during the treatment pathway. Nutritional problems do not finish at the end of treatment. Increasingly, it is becoming clear that problems may arise weeks, months or years after treatment has finished. Patients should be made aware that follow-up after treatment will focus not only on disease-free survival but also on potential side effects that can impact on quality of life. These are outlined in the chapter on late effects of treatment. Nutrition may continue to be important for patients for whom a cure is not possible and should be included in holistic assessment and care. The second part of the book looks in more detail at particular diagnoses that have specific nutritional needs. Knowledge of the potential nutritional problems that may occur in the short and long term enables these aspects of care to be monitored and appropriate interventions to be planned. Increasingly, new treatments are being introduced, particularly multimodality treatments that may have a greater impact on nutritional status. A more detailed knowledge of these enables better planning, monitoring and ultimately better patient outcomes. Survivorship issues, in particular diagnoses, focus on the need for longterm healthy eating and lifestyle advice to potentially impact on recurrence of cancer and to reduce the chance of comorbidities such as heart disease, diabetes and obesity. Research on nutrition for the cancer patient is sadly lacking. Whilst the implications of reduced performance status and poor nutritional status on patient outcomes are documented, there is still a lack of conclusive research data on the potential effect of improvement in nutritional status and clinical outcomes such as morbidity and mortality. Where data exist it is often very specific, clearly defined and in particular diagnostic groups. In the absence of such data, the health care professional may need to turn to general nutrition recommendations and position papers produced by expert groups such as ESPEN and ASPEN. This book aims to be patient focused and not specific to the provision of health care in either a hospital or community care. Authors who have contributed to this book have brought together research evidence, generic nutrition recommendations and a wealth of clinical expertise from their area of work to help guide the reader to understand the nutritional problems patients may experience, methods of providing optimal support, where research evidence exists and where it does not. It is anticipated that the reader may not read the book as a whole but may identify sections relevant to their patient group or particular nutritional problem. Ultimately, it is hoped that nutrition will become a more integral part of the cancer patient’s care from diagnosis to end of life, wherever that care may be provided. Clare Shaw

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Chapter 1

Cancer in the twenty-first century Natalie Doyle and Clare Shaw

Introduction Cancer was recognised as a disease many centuries ago, being mentioned by the ancient Egyptians in 1500 bc. Much later, Hippocrates used the Greek words to describe a crab, carcinos and carcinoma, to describe tumours. The Greek word ‘karkinoma’, meaning a crab, was used because of the likeness of blood vessels extending out of a tumour to a crab’s body and legs. It is known from early Egyptian papyrus that attempts were made to burn or cauterise tumours but that this was always to no avail. Much has changed since ancient times. Cancer is now part of everyday vocabulary around the world, and although cancer remains the leading cause of death, much has changed with respect to its diagnosis and treatment. Today, it is recognised that about one-third of all cancers are preventable, and improvements in detection and treatment have meant that many people survive the cancer and treatment. Survival rates around the World, however, vary greatly (Coleman et al., 2008). Most of the wide global range in cancer survival is attributable to differences in access to diagnostic and treatment services.

What is cancer and what causes it? Cancer is not a single disease but rather a group of diseases characterised by uncontrolled cellular growth. There are over 200 different types of cancer arising from different cells of the body. In normal circumstances of cell and tissue division, differentiation and cell death are carefully regulated processes. Cancer can arise when a single cell has lost control of the normal balance of cell proliferation and cell death and appropriate cell differentiation. Usual cell division involves the exact replication of the DNA helix. For this to take place accurately, a number of mechanisms are in place, and these are influenced by chemicals from within the cell itself, from different cells or by hormones produced by distant tissues and transported in the bloodstream. These influence cell division by binding to receptors on the cell surface and transmitting signals to the cell to stop or start the process of division. Nutrition and Cancer, First Edition, edited by Clare Shaw
C 2011 Blackwell Publishing Ltd

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Table 1.1 Different cancer-causing genes Type of genes

Action

Oncogenes

Initiate cell division, when faulty increases the rate of transformation from a normal cell to a cancer cell.

Tumour-suppressor genes

Prevent excessive growth of a cell either by control of cell proliferation or by control of DNA repair rate.

DNA repair genes

Work in different ways to repair damaged DNA, for example, to correct mismatched bases, copying errors, errors that distort structure of DNA.

Apoptosis genes

Cells are programmed to reproduce a certain number of times and then they die. There are genes within the cell that control the process. There is much interest in these genes as they may help the understanding of how cells start to self-destruct.

Binding with cell receptors involves the process of phosphorylation or dephosphorylation, which is necessary to transmit the appropriate signal within the cell. Hundreds of proteins, or genes, are involved in the processes within the cell that involve the exact replication of the DNA helix. Transcription factors are the proteins involved in the regulation of gene expression and carry the signals from the cell surface to the nucleus of the cell and therefore the DNA. Genes involved in cell division can be divided into four main types, and it is thought that tumours have a fault or mutation in one or more copies of these genes (see Table 1.1). Knowledge of the underlying genetic causes of cancer has increased rapidly particularly within the past 30 years and has resulted in improvements in the prevention, detection and treatment of cancer. Significant progress has been made in the identification of genes responsible for both sporadic and familial cancers such as BRCA1, BRCA2 (breast, ovarian, colon and prostate cancer) and APC (familial adenomatous polyposis for colon cancer). It is also now accepted that as well as genetic mutations, epigenetic changes and the interactions of genes with lifestyle factors, such as smoking, diet, body weight and exercise, affect the development of cancer. This knowledge brings with it the challenge of how to develop measures to prevent cancers forming. In some familial cancers, this may be through screening, chemoprevention, prophylactic surgery and lifestyle changes. The environmental factors for cancer development also vary greatly around the world. Increasingly, it is recognised that it is this interaction between genetics and the environment that plays a role in the development of cancer. The known lifestyle, infectious agents or genetic abnormalities that can cause cancer are outlined in Table 1.2. The causes of cancer are multifactorial, and in any individual different factors will either contribute or protect against the development of cancer.

Development and spread of cancer Cells, whether they are normal or cancerous, grow and interact with adjacent cells and tissues through a complex network of control signalling, which involves communication

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Cancer in the twenty-first century

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Table 1.2 Factors contributing to the development of cancer Carcinogens

Substances such as asbestos and tobacco smoke are known carcinogens although not all those exposed will necessarily develop cancer.

Age

Three non-mutually exclusive factors may explain the association of ageing and cancer: (1) the lengthy process of carcinogenesis, (2) molecular changes to tissue with age and (3) age-related environmental changes favouring the growth of cancer cells.

Genetic make-up

A proportion of cancers occur in individuals who are genetically predisposed to develop these cancers. This is about 5–10% of common cancers. The most common abnormality is the BRCA1 and BRCA2 genes that increase the risk of breast and ovarian cancer in women and prostate cancer in men.

The immune system

Cancer is more common in people who have a suppressed immune system which may be due to drugs, for example after organ transplantation, disease affecting the immune system such as HIV or AIDS or in rare medical conditions where the immune system is affected. These conditions tend to increase the rate of cancers caused by viruses such as cervical cancers or in the development of lymphomas.

Body weight, diet and physical activity

Increased body weight, diet and lack of physical activity are thought to contribute to approximately one-third of all cancers worldwide. A thorough and comprehensive review of the evidence has been undertaken by the World Cancer Research Fund and enabled dietary recommendations relating to food intake, body weight and physical activity that are aimed to reduce the risk of cancer (World Cancer Research Fund, 2007). Generally, higher rates of cancer are observed in countries where the diet is lower in fruits, vegetables and plant-based foods and higher in animal products such as meat. The consumption of alcohol, salty foods and mouldy foods also contributes to an increased risk of cancer.

Environment

Environmental hazards include exposure to tobacco smoke, radiation, work-related carcinogens such as asbestos and exposure to the sun. It is difficult to quantify the actual contribution of all these elements to cancer risk.

Viruses

Some cancers can be attributed to viral infections, and it is thought that these may represent approximately 15% of all cancers. Cervical cancer, Kaposi’s sarcoma and hepatocellular cancer are all caused by viruses. It is thought that the action is by stimulation of cellular proliferation that is not inhibited by normal cellular or immune control mechanisms.

Bacterial infection

Some bacterial infections cause cancer; for example, Helicobacter pylori causes approximately 60% of stomach cancers in developed countries. It works by invading the stomach lining and causing chronic gastritis.

Doll and Peto (1981), World Cancer Research Fund (2007) and Cancer Research UK (2010a).

via both compounds within the membrane of the cell and extracellular growth factors and cytokines. These bind to receptors on the membrane of the cell and influence cell proliferation and differentiation. In cancer, these processes may be altered to produce an unregulated growth of abnormal cells. As cancer cells divide and grow, they occupy space in the surrounding normal tissue. This is known as local invasion and can result in the cancer-infiltrating local tissue, blood

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vessels and the lymph system. When the cancer cells become detached from the primary tumour and enter the bloodstream or the lymphatics, they can become lodged in other tissues in the body. This is a complex process as the cells must penetrate blood vessels or lymphatics to spread throughout the body. Eventually, the cancer cells must develop a new blood supply to grow into a secondary or metastatic cancer. It is likely that some of the cells that spread are killed by the body’s immune system but others may lodge in tissues separate from the primary site of the cancer, causing secondary tumours or metastasis. Often this initial spread will not be detectable by current methods of scanning and is deemed as micrometastases. The pattern of spread is particular to different primary diagnoses but may include spread to essential organs such as the lungs, liver, brain and bones. For some diseases, this spread may have already occurred and therefore may be already present at the initial diagnoses, whilst for others they live with the uncertainty of whether the cancer will recur as metastases. For some types of cancer, this intervening period between treatment of the initial primary cancer and detection of metastases may be a number of years, indicating that the cells may remain dormant or very slow growing during this period. The aim of the treatment of cancer is not only to eradicate the initial site of cancer growth but also to treat or prevent the spread of cancer cells to other tissues and organs in the body (see Chapter 3 on treatment of cancer). This requires both the detection of such disease and appropriate methods of destroying these cancer cells whilst maintaining the integrity and function of the remaining tissues and organs.

What is the global burden of cancer? Cancer is an important cause of ill health worldwide. In 2008, an estimated 12.4 million people were diagnosed with cancer. The most common cancers, primarily breast, lung, stomach, bowel or prostate cancer, accounted for 50% of diagnoses. The large populations in Asia mean that they account for a large number of the total global cancer burden and actually represent 45% of all those diagnosed with the most common cancers listed. The contribution of cancer as the cause of death varies around the world (see Figure 1.1). This figure is influenced by the age demographics of the population and access to health care. Generally, survival is positively associated with gross domestic product and the amount of investment in health care. For example, for colorectal cancer, 5-year survival for patients ranges from around 60% in North America, Japan, Australia and France down to 40% in Algeria, Brazil, Czech Republic, Estonia, Poland, Slovenia and Wales (Coleman et al., 2008). Rates also vary within a country with those having access to health insurance showing higher rates of survival. There are 6.7 million reported deaths from cancer annually; again half of these deaths are in Asia, making up 12% of deaths worldwide. This is more than HIV/AIDS, malaria and tuberculosis combined. It is estimated that there are 24.6 million people alive who have been diagnosed with cancer in the last 5 years; half of these people live in Europe or North America. Survival figures for different types of cancer vary greatly (see Figure 1.2). Advances in treatment have seen survival rates for many cancers increase, and in the United Kingdom over 50% of cancer patients will be alive 5 years after diagnosis.

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Cancer in the twenty-first century Asia

Africa

5

Europe

4% 12% 19%

Latin America and the Carribbean

Northern America

13%

23%

Oceania 21%

Figure 1.1 Percentage of all deaths due to cancer in the different regions of the world. (Reproduced with kind permission of Cancer Research UK, 2010b.)

Whom does cancer affect? Cancer can affect anyone of any age. Childhood cancer (below the age of 15) affects about 1500 children a year in the United Kingdom, with a risk factor of 1 in 500. The cancers seen commonly in adults in developed countries are rarely seen in children, and the common childhood cancers are equally rare in adults. It is important to note that the population of the world is ageing; this is significant because cancer is predominantly a disease of the elderly. Principally, as a result of the post-war baby boom, 10% of the world’s population is currently 60 years or older, varying from 20% in the developed world to 8% in the less developed areas. By 2050, the overall percentage will rise to 22%, 33% in the developed world and 19% elsewhere. Consequently, there will be an increase in the number of cancer diagnoses. The many and varied complications of old age are well documented. Hypertension, heart conditions, arthritis and gastrointestinal problems are the most common comorbid illnesses in the elderly population who have cancer, and by the age of 75 a typical patient will have four comorbidities, which also require assessment and apposite treatment (Hurria, 2008). By the age of 85, frailty increases with a decline in vision and hearing, which can make people more prone to injury and functional dependence (Balducci & Extermann, 2000). This will undoubtedly contribute to the assigning of performance status, which will in turn affect the treatment options available.

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Women

Men

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Testis Hodgkin's lymphoma Melanoma Bladder Larynx Prostate NHL Colon Rectum Kidney Leukaemia Multiple myeloma Brain Stomach Oesophagus Lung Pancreas Melanoma Hodgkin's lymphoma Breast Uterus Cervix Bladder NHL Rectum Colon Kidney Leukaemia Ovary Multiple myeloma Brain Stomach Oesophagus Lung Pancreas

95% 84% 78% 71% 67% 61% 51% 46% 45% 45% 38% 24% 13% 12% 7% 6% 3%

More than 50% survival: 38% of cases diagnosed

10–50% survival: 29% of cases diagnosed

Less than 10% survival: 24% of cases diagnosed 90% 83% More than 50% 79% 76% survival: 68% 50% of cases 61% diagnosed 52% 48% 45% 43% 10–50% survival: 36% 27% of cases diagnosed 34%

22% 15% 13% 8% 6% 2%

Less than 10% survival: 15% of cases diagnosed

Five-year relative survival

Figure 1.2 Relative 5-year survival estimates based on survival probabilities observed during 2000–2001, by sex and site, England and Wales. (Reproduced with kind permission of Cancer Research UK, 2002.)

Historical perspective on cancer treatment The history of cancer diagnosis and treatment options is long and varied but allows us to understand the complex global situation of today. Several thousand years bc, the Chinese and the Egyptians both made descriptions of tumours and the therapies used to treat them, ranging from surgery to five forms of therapeutic care including diet. In 460 bc, Hippocrates, the father of medicine, was born and texts on the treatment of tumours have been subsequently attributed to him. By ad 129, the world saw the birth of Galen, the first person to suggest that breast cancer arose from melancholia. However, it was not until 1829 that Joseph Recalmier, a French gynaecologist, first used the term ‘metastasis’ to describe the spread of cancer and 1867 before this mechanism was investigated by Wilhelm Gottfried Waldeyer-Hartz, a German anatomist. In 1830,

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the first book containing illustrations of cancer cells as seen under a microscope was published by English surgeon Everard Home, and by 1851 the first hospital in Britain devoted to cancer was opened by William Marsden. In 1895, antibody treatment for cancer was first described by Hericourt and Richet, with several patients receiving an individual antiserum. Despite treatment not resulting in cure, they showed significant improvements in their symptoms. This line of investigation was abandoned in 1929, reappearing in 1975, when Kohler and Milstein’s work on monoclonal antibodies was published. This work continues to evolve in the twenty-first century. Another significant milestone in the diagnosis of cancer was also made in 1895 when Wilhelm Konrad Rontgen discovered X-rays able to visualise bones and soft tissues; within a year of this discovery, there were reports of damage to human tissue caused by the X-rays. By 1898, Marie and Pierre Curie had isolated the radioactive elements of polonium and radium, and by 1904 it was confirmed that radium rays destroyed diseased cells. The use of radiation treatment for cancer remains one of the most significant treatment developments. In 1902, the Imperial Cancer Research Fund was founded in the United Kingdom, followed in 1907 by the American Association for Cancer Research and in 1909 by the Institute Curie in Paris. International cancer statistics were first published in 1915, and in 1919 James Ewing established oncology as a medical speciality in the United States. These treatment-focused initiatives were complemented in 1911 by the founding of the UK National Society for Cancer Relief by Douglas Macmillan following his father’s death from cancer. This experience highlighted to him the importance of the holistic needs of people affected by cancer. During this time individuals working with specific tumours also made significant discoveries, for example the association of aniline used in the dye industry and cancer of the bladder was demonstrated by Lueunberger in 1912 and the eponymous James Ewing described an endothelial tumour of the shaft of long bones in 1920. The specific classification of tumours began in 1920 when an US pathologist classified tumours into four groups on the basis of differentiation of cells, and in 1944 the TNM (tumour, node, metastasis) classification was proposed. The 1930s saw the combining of radiotherapy and surgery as an effective treatment modality in certain tumours and the passing of the Cancer Act by the British government to aid the early diagnosis and treatment of the disease. At the same time, reports appeared in the literature about how nutritional status may influence the outcome of patients being treated in hospitals. Studley (1936) reported that patients undergoing surgery had a poorer outcome if they had lost weight prior to surgery. However, there is little in the literature about whether nutrition was addressed as part of the treatment or care of the cancer patient (Studley, 1936). Around this time, advances in treatment were being made with the discovery of the therapeutic effects of radiation. The next notable landmark in systemic anticancer treatment was the announcement in 1946 of the successful use of nitrogen mustard in the treatment of some lymphomas and leukaemia resulting from observations on the blood counts of troops gassed in World War I. The post-war era brought the founding of the United Nations and the World Health Organization. By 1950, Doll and Hill had demonstrated an indisputable link between cigarette smoking and lung cancer, and in 1959 work was first published on the role of

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hereditary factors in breast cancer. Laboratory work also looking at the growth of breast cancer indicated that diet may have a role to play influencing the growth of mammary cancer cells in mice (Silverstone & Tannenbaum, 1950). During the 1960s and 1970s, major advances were made in the use of chemotherapy in addition to surgery in the treatment of cancer, resulting in an increase in the number of drugs developed. During this time, the developments in intravenous therapy enabled the administration of many more drugs, blood products and electrolyte solutions, thereby allowing the more effective management of critically ill patients (Dougherty & Lamb, 2008). These years also saw the therapeutic advancement of bone marrow transplantation, and by 1971 a cure for childhood leukaemia had been found using a combination of radiotherapy and chemotherapy. With the aim of making the conquest of cancer, a national crusade, the National Cancer Act, was passed in the United States in 1971, with an initial budget of US$500 million. In 1973, another milestone in diagnostics had been reached with the simultaneous trans-Atlantic discovery of computerised axial tomography (CT scanning). However, advances in the treatment of cancer were not universal, and in 1975 a report from the WHO noted that deaths from breast cancer had not decreased since 1900. This acted as a strong advocate for the use of combination therapies, demonstrating that surgery alone was not sufficient to successfully treat cancer. By 1975, the cancer-suppressor P53 gene had been isolated, and the 1980s brought the publication of landmark papers to support the effects of lifestyle on cancer causation. In ‘The Causes of Cancer’ (1981), Sir Richard Doll suggested that 70% of cancers were connected to diet, and in 1992 the evidence was presented establishing the relationship between ageing and development of cancer (Doll & Peto, 1981). Throughout these developments, there continued to be advances in the support of patients during their treatment. The 1980s proclaimed the development of fine-bore feeding tubes and almost simultaneously percutaneous endoscopic gastrostomy to allow delivery of the vital adequate nutrition needed by people during cancer treatment. The 1980s also saw the role of oncogenes and tumour-suppressor genes in cancer isolated and the 1990s the identification of two breast cancer genes, BRCA1 and BRCA2; by 1999 the human papilloma virus was shown to be present in 99.7% of all cases of cervical cancer. The twentieth century has witnessed the development of targeted cancer therapies in both radiotherapy and chemotherapy as a result of the discovery of the role of oncogenes. There has also been an increased use of systemic therapy to combat metastatic disease, resulting in a reduction in the amount of radical surgery carried out and an increase in the use of techniques such as laparoscopic and robotic surgery. The century has also seen the further development of biological and hormone treatments and their use as a preventive measure in, for example, prostate cancer. The future of systemic cancer treatments is increasingly tailored towards the individual utilising the significant progress made in three main areas of research: (1) the inhibition of the angiogenesis factor, to destroy the vital blood supply to a tumour; (2) the interruption of single transduction, the signalling mechanism to the nucleus of a cell; and (3) the introduction of genes into cancer cells for treatment purposes (see Chapter 3). Increasingly, cancer is now identified as a preventable disease, and whilst much emphasis has been placed on finding a cure, the focus for the twenty-first century is on strategies

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that prevent, cure and care with respect to cancer (World Health Organization, 2007). Effective approaches to prevention have been demonstrated around the world, including in less developed countries such as Brazil where tobacco control measures have had an impact on the rates of lung cancer. Other countries are tackling other lifestyle issues such as diet, obesity, physical exercise and alcohol consumption, which will impact on not only cancer but also other chronic diseases. The global burden of cancer also focuses on access to screening, early detection of cancer, and access to treatment. Some countries are receiving advice on acquiring health devices and technologies that will enable them to offer screening and treatment more effectively to their population (World Health Organization, 2007). There is a particular burden on low- and middle-income countries where the cost of treating cancer, particularly the use of expensive chemotherapy, may prevent access to appropriate treatment. This may also be the case for drugs that palliate symptoms, particularly the use of morphine for pain control.

Cancer survivorship – living with and beyond cancer A cancer survivor is anyone who has received a cancer diagnosis during his or her life. In the UK, for example there are approximately 2 million cancer survivors; 13% or 1 in 8 of the population over the age of 65 are cancer survivors (Maddams et al., 2009). It is also estimated that 15 years post-diagnosis 40% of people still receive some form of cancer-related care (Corner, 2008). These figures will vary worldwide, where other factors constitute a threat to life. The concept of surviving cancer is complex; the experience will be unique to the individual but have universal aspects, change over time and be life changing. There will be positive and negative aspects to the experience, and the person will live with an element of uncertainty thereafter. The consequences of receiving a cancer diagnosis and living with and beyond it can be physical, psychological, social or spiritual (Doyle, 2008). Cancer is now classified as a chronic life-threatening illness and in the developed world where more people are living longer but not necessarily healthier lives. A new attitude to disease management is needed to reflect this, particularly as previously described, cancer is a complex disease. A cancer diagnosis often leads to what Bury describes as ‘biographical disruption’ where a person is forced to reassess their life (Bury, 1982). Recently, writing autobiographical accounts of the cancer experience has become increasingly prevalent as has the use of daily blogs and tweets, giving the public immediate access to the daily activities and thoughts of people affected by cancer (Picardie, 1998; Armstrong, 2001). These accounts allow for cancer and its meanings to feature in the public psyche, more than ever before, creating a culture where cancer touches everyone’s lives. Little et al. comment on the state of limbo people find themselves in between health and wellness, depicting a state of liminality (Little et al., 2000). It is important to note that a cancer diagnosis carries a particular message to the world, and although this is beginning to change, that message remains one of inevitable fatality (Tritter & Calnan, 2002). Up until now, it has been relatively easy for people to abdicate responsibility for health concerns to health care professionals by the very nature of health service structure and

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ethos – the doctor knows best. The changing social, financial and political climate that dominates the advent of the twenty-first century means that individuals will need to start to accept personal responsibility for aspects of their health. Wherever possible, the use of chronic disease management on an individual, population and system level and supported self-management techniques needs to be employed to promote empowerment and independence (Forbes & While, 2009). The basic principles of self-management are basic problem-solving skills, decision-making, the finding and utilisation of resources, developing partnerships with health care providers and taking action (Lorig & Holman, 2003). Health literacy levels will vary worldwide, and until people affected by a disease such as cancer understand its causes and consequences, little progress will be made towards creating the empowered survivor (Nutbeam, 2008). The cancer survivor has many needs, but there must also be a cultural shift in society towards the care and support for people affected by cancer with a greater focus on recovery, health and well-being. The United Kingdom is working on a National Cancer Survivorship Initiative, which looks at improving the care pathway for survivors (Department of Health, 2010). A diagnosis of cancer is known to affect more than just the individual concerned; this heightening of awareness of health issues can and should be capitalised on for the benefit of public health. The ‘teachable moment’ as described by Demark-Wahnefried presents an ideal way of introducing important public health initiatives such as smoking cessation, the importance of exercise and healthy eating advice such as reducing fat intake, limiting intake of red meat and consuming at least five portions of fruits and vegetables daily (Demark-Wahnefried et al., 2005). However, the uptake of these lifestyle messages is variable; for example studies suggest that only 25–42% of survivors consume at least five portions of fruits and vegetables daily, indicating that such behavioural interventions are not embraced by all. Health promotion guidance is provided by only 20% of oncologists, and further work needs to evaluate how this advice applies to particular diagnostic groups or whether it is suitable for all (see Chapter 9 on late effects of cancer treatment). Increasingly, it is recognised that patients may require support services and rehabilitation in relation to their cancer, at any point along their care pathway. Often these needs, which may include nutrition, are overlooked, and patients are left without the appropriate assessment and intervention. In the United Kingdom, a national project has been undertaken to produce rehabilitation guidelines which have linked the evidence base to therapy interventions in different cancer diagnoses (NHS Cancer Programme for England, 2007). Nutrition and dietetics features in all the rehabilitation pathways and provides an excellent basis for highlighting patients’ need and planning service delivery to those undergoing treatment, post-treatment and for those surviving after a cancer diagnosis.

Nutrition and cancer Nutrition has been demonstrated to have a key role and influence in many aspects of the development of cancer not only through the direct role of food components and nutrients but also through its influence on body composition, hormones and growth factors. The influence of diet in the causation of cancer is discussed in detail elsewhere in the excellent review by the World Cancer Research Fund (World Cancer Research Fund, 2007).

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Once cancer has developed in an individual then a variety of nutritional problems may develop. The interaction of metabolic and nutritional changes may influence body composition, performance status, psychological state and ability to withstand cancer treatment. Treatment in the malnourished patient may pose challenges as it is associated with increased morbidity and mortality. These changes can have a profound impact on the quality of life of the cancer patient and their carers. Nutrition is therefore crucial in the support of cancer patients undergoing intensive treatment, in the lifestyle changes that cancer survivors may make and in the management of some of the side effects of cancer treatment. For those patients who cannot hope for a cure, food and nutrition may continue to be an important part of ensuring their quality of life, and for all patients, food may remain central to the social aspects of being with family and friends. This book aims to examine the role of food and nutrition for the cancer patient and the complex interaction of nutrition, the metabolic changes that occur in cancer, nutritional requirements and the provision of appropriate nutritional support for the cancer patient. The provision of dietary advice and nutritional support for the cancer patient must be timely and consider the potential benefits and burden to the patient. It should be in a way that supports the patient to the best effect, taking into account their cancer, treatment, lifestyle and prognosis and be with maximal benefit and minimal risk. Evidence-based practice is the cornerstone of planning nutritional interventions, but in the absence of evidence, good practice guidance and patient’s experience contribute to our knowledge of the best methods of support. As the chance of survival after a diagnosis of cancer increases then it is likely that the nutritional problems that present will also increase and change. The search for the optimal diet for cancer survivors must continue and needs to consider any dietary changes that may influence the chance of recurrence or the development of new primary tumours. It must also consider the potential effect on other chronic diseases such as heart disease and stroke. Increasingly, there will be the presentation of chronic side effects of treatment that influence dietary intake, for example chronic gastrointestinal symptoms or dysphagia caused by radiotherapy. These symptoms have profound physical and psychological consequences for the patient and should be recognised early and managed appropriately. Good nutrition is essential for all and should be considered at all stages of the development and management of cancer.

References Armstrong, L. (2001) It’s Not About the Bike: My Journey Back to Life. London: Yellow Jersey Press. Balducci, L. and Extermann, M. (2000) Management of cancer in the older person: a practical approach. Oncologist 5(3), 224–237. Bury, M. (1982) Chronic illness as a biographical disruption. Sociology of Health and Illness 4(2), 167–182. Cancer Research UK (2002) Relative five-year survival estimates based on survival probabilities observed during 2000–2001, by sex and site, England and Wales. Available at: http://info. cancerresearchuk.org/cancerstats/survival/latestrates/index.htm (accessed 21 January 2010).

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Cancer Research UK. (2010a) Causes of cancer. Available at: http://info.cancerresearchuk. org/cancerstats/causes/index.htm (accessed 15 January 2010). Cancer Research UK. (2010b) Percentage of all deaths due to cancer in the different regions of the world. Available at: http://info.cancerresearchuk.org/cancerstats/world/mortality/index.htm (accessed 25 January 2010). Coleman, M.P., Quaresma, M., Berrino, F., et al. (2008) Cancer survival in five continents: a worldwide population-based study (CONCORD). The Lancet Oncology 9(8), 730–756. Corner, J. (2008) Addressing the needs of cancer survivors: issues and challenges. Pharmoeconomics Outcomes Research 8(5), 443–451. Demark-Wahnefried, W., Aziz, N.M., Rowland, J.H., et al. (2005) Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer. Journal of Clinical Oncology 23(24), 5814–5830. Department of Health, Macmillan Cancer Support and Improvement, N. (2010) The National Cancer Survivorship Initiative vision. Available at: http://www.dh.gov.uk/en/ Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH 111230 (accessed 27 January 2010). Doll, R. and Peto, R. (1981) The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. Journal of the National Cancer Institute 66(6), 1191–1308. Dougherty, L. and Lamb, J. (2008) Intravenous Therapy in Nursing Practice. Oxford: Blackwell Publishing Ltd. Doyle, N. (2008) Cancer survivorship: evolutionary concept analysis. Journal of Advanced Nursing 62(4), 499–509. Forbes, A. and While, A. (2009) The nursing contribution to chronic disease management: a discussion paper. International Journal of Nursing Studies 46(1), 119–130. Hurria, A. (2008) Assessment of the older adult with cancer. The Journal of Supportive Oncology 6(2), 80–81. Little, M., Sayers, E.J., Paul, K., et al. (2000) On surviving cancer. Journal of the Royal Society of Medicine 93(10), 501–503. Lorig, K.R. and Holman, H. (2003) Self-management education: history, definition, outcomes, and mechanisms. Annals of Behavioral Medicine 26(1), 1–7. Maddams, J., Brewster, D., Gavin, A., et al. (2009) Cancer prevalence in the United Kingdom: estimates for 2008. British Journal of Cancer 101(3), 541–547. NHS Cancer Programme for England (2007) Raising the bar for rehabilitation service provision in cancer and palliative care. Available at: http://www.cancer.nhs.uk/rehabilitation/index.htm (accessed 21 January 2010). Nutbeam, D. (2008) The evolving concept of health literacy. Social Science and Medicine 67(12), 2072–2078. Picardie, R. (1998) Before I Say Goodbye. London: Penguin. Silverstone, H. and Tannenbaum, A. (1950) The effect of the proportion of dietary fat on the rate of formation of mammary carcinoma in mice. Cancer Research 10, 448–453. Studley, H.O. (1936) Percentage of weight loss. A basic indicator of surgical risk in patients with chronic peptic ulcer. Journal of the American Medical Association 106(6), 458–460. Tritter, J.Q. and Calnan, M. (2002) Cancer as a chronic illness? Reconsidering categorisation and exploring experience. European Journal of Cancer 11, 161–165. World Cancer Research Fund (2007) Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective. Washington DC. World Health Organization. (2007) The World Health Organization’s fight against cancer. Strategies that prevent, cure and care. Available at: http://www.who.int/cancer/publicat/ WHOCancerBrochure2007.FINALweb.pdf (accessed 22 January 2010).

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Chapter 2

Cancer and nutritional status Alessandro Laviano, Isabella Preziosa and Filippo Rossi Fanelli

Introduction Progressive nutritional depletion is frequently found in cancer patients. Reduced energy intake and increased wasting are the factors determining the different phenotypes of this syndrome, whose main feature is a varying combination of reduced food intake, weight loss and changes in body composition. The clinical relevance of the progressive nutritional depletion of cancer patients is underlined by its high prevalence and its impact on patients’ morbidity and mortality. However, only recently, the clinical relevance of the better understanding of the molecular mechanisms leading to weight loss in cancer patients has been recognised. Different catabolic pathways have been identified and characterised, providing potential targets for the development of effective therapeutic strategies to prevent or counteract nutritional depletion.

Nutritional status and outcome in cancer patients Epidemiology Nutritional depletion is frequently found in cancer patients. The prevalence of patients reporting weight loss may amply vary according to the stage of the disease and the site of origin of the tumour. Indeed, patients with gastrointestinal cancers and/or with advanced diseases show the highest prevalence of weight loss (Meguid & Laviano, 1996).

Impact of nutritional status on outcome The negative impact of nutritional depletion on cancer patients’ outcome has been recognised since the early 1980s (DeWys et al., 1980). Medical therapy significantly improved during the past 30 years, and the efficacy of antitumour therapies has greatly improved. Therefore, one would be inclined to believe that the impact of nutritional status on patients’ morbidity and mortality has dramatically declined. Actually, robust clinical evidence shows that depletion of nutritional status remains a negative prognostic factor Nutrition and Cancer, First Edition, edited by Clare Shaw
C 2011 Blackwell Publishing Ltd

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for treatment-associated toxicity and survival for cancer patients, either when undergoing surgery (Tewari et al., 2007) or receiving chemotherapy (Meyerhardt et al., 2004). During the past decade, the progressive rise of the prevalence of obesity increased the number of obese cancer patients. Interestingly, obesity seems to confer protection against treatment-associated toxicity, but remains a negative prognostic factor for cancer patients, particularly for those patients with a body mass index more than 35 kg/m2 (Dignam et al., 2006).

Impact of nutritional status on quality of life Quality of life is an important endpoint in the management of cancer patients. As an example, many cancer patients would not choose chemotherapy for a likely survival benefit of few months, but would if it improved quality of life (Sculpher et al., 2004). Nutritional status may profoundly influence patients’ quality of life. It has been calculated that weight loss and nutritional intake contribute to quality-of-life function scores by 30 and 20%, respectively (Ravasco et al., 2004). Several mechanisms may explain how nutritional status influences quality of life (Marin Caro et al., 2007). Weight-losing cancer patients have increased post-operative complication rate, higher chances to develop fatigue, and reduced tolerance/response to chemo- and radiotherapy. These clinical consequences of weight loss contribute to reduce the autonomy of cancer patients, thereby impinging on patients’ quality of life. The possibility to improve quality of life by improving nutritional status remains a debated issue. However, recent evidence suggests that nutritional intervention is likely to yield positive effects on quality of life when it is started early in the clinical course of the disease (Huhmann & Cunningham, 2005). Therefore, the timely nutritional intervention, aimed at addressing the specific needs of each patient, has greater chances to result in significant clinical benefits.

Cancer cachexia Clinical features Although it may be very simple to recognise at first sight a nutritionally depleted cancer patients, a general consensus does not exist on the term better describing this syndrome. Cancer-associated weight loss cannot be simply defined as malnutrition. Malnutrition usually refers to the nutritional depletion associated with uncomplicated starvation, which promptly responds to nutritional supplementation. Also, starvation triggers a number of biological mechanisms, which minimise energy needs by reducing energy expenditure, and preserve muscle mass at the expense of fat mass. In cancer patients, and more generally in the presence of acute or chronic diseases, these protective pathways are not operating, which accelerates nutritional depletion and progressive loss of muscle and fat mass. Also, cancer-induced weight loss is minimally responsive to standard nutritional support, particularly in the advanced stages of the disease. Nutritional depletion in cancer patients is characterised by the development of a number of different symptoms, the most important being anorexia (i.e. the loss of desire to

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eat), reduced food intake, weight loss, fatigue, muscle wasting, fat mass loss and impaired immune function. Highlighting the clinical relevance of the individual genetic profile, patients with similar cancers may present all, some or even none of the previously mentioned symptoms. Cancer-associated nutritional depletion is usually defined as anorexia–cachexia syndrome, the term which acknowledges the two most prominent symptoms determining weight loss, that is, anorexia and wasting (cachexia – bad conditions, from Greek words). ‘Cachexia’ is a term which is also frequently used per se, to highlight the metabolic changes rather than the behavioural alteration (i.e. anorexia), whose effects on energy balance cannot completely account for the observed weight loss. However, data suggest that the molecular mechanisms responsible for wasting and anorexia may share a number of common pathways (Laviano et al., 2008). Therefore, it may appear more pathogenesis-based the use of the term ‘cachexia’ to indicate the complex clinical syndrome, in which the specific contributions of changes in eating behaviour, energy expenditure or intermediary metabolism largely vary from patients to patients.

Diagnosis Although a universally accepted definition of cachexia does not exist yet, a number of proposals have been suggested. In particular, cancer cachexia has been related to increased inflammatory response (as defined by increased C-reactive protein levels), reduced energy intake (⬍1500 kcal/day) and weight loss (⬎10% vs usual body weight) (Fearon et al., 2006). Although this definition allows it to identify cancer patients at the risk of poorer outcome, on the other hand, patients meeting this three-factor definition of cancer cachexia are likely in an advanced stage of nutritional depletion, which may limit the benefit of nutritional intervention. In an alternative approach to define cancer cachexia, it has been proposed that cachexia is diagnosed based on weight loss and poor responsiveness to standard nutrition support (Bozzetti & Mariani, 2009). Recently, cachexia has been defined as a complex metabolic syndrome associated to an underlying illness, and characterised by loss of weight and muscle mass with or without the loss of fat mass (Evans et al., 2008). Consequently, the diagnostic criteria for cachexia in adults are weight loss of at least 5% in 12 months or less in the presence of underlying cancer, plus three of the following criteria: decreased muscle strength, fatigue, anorexia, low fat-free mass index and abnormal biochemistry (i.e. increased inflammatory markers, anaemia, low serum albumin) (Evans et al., 2008) As discussed later in this chapter, recent data show that the complex constellation of behavioural and metabolic alterations observed in weight-losing cancer patients may recognise common pathogenic mechanisms. Therefore, cachexia could also be defined as a multifactorial syndrome characterised by weight loss due to underlying disease, contributory factors being anorexia and metabolic alterations (i.e. increased inflammatory status, increased muscle proteolysis, impaired carbohydrate, lipid and protein metabolism). The advantage of this definition lays in being consistent with the clinical practice, in which cancer patients’ weight loss could result from anorexia, wasting or both. The major limitation of the search for a universally accepted definition of cachexia is its focus on patients who are already cachectic, and therefore with limited chances

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to benefit from nutritional intervention. There is now general agreement that cancer cachexia is a continuum, ranging from biochemical alterations with minimal or any weight loss, to severe nutritional depletion (Fearon, 2008). Therefore, it would be important to develop diagnostic tools to identify those patients who will become cachectic. Indeed, treating all new cancer patients to address those who will develop cachexia is not feasible. Currently, an established marker of ‘pre-cachexia’ has not been identified, but a number of tools have been proposed. Anorexia is often the presenting symptom of cancer and may precede the development of weight loss. A number of questionnaires have been devised to assess the presence of anorexia (NCCTG questionnaire, FAACT questionnaire), but their compilation may be time-consuming and not well accepted by cancer patients. A list of symptoms likely related to the neurochemical derangements responsible for cancer anorexia have been proposed (i.e. meat aversion, changes of taste/smell, nausea/vomiting and early satiety), and the presence of at least one of them allows to consider the patient as anorexic. Also, the use of a visual analogue scale may be useful in screening anorexic patients, although its use appears more suitable for the follow-up of cancer anorexia than for its diagnosis. Recently, the mere subjective assessment of reduced appetite has been shown to represent a negative prognostic factor in a large population of hospitalised patients, being more reliable than weight loss (Hiesmayr et al., 2009). These results suggest that anorexia could be used as an early marker for cachexia, at least in those cancer patients who develop it. Biochemical alterations may well represent markers of ‘pre-cachexia’. Tumour growth is frequently associated to the development of insulin resistance, and therefore impaired oral glucose tolerance test may serve to identify patients at higher risk of wasting. Increased expression and activity of proteolytic systems involved in muscle wasting have been demonstrated in cancer patients, even in the early stages of the disease and in the absence of significant weight loss (Bossola et al., 2003). The complexity of the analytical methods used to quantify their expression and activity currently prevents their routine utilisation as early markers. As previously mentioned, the clinical features of cachexia are influenced by individual genetic profile. Recent studies have shown that specific polymorphisms of key genes, including those of the cytokines interleukin-6 (IL6), IL-10, tumour necrosis factor-␣ (TNF-␣) among other candidate genes, are related to the development of cachexia (Deans et al., 2009). Therefore, it is likely that in the next future the characterisation of the polymorphisms of a few genes may disclose those patients at higher risk of developing cachexia, thereby prompting an early nutritional intervention.

Pathogenesis of anorexia and reduced energy intake The symptoms and signs mainly characterising cancer cachexia are anorexia and metabolic derangements leading to wasting. In this section, the pathogenesis of anorexia in cancer patients is discussed in detail.

Regulation of food intake Under physiological conditions, the homeostasis of food intake is controlled by complex and redundant mechanisms (Ellacott & Cone, 2006). Neural, metabolic and humoral

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signals from peripheral tissues inform the brain whether energy stores are being repleted or depleted. The hypothalamus receives and integrates peripheral signals. Within the hypothalamus, the infundibular nucleus in humans (i.e. the arcuate nucleus in rodents) is considered to act as an important sensor of alterations in energy stores to control appetite and body weight. Involved in this role are two distinct subsets of neurons. The first population of neurons express pro-opiomelanocortin (POMC). POMC is an inert polypeptide precursor which is cleaved into the biologically active melanocortins, that is, ␣-, ␤-, ␥ -melanocyte-stimulating hormones (MSH). The biological effects of melanocortins are mediated through a family of five melanocortin receptors, termed MC1R to MC5R. Among them, MC4R is a crucial molecular component of the homoeostatic circuit that regulates energy balance by mediating anorectic and catabolic responses. The second subset of neurons expresses the potent orexigenic peptides neuropeptide Y (NPY) and agouti-related protein (AgRP). Interestingly, AgRP is the endogenous antagonist of MC4Rs, thereby antagonising the anorexigenic effects of melanocortins. This evidence underlines the reciprocal functional relationship between the two subsets of hypothalamic neurons. The POMC and NPY/AgRP neurons project to related hypothalamic nuclei, and these downstream second-order neurons expressing melanocortin receptors are included in the hypothalamic melanocortin system. The melanocortin system plays a crucial role in the homeostasis of energy metabolism. In the presence of excess energy, POMC neurons are activated and trigger the release of melanocortins, which activate MC4R, thereby leading to suppressed food intake and increased energy expenditure. Simultaneously, the activity of arcuate AgRP/ NPY system is suppressed, which would otherwise antagonise the effects of melanocortins on MC4R. In contrast, in times of energy depletion, the activity of anorexigenic POMC neurons is decreased but the activity of orexigenic NPY/AgRP neurons is increased.

Peripheral factors and cancer anorexia Under physiological conditions, the hypothalamus integrates a number of peripheral inputs and modulates eating behaviour accordingly. These signals arise from peripheral tissues, mainly from the gastrointestinal tract, and are conveyed to the hypothalamus (Wren & Bloom, 2007). The biological functions of these signals are different and time-specific. Consequently, peripheral signals are usually classified as short-term, medium-term and long-term signals. Short-term signals contribute to start/stop eating: visual-oro-nasal stimuli influence the cognitive aspects of eating and contribute to maintain/stop eating; ghrelin, an orexigenic peptide/neuropeptide secreted by the stomach in response to fasting, promotes food intake; cholecystokinin, an anorexigenic peptide secreted by the duodenum in the presence of food, signals when digestion is started and promotes inhibition of food intake; mechanical distension of gastric walls is conveyed to the brain via vagal afferents and contributes to inhibit eating. Medium-term signals enhance and corroborate the termination of eating: the rising concentrations in plasma of specific nutrients, particularly amino acids, free fatty acids and glucose, a signal that the absorptive phase is initiated. Polypeptide YY, an anorexigenic peptide secreted by the colon, signals that digestion is almost completed.

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Long-term signals, also known as adiposity signals, are critical factors because they provide the general metabolic background on which the short- and medium-term signals operate. The most important long-term signals are leptin, an anorexigenic peptide mainly produced by the adipose tissue in proportion to its extent, and insulin, which regulates glucose levels and cooperates with leptin to regulate long-term body weight. Considering the role of peripheral signals in mediating the onset of appetite and satiety, it was tempting to speculate that changes in peripheral signals could mediate the development of cancer anorexia. In particular, it was hypothesised that during cancer the circulating levels of the orexigenic hormone ghrelin decrease, while those of the anorexigenic hormone leptin increase, yielding to suppression of appetite and food intake. Actually, consistent experimental data show that in weight-losing, anorexic cancer patients, leptin levels are decreased, while ghrelin levels are normal or elevated. Nevertheless, energy intake is not increased as expected. These results suggest that cancer anorexia mainly results from the resistance of hypothalamic neurons to peripheral signals.

Brain neurochemistry and cancer anorexia The hypothalamic inappropriate response to these peripheral signals appears to be mediated by the persistent activation of POMC neurons (Marks et al., 2001). Consistent evidence indicates that MC4Rs are key factors in mediating anorexia and body weight loss during cancer (Marks et al., 2003). In experimental models of cancer, the blockade of MC4Rs achieved via central infusion of the endogenous MC4R antagonist, AgRP, or via peripheral/oral administration of an MC4R antagonist or inverse agonist ameliorates anorexia, prevents body weight loss and particularly muscle wasting, and improves basal metabolic rate, which is frequently found accelerated in cancer. Experimental data suggest that decreased activity of NPY/AgRP neurons should parallel the hyperactivation of POMC neurons during cancer. Immunocytochemical studies in tumour-bearing rats with anorexia–cachexia show decreased NPY innervation of hypothalamic nuclei, which is reversed by tumour resection (Makarenko et al., 2005). Direct measurement of NPY concentrations in the hypothalamus of tumour-bearing rats with anorexia–cachexia reveals a significant decrease of this orexigenic peptide. Furthermore, mRNA levels and immunostaining of the NPY receptor, the Y(1) receptor, are decreased in the hypothalamus of tumour-bearing rats, while tumour resection restores normal hypothalamic NPY levels. In humans, data on hypothalamic NPY levels and activity during cancer are lacking. However, significantly lower plasma levels of NPY have been measured in anorectic cancer patients when compared to controls. Furthermore, animal studies show that megestrol acetate, an orexigenic drug used in the treatment of human cachexia, increases hypothalamic NPY levels. The mechanisms responsible for the dysfunction of the melanocortin system have been investigated in experimental studies, and results suggest the involvement of proinflammatory cytokines and hypothalamic serotonergic neurons (Laviano et al., 2008). The role of pro-inflammatory cytokines, and particularly IL-1, IL-6 and TNF-␣, in the pathogenesis of cancer anorexia has been recognised for many years. In tumour-bearing rats with anorexia, hypothalamic IL-1 mRNA expression is significantly increased. In

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humans, IL-1 appears to play a significant role in mediating anorexia because megestrol acetate has been shown to improve appetite and food intake via reduced expression of IL-1 by mononuclear cells, which may explain its effects on hypothalamic NPY concentrations. Interestingly, POMC neurons express the type I IL-1 receptor, and intracerebroventricular injection if IL-1 increases the frequency of action potentials of POMC neurons and stimulates the release of ␣-MSH. These data strongly suggest that IL-1 is involved in mediating the dysfunction of the melanocortin system by increasing the activity of POMC neurons in the hypothalamus. Serotonin is a neurotransmitter that contributes to the regulation of energy balance, by mediating satiety through its effects in the hypothalamus (Meguid et al., 2000). Thus, it represents a suitable potential mediator of cancer anorexia. In experimental tumour models, the onset of anorexia is associated with increased hypothalamic serotonin levels, as assessed by in vivo microdialysis, and increased expression of serotonin receptors (5HTRs). Also, tumour resection restores energy intake, which is associated to normalised hypothalamic serotonin concentrations and receptor expression. In cancer patients, the role of serotonin in cancer anorexia has been inferred by measuring increased plasma and cerebrospinal fluid levels of the precursor of serotonin, the amino acid tryptophan, in anorectic cancer patients. Also, therapeutic strategy aiming at reducing brain supply of tryptophan has met with improved energy intake and nutritional status in cancer patients (Laviano et al., 2005). Intriguingly, the anorectic effects of serotonin appear to be mediated by the melanocortin system. The administration of fenfluramine, a serotonin reuptake inhibitor, has been shown to activate central melanocortin pathways. The use of serotonin agonists influenced the activity of POMC and NPY/AgRP neurons in a reciprocal manner, because they hyperpolarised NPY/AgRP neurons while suppressing inhibitory postsynaptic potentials in POMC neurons. Serotonin, IL-1 and TNF-␣ do not appear to represent separate pathways independently influencing the activity of the central melanocortin system. Peripheral infusion of IL-1 induces anorexia and raises brain tryptophan levels, thereby suggesting increased serotonin synthesis. Interleukin-1 intrahypothalamic injection depresses food intake and increases release of serotonin. Tumour necrosis factor-␣, as well as IL-1, acutely regulates neuronal serotonin transporter. These data indicate that during cancer, increased hypothalamic expression of IL-1 occurs in conjunction with increased release of serotonin. Serotonin and IL-1 interact within the arcuate nucleus (infundibular nucleus in humans) to influence the activity of the melanocortin system, yielding and maintaining the inhibition of NPY/AgRP neuronal activity. These biochemical events facilitate the release of the endogenous MC4R agonist, ␣-MSH, while suppressing the release of the endogenous MC4R antagonist, AgRP, thus resulting in dysfunction of the melanocortin system.

Hypothalamic energy metabolism and cancer anorexia The hypothalamic regulation of food intake involves different pathways. Indeed, fatty acid metabolism within hypothalamic neurons controls food intake and energy metabolism in a leptin-independent way (Laviano et al., 2008). In particular, inhibition of fatty acid synthase (FAS) blocks fasting-induced upregulation of orexigenic neuropeptides and

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downregulation of anorexigenic neuropeptides. Hypothalamic malonyl-coenzyme A (CoA), a substrate of FAS, is an indicator of global energy status. Its concentration is low in fasted mice and rapidly increases on refeeding. Therefore, high intrahypothalamic malonyl-CoA induces anorexia by inhibiting fatty acid oxidation, whereas low levels have the converse effect and elicit food intake. The FAS/malonyl-CoA pathway could be involved in the pathogenesis of cancer anorexia, because in vitro studies show that pro-inflammatory cytokines, particularly TNF-␣ and IL-1, inhibit fatty acid oxidation. If this effect also applies to the in vivo situation, then pro-inflammatory cytokines, and particularly IL-1, may cause an inappropriate switch in hypothalamic neurons from fatty acid oxidation to fatty acid synthesis, increase hypothalamic malonyl-CoA concentrations and suppress food intake.

Pathogenesis of wasting Changes in intermediary metabolism largely contribute to wasting and mediate a number of clinically relevant symptoms and signs in cancer patients. Robust experimental and clinical data indicate that chronic inflammation, as already discussed for the pathogenesis of cancer anorexia, represents the main trigger of the changes in intermediary metabolism.

Protein metabolism in cancer patients Under physiological conditions, protein degradation in muscle is offset by compensatory protein synthesis to preserve muscle mass. During cancer, muscle catabolic pathways are hyperactivated, while a compensatory increase of muscle anabolism does not occur. The net result is the progressive loss of muscle mass and muscle function. There are three main proteolytic pathways that are responsible for protein catabolism in skeletal muscle (Acharyya & Guttridge, 2007). The first pathway is the lysosomal system, which is involved in proteolysis of extracellular proteins and cell surface receptors. The second pathway is the cytosolic calcium-regulated calpains, which are mainly involved in tissue injury, necrosis and autolysis. The third pathway, and probably the most significant proteolytic contributor to muscle wasting in cancer cachexia, is the ATP ubiquitin-proteasome proteolytic pathway, whose preferred substrate is myosin heavy chain. Interestingly, the ubiquitin system is also hyperactivated in weight-stable cancer patients. This evidence highlights the need to start the nutritional intervention as early as possible, since absence of clinical signs may not be absence of metabolic derangements. A number of mediators of muscle wasting have been identified. The pro-inflammatory cytokines, TNF-␣ and IL-1, have been demonstrated to activate the ubiquitin-proteasome system. Similar effects have been suggested to be mediated by the tumour-derived 24 kDa sulfated glycoprotein proteolysis-inducing factor, whose role in cancer cachexia has been questioned (Wieland et al., 2007). In addition, there has been significant progress in identifying new signalling pathways that contribute to muscle atrophy that are potentially pertinent in cancer. These include the downregulated insulin and insulin-like growth factor pathways that lead to Akt inactivation and reversal of muscle hypertrophy, the

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angiotensin system that operates through the activation of caspases, the transforming growth factor-␤ family member myostatin, the mediator of terminal muscle differentiation MyoD, the p38 mitogen-activated protein kinase, Foxo, nuclear factor-␬B (NF-␬B), activator protein-1, and p53 transcription factors, as well as a newly described pathway involving the dystrophin glycoprotein complex. Interestingly, most, if not all, of these emerging pathways seem to mediate their effects through the activation of the ubiquitinproteasome system, which is now most commonly measured through the induction of the ubiquitin E3 atrophy markers, muscle RING finger-1 (MuRF1), muscle atrophy F-Box (MAFBx) or atrogin-1, and, more recently, E3␣-II (Acharyya & Guttridge, 2007).

Carbohydrate metabolism in cancer patients In the 1920s, Warburg demonstrated that tumours differ in glucose metabolism from normal tissues by exhibiting an enhanced glycolytic pathway. Under normal oxygen-rich conditions, tissues metabolise glucose to pyruvate, which is then completely oxidised to CO2 and H2 O via the tricarboxylic acid cycle and oxidative phosphorylation. Conversely, under states of low oxygen tension, as may occur in some solid tumours, cells can rely solely on anaerobic glycolysis, in which glucose is converted to pyruvate and then lactate in the cytosol to meet energy needs; this is known as the Pasteur effect. Many invasive cancer cells selectively metabolise glucose to lactic acid in the presence of oxygen, a phenomenon known as the Warburg effect. There are several defects in cell biochemistry that may facilitate the anaerobic glycolytic phenotype in cancer cells over the more efficient oxidative phosphorylation (Gatenby & Gillies, 2004). The glucose transporter proteins, GLUT 1 and GLUT 3, are greatly upregulated in cancer, allowing for large amounts of extracellular glucose to be rapidly transported intracellularly. In many invasive cancers, hexokinase, the first enzyme of the glycolytic pathway, is markedly elevated and essential for maintaining the high glycolytic phenotype. These observed cellular alterations allow cancer cells to rapidly consume large amounts of glucose from body stores, exogenous sources, or from gluconeogenic processes. The excess of lactate surrounding tumour cells is transported to the liver, where the carbon skeleton undergoes an energy-consuming gluconeogenic process to re-form glucose. The hepatic production of glucose is released into the circulation, again taken up by the tumour cells and converted to lactate, creating a futile Cori cycle that can account for as much as a 300 kcal/day energy loss (Delano & Moldawer, 2006). Tumour-induced alterations in glucose metabolism include insulin resistance because 37% of all patients with cancer show glucose intolerance and abnormal insulin responses. Many stimuli, particularly the release of pro-inflammatory cytokines, can activate the hypothalamic–pituitary–adrenal axis, which contributes to elevation of blood glucose levels and stimulation of glycogenolysis and gluconeogenesis. Consistent evidence implicates the action of cytokines on glucose metabolism directly or by stimulation of glucoregulatory hormones.

Lipid metabolism in cancer patients White adipose tissue plays a crucial metabolic role by storing triacylglycerol (lipogenesis) when energy input exceeds expenditure, and subsequently releasing free fatty acids

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(lipolysis) during energy deprivation. In cancer patients, an extensive depletion of adipose tissue is frequently observed, which is generally characterised by smaller visceral adipose tissue area. Also, in progressive cancer cachexia, the loss of body fat is more rapid than that of lean mass and occurs preferentially from the trunk followed by leg and arm adipose tissue. Extensive adipose tissue loss may lead to hyperlipidemia and insulin resistance. The loss of fat stores cannot be explained by reduced appetite alone (Delano & Moldawer, 2006). Morphological examination has revealed shrunken adipocytes and a dilated interstitial space. Increased lipolysis appears to be a key factor underlying the loss of adipose tissue in cancer cachexia. Enhanced expression and activity of hormonesensitive lipase, a rate-limiting enzyme of the lipolytic pathway, is thought to underlie the increase in lipolysis. In addition to increased lipolysis, there is a fall in lipoprotein lipase activity. Fat loss may also be attributable to a decrease in lipid deposition because lipogenesis in adipose tissue is reduced in the tumour-bearing state. Finally, there is also evidence that loss of adipose tissue in cancer cachexia could be the result of impairment in the formation and development of adipose tissue. Various factors produced by tumours, or by the host’s immune cells responding to the tumour, can alter lipid metabolism (Skipworth et al., 2007). Pro-inflammatory cytokines such as TNF-␣, IL-1 and IL-6 have been implicated in adipose atrophy in cachexia. Certain tumours produce circulating factors such as the 41 kDa zinc-␣2-glycoprotein (ZAG). The biological functions of ZAG were largely unknown until a lipid-mobilising factor, purified from the urine of cancer patients with cachexia, was shown to be identical to ZAG.

Energy metabolism in cancer patients Coupling of caloric intake with energy production is a mechanism to conserve calories when caloric intake is low while disposing of excess ingested calories when caloric intake is excessive. However, in cancer patients there is an uncoupling of the balance between energy production and energy intake in favour of increased energy production (Delano & Moldawer, 2006). One potential explanation for this increased energy expenditure is that the tumour-bearing host metabolism is energetically inefficient due to increased futile cycle activity. The recycling of lactate between the tumour and the host is certainly energetically inefficient. Pro-inflammatory cytokines, IL-6 and TNF-␣, have been implicated in stimulating gluconeogenesis and activating a futile cycle of glucose use and lactate formation in hepatocytes and myocytes, respectively. Another futile energy expending cycle involves the sodium, potassium transporter Na+ K+ ATPase, an enzyme complex that uses ATP to pump Na+ out of cells. Non-shivering thermogenesis takes place in brown adipose tissue (BAT), whereby energy uncoupled from oxidative phosphorylation is released as heat energy instead of fuelling ATP production. During cachexia, there is an increase in BAT thermogenesis. Brown adipocytes contain mitochondria that are characterised by the presence of uncoupling proteins 1,2,3 (UCP1, UCP2, UCP3). The UCP proteins are a family of mitochondrial membrane proteins that decrease the coupling of oxidative phosphorylation to ATP formation, culminating in the production of heat rather than ATP. Increased

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UCP-mediated thermogenesis in BAT increases energy expenditure and may exacerbate cancer cachexia. UCP expression has also been linked to cytokine and tumour factors, further implicating their role in the development and propagation of cachexia. In addition to UCP upregulation, TNF-␣ and IL-6 also contribute to the increased protein synthesis that requires energy expenditure (i.e. the increased protein synthesis associated with hepatic acute phase and leukocyte proteins during cachexia development is energetically expensive and contributes to the increased expenditure).

Cancer cachexia: a neurological disease? For decades, the accepted model of the pathogenesis for cancer cachexia was based on the assumption that behavioural changes (i.e. anorexia) and metabolic alterations (i.e. muscle wasting and increased energy expenditure) were mediated by the derangement of different molecular pathways. Accumulating evidence now challenges this approach by suggesting that anorexia and wasting represent in part different phenotypes of common neurochemical/metabolic alterations (Laviano et al., 2008).

Hypothalamic signalling and changes in energy expenditure As previously described in detail, the inhibitory effects of pro-inflammatory cytokines on fatty acid oxidation contribute to dysregulation of the melanocortin system, thus leading to reduced energy intake. However, inhibition of fatty acid oxidation within hypothalamic neurons influences metabolism in peripheral tissues. The ‘malonyl-CoA signal’ is rapidly transmitted to peripheral tissues by the sympathetic nervous system, increasing mitochondrial biogenesis, fatty acid oxidation and uncoupling protein-3 expression, and thus energy expenditure. Also, because mitochondria are among the main sources of reactive oxygen species production, it is postulated that this ‘brain–muscle axis’ may contribute to increased oxidative stress, which in turn increases muscle protein degradation.

Hypothalamic signalling and muscle mass regulation Experimental studies aimed at suppressing the activity of the central melanocortin system during cancer resulted in increased food intake, which was paralleled by amelioration of energy expenditure and improved lean body mass. The mechanisms by which MC4R antagonism in cancer models exerts its metabolic effects are still matter of investigation. Recent data suggest that the improvement of basal metabolic rate is partly mediated by the normalisation of the expression of uncoupling proteins. Much less is known about the mechanisms leading to preserved body weight and lean body mass. In particular, it is yet to be determined whether central melanocortin antagonism influences the activity of the peripheral ATP-dependent ubiquitin-proteasome system. Nevertheless, the existence of a ‘brain–muscle axis’ is likely, in which the brain not only regulates energy intake but also influences metabolic rate and the balance in muscles between anabolism and catabolism.

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The exact mechanisms of the interplay between central and peripheral pathways await better detailing; however, it appears to involve the balance between inhibitory and stimulatory factors of the regulation of muscle mass, as recently demonstrated in an animal model of uraemic cachexia. In particular, the expression of myostatin, an important inhibitory factor of muscle mass accretion, is increased in the muscles of uraemic rats. In contrast, the expression of insulin-like growth factor-I, a factor promoting muscle accretion, is reduced. Interestingly, the injection of AgRP in the third ventricles of uraemic rats partially corrected these uremia-induced changes, resulting in a gain of body mass.

Summary Cancer cachexia is a clinically relevant syndrome negatively influencing patients’ outcome. The pathogenesis is multifactorial, but consistent evidence seems to suggest that tumour growth is sensed by the vagus nerve, possibly by local interaction with proinflammatory cytokines. This information is transmitted to brainstem areas and then to the hypothalamus, yielding to the activation of the melanocortin system via cholinergic, noradrenergic or serotonergic innervation. The activated melanocortin system induces the expression of pro-inflammatory cytokines to maintain the catabolic response. The metabolic and behavioural effects of melanocortin activation are then triggered in peripheral tissues, at least in part, via sympathetic outflow. Increased cytokine expression in the hypothalamus may also cause an inappropriate switch in hypothalamic neurons from fatty acid oxidation to fatty acid synthesis, increase hypothalamic malonyl-CoA concentrations and synergistically suppress food intake. Our current knowledge of the mechanisms regulating the onset and progression of cancer cachexia has significantly improved. However, a critical step is still missing in the complete understanding of its pathogenesis, that is, the contribution of the polymorphisms of specific genes. By being able to predict the behavioural and metabolic responses to tumour growth, preventive measures or anticatabolic strategies will be tailored on each patient’s needs.

References Acharyya, S. and Guttridge, D.C. (2007) Cancer cachexia signaling pathways continue to emerge yet much still points to the proteasome. Clinical Cancer Research 13, 1356–1361. Bossola, M., Muscaritoli, M., Costelli, P., et al. (2003) Increased muscle proteasome activity correlates with disease severity in gastric cancer patients. Annals of Surgery 237, 384–389. Bozzetti, F. and Mariani, L. (2009) Defining and classifying cancer cachexia: a proposal by the SCRINIO Working group. Journal of Parenteral and Enteral Nutrition 33(4), 361–367. Deans, D.A., Tan, B.H., Ross, J.A., et al. (2009) Cancer cachexia is associated with the IL-10–1082 gene promoter polymorphism in patients wit gastroesophageal malignancy. American Journal of Clinical Nutrition 89, 1164–1172. Delano, M.J. and Moldawer, L.L. (2006) The origins of cachexia in acute and chronic inflammatory diseases. Nutrition in Clinical Practice 21, 68–81.

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DeWys, W.D., Begg, C., Lavin, P.T., et al. (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. American Journal of Medicine 69, 491–497. Dignam, J.J., Polite, B.N., Yothers, G., et al. (2006) Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. Journal of the National Cancer Institute 98, 1647–1654. Ellacott, K.L. and Cone, R.D. (2006) The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons form mouse models. Philosophical Transactions of the Royal Society London B: Biological Sciences 361, 1265–1274. Evans, W.J, Morley, J.E., Argiles, J., et al. (2008) Cachexia: a new definition. Clinical Nutrition 27, 793–799. Fearon, K.C. (2008) Cancer cachexia: developing multimodal therapy for a multidimensional problem. European Journal of Cancer 44, 1124–1132. Fearon, K.C, Voss, A., Hustead, D.S, et al. (2006) Definition of cancer cachexia: effects of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. American Journal of Clinical Nutrition 83, 1345–1350. Gatenby, R.A. and Gillies, R.J. (2004) Why do cancers have high aerobic glycolysis? Nature Reviews Cancer 4, 891–899. Hiesmayr, M., Schindler, K., Pernicka, E., et al. (2009) Decreased food intake is a risk factor for mortality in hospitalised patients. The NutritionDay survey 2006. Clinical Nutrition 28(5), 484–491. Huhmann, M.B. and Cunningham, R.S. (2005) Importance of nutritional screening in treatment of cancer-related weight loss. Lancet Oncology 6, 334–343. Laviano, A., Muscaritoli, M., Cascino, A., et al (2005) Branched-chain amino acids: the best compromise to achieve anabolism? Current Opinion in Clinical Nutrition and Metabolic Care 8, 408–414. Laviano, A., Inui, A., Marks, D.L., et al. (2008) Neural control of the anorexia-cachexia syndrome. American Journal of Physiology – Endocrinology and Metabolism 295, E1000–E1008. Makarenko, I.G., Meguid, M.M., Gatto, L., et al. (2005) Normalization of hypothalamic serotonin (5-HT1b ) receptor and NPY in cancer after tumor resection: an immunocytochemical study. Neuroscience Letters 383, 322–327. Marin Caro, M.M., Laviano, A. and Pichard, C. (2007) Nutritional intervention and quality of life in adult oncology patients. Clinical Nutrition 26, 289–301. Marks, D.L., Ling, N. and Cone, R.D. (2001) Role of the melanocortin system in cachexia. Cancer Research 61, 1432–1438. Marks, D.L., Butler, A.A., Turner, R., et al. (2003) Differential role of melanocortin receptor subtypes in cachexia. Endocrinology 144, 1513–1523. Meguid, M.M. and Laviano, A. (1996) Nutritional issues in cancer management. Nutrition 12, 358–371. Meguid, M.M., Fetissov, S.O., Varma, M., et al. (2000) Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 16, 843–857. Meyerhardt, J.A., Tepper, J.E., Niedzwiecki, D., et al. (2004) Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from intergroup trial 0114. Journal of Clinical Oncology 22, 648–657. Ravasco, P., Monteiro-Grillo, I., Vidal, P.M., et al. (2004) Cancer: disease and nutrition are key determinants of patients’ quality of life. Supportive Care in Cancer 12, 246–252. Sculpher, M., Bryan, S., Fry, P., et al. (2004) Patients’ preferences for the management of non-metastatic prostate cancer: discrete choice experiment. British Medical Journal 328, 382.

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Skipworth, R.J.E., Stewart, G.D., Dejong, C.H.C., et al. (2007) Pathophysiology of cancer cachexia: much more than host-tumour interaction? Clinical Nutrition 26, 667–676. Tewari, N., Martin-Ucar, A.E., Black, E., et al. (2007) Nutritional status affects long term survival after lobectomy for lung cancer. Lung Cancer 57, 389–394. Wieland, B.M., Stewart, G.D., Skipworth, R.J., et al. (2007) Is there a human homologue to the murine proteolysis-inducing factor? Clinical Cancer Research 13, 4984–4992. Wren, A.M. and Bloom, S.R. (2007) Gut hormones and appetite control. Gastroenterology 132, 2116–2130.

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Chapter 3

Treatment of cancer Sanjay Popat

Introduction The hallmark of cancer is poorly controlled cellular growth. If left untreated, cancer is almost universally a progressively disease that results in significant morbidity and ultimately death. The treatment of cancer is therefore a complex arena involving differing therapeutic modalities: surgery, systemic (drug) therapy, radiotherapy, palliative care and a combination of these. Each has its advantages and disadvantages, and must be used with caution due to their adverse event profile. In this chapter, the differing modalities used to treat cancer are discussed along with their benefits, disadvantages, and how they might be used in the patient journey.

Treatment intent Whenever contemplating definitive treatment of cancer, clinicians involved must know the ultimate intent of treatment. This is broadly divided into ‘radical’ or ‘palliative’, colloquially termed ‘potentially curable’ or ‘controllable’. The basis of these intentions can depend on a number of factors, but is essentially primarily dependent on prior defining the tumour stage. Once baseline staging investigations have been completed for any given tumour, the final stage will best determine likely prognosis, which in turn will determine therapeutic strategy. Thus, patients with early-stage disease are generally treated ‘radically’, with intent of long-term disease remission, and in some cases cure. With this intention, the adverse effect or toxicity profile of any treatment paradigm can sometimes be severe given the potential gains. Patients treated ‘palliatively’ (generally patients with advanced stage disease) are treated with the intent of improving symptoms of disease and improving survival (for some cancers), whilst realising that long-term disease remission or even cure is extremely unlikely or impossible. Thus, the levels of treatment-related toxicity expected and allowable must be carefully balanced against each treatment modality, with the ultimate aim of improving the patient’s quality of life.

Nutrition and Cancer, First Edition, edited by Clare Shaw
C 2011 Blackwell Publishing Ltd

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Treatment setting When treating cancer, a number of terms are applied to indicate the clinical setting. ‘Adjuvant’ therapy usually refers to systemic therapy that is given after potentially curative surgery to reduce the risk of relapse. Here, disease has been entirely resected and no disease is evident on radiological imaging. Despite resection of an operable cancer, disease relapses in many patients. This relapse is usually in the form of metastases distant to the site of the original primary cancer suggesting that micrometastatic disease was present at the time of resection and has now established itself. Adjuvant therapy is therefore given with radical intent and has proved value in breast, colon and lung cancers. ‘Neoadjuvant’ or ‘induction’ treatment again usually refers to systemic therapy. In this setting, treatment is given prior to a potentially radical resection, usually to try to downstage (shrink) the tumour. Chemotherapy when given in this setting offers a number of advantages over adjuvant therapy: it is often better tolerated than in the adjuvant setting; direct observations can be made to whether the tumour is sensitive or resistant to the drugs given; and this strategy can sometimes downstage tumour to the extent that a smaller operation is required than that initially considered at presentation. An example of the latter benefit is in patients with breast cancer that might require a mastectomy at presentation. These patients may be able to undergo a wide local excision after successful response of the tumour to systemic therapy. Neoadjuvant therapy is common for a number of tumour types such as breast and rectal cancers, but is more controversial for other cancers, such as lung cancer.

Treatment modalities Surgery Surgery is the cornerstone of cancer treatment. It is not only the oldest form of anticancer therapy but also the most likely to result in a cure. Advances in surgical techniques and supportive measures are now permitting surgeons to perform more challenging resections with greater accuracy and shorter post-operative stays. A key advance in attaining a reduced surgical morbidity has been the development of laparoscopic techniques. Combined with advances in other therapeutic modalities, the effectiveness of surgery remains at the forefront of the radical approach to patient treatment. Modern surgery for cancer began to be recognised in the early 1800s. Thereafter, advances in anaesthetic agents and antisepsis methods allowed surgical procedures to take the helm of anticancer treatment. Recent advances have concentrated on reducing post-operative morbidity and recovery by minimally invasive methods, and combined with advances in anaesthesia, the medical support of these patients has resulted in major improvements in outcome. As with any treatment, the risks of surgery should be weighed against their benefits, and operative mortality (defined as deaths within 30 days of surgery) is a standard measure of surgical complication. A number of factors contribute to this, including the underlying disease process, its impact on patient physiology, anaesthetic technique, operative complication and patients’ physical fitness. Operative risks are further confounded by patients’

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age and comorbidity. Cancer is predominantly a disease of the elderly, and surgery in the elderly should be considered carefully. Given that expected survival in this group, if cured by surgery, may still be measured in years, then aggressive curative surgery may be warranted if the risks are tolerable. A number of different surgical intentions for cancer surgery are recognised: Prophylactic surgery: Here, a healthy organ at significantly increased future risk of cancer is electively removed to prevent cancer developing. Examples of this include prophylactic mastectomy in patients with inherited BRCA1/2 mutations, or colectomy in patients with inflammatory bowel disease or inherited APC mutation. Curative surgery: This is the commonest intent of surgery for cancer patients. Here, definitive resection of the primary cancer is performed, with curative intent. Data from the Royal College of Radiologists assess that approximately 49% of all cancers are cured by surgery (Board of the Faculty of Clinical Oncology, 2003). Curative surgery is therefore a form of ‘local therapy’ and is the mainstay for most cancers if diagnosed at early enough, a stage that resection is technically feasible and clinically appropriate. This varies by the tumour type. Examples include lung lobectomy for early non-small cell lung cancer (NSCLC), hemicolectomy for colon cancer, and wide local excision for breast cancer. In many cases, surgical resection of the primary tumour is by itself the definitive treatment of the underlying cancer without any further treatment required. When definitive surgery is performed, the aim is not only to resect the entire tumour but also to leave a sufficient margin of healthy normal non-malignant tissue around the tumour to be sure that the entire tumour has been resected. This ‘margin’ is important to ensure a ‘complete resection’ has occurred. Ensuring that the surgical margins are microscopically clear of tumour at some distance is important, because involved or threatened margins may indicate incomplete excision and an increased risk of relapse. The terms ‘R0’, ‘R1’ and ‘R2’ have come into use to reflect the extent to which all tumours have been resected. Thus, an R0 resection is one where complete resection of the tumour with clear margins or adequate size has been performed. An R1 resection is one with resection of the tumour but with microscopic tumour still present (e.g. involved margins), and an R2 resection is one with residual macroscopic tumour. For curative resection of the primary tumour, R0 resection is the goal, and if this cannot be expected to be achieved when reviewing pre-operative imaging, then careful consideration should be given to whether surgery is appropriate. Whether to electively resect or sample regional lymph nodes draining the tumour is dependant on the tumour type. For some tumour types, local nodes are resected as much as possible, with the number involved giving prognostic information (e.g. axillary dissection for breast cancer), and in some cases local nodal surgery is not warranted (e.g. wide excision for cutaneous melanoma). For many cancers, such as colon cancer, malignant involvement of the local lymph nodes gives additional prognostic information, and may indicate whether additional post-operative treatment is required to further reduce relapse risk. In some cases, complete removal of the primary tumour by R0 resection is impossible, but good clinical benefit may be gained by removing as much tumour as

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possible, resulting in an R1 or R2 resection. This is termed ‘debulking’ or ‘cytoreductive’ surgery. An example of this is the treatment of ovarian cancer, where after a staging laparotomy, a surgeon might perform debulking surgery to excise as much tumour as possible, with a view to the patient receiving post-operative chemotherapy to further reduce the disease burden. Reconstructive surgery: This approach is complementary to that performed with curative intent. Here, surgery is performed with the aim of either restoring organ function or restoring cosmesis. Examples include breast reconstruction after mastectomy or flap reconstruction after laryngectomy. Staging surgery: Here, a surgical procedure is performed to adequately stage the tumour prior to definitive treatment. Examples include laparoscopy for oesophageal cancers to define whether peritoneal involvement is present, and laparotomy for staging of ovarian cancer. In the latter example, the staging laparotomy is usually combined with surgical debulking or excision of the primary tumour. Palliative surgery: Here, surgery is used for the primary intent of improving patients’ symptoms. This type of surgery is not performed with a view to a complete R0 resection. An example of this approach is bowel resection in the surgical management of patients with advanced ovarian cancer. When considering surgery with this intent, the risk–benefit ratio should be carefully considered. Patients usually have advanced cancer, which may compromise their physiology, and may also have other comorbidities. The type of surgery being considered, in addition to the post-operative recovery period, and likely prognosis of the patient need careful consideration before committing to surgery for palliative situations because any form of surgical intervention is associated with risk and may introduce a risk of morbidity. Supportive surgery: Here, a minor surgical procedure is performed to support ongoing anticancer therapy. A good example is the placement of a central venous cannulation R ) to aid chemotherapy delivery. device (e.g. Port-a-Cath


Systemic therapy Since nitrogen mustard was introduced into clinical practice in 1946, systemic therapy has been a major anticancer treatment paradigm, particularly for cancers that are considered systemic diseases. For these cancers, surgery is not generally an appropriate modality, and examples of this include the lymphomas, leukaemias and small cell lung cancer. Until the early 2000s, most anticancer drugs developed were cytotoxic chemotherapy agents. Thereafter, with the advent of novel methods in biotechnology and chemical synthesis, small molecule inhibitors and genetically modified monoclonal antibodies have been developed and are now used in routine clinical practice. Whilst the overall impact on some of these newer agents has been small, in selected cases inhibition of specific cellular pathways has resulted in dramatic anticancer responses. The range of anticancer therapies available is large, and key to understanding drug combinations is an understanding of potential mechanisms of action of the component drugs. Thus, cancer cell growth can be inhibited in several ways, including inhibition of tumour DNA replication and therefore inhibition of cellular division, inhibition of

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tumour cellular mechanisms (e.g. inhibition of mitotic spindles), and inhibition of specific pathways involved in tumour cell growth (e.g. inhibition of the epidermal growth factor receptor, EGFR). Below is an overview of the issues pertaining to cytotoxic chemotherapy and then a summary of the issues of targeted therapy.

Cytotoxic chemotherapy Most anticancer drugs are effective through reducing the rate of cell growth and division in tumours more effectively than in non-cancerous (or normal) tissues. If active against the disease being treated, this results in tumour stability (stable disease, SD) or tumour shrinkage (tumour response, the latter being classified into either complete remission, CR, or partial remission, PR, depending on the extent of shrinkage). Naturally, some tumours exhibit primary resistance to anticancer therapy. In this case, tumour growth continues regardless resulting in progressive disease (PD). Others initially respond (CR or PR) or remain stable (SD), but subsequently relapse (PD) (acquired resistance). Cytotoxic chemotherapy primarily functions by inhibiting cancer cells at various points of the cell cycle. This cycle describes a variety of cellular phases associated with cell growth, division and replication (Figure 3.1). After cell division, cells enter a growth phase (G1 ) or do not undergo growth, remaining stable in the G0 phase. After G1 cells start to prepare for cell division and replication by synthesising DNA (S phase) during which the amount of chromosomal material is doubled, cells then pass through another growth phase (G2 ) after which they enter mitosis (chromosomal separation and cell division, the M phase). Different cell types in the body undergo this cycle at different times and rates depending on the need for cell growth and turnover. Tumour growth is also contingent on the ‘growth fraction’. This is the number of tumour cells dividing at any one time, and is variable between tumours. Thus, a high-grade tumour has a high

M

G2

G0, resting G1 S

Figure 3.1 The differing phases of the cell cycle.

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growth fraction, in which most, if not all, of the tumour cells are dividing. This is also termed the ‘proliferation index’ and can be assessed by immunohistochemistry in the pathology laboratory (e.g. using the MIB1 antibody to assess the nuclear Ki67 antigen). Tumours with a high growth fraction or proliferation index include Burkett’s lymphoma or small cell lung cancer (SCLC). These tumours are therefore associated with high rates of tumour doubling. By contrast, low-grade tumours have a low growth fraction or low proliferation index. An example of this is carcinoid tumours, with proliferation indices of approximately 1–5% and typically a very slow growth rate. Because cytotoxic drugs produce their effect by damaging cell reproduction, tumours that are rapidly growing with a high proliferation index or growth fraction are more likely to respond to this type of therapy. Whilst this is a generalisation, it does go some way to explaining the marked chemosensitivity of SCLC and intrinsic chemoresistance of carcinoid tumours. This is because cancers with a large proportion of cells rapidly dividing have more cells susceptible to anticancer drugs than the cancers in which most cells are not dividing. Cytotoxic chemotherapy is usually given in pulsed cycles for limited duration. This is for a number of reasons, and is essentially due to the fractional cells kill hypothesis. This hypothesis is derived from observations on effectiveness of cytotoxic chemotherapy in model systems. It states that with each anticancer drug administration, the same proportion of cells are killed, rather than the absolute amount. Thus, a single dose of cytotoxic drug may kill 99% of cells and will do so if the tumour is large or small. Therefore, less chemotherapy will be required for a smaller tumour to go into complete remission than a larger one. Because less chemotherapy is required to kill a small tumour, there will be less exposure of the tumour to chemotherapy and it will be less likely that resistance will emerge. Furthermore, classically for chemotherapy, there is a steep dose–response curve, with a linear relationship between the dose of drug and efficacy. Thus, the highest possible tolerated dose is aimed to be administered at the lowest possible intervals. To ensure maximal tumour killing, cytotoxic chemotherapy should be scheduled to ensure a balance between the rate of regrowth of the tumour and of the normal tissues. Chemotherapy will kill both tumour and normal cells, and the rate of regrowth of tumour and normal cells after a cycle of chemotherapy will determine when the next dose can be given (frequency of a cycle). The normal tissues are usually the bone marrow (with the resulting toxicity of myelosuppression) and gastrointestinal tract epithelium (with the resulting toxicity of stomatitis or diarrhoea). These normal tissues regenerate quicker than most cancers, and thus pulsed intermittent therapy, with time for the normal tissues to recover in between cycles, has become the usual method for cytotoxic scheduling. A consequence of this model is that the greatest cytotoxic effect is with the first cycle of therapy, and the extent of this effect reduces with each subsequent cycle. Similarly, although normal tissues recover quickly, with successive cycles, recovery is less complete and toxicity more apparent. Cytotoxic chemotherapeutics are usually given in combination. This is usually performed using drugs with non-cross-resistant mechanisms of action with the specific aim of reducing likelihood of acquired tumour resistance. When used in combination, these drugs should ideally be known to be active as a single agent against the disease. In practice, most combinations are of drugs with some activity against the target disease,

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but importantly, have non-overlapping toxicities to ensure therapy is clinically tolerable. Here, synergistic combinations are used whenever possible. Chemotherapy encompasses a number of agents with the common feature of resulting in cell death. These drugs can be classified into differing classes: r Alkylating agents: These agents covalently bind an alkyl group to cellular nucleic acids and proteins, which is effective through a number of mechanisms including inhibiting DNA replication by forming cross-links. Examples of this group include cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, cisplatin and carboplatin. r The antimetabolites: These agents inhibit formation of nucleic acids, and thereby inhibit DNA synthesis. Examples of this group include methotrexate, fluorouracil, pemetrexed, raltitrexed, azathioprine and 6-mercaptopurine. r The spindle poisons: These agents inhibit adequate function of the cellular mitotic spindle. Microtubules are proteins that form a scaffold to hold replicating chromosomes during cell division. Spindle poisons therefore inhibit cell division, resulting in cell death. Examples of thus group include the vinca alkaloids (vincristine, vinblastine, vinorelbine), paclitaxel and docetaxel. r The topoisomerase inhibitors: These agents alter the coiling of DNA within a nucleus and therefore alter its ability to replicate. Examples include irinotecan, topotecan and etoposide. r The cytotoxic antibiotics: These agents were originally identified from fungal and bacterial cultures. They are generally effective by intercalating between DNA base pairs and thereby inhibiting cell division. Examples include actinomycin-D, bleomycin and doxorubicin.

Endocrine therapy Hormonal manipulation has long been known to have an anticancer effect. In the nineteenth century, Beatson reported responses in inoperable breast cancer with oophorectomy, and thereafter Huggins reported cases of advanced prostate cancer responding to orchidectomy. Over recent years clearer insights into the pathobiology of specific cancers and in particular the role of hormones in tumourigenesis have allowed advances in the treatment of hormone-sensitive tumours. The two most notable endocrine-sensitive diseases are breast and prostate cancer. In hormone-sensitive subtype of breast cancer, anti-oestrogen therapy plays a major role in the treatment of this disease, from neoadjuvant therapy to shrink large tumours prior to surgery, adjuvant therapy used to reduce the risk of relapse, to their effective use in the treatment of advanced disease. Results from trials blocking oestrogen activity have demonstrated the high dependence of breast cancers expressing hormone receptors (oestrogen receptor, ER, and progesterone receptor, PR) on their cell surface. Antihormonal therapies essentially function by blocking the activity of steroid hormone receptors. These are in the cell cytoplasm, nucleus and cell membrane, and binding of hormone to their specific receptor normally results in downstream cell growth and replication. A number of mechanisms exist by which endocrine therapy achieves a therapeutic effect, and examples of the commoner antihormonal therapies are given below.

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Luteinising hormone-releasing hormone agonists

Luteinising hormone-releasing hormone (LHRH) is a peptide normally released from the hypothalamus, which then acts on the pituitary (Figure 3.2). This, in turn, produces a second hormone messenger (luteinising hormone, LH) to act on the primary endocrine organ (such as the testis or ovary) to produce the end-point hormone (testosterone or estrodiol). LHRH agonists such as goseralin (Zoladex) are given parenterally by subcutaneous injection to downregulate off this endocrine axis. Paradoxically, this class of drug initially stimulates the pituitary gland, therefore resulting in a temporary rise in end-point hormone (testosterone or oestrogen), and sometimes a flare on symptoms. With continued use, the axis is inhibited, with a subsequently inhibition of LH release, and therefore inhibition of plasma testosterone or estrodiol.

Hypothalamus

LHRH

Pituitary

Luteinising hormone

Ovary

Oestrogens

Testis

Testosterone

Figure 3.2 The mechanism of action of luteinising hormone-releasing hormone analogues. These initially stimulate and then inhibit LH release, thereby suppressing plasma testosterone.

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Tamoxifen and aromatase inhibitors

Until relatively recently, tamoxifen was one of the most widely used medical methods of anti-oestrogen therapy for the treatment of hormone-sensitive breast cancer. The action of tamoxifen is not fully understood. However, it seems to act by blocking the ability of oestrogen to act, in part, through blocking its ability to bind to the cytoplasmic oestrogen receptor (receptor antagonist). A newer method of medical anti-oestrogen therapy is aromatase inhibition. Examples of this class of drug include anastrozole, letrozole or exemestane. Importantly, the aromatase inhibitors are effective only in post-menopausal women. This is because they inhibit aromatase, an enzyme primarily found in the adrenal gland, which functions to convert androgens into oestrogens. Aromatase is the major method of oestrogen synthesis in postmenopausal women, and is therefore an effective method of reducing oestrogen levels. In pre-menopausal women, however, the major site of oestrogen formation is the ovary, which is still functioning, and therefore peripheral oestrogen blockade contributes little to plasma oestrogen levels.

Targeted therapy The section above demonstrates how most traditional anticancer drugs directly interfere with cell replication, DNA synthesis and DNA repair systems. Two new classes of agents tend to cause cancer cytostasis (cancer growth retardation) or marked cytotoxicity (in tumour types with specific DNA mutations) by exploiting the abnormal cancer microenvironment (tumour stroma), tumour vasculature or tumour cellular signalling mechanisms. These are the humanised monoclonal antibodies (MAbs) and the small molecule tyrosine kinase inhibitors (TKIs). The introduction of these agents into routine clinical practice has heralded a new era in anticancer drug therapy, with their development underpinned by major advances in biotechnology and chemical synthesis fields. These newer anticancer drugs differ from traditional cytotoxics not only by their mechanism of action, but have significantly different toxicity profiles. They are generally far better tolerated than chemotherapy, and by-and-large do not demonstrate dose-limiting toxicities. One of the major observations noted from targeted therapeutics has been the concept of ‘oncogene addiction’. Here, tumours have been demonstrated to be dependent on abnormal constitutive activation of a single cellular signalling pathway. Therefore, inhibiting this pathway by a targeted therapeutic approach has had dramatic impact in the treatment of these specific cancers. An example of this is the treatment of NSCLC characterised by acquired mutation in EGFR with gefitinib or erlotinib.

Tyrosine kinase inhibitors

Many tumour cell surface receptors transmit signals intracellularly by the activation of tyrosine kinase enzyme domains. Such cell surface receptors include EGFR, HER2 or Kit, and have three domains: extracellular, cytoplasmic and intracellular. On binding ligand to receptor, this signal needs to be transmitted intracellularly for the actions of

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the ligand to be translated. In general, this is achieved through activation of a cascade of downstream signalling events, contingent on initial activation of the intracytoplasmic part of the receptor through activation of its tyrosine kinase. On activation, this tyrosine kinase enzyme functions to phosphorylate other downstream proteins, thereby activating them, and ultimately resulting in a cascade of molecular events ultimately resulting in changes in DNA expression, and thereby increased cellular proliferation, the promotion of angiogenesis and metastasis. Abnormal tyrosine kinase signalling has been shown to be pivotal to cancer development in a number of ways, all resulting in a permanently activated tyrosine kinase domain and cells therefore ‘addicted’ to that oncogene. Thus, activated oncogenic signalling pathways driven by activated tyrosine kinases drive the malignant process. Examples of this include the t(9;22) chromosomal translocation in chronic myelogenous leukaemia (CML) resulting in the formation of a novel tyrosine kinase BCR-ABL fusion protein (this time not associated with a receptor) that is constitutively activated, mutation in EGFR in NSCLC, resulting in a constitutively activated receptor-associated tyrosine kinase, and mutation in KIT in gastrointestinal stromal tumours (GISTs), which also result in a constitutively activated kit receptor. TKIs are therefore drugs that inhibit this enzyme, and thereby its ability to phosphorylate downstream proteins, effectively ‘switching off’ the constitutively active signalling cascade in tumours where this is continuously activated. In the majority of cancer types, such receptors are not constitutively activated through acquisition of mutation, but are active as required. Here, TKIs again function to inhibit the downstream signalling cascade, but because the pathway inhibited may not be driving the cancer cell, then the clinical effects may not be so dramatic. Nevertheless, the effects may be enough to result in a clinically meaningful response or disease control. Inhibitory TKIs based on a small molecule structure tend to have the suffix ‘-nib’ indicating their biological characteristic and function. Thus, imatinib (Gleevec) inhibits the BCR–ABL fusion protein tyrosine kinase in CML, and also inhibits the kit-associated tyrosine kinase in GISTs, whilst erlotinib (Tarveca) inhibits the EGFR-associated tyrosine kinase in NSCLC. In these three examples, TKIs have resulted in dramatic responses in patients with tumour ‘addicted’ to these pathways (Weinstein & Joe, 2006), and in NSCLC, this has been termed the ‘Lazarus response’ (Langer, 2009) because moribund patients have been salvaged with this type of therapy. Given the effectiveness of these agents and the ability to inhibit tyrosine kinases in a number of pathways, a large number of TKIs are in development. Table 3.1 overviews some TKIs either licensed or in development, their targets and indication. A classic example of the clinical utility of TKIs is in the treatment of GISTs. These are rare mesenchymal tumours clinically characterised by chemoresistance. Activating mutations in KIT in GISTs were demonstrated in the late 1990s. Imatinib had proved activity in CML characterised by the BCR-ABL translocation, and was also active against PDGFR. KIT is structurally similar to PDGFR, and therefore imatinib was a logical therapeutic choice to inhibit KIT. Imatinib was first trialled in GIST in a Finnish patient whose tumour was known to harbour a KIT mutation. The patient had progressive, widely metastatic tumours after failure of previous extensive therapy, including multiple surgical procedures and chemotherapy. Within a few weeks of starting daily oral imatinib, the

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Table 3.1 Selected tyrosine kinase inhibitors, their targets and state of clinical development Drug

Target

Trial stage

Erlotinib (Tarceva) Gefitinib (Iressa) Lapatinib (Tykerb) BIBW2992 XL-880 ARQ-197 OSI-906 XL-228 Dasatinib (Sprycel) Bosutinib AZD-0530 Temsorilimus (Torisel) Rapamycin (Rapamune) Everolimus (Certican) Perifosine Tipifarnib (Zarnestra) Lonafarnib (Sarasar) Sorafinib (Nexevar) Suinitinib Pazopanib

EGFR EGFR EGFR, HER2 EGFR, HER2 MET MET IGF-1R IGF-1R Src Src Src mTOR mTOR mTOR Akt FTS FTS Raf, VEGF, PDGF, KIT VEGFR, PDGF, KIT, FLT3 VEGFR, PDGFR, Kit

Licensed (lung cancer) Licence pending (lung cancer) Licensed (breast cancer) Phase 3 (lung cancer) Phases 1–2 Phase 1 Phase 1 Phase 1 Licensed (leukaemia) Phase 2 (breast, leukaemia) Phase 1 Licensed (renal) Phase 2 Phase 2 Phase 2 Phase 3 (leukaemia) Phase 2 Licensed (renal, hepatocellular) Licensed (renal, GISTs) Phase 2

patient objectively clinically responded, and this was maintained for more than 18 months (Joensuu et al., 2001). This remarkable response and others led to subsequent trials including a multicentre trial demonstrating a response rate of 54% in patients with this chemoresistant disease, and a duration of response that had yet to reach the median at 24 weeks when the study was published (Demetri et al., 2002). This contrasts to the pre-imatinib era with responses to chemotherapy rare and survival poor. Given that the early TKIs targeted a narrow spectrum of tyrosine kinases (e.g. erlotinib targeting only EGFR), the toxicity associated with such agents was predictable and markedly improved compared to cytotoxic chemotherapy. Thus, myelosuppression is not observed, and neither is emesis or alopecia. TKIs are also generally administered orally. By contrast, the TKIs have their own specific toxicities relating to their targets. Thus, the TKIs that target EGFR all result in an acneiform rash and diarrhoea, because EGFR is expressed on the skin surface and on the gastrointestinal tract mucosa. The VEGF inhibitors such as sorafenib and axitinib can case hypertension and proteinuria, highlighting the role of VEGF in regulating renal and systemic vasculature (as can monoclonal antibodies targeting VEGF – see below). However, as these TKIs have been developed further, in a bid to overcome drug resistance, the number of targets inhibited has broadened, and thus toxicity has become greater. An example of this is sunitinib (which targets VEGFR, PDGFR, KIT and FLT3), which demonstrates appreciable levels of diarrhoea, vomiting, hypertension and hand–foot syndrome. Nevertheless, the seriousness of these toxicities observed is far less than that with cytotoxic chemotherapy. Another worrying finding is that many targeted therapies can result in hypothyroidism and cardiac failure due to unwanted (off-target) effects.

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Light chain

Heavy chain

Fc region

Figure 3.3 The structure of a typical antibody.

Monoclonal antibodies

Kohler and Milstein pioneered the consistent production of MAbs in 1975 through their development of hybridoma technology. MAbs are essentially antibodies generated from an immortal cell, with all antibodies directed against a pre-specified target, usually a membrane-bound target. The basic structure of an antibody is shown in Figure 3.3. These antibodies have enabled huge bounds in laboratory research methods to be undertaken but had little/no clinical value. This was principally because they were of animal origin, and when used clinically resulted in marked immune-mediated toxicity. More recent biotechnology developments have allowed the formation of ‘humanised’ MAbs, in which the majority of the antibody is of human origin, and only the portion that binds target (part of the Fab) is of non-human origin. As a result, these antibodies are, in general, tolerated remarkably well, but allergic reactions are recognised due to the presence of residual non-human components, and usually require pre-medication with steroids. More recent advances in transgenic mouse technology coupled with hybridoma technology have enabled the formation of fully human MAbs. As expected, these agents have significantly less allergic toxicity, and are therefore better tolerated. Several MAbs are now licensed both in Europe and in the United States for the treatment of cancer. These agents target specific antigens, and these are mostly cell surface antigens. However, some licensed antibodies are directed against stromal elements, and some against secreted peptides. Table 3.2 gives a list of some MAbs in development, and in clinical use, their targets, and their indication. All MAbs have a generic name ending in the suffix ‘-mab’, reflecting their biological properties. Binding of an MAb to target can result in either inhibition of that pathway or stimulation. In anticancer therapy, these drugs are predominantly inhibitory agents that lead to cell

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Table 3.2 Selected monoclonal antibodies, their targets and state of clinical development Target

MAb

Trial stage

Cetuximab (Erbitux)

EGFR

Licensed for colorectal, head and neck Lung, pending licence

Panitumumab (Vectibix) Trastuzumab (Herceptin) AMG-102 OA-5D5 CP-751,871

EGFR HER2 cMET cMET IGF-1R

Colorectal Breast Phase 1 Phase 1 Phase 3 (lung), phase 2 (breast, colorectal, prostate, Ewing sarcoma)

AMG-479

IGF-1R

Phase 2 (breast, lymphoma, ovarian, pancreatic, sarcoma)

IMC-A12

IGF-1R

Phase 2 (breast, colorectal, head and neck, liver, pancreatic)

Bevacizumab (Avastin) VEGF-Trap (Aflibercept)

VEGF-A VEGF

Licensed for breast, colorectal, lung Phase 2 (brain, colorectal, leukaemia, lung, melanoma)

death or cytostasis. Mechanisms of how this is achieved are unclear, but are probably due to internalisation of the receptor/antibody complex by the cell (for cell surface targets) and downregulation of receptor expression. However, due to the biological properties of MAbs, these agents can also exert anticancer effects through other mechanisms. One of the major other mechanisms thought to influence cytotoxicity is termed ‘antibody-dependent cell cytotoxicity’. Here, binding of common terminal region (the Fc region) to effector cells carrying receptors directed against the Fc region (FcR) (e.g. natural killer cells or monocytes) mediates immune-directed cytotoxic responses. Examples of this include trastuzumab (Herceptin) and rituximab (MabThera) in which a number of studies have shown that the level of anticancer activity demonstrated by these MAbs is influenced by the nature of FcRs. The classical example of how MAb-directed approaches have played a major influence in the treatment of cancer is in the management of HER2-amplified breast cancer with trastuzumab (Herceptin), the humanised MAb directed against HER2. Here, amplification or overexpression of the HER2 gene in around 20% of all breast cancers had been well demonstrated, and that this was an independent marker of poorer survival. With advanced disease, in the pivotal trial of chemotherapy with/without trastuzumab, patients randomised to trastuzumab had a significantly longer time to disease progression, higher rate of tumour response, longer duration of response, lower rate of death at 1 year, and longer survival (median survival, 25.1 months vs 20.3 months) (Slamon et al., 2001). Having proven efficacy in advanced disease, trastuzumab was trialled in the adjuvant setting, in patients after potentially curative resection of breast cancer. Here, several trials have all demonstrated a significantly improved survival in patients with HER2-amplified/overexpressing breast cancer (Mariani et al., 2009). The magnitude of this survival benefit has been overwhelming, with joint analysis of the NSABP-31 and NCCTG N9831 trials demonstrating a 33% reduced risk of death by the addition of trastuzumab to standard adjuvant therapy. Moreover, the risk of distant relapse was

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53% improved in patients receiving trastuzumab than not (Mariani et al., 2009). Thus, trastuzumab has become standard of care in patients with breast cancer with overamplification/overexpression of HER2, and remains a classic example of how ‘oncogene addiction’ to a single pathway (HER2) can be demonstrated and treated effectively through a drug that has been rationally designed for that specific purpose.

Immunotherapy Despite major advances in basic tumour immunology, these have not been translated into effective clinical immunotherapeutics. A previous comprehensive review identified a response rate of 3.3% in 1306 vaccine treatments for metastatic cancer patients. Thus, this modality should be considered experimental. Nevertheless, this is an area of active research with newer types of biotechnologically engineered vaccine available.

Radiotherapy Radiotherapy is one of the major modalities used in the treatment of cancer, and has potent anticancer effects. Indeed, it has been estimated that it may account for approximately 40% of all cancer cures (Board of the Faculty of Clinical Oncology, 2003). Radiotherapy is delivered by exposure to electromagnetic radiation of primarily X-rays and ␥ -rays because these are of sufficiently high energy to produce ionisation of atoms (and hence, the term ‘ionising radiation’). In this process of ionisation, an electron is displaced from its normal orbit from a nucleus, captured by a neighbouring atom, which in turn becomes unstable, and the process repeats, and ultimately leads to cell destruction. Controlling radiation beams using modern methods therefore allows the controlled cellular destruction of target tissue areas, with lesser effects on surrounding areas. The emission of radiation occurs naturally in the physical decay of naturally occurring elements with inherently unstable atoms, which then results in a final and more stable atomic state. Radiation-emitting materials occur naturally, and a wide range of such materials is observed. The nature of the radiation emitted by these materials is classically divided into ␣- and ␤-particles, and ␥ -waves depending on their characteristics. ␣-Particles are essentially helium nuclei (two protons and two neutrons), which are positively charged and have substantial mass. ␤-Particles are essentially electrons and have a negative charge but little mass. By contrast, ␥ -rays are best thought of a wave, rather than particles, and carry no charge. ␥ -Rays are the most frequently natural radiation source used in clinical practice although all three radiation types produce ionisation in tissues. The division between ␥ -rays and X-rays is arbitrary depending on context, and both are a type of high-energy radiation. Both can also be thought of as photons because this latter term only refers to a quantum (packet) of energy. Although the early radioactive isotopes discovered were all naturally occurring, modern physics has enabled the artificial manufacture of radionuclide isotopes that closely relate to the clinical ideal for radioactive half-life, ␥ -ray characteristics and intensity. These compounds include sealed and unsealed radiation sources. In sealed sources, the radioactive material is enclosed by an impenetrable barrier: an example being platinum casing of a caesium needle, so the source can be inserted into the tissue to be irradiated,

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and then removed after a pre-specified time. For unsealed sources, the radioactive source is physically ingested and systemically absorbed, accumulating in the end organ, where the effects of radioactivity cause local tissue ionisation: an example being 131 I therapy for thyroid carcinoma, an example of radionuclide therapy. However, with the advent of modern radiation delivery systems, and the development of linear accelerators to allow the generation of high-energy X-rays or photons, delivery of ␥ -rays through a natural isotope (such as 60 Co) has become rare, and delivery of high-energy photons to deliver ionising radiation has become the norm. This modality is usually used when external beam radiation is prescribed.

External beam radiotherapy Tumours needing radiotherapy occur at a variety of depths on or below the skin surface, and most patients receive traditional external beam radiotherapy as a treatment for this, if indicated. Here, the treatment beam is generated and delivered from outside the body. These beams usually consist of high-energy photon beams that then penetrate tissue and allow the treatment of deep-seated tumours. Photons are massless packets of energy that are absorbed by tissue or result in the formation of secondary electrons when encountering tissue. These electrons travel through tissue matter and result in ionisation, leading to direct and indirect cell killing. When treating with such external beam therapy, minimisation of normal cell killing is important to minimise toxicity. Thus, beams are arranged to enter the patient from several different directions and to intersect at the centre of the tumour (called the treatment isocentre). Modern photon beam treatment machines allow great precision of beam delivery to target. The process of ensuring localisation of the patient’s tumour avoiding normal tissue is important and can be performed using two main methods: patient immobilisation (reducing the patient’s movement during treatment) and localisation (knowing the precise position of tumour and normal tissues). Immobilisation devices such as foam moulds can be used to hold patients comfortably in a specific treatment position. Additionally, lowpower laser beams can be aligned to skin marks allowing localisation of the immobilisation device to the treatment couch. However, to be entirely precise about localising tumour, a number of different methods have been developed including in-room imaging, and implanted radio-opaque markers. Using such systems can result in marked reproducibility of patient’s position to within a few millimetres over a course of treatment lasting 5–8 weeks. These systems track tumour size in real time, and can allow a reducing field of radiation to be given as the tumour shrinks. The delivery of radiotherapy is contingent on the course of radiotherapy being appropriately planned. In theory, this is as simple as selecting a sufficient number of beam angles to allow the desired dose in the region of overlap, and then to design the beam apertures to shape the edges of the beam to match the shape of the target. However, in reality normal tissue often lies in close proximity if not within the planned beam. This tissue is often more sensitive to radiotherapy than tumour tissue, and thus may be dose-limiting. Modern planning is now therefore computer assisted for exactly this reason, in order to develop anatomically correct models which are then used with beam-specific properties derived

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from phantom measurements to select beam angles, shapes and intensities to meet the desired prescription. Effectiveness of radiotherapy can be influenced by a number of prescribed parameters. These include total dose given and the amount of dose given per radiation treatment (fraction). A standard fraction of radiotherapy is one delivery of 1.8–2.25 Gy per day. In ‘hyperfractionated’ schedules, more than one fraction is administered per day, with a dose per fraction that is less than standard. By contrast, ‘hypofractionated’ schedules give a smaller number of larger fractions than standard, and are expected to cause more late toxicity under normal circumstances. However, using image guidance methods to limit the dose given to normal tissues has allowed hypofractionated scheduling to be applied safely to prostate and lung cancers with excellent outcomes. When considering effectiveness of radiation, patient factors must also be taken into account. For radiation to achieve an ionising effect, oxygen must be in close proximity to the target cell. In hypoxic conditions, DNA damage as a result of ionisation can be repaired much more readily than under adequately oxygenated conditions, and may therefore influence radiotherapy outcomes by reducing efficacy. Because haemoglobin is the major carrier of oxygen, anaemia may potentially reduce radiation efficacy. Thus, efforts should be maintained in ensuring adequate haemoglobin levels during radiotherapy, and this may require transfusion, if indicated. Conformal, stereotactic and intensity-modulated radiotherapy

These are newer developments in radiotherapy methodology, in which high-dose volume of radiation is designed to contour more closely with the tumour target volume, and thereby allow higher doses to be delivered with less surrounding normal tissue irradiated and therefore less toxicity. With conformal or stereotactic therapy, external beam radiation is given by reducing the amount of normal tissue irradiated, thereby allowing an increased dose that can be safely applied to the tumour. Trials of these newer modalities are underway, and case series report excellent outcomes in the treatment of brain metastases, early prostate cancer and lung cancer. Intensity-modulated radiation therapy is another technique that allows a degree of individualisation of irradiation. Here, computer-controlled linear accelerators are used to deliver precise radiation doses, which are designed to conform to the three-dimensional shape of the tumour by modulating the intensity of radiation beam to focus a higher dose to the tumour, whilst minimising dose to the surrounding normal tissue. Typically, combinations of several intensity-modulated fields coming from different beam directions are used to produce a customised radiation volume. These approaches are increasingly being applied to cancers of the head and neck, lung, prostate and bladder.

Brachytherapy Brachytherapy is a specialised form of radiotherapy delivery that uses direct placement of a radioactive source within tumour tissues (or body cavities) to deliver optimal radiation doses. The radioactive isotopes used in this modality are usually contained within small

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sealed enclosures to prevent infectious contamination between different patients. Isotopes can be administered either permanently (allowing for full decay of a short-lived isotope) or temporarily (over several applications). The dose provided by this method is very high near the source but falls away rapidly thereafter, allowing conformal treatments with low normal tissue doses. Brachytherapy treatments are generally divided into two categories: low-dose rate and high-dose rate. In the former, treatment is given via continuous radiation from an implanted source over several days. In the latter, a source stored away from the patients is applied via an applicator to give one or more treatments.

Combined modality therapy Chemoradiotherapy Combining chemotherapy with radiotherapy has resulted in improved outcomes compared to using either modality alone or in sequence. Concurrent chemoradiation has become the standard for the treatment of some tumour types, such as head and neck, cervix, anus and locally advanced lung. Here, the combination improves outcomes by two methods: radiosensitisation and spatial additivity. With the former, concurrent use of both modalities improves outcomes synergistically, because the use of chemotherapy may improve the cytotoxicity of radiotherapy. With the latter, radiation leads to improved local control, and systemic chemotherapy gives good distant control. In practice, these effects cannot be separated and they both play a role in the improved efficacy seen with concurrent schedules. Whilst effective, this combined modality approach can be limited by marked toxicity, and it is widely accepted that concurrent chemoradiotherapy leads to more toxicity than sequential chemoradiotherapy (where a course of radiation is given after the schedule of chemotherapy has been completed). In the case of head and neck cancer patients, enteral feeding tube placement is likely required due to the marked stomatitis observed. For lung cancer, whilst severe mucositis is uncommon and enteral feeding requirement is rare, performance status needs to be extremely good (at most 1) to cope with the rigours of this therapy. Other issues include the radiosensitisation effect that might limit the overall dose of chemotherapy. Thus, gemcitabine is such a good radiosensitiser that significantly reduced doses need be used with radiotherapy, or risk marked toxicity (e.g. mucositis and oesophagitis).

Conclusion This chapter gives an overview of the major therapeutic modalities used in the treatment of cancer, the terms used to describe these modalities, and the intent of therapy. The treatment of cancer is a vast area, and whilst there is often great debate between specialists in issues pertaining to timing, technique, dose and scheduling of therapy, the major modalities used in treatment of any one particular patient are usually well defined according to the stage and performance status of the patient. Over the past 30 years, major advances have been made at many levels that have allowed a paradigm shift in the treatment of some cancer types. Despite this, the three

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major modalities of surgery, systemic therapy and radiation therapy will continue to play major roles in the treatment of cancer.

References Board of the Faculty of Clinical Oncology (2003) Equipment, Workload and Staffing for Radiotherapy in the UK 1997–2002. London: The Royal College of Radiologists. Demetri, G.D., von Mehren, M., Blanke, C.D., et al. (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. The New England Journal of Medicine 347(7), 472–480. Joensuu, H., Roberts, P.J., Sarlomo-Rikala, M., et al. (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. The New England Journal of Medicine 344(14), 1052–1056. Langer, C.J. (2009) The ‘Lazarus Response’ in treatment-naive, poor performance status patients with non-small-cell lung cancer and epidermal growth factor receptor mutation. Journal of Clinical Oncology 27(9), 1350–1354. Mariani, G., Fasolo, A., De Benedictis, E., et al. (2009) Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer. Nature Clinical Practice Oncology 6(2), 93–104. Slamon, D.J., Leyland-Jones, B., Shak, S., et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. The New England Journal of Medicine 344(11), 783–792. Weinstein, I.B. and Joe, A.K. (2006), Mechanisms of disease: oncogene addiction – a rationale for molecular targeting in cancer therapy. Nature Clinical Practice Oncology 3(8), 448–457.

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Chapter 4

Effect of malnutrition on cancer patients Louise Henry

Introduction The terms ‘malnutrition’ and ‘cachexia’ are used interchangeably in research pertaining to nutrition and oncology. This inconsistency arises due to the imprecise nature of the definition of cancer cachexia (Fearon et al., 2006; Evans et al., 2008; Bozzetti & Mariana, 2009a; Fox et al., 2009). Many authors have attempted to define cachexia with definitions tending to be qualitative descriptions of the syndrome (Evans et al., 2008; Bozzetti & Mariana, 2009b). In the absence of a clear, universally agreed definition, it is difficult to measure and classify cachexia (Fearon et al., 2006; Bozzetti & Mariana, 2009a). However, there is a general trend to view cachexia as a syndrome characterised by ongoing weight loss (usually in the region of 10% or more) combined with the presence of a symptom such as anorexia, fatigue or reduced food intake, and according to some authors, raised C-reactive protein (as an indicator of systemic inflammation) (Fearon et al., 2006; Evans et al., 2008; Bozzetti & Mariana, 2009b). Malnutrition can be defined as a ‘state of nutrition in which a deficiency, excess or imbalance of energy, protein, and other nutrients causes measurable adverse effects on tissue (shape, size, composition), function and clinical outcome’ (Elia, 2003). Differentiating between malnutrition as an effect of cancer treatment and cachexia is very difficult, and for the purposes of this chapter, the term ‘malnutrition’ will be used to describe the changes in nutritional status observed in cancer patients (Von Meyenfeldt et al., 1988). Malnutrition can encompass wasting (undernutrition) and obesity (overnutrition); however, the term is more commonly used to refer to undernutrition rather than overnutrition. For the purposes of this chapter, the term malnutrition will be used to denote undernutrition. Malnutrition may be seen as a deficiency of micronutrients or macronutrients and a clinical condition arising from a substantial loss of muscle and subcutaneous fat. There is no ‘gold standard’ for determining nutritional status (Schneider & Hebuterne, 2000; Pereira Borges et al., 2009). Techniques such as bioelectrical impedance, skinfold thickness and subjective global assessment (SGA) have been used, but these methods of assessment can be influenced by a variety of factors including fluid imbalance, use of painkillers and observer error (Kyle et al., 2005a). The inconsistency in measurements used and in the

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Table 4.1 Possible causes of weight loss and malnutrition in cancer patients Catabolic effects of the tumour/abnormal metabolism of nutrients Inadequate intake due to tumour-induced anorexia Reduced food intake secondary to treatment side effects such as nausea, vomiting, stomatitis, constipation and malabsorption (Tubiana et al., 1971; Nitenberg & Raynard, 2000) Obstruction from tumour or as a consequence of treatment, for example, dysphagia secondary to cancer of the oesophagus, bowel obstruction secondary to disease and dysphagia as a consequence of radiotherapy to the pharynx Pain, anxiety and depression

variety of definitions used for malnutrition and cachexia partly explains the wide variation in the reporting of the prevalence of malnutrition (Von Meyenfeldt et al., 1988). The causes of weight loss and malnutrition in cancer patients are multifactorial (see Table 4.1). Site and extent of tumour, cancer treatments and medication used to palliate the side effects of treatment and disease-related symptoms will determine the presence and extent of undernutrition. Overnutrition is often associated with the use of corticosteroids, immobility secondary to disease or side effects of treatment and use of hormone therapy. Malnutrition, in particular weight loss, is associated with lower survival, poor response and decreased tolerance to anticancer therapy, higher health care costs and longer hospitalisation (Butterworth, 1974; DeWys et al., 1980; Andreyev et al., 1998; Nitenberg & Raynard, 2000). It is generally accepted as a good predictive parameter of mortality, morbidity and length of hospital stay (Kyle et al., 2005a). The relationship between malnutrition and the risks of major surgery has been extensively studied (Windsor & Hill, 1988; Bozzetti et al., 2007; Norman et al., 2008). Wound healing, muscle function and immune function are all thought to be affected by malnutrition, with degree of malnutrition correlating with the higher post-operative risk of infections and non-infectious complications (Elia et al., 2006; Bozzetti et al., 2007). Consideration of micronutrient deficiency as part of the phenomenon of malnutrition has had very little attention in the field of oncology research. This might reflect the difficulties in conducting such studies (e.g. collecting intake data and difficulty in measuring status).

Prevalence of malnutrition amongst cancer patients Prevalence rates of malnutrition vary considerably depending on the population studied, criteria used to define malnutrition and disease site and stage (Von Meyenfeldt et al., 1988; McWhirter & Pennington, 1994; Kyle et al., 2005a; Arends et al., 2006; Fox et al., 2009). Rates recorded range from 8 to 84% (see Table 4.2). Despite several studies highlighting the prevalence of malnutrition, it continues to be widespread in this patient population. Most of the data on prevalence are derived from hospital inpatients prior to starting treatment. Both mixed diagnostic groups and single disease groups have been studied, and a limited number of studies have been conducted in patients with advanced disease (see Tables 4.2–4.6).

32% of patients (all diagnoses) had experienced a weight loss of more than 5% in previous 6 months. Incidence by diagnostic group: Breast cancer 14% Sarcoma 18% Colon 28% Small cell lung cancer 34% Lung non-small cell 36% Pancreas 54% Gastric cancer 65% Weight loss from usual weight = 10.8% ± 0.9 Mean BMI = 22.3 kg/m2 in weight loss group, 25.7 kg/m2 in weight-stable group

Weight loss 5% usual body weight = 59% (with 11% having weight loss >20%)

Weight loss >5% in 6 months

Weight loss >5% in 3 months MAC, skinfold measurements, albumin concentration, dietary record

Weight loss (%)

Weight loss (0 to >20%)

3047 patients with a mix of cancers (United States)

104 patients with performance status of 0–1 (as defined by Eastern Cooperative Oncology group). Small cell lung cancer, metastatic breast disease, ovarian cancer (Denmark)

530 patients (multicentre, solid tumours, receiving palliative care) (Italy)

644 ambulatory cancer patients at an outpatient cancer centre (USA)

For patients with metastatic disease, weight loss >5% usual body weight = 62% (with 15% having lost >20%) (Continued )

Tchekmedyian (1995)

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DeWys et al. (1980)

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Anthropometric measurements statistically significantly different between groups

Incidence of malnutrition

Definition of malnutrition

Patient population

Table 4.2 Incidence of weight loss by diagnosis: mixed groups

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2. Moderate = 1.2% 3. Severe = 0.6% 4. BMI 10% of body weight during the 6 months immediately preceding hospital admission = 1.8% 5. BMI ≥20 kg/m2 and unintentional weight loss >10% of body weight during the 6 months immediately preceding hospital admission = 8.7% 6. BMI