Cancer in the Elderly [1 ed.] 9781614707615, 9781614706380

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Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Cancer in the Elderly, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Cancer in the Elderly, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,

CANCER ETIOLOGY, DIAGNOSIS AND TREATMENTS

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CANCER IN THE ELDERLY

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AGING ISSUES, HEALTH AND FINANCIAL ALTERNATIVES

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CANCER ETIOLOGY, DIAGNOSIS AND TREATMENTS

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CANCER IN THE ELDERLY

Ivan Todorov and Filip Novak EDITOR

Nova Science Publishers, Inc. New York

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Copyright © 2012 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. Library of Congress Cataloging-in-Publication Data Cancer in the elderly / editors, Ivan Todorov and Filip Novak. p. ; cm. Includes bibliographical references and index.

ISBN: (eBook)

1. Geriatric oncology. I. Todorov, Ivan, 1972- II. Novak, Filip. [DNLM: 1. Neoplasms. 2. Age Factors. 3. Aged. 4. Neoplasms--therapy. 5. Risk Factors. QZ 200] RC281.A34C3683 2011 618.97'6994--dc23 2011024683 Published by Nova Science Publishers, Inc. † New York

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Contents

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Preface

vii

Chapter 1

Cancer-Related Fatigue in Elderly Patients Annalisa Giacalone, Daniela Quitadamo, UmbertoTirelli, and Simon Spazzapan

Chapter 2

Hormone Therapy: The Only Treatment in Elderly Patients with Hormone-Sensitive Breast Carcinoma Unsuitable to Surgical Treatment Laura Melado Vidales and Ginés Hernández Cortés

Chapter 3

Chapter 4

Correlations between Metabolic and Hormonal Cancer Risk Factors and Aging:Age-and Gender-Related Risk for Oral Cancer Zsuzsanna Suba Ethic Reflexion on Cancer Treatment for Patients with Alzheimer Disease: Literature’s Point of View S. Moulias, T. Cudennec, W, Moussous, J. Lagrandeur, and L. Teillet

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33

59

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vi

Contents

Chapter 5

Esophageal Cancer in the Elderly Guy Pines and Hanoch Kashtan

Chapter 6

Surgical Management of Cancer in the Elderly Emile C. H. Woo, and Kok-Yang Tan

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Index

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93 105 121

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Preface This book gathers current research from across the globe in the study of cancer in the elderly. Topics discussed include cancer-related fatigue in elderly patients; rectal cancer staging; hormone therapy treatment in elderly patients with hormone-sensitive breast cancer; age and gender-related risk for oral cancer; cancer treatment for patients with Alzheimer's disease and esophageal cancer in the elderly. Chapter 1- I am old, I’m affected by cancer, I’m tired and I feel weak. Am I fatigued? No, feeling a lack of energy is normal when you are on anticancer therapies and you are aged. This is what many elderly cancer patients usually think about their fatigue, and this is what physicians most likely suppose about the fatigue symptoms experienced by their older patients. This was what clinicians believed about any cancer patient. Chapter 2- During the twentieth century in the most developed countries, there has been a decline in fertility and an increased in life expectancy. This situation has created an epidemiological transition in the leading causes of death from infections in the past to chronic diseases such as cardiovascular disease or cancer at the present time. Breast cancer is a major public health problem because its incidence is the highest among malignant tumors in women, as evidenced by statistics from the International Agency for Research on Cancer, WHO. Chapter 3- Ageing and cancer development seem to be completely controversial processes affecting the proliferative homeostasis apparently quite inversely. However, the results of experimental, clinical and epidemiological studies support that ageing and carcinogenesis are in intimate correlation [1].

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viii

Ivan Todorov and Filip Novak

Chapter 4- Alzheimer's disease is a neurodegenerative disease that causes progressive loss of mental function, following the deterioration of brain tissue. In France, in 2007, approximately 860,000 people were affected by Alzheimer's disease or related disorders, to 4.5 millions in U.S. Like all people of their age, patients over 75 years with Alzheimer's disease, may develop other chronic diseases, including cancers. In Europe and the United States, over 60% of new cancer cases and over 70% of cancer deaths occur among patients over 65 years [1]. The action to be taken before each type of cancer is well known for adults under 65, the diagnostic method is the same regardless of age. Among people over 65 years, studies are lacking and the care management is often free. Chapter 5- Life expectancy in the western world is increasing and as a result, the elderly represent a rapidly growing sector in industrialized countries. Elderly patients are considered to be a unique subpopulation compared to younger patients due to higher incidence of comorbidities, poorer functional status, and increased likelihood to present with more advanced disease and as an emergency. It is an ethical dilemma how aggressive one should be when it comes to treating cancer in the older population. Presumed concern of increased postoperative morbidity and mortality may result in suboptimal cancer surgery. Chapter 6- Through-out the developed world, whether from Singapore, to Japan, and to the United States, the proportion and absolute numbers of patients entering into the geriatric age bracket is growing. With this inexorable increase in elderly people, the incidence of cancers that are age related will also steadily grow. Using colorectal cancer as an example, it has been forecasted that by 2025, colorectal cancer procedures will become one of the fastest growing operations in the US. Our ability to cure has steadily improved. In colorectal cancer, the 5 year survival rate has been climbing from 51% in 1965 to 65% in 2003. Patient acceptance in the older population has also increased. The Danish Registry data showed a decrease in the number of patients over 75 who were receiving palliative treatment from 19.8% in the period between 1977-1982 down to 13.1% in the period from 1995 to 1999. This presents a rapidly growing challenge to all oncology surgeons as to how best to manage these patients.

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In: Cancer in the Elderly ISBN 978-1-61470-638-0 Editor: Ivan Todorov and Filip Novak © 2012 Nova Science Publishers, Inc.

Chapter 1

Cancer-Related Fatigue in Elderly Patients Annalisa Giacalone1*, Daniela Quitadamo2, UmbertoTirelli3, and Simon Spazzapan4 1

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Medical Oncology Department, National Cancer Institute – IRCCS, Aviano (PN), Italy 2 Biological, Scientific Directorate, National Cancer Institute – IRCCS, Aviano (PN), Italy 3 Medical Oncology Department, National Cancer Institute – IRCCS, Aviano (PN), Italy 4 Medical Oncology Department, National Cancer Institute – IRCCS, Aviano (PN), Italy

Abstract Fatigue is one of the most common and debilitating symptoms experienced by cancer patients and cancer survivors (incidence 2090%). Cancer-related fatigue involves all the phases of cancer, even after the discontinuation of treatments. It may worsen the quality of life, force the patient to give up treatment and increase Health Care costs. Research has shown that cancer-related fatigue has a multi-factorial *

Correspondence to: Annalisa Giacalone, Psychol D, PhD, Department of Medical Oncology National Cancer Institute – IRCCS, Via Franco Gallini 2, 33081 Aviano (PN) – Italy, Tel. +39 0434 659649, Fax. +39 0434 659531 e-mail: [email protected]

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Annalisa Giacalone, Daniela Quitadamo, UmbertoTirelli et al. aetiology that necessitates appropriate pharmacological and/or nonpharmacological treatments based on the correct evaluation of the symptoms and the pre-existing causes e.g. anaemia, endocrine, metabolic and mood disorders. Even if fatigue rates of between 70 and 99% occur in patients older than 70 years, this has not translated into an increase in clinical trials for the assessment and therapy of cancer-related fatigue in this population group. The early recognition and formal assessment of this symptom in a population group with a high risk for frailty is important in order to be able to treat it before it impacts negatively on the patient’s quality of life. This chapter aims to give a brief overview of cancer-related fatigue in elderly cancer patients.

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Introduction I am old, I’m affected by cancer, I’m tired and I feel weak. Am I fatigued? No, feeling a lack of energy is normal when you are on anticancer therapies and you are aged. This is what many elderly cancer patients usually think about their fatigue, and this is what physicians most likely suppose about the fatigue symptoms experienced by their older patients. This was what clinicians believed about any cancer patient. Until the past decade, fatigue was considered as an insignificant symptom, the neglected one, giving all the attention to pain or nausea and vomiting [1,2]. Both cancer patients and clinicians viewed fatigue as something to be endured rather than a symptom open to differential diagnosis and treatment. In one of the first studies on cancer-related fatigue, patients and oncologists agreed on the presence of significant fatigue in 75% of patients, but they disagreed on its importance. While 61% of patients reported that fatigue affected their lives more than pain, only 37% of oncologists thought that this was true [3]. The beginning of change began when fatigue in cancer patients was recognized as a specific symptom. It was defined as a multifaceted condition characterized by diminished energy and a disproportionately increased need for rest with respect to any recent change in activity levels [4]. The first guidelines on evaluating and managing fatigue were published by Porteney and colleagues in 1999 [5].

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Cancer-Related Fatigue in Elderly Patients

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Fatigue has been described as a common problem for patients receiving cancer treatment, and it often persists beyond the conclusion of active treatment, seriously compromising patients’ quality of life (QOL) and ability to function on a daily basis [6-11]. Notwithstanding this, cancer fatigue is still ignored because it is mainly a subjective experience that is assessed by patient self-report, and it is not lifethreatening. This is especially common in elderly patients who consider fatigue to be part of the usual course of aging, and they may not even disclose thes symptom to their clinicians. There are several barriers in the patient-clinician communication about fatigue. Passik and colleagues reported that the most frequent problems included the clinician’s failure to offer interventions (47%), the patient’s lack of awareness of effective treatments for fatigue (43%), a desire on the patient’s part to treat fatigue without the use of medications (40%), and a tendency of the patient to be stoic about fatigue to avoid being labelled as a ―complainer‖ (28%) [12]. Another important barrier to the recognition and management of fatigue in the elderly may be the physicians’ personal ageist attitudes [13]. Physicians tend to spend less time with older patients than with younger ones, paying less attention to their unexpressed needs and values. On the other hand, elderly patients may also be affected by sensory deficits, cognitive impairment and functional deficits that may require a higher level of thoughtfulness and consideration. All the above has probably caused the absence of studies and data pertaining specifically to fatigue in elderly cancer patients, even though cancer is mainly a disease of the elderly, with 60% of tumours occurring in patients over 65 years of age.

Definition of Cancer-Related Fatigue and Incidence Different definitions of cancer-related fatigue (CRF) have been proposed throughout the years because the clinical expression of CRF is multidimensional. Fatigue may be experienced and reported differently by each patient. Some patients identify the main features of their fatigue as a loss of efficiency, mental fogginess, inertia, and sleep that is not restorative, whereas others describe an excessive need for rest, an inability to recover promptly from exertion, muscle heaviness and/or weakness [14-16].

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Annalisa Giacalone, Daniela Quitadamo, UmbertoTirelli et al.

To address the important problem of cancer fatigue, in the year 2000 the National Comprehensive Cancer Network (NCCN) convened a panel of experts and published the first NCCN cancer-related fatigue guidelines. Annually updated, NCCN defines CRF as a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning [17]. On the basis of the 10th International Classification of Disease criteria for the diagnosis of CRF, fatigue in cancer is more severe and more distressing compared to fatigue in healthy individuals, has an adverse impact on function and is unrelieved by rest or sleep [7]. To make the diagnosis of CRF, fatigue must be persistent, be present every day or nearly every day during the same 2-week period in the past month, and be accompanied by associated symptoms such as an increasing need for rest, limb heaviness, diminished concentration, inertia, emotional lability, and postexertional malaise. There must be evidence that the underlying cause of fatigue is cancer and/or its treatment. Depending upon how CRF is defined and measured, prevalence estimates throughout the course of disease range from 20-95% in the general cancer population [8, 18-20] and from 70-99% in elderly patients [7, 21]. In a survey of 534 patients, fatigue was considered as the most important symptom or concern across all cancer types [22]. Longitudinal and comparative studies indicate that fatigue may also be a significant problem for cancer survivors, with a significant proportion of these reporting fatigue scores greater than that of an age-matched general population [10, 11, 23, 24]. CRF is also present in the advanced cancer setting. In their national survey, Johnsen and colleagues found that almost 60% of evaluated patients (with a mean age of 64 years) still experienced fatigue, while 25% reported severe fatigue [25].

Factors Associated with CRF CRF often occurs as a component within a cluster of other symptoms and may be accompanied by conditions that are likely to contribute to the development of fatigue. For example, in a study with 373 breast cancer patients undergoing hormonal cancer therapy (39% of whom were older than 65 years), fatigue was experienced by 45% of patients with menopausal symptoms. The authors suggested that the fatigue influenced the experience of menopausal

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Cancer-Related Fatigue in Elderly Patients

5

symptoms, even if the question of whether fatigue causes more menopausal symptom distress or whether menopausal symptom distress causes more fatigue could not be answered [26]. Many studies have demonstrated a relationship between anaemia and fatigue [27]. Anaemia is a highly prevalent symptom in elderly people, especially among the over-70 population group, with prevalence ranging from 3-60%. A European survey on over 15,000 patients reported that anaemia affects about two thirds of cancer patients [28]. Its incidence varies by type, stage and duration of the disease as well as its treatment, such as myelosuppresive chemotherapy. Data concerning the exact prevalence of anaemia in elderly cancer patients are still lacking. The association of fatigue with pain and depression was evaluated in a survey of adults  50 years of age, both with and without a history of cancer in the Health and Retirement Study [29]. Sixty-seven percent of the patients with cancer were over 65 years of age, and approximately 50% had one or two coexisting medical conditions. Authors found that patients with cancer had a higher risk for fatigue (OR 1.45; P136

131-135

126-130

6.0

ECG

Normal

Atria fibrillation (rate 60-90/min)

Any abnormal rhythm, >5 ectopics/min, Q waves, ST/T wave changes

Severity Score

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Multiple Procedures Blood Loss (mls) Contamination

POSSUM Operative Severity Score 1 2 4 8 Minor Moderate Major Major + (colectomies) (APR) 1 2 >2 999

None

Minor (serous)

Local pus

Free bowel content, pus or blood Distant mets

Presence of None Primary Ca Mode of Elective Surgery x = (0.16* physiologic score)+(0.19*operative score)- 5.91 Predicted Morbidity Rate = 1/(1+ e(-x)) y = (0.13* physiologic score)+(0.16*operative score)-7.04 Predicted Mortality Rate = 1/(1+ e(-y))

Nodal mets Urgent

Emergency (immediate 121 or 15

4 71 – 80

8 >81

Colorectal POSSUM Operative Severity Score Operation Type Peritoneal Contamination Malignancy Status Nature of Surgery

1 Minor None or serous fluids

2

No cancer/ Dukes A or B Elective

Dukes C

Local pus

3 Intermediate Free bowel content, pus or blood Dukes D Urgent

4 Major

8 Complex major

Emergency (within 2hrs)

Surgical Management of Cancer in the Elderly

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The extent of surgery is also important in reaching the stated treatment objectives. On the one hand, the most aggressive surgery may not always be the most suitable to achieve treatment goals. Similarly, conservatism may lead to inadequate surgery which may prevent the patient from obtaining a potential cure. This is especially important in that many geriatric patients may not be eligible or be able to tolerate adjuvant therapy and thus loose their best chance at cure. Finally, the type of surgery needs to be tailored to the patient’s expectation with regards to post operative function which may need to be balanced with the risk that may be associated with surgery or the patients baseline level of function. For instance, in colorectal surgery, is a patient with rectal cancer better off with an abdominoperineal resection where there is evidence of lower morbidity and mortality compared with an anterior resection where there is a risk of leak? Will the patient or care givers be comfortable with managing a stoma afterwards? Is the patient’s own baseline level of continence adequate? These types of decisions are made even more difficult if a substitute decision maker is required.

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Psychosocial Considerations Preoperative planning must not proceed with the view of the patient in isolation without his or her psychosocial milieu. The undertaking of oncologic surgery in the elderly is a major life event, if not a possible terminal event, in a patient population that is already at the distal end of the birth to death narrative. The possibility of loss of independence or increasing dependence has a profound psychological impact on the patient that needs to be considered and addressed. Part of the patient education and decision making that is so difficult is the aforementioned difficulty that quality of life may be vying for quantity of life. For an elderly surgical patient with chronic illnesses and disabilities, long-term survival may not be a priority. The concerns of loss of independence or burden to caregivers may take greater precedence. With the possibility of at least a short term loss of independence, it is important also to review the patient’s home and family situation as well as social support structures. Identifying a primary care giver is important and care giver training may also be required. If identified during preoperative

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work up, a plan should be in place in case of the need for step-down or rehabilitation facilities after the acute surgical phase. Lastly, it is important to also know the patient’s own motivations and preferences including the identification of a living will as well as who is the substitute decision maker. Within this discussion, considerations with respect to level and aggressiveness of post operative care, i.e. Resuscitation Guidelines, need to be elucidated and addressed.

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Intraoperative Management The choice of anesthetic technique and medications should previously have been determined during the initial work up of the patient. Careful titration of drugs and their dosages and frequency is of utmost importance to prevent overdose and slower onset of these drugs should be anticipated owing to lower cardiac output. As well, medications in the elderly may exert a more prolonged pharmacological effect due to lower rates of elimination. Anesthetists should be experienced and knowledgeable in the management of this age group. Venous thromboembolism (VTE) is a definitely risk in these patients given their poorer functional ability and pre-existing malignancy. Most guidelines advocate the use of elastic stockings and/or pneumatic calf compressors depending on the length and scope of surgery. As well, the prophylactic use of heparin is usually indicated in most cancer surgeries and should be continued until discharge. More recent data indicates that the risk of VTE may extend up to a month post surgery. Of course, the use of anticoagulation needs to be weighed against the risk of bleeding. Hypothermia is also an important consideration owing to the reduced ability of elderly patients to thermoregulate either due to disease or age. Even mild hypothermia is associated with more than a two fold increase in post operative myocardial events. As well, hypothermia also has been associated with increased perioperative blood loss and also in an increase in wound infections. There are also adverse effects on immune function and delivery of oxygen to peripheral tissues [11]. Perhaps the most difficult aspect of anesthetic management lies in fluid management in the intraoperative period as elderly patients have less ability to deal with both under- as well as over-hydration. On the one hand, these patients have numerous risk factors for being dehydrated due to poor oral

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Surgical Management of Cancer in the Elderly

117

intake, illness, medications and also intraoperative fluid and blood loss. Giving fluid to maintain preload to the heart is therefore important in the elderly as afterload is usually increased due to decreased vessel compliance along with a dampend sensitivity to vasoconstrictive factors. Failure to maintain preload will often lead to hypotension during induction and worsened diastolic function. On the other hand, over-hydration can lead to fluid overload, pulmonary edema, and systolic failure. There is ongoing debate as to what is the best indicator for fluid status and the usefulness of an indicator may need to be balanced against the risk of how invasive the measurement may require [12]. Lastly, surgical care should focus on minimizing tissue trauma and blood loss. Ideally operations in the elderly, especially those with multiple co morbidities, should not be performed by trainee surgeons.

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Post Operative Care Given the higher risk of complications after surgery and the difficulties with maintaining optimum fluid status, patients should be managed initially in a high dependency unit as a matter of routine. This affords more vigilant monitoring and faster access to more invasive care if necessary. For instance, a delay in the management of post operative tachycardia or tachy-arrthmias may result in myocardial ischemia or infarction. Inadequate post operative pain control is a significant problem in the elderly often owing to a combination of reluctance in using potent analgesics or to the misconception that older patients have diminished pain sensation. Patients should be routinely asked for and pain scores should be documented. It is more optimal to give analgesics according to their anticipated needs as opposed to on an ―as-needed‖ basis. Regularly scheduled use of analgesics such as acetominophen/paracetamol and NSAIDS may be of value. The presence of an Acute Pain Service is invaluable in helping manage these sometimes complex issues. As noted above, delirium has a large impact on post operative recovery and may affect up to 61% of elderly patients undergoing surgery. Although the single biggest predictor for delirium is pre-existing dementia, other factors such as dehydration, electrolyte imbalances, immobilization, and poly-pharmacy may be overlooked. As well, the signs and symptoms can at

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Emile C. H. Woo and Kok-Yang Tan

times be subtle especially if there is a significant language barrier or factors such as poor hearing [5]. Family visitations should be encouraged as this can help with prompt diagnosis as well as help manage or prevent delirium. Frequent and abrupt changes in location and environment should be discouraged. As well, patients should be provided with their hearing aids and glasses. Early mobilization and ambulation should be encouraged as well as making sure that fluid and electrolytes are balanced. Drugs that may predispose to delirium such as anticholinergics should also be avoided [13]. If non-pharmacological methods fail, antipsychotics such as risperidone, haloperidol, olanzapine, and quetiapine may be used cautiously to improve symptoms. The presence of a geriatrician well versed in managing post operative patients is indispensible. Lastly, the indwelling catheters should be removed as early as possible and should be avoided beyond 48h unless there is good reason to leave it in for fluid issues or urinary retention. In generally, urinary retention may be better treated with intermittent catheterization if possible. Judicious use of nasogastric tubes is also important as a recent meta-analysis has shown that they are associated with an increased risk of post operative swallowing dysfunction as well as aspiration that could lead to atelectasis or pneumonia. Elderly patients with clear indications such as gastric distension and vomiting are more likely to benefit as they are at high risk of aspiration. Other tubes should be remove as soon as feasible to minimize discomfort and to facilitate mobility. Lastly, global function of the patient should be thoroughly reassessed in the post operative period after the initial acute care stay.

Referrences [1] [2] [3]

Chee J, Tan KY. Outcome studies on older patients undergoing surgery are missing the mark. J Am Geriatr Soc 2010; 58(11):2238-40. Tan KY, Konishi F, Tan L, et al. Optimizing the management of elderly colorectal surgery patients. Surg Today 2010; 40(11):999-1010. Tan KY, Chen CM, Ng C, et al. Which octogenarians do poorly after major open abdominal surgery in our Asian population? World J Surg 2006; 30(4):547-52.

Cancer in the Elderly, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,

Surgical Management of Cancer in the Elderly [4] [5] [6]

[7]

[8]

[9] [10]

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[11]

[12] [13]

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Christmas C, Makary MA, Burton JR. Medical considerations in older surgical patients. J Am Coll Surg 2006; 203(5):746-51. Cicerchia M, Ceci M, Locatelli C, et al. Geriatric syndromes in perioperative elderly cancer patients. Surg Oncol 2010; 19(3):131-9. Beers M, Baran R, Frenia K. Drugs and the elderly, Part 1: The problems facing managed care. Am J Managed Care 2000; 6(12):131320. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40(5):373-83. Tan KY, Kawamura Y, Mizokami K, et al. Colorectal surgery in octogenarian patients--outcomes and predictors of morbidity. Int J Colorectal Dis 2009; 24(2):185-9. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56(3):M146-56. Bergman H, Ferrucci L, Guralnik J, et al. Frailty: an emerging research and clinical paradigm--issues and controversies. J Gerontol A Biol Sci Med Sci 2007; 62(7):731-7. Frank SM, Fleisher LA, Breslow MJ, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. Jama 1997; 277(14):1127-34. Rosenthal RA, Kavic SM. Assessment and management of the geriatric patient. Crit Care Med 2004; 32(4 Suppl):S92-105. Halter J, Ouslander J, Tinetti M, et al. Hazzard's Geriatric Medicine & Gerontology. McGraw-Hill, 2009.

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Index

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A abuse, 42, 52, 110 access, 63, 86, 87, 88, 90, 93, 119 acetylcholinesterase inhibitor, 18 acid, 65, 81 activity level, 2, 19, 113 adaptation, 90, 104 adenocarcinoma, 96, 104 adenosine triphosphate, 10 adjustment, 5, 12, 19, 26, 92 adults, viii, 5, 9, 11, 15, 26, 30, 32, 64, 67, 84, 86, 90, 103, 121 advancements, 100 adverse effects, 12, 16, 102, 118 adverse event, 16 aerobic capacity, 9, 18 aetiology, 2, 6, 7, 19 afferent nerve, 10 age, vii, viii, 3, 4, 5, 7, 8, 9, 10, 12, 16, 17, 19, 26, 27, 34, 35, 40, 41, 42, 43, 49, 50, 51, 54, 56, 62, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 86, 87, 89, 91, 93, 94, 98, 99, 103, 107, 108, 118 age-related diseases, 63, 65, 66 aging process, 8, 10, 63, 72 AIDS, 42 airways, 109 albumin, 111

alcohol abuse, 42, 110 alcohol consumption, 64, 78, 80 algorithm, 93 anastomosis, 100, 103 androgens, 10, 39 anorexia, 6, 16, 17, 20, 23, 31 antibody, 8, 55 anticoagulation, 118 antidepressants, 15, 111 antiemetics, 15 antihistamines, 15 anxiety, 20, 26 apoptosis, 63 appetite, 17, 110 arginine, 10 aspiration, 44, 110, 120 assessment, 2, 10, 11, 12, 14, 20, 24, 29, 49, 51, 55, 57, 58, 59, 90, 94, 98, 103, 110, 111, 112, 113 assessment tools, 111 atelectasis, 120 ATP, 10, 28 autonomy, 89, 93 autopsy, 88 avoidance, 100 B baroreceptor, 108 barriers, 3, 24, 94

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Index

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122

basal metabolic rate, 27 base, 23, 27, 31, 54, 91, 93, 102 basement membrane, 36 beneficial effect, 18, 19 beneficiaries, 90 benefits, 15, 17, 39, 50, 53, 58, 113 binding globulin, 39 biological behavior, 37 biopsy, 44 bleeding, 118 blood, 7, 37, 38, 69, 101, 115, 118, 119 BMI, 112 body composition, 9, 18 body mass index, 111 bone, 19, 46, 50, 52, 53, 56 bowel, 110, 115, 116 bradycardia, 15 brain, viii, 30, 46, 86, 88 brain tumor, 30 breast cancer, vii, 4, 18, 24, 25, 26, 29, 30, 34, 35, 36, 37, 38, 40, 41, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 82, 88, 89, 91, 93, 94 breast carcinoma, 25, 34, 36, 43, 52, 56, 58 breathing, 6, 109 C cachexia, 6, 17, 23, 31, 111 calcification, 109 calcium, 10 cancer, vii, viii, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 40, 41, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 72, 75, 78, 79, 80, 82, 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 108, 116, 117, 118, 121 cancer care, 56, 86, 87, 89, 90 cancer death, viii, 35, 86 cancer patient, vii, 1, 2, 3, 4, 5, 10, 11, 12, 13, 14, 16, 24, 25, 26, 27, 28, 29, 30,

31, 32, 34, 54, 55, 58, 59, 71, 89, 103, 121 cancer-related fatigue (CRF), vii, 1, 2, 3, 4, 16, 18, 24, 26, 28, 30, 31, 32 candidates, 51, 90 carbohydrate, 9, 111 carcinogenesis, vii, 61, 62, 63 carcinoma, 25, 34, 36, 43, 44, 52, 56, 58, 83, 84, 96, 97, 99, 100, 101, 102, 103, 104 cardiac output, 118 cardiac reserve, 108 cardiac surgery, 109 cardiovascular disease, vii, 35, 66, 81, 83 caregivers, 51, 88, 117 cartilage, 109 castration, 38, 39 cell biology, 80 cell death, 8, 63 cervical cancer, 82 chemical, 39, 64 chemoprevention, 82 chemotherapy, 5, 7, 11, 16, 17, 18, 24, 25, 26, 30, 31, 34, 40, 41, 49, 50, 51, 52, 53, 55, 58, 87, 88, 89, 90, 91, 93, 94, 96, 101, 104 cholesterol, 83 chronic diseases, vii, viii, 35, 86, 113 chronic illness, 117 circadian rhythms, 10, 28 clarity, 13 classes, 15, 23 classification, 41, 43, 104 clinical application, 38 clinical assessment, 14 clinical diagnosis, 17 clinical examination, 41 clinical presentation, 27 clinical symptoms, 67 clinical trials, 2, 14, 15, 28, 29, 33, 40, 48, 52, 53, 86, 91, 94 CNS, 11 cognition, 108 cognitive dysfunction, 30

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Index cognitive function, 52, 98, 110 cognitive impairment, 3, 91 colorectal cancer, viii, 98, 107 common symptoms, 5 communication, 3, 24 communities, 36 community, 26 comorbidity, 40, 49, 50, 52, 54, 89, 90, 93, 94, 99, 109, 112, 121 complexity, 7, 13, 79 compliance, 108, 109, 119 complications, 40, 67, 98, 99, 100, 101, 113, 119 composition, 9, 18 conceptualization, 12 congestive heart failure, 56 Congress, 80, 81 congruence, 28 consensus, 11, 12, 14, 55, 113 consent, 68, 86, 91, 92, 93, 94 conservation, 55, 57 consolidation, 114 consumption, 64, 78, 80 control group, 69, 76, 78 controlled trials, 17 controversial, vii, 61, 62, 97, 101, 109 controversies, 113, 121 coordination, 49 COPD, 114 coronary heart disease, 65 correlation, vii, 5, 61, 62, 63, 64, 68, 79, 92 correlations, 63, 65, 67, 79, 84 corticosteroids, 15, 17 cortisol, 10 cumulative percentage, 44 cure, viii, 87, 93, 108, 117 cycles, 18, 66 cycling, 18 cytochrome, 39 cytokines, 7, 63 cytology, 44

123 D daily living, 13, 90, 98 Danish Registry, viii, 108 database, 86 death rate, 35, 42 deaths, viii, 42, 46, 55, 86 deductive reasoning, 86 defense mechanisms, 78 deficiency, 64, 66, 69, 73, 79, 80, 84 deficit, 11, 66 dehydration, 119 delirium, 99, 103, 110, 111, 119, 120 dementia, 51, 90, 92, 94, 110, 119 dendritic cell, 8 denial, 85, 87 depression, 5, 9, 12, 15, 16, 17, 19, 20, 26, 31, 32, 51, 98 derivatives, 39 detection, 19 developed countries, vii, 35 deviation, 42 diabetes, 62, 65, 66, 69, 78, 79 diabetic patients, 84 diagnostic criteria, 49 differential diagnosis, 2 diploid, 49 discomfort, 120 disease progression, 42, 49 diseases, vii, viii, 9, 10, 35, 36, 39, 40, 41, 51, 63, 65, 66, 67, 81, 85, 86, 87, 113 disorder, 9, 26, 65, 69 distress, 5, 12, 13 distribution, 43, 62, 68, 72, 73, 75, 76, 77 DNA, 49, 63 docetaxel, 7, 18, 55 DOI, 26, 28 double-blind trial, 17, 30, 31 drug treatment, 17 drug withdrawal, 46 drugs, 15, 17, 20, 39, 41, 88, 90, 91, 118 dyslipidemia, 10 dysphagia, 99

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124

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E Eastern Europe, 35 economic problem, 52 edema, 99, 119 education, 19, 117 elderly population, 14, 27, 86, 100 electrolyte, 20, 110, 119 electrolyte imbalance, 20, 119 elevated fasting glucose level (EFG), 68, 75, 79 elucidation, 8 emboli, 37 embolization, 37 emergency, viii, 92, 95, 98 emotion, 19 endocrine, 2, 6, 7, 10, 38, 56, 58 endocrine disorders, 6 endurance, 7, 14, 26 energy, vii, 2, 7, 9, 11, 27 energy expenditure, 9 England, 92, 94 enrollment, 94 environment, 37, 63, 120 enzymes,39, 63 epidemiology, 62, 66, 67, 79 epithelial cells, 64 epithelium, 36 equilibrium, 64, 65, 70, 78, 79 erythropoietin, 16 esophageal cancer, vii, 96, 100, 101, 103, 104 esophagus, 96, 99, 103, 104 estrogen, 38, 39, 40, 41, 50, 56, 64, 66, 70, 71, 73, 80, 82 estrogen receptor modulator, 41 etanercept, 18 ethics, 87, 88 Europe, viii, 35, 86 European Community, 35 evidence, 4, 11, 15, 18, 19, 30, 40, 89, 91, 93, 98, 100, 101, 109, 111, 117, 121 exclusion, 86, 87, 89, 91, 93, 98 exercise, 18, 19, 32, 81, 109 exertion, 3

exposure, 63 F families, 87 family members, 11 fasting, 62, 68, 69, 75, 77, 79 fasting glucose, 62, 68, 69, 75, 77, 79 fat, 10, 84 fears, 85 female rat, 62, 65, 68, 70, 71, 79 fertility, vii, 35 fiber, 10 fibrillation, 114 fibrosarcoma, 96 fibrosis, 114 fish, 70 fitness, 32 fluid, 110, 118, 119, 120 food intake, 20 force, 1, 11, 14 Ford, 84 fractures, 50, 52 France, viii, 85, 86 G gender differences, 62, 73 gene expression, 53 general surgery, 98 genes, 84 genetic programs, 63 glasses, 120 glucose, 9, 62, 65, 68, 69, 75, 77, 79, 81 glucose tolerance, 65, 81 group therapy, 19 growth, 36, 37, 38, 39, 49, 63, 64, 73 growth factor, 37, 38, 49, 63, 64 growth hormone, 64 guidelines, 2, 4, 11, 17, 19, 24, 48, 52, 83, 118

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Index

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H headache, 16 healing, 109 health, vii, 12, 13, 35, 56, 84, 87, 111 heart disease, 65, 67 heart failure, 56, 86 heart rate, 18 hemoglobin, 17, 108 heterogeneity, 111 hirsutism, 66 history, 5, 17, 26, 41, 66, 89 homeostasis, vii, 9, 61, 62, 63, 64, 80 hormone, vii, 9, 34, 37, 38, 41, 42, 47, 49, 50, 56, 64, 66, 67, 69, 70, 81, 82, 84 hormone levels, 67 hormones, 37, 38, 65 host, 37, 50 HPA axis, 10 human, 10, 27, 28, 37, 65, 81, 84, 88 human health, 84 Hungary, 61, 67, 70, 78, 84 hyperinsulinemia, 65, 80 hyperplasia, 36 hypertension, 65 hyperthyroidism, 9, 27 hypotension, 119 hypothalamus, 39 hypothermia, 118 hypothesis, 16 hypothyroidism, 9, 27, 64, 67, 78, 79, 80, 83, 84 hypoxia, 109 hysterectomy, 66 I iatrogenic, 11 identification, 19, 90, 118 imbalances, 119 immune function, 8, 118 immune system, 8, 9, 18 immunity, 8, 9, 27 immunohistochemistry, 49 in vivo, 28

125 incidence, vii, viii, 1, 5, 8, 18, 26, 35, 50, 52, 62, 63, 64, 67, 68, 70, 71, 72, 73, 75, 78, 79, 95, 96, 97, 102, 107, 109, 121 independence, 98, 108, 117 individuals, 4, 9, 25, 92 induction, 119 industrialized countries, viii, 95 inertia, 3, 4 infarction, 83, 99, 119 infertility, 66, 79 inflammation, 7, 8, 9, 26, 63 inflammatory mediators, 19 informed consent, 68, 92, 94 inhibitor, 18, 39 initiation, 11, 27, 62, 64, 70, 72, 73 injury, 94 innate immunity, 8 insomnia, 5, 10, 16, 32 insulin, 62, 64, 67, 73, 78, 79, 80, 81 insulin resistance, 62, 64, 65, 67, 73, 78, 79, 80, 81 insulin sensitivity, 65, 81 interference, 13, 39 intervention, 19, 31, 110, 113 irradiation, 55, 88 ischemia, 112, 119 isolation, 117 Israel, 26, 95 issues, 56, 57, 119, 120, 121 Italy, 1, 54 J Japan, viii, 107 justification, 86, 87 K kyphosis, 109 L laboratory tests, 20, 41

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126

language barrier, 120 languages, 13 lead, 52, 97, 111, 117, 119, 120 leakage, 100 lesions, 36, 65, 88, 97 life expectancy, vii, 33, 35, 36, 39, 40, 48, 51, 52, 96, 99 light, 70 lipid oxidation, 9 liver, 42, 46, 66 local anesthesia, 44 longevity, 83 lung cancer, 6, 97, 98 lymph, 27, 37, 43, 49, 55, 89, 100, 101, 104 lymph node, 27, 37, 43, 49, 55, 89, 100, 101, 104

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M macrophages, 8 major depression, 5, 17, 31 major public health problem, vii, 35 majority, 49, 73 malaise, 4 malignancy, 49, 64, 81, 98, 108, 110, 118 malignant tumors, vii, 35, 78 malnutrition, 17 mammography, 41 management, viii, 3, 18, 19, 24, 26, 28, 30, 32, 51, 52, 57, 58, 59, 83, 86, 93, 96, 100, 103, 110, 118, 119, 120, 121 mass, 111 mastectomy, 47, 55 matter, 80, 119 measurement, 14, 28, 41, 98, 119 median, 12, 16, 34, 43 mediastinitis, 100 medical, 5, 20, 38, 40, 42, 51, 52, 57, 58, 93, 99, 111, 112 medication, 15, 29 medicine, 86, 87, 93 melatonin, 10, 64, 80 menarche, 41, 43

menopause, 38, 41, 43, 62, 65, 66, 69, 70, 71, 73, 76, 78, 79, 81, 88 meta-analysis, 16, 26, 31, 57, 120 Metabolic, v, 9, 10, 20, 61 metabolic changes, 65 metabolic disorders, 6, 28 metabolic syndrome, 65, 79, 81, 84 metabolism, 9, 69, 79 metastasis, 19, 34, 36, 37, 38, 44, 45, 46 methodology, 92 methylphenidate, 15, 30 MFI, 21, 29 mitogen, 37 models, 51, 113 monoclonal antibody, 55 mood disorder, 2, 5 morbidity, viii, 39, 40, 42, 51, 91, 95, 96, 98, 99, 100, 101, 103, 105, 108, 111, 112, 113, 117, 121 mortality, viii, 16, 27, 34, 35, 36, 40, 67, 89, 95, 96, 97, 98, 99, 100, 101, 102, 103, 108, 112, 113, 117 mortality rate, 35, 96, 97, 99, 101 mortality risk, 40 motor skills, 108 mucosa, 83 multidimensional, 3, 12, 14, 26, 29 multivariate analysis, 91 muscles, 109 mutations, 63 myocardial infarction, 83, 99 myocardial ischemia, 119 myxedema, 67 N narcotics, 100 nasogastric tube, 120 National Comprehensive Cancer Network (NCCN), 4, 11, 25 nausea, 2, 16 necrosis, 18, 31 nerve, 10, 11 nervous system, 11 Netherlands, 54, 59

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Index neurological disease, 90 neutropenia, 19 neutrophils, 7 New England, 94 nodal involvement, 41 nodes, 37, 55, 58, 100, 104 non-pharmacological treatments, 2 non-smokers, 64, 69, 73, 75, 76 norepinephrine, 7 normal aging, 63 North America, 35 nutrients, 65 nutrition, 110, 111

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O obesity, 66 oesophageal, 102, 103 olanzapine, 120 old age, 17, 42, 93 oncogenes, 37 oncology surgeons, viii, 108 openness, 86, 87 operations, viii, 97, 108, 119 oral cavity, 83 organ, 8, 63 organism, 9, 63 organs, 38, 40, 63, 66 osteoarthritis, 91 outpatients, 44 ovariectomy, 38 ovulation, 79 oxidation, 9 oxygen, 118 P p53, 49, 80 pain, 2, 5, 119 palliative, viii, 16, 17, 26, 31, 33, 48, 88, 90, 94, 108 palpitations, 16 pancreas, 97 parallel, 88 parasite, 8

127 parenchyma, 109 parity, 41 paroxetine, 17, 31 participants, 19, 92 patents, 6 pathology, 41 pathways, 9, 28, 65, 79, 103 patient care, 113 peptide, 37 peripheral nervous system, 11 permission, iv permit, 53 pharmaceuticals, 88 pharmacological treatment, 2, 15 phenotype, 63, 80, 121 physical activity, 65, 113 physical exercise, 19, 32 physical fitness, 32 physicians, vii, 2, 3, 24, 25, 28 Physiological, 98, 108, 114, 116 physiology, 10, 111 placebo, 14, 16, 17, 18, 30, 31 plasma cells, 8 PM, 28, 32, 56, 82, 83 pneumonia, 99, 109, 120 population, viii, 2, 4, 5, 14, 15, 24, 27, 29, 35, 36, 54, 62, 66, 67, 72, 75, 76, 78, 79, 86, 92, 95, 96, 97, 98, 99, 100, 102, 108, 109, 110, 111, 112, 117, 120 population group, 2, 5 postoperative outcome, 103, 111 potential benefits, 39 preparation, iv, 110 prevention, 62, 64, 79 primary tumor, 37 probability, 50, 70 problem solving, 19 professionals, 25 progesterone, 38 prognosis, 57, 58, 96, 97, 101 pro-inflammatory, 7 proliferation, 27, 36, 39, 49, 63 propagation, 14 prophylactic, 118 prostate cancer, 14, 29

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Index

128 protection, 66, 89 protective mechanisms, 109 proteins, 10 psychometric properties, 12, 14 psychostimulants, 15 psychotherapy, 32 public health, vii, 35 pulmonary edema, 99, 119 pus, 115, 116 Q

quality of life, 1, 2, 3, 12, 13, 24, 31, 32, 39, 41, 48, 52, 53, 89, 108, 117 questionnaire, 13, 24, 98 quetiapine, 120

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R radiation, 7, 14, 26, 29, 30, 38, 55, 64, 94, 96, 101 radiation therapy, 7, 14, 29, 30, 55, 96, 101 radiography, 41 radiotherapy, 7, 47, 51, 55, 88, 89 rationality, 87 reasoning, 85, 87, 91 recall, 14 receptors, 37, 38, 49, 50 receptors cytosolic (RE), 38 recognition, 2, 3 recommendations, iv, 14, 19, 85, 87 recovery, 7, 119 recurrence, 39, 45, 53 red blood cells, 7 Registry, viii, 108 regression analysis, 70 regulatory systems, 10, 64 rehabilitation, 32, 118 rejection, 41 relaxation, 19 relevance, 40 reliability, 29 remodelling, 8 renal dysfunction, 6

repair, 7, 63 reparation, 110 replication, 63 requirements, 7 researchers, 14, 92 resection, 96, 97, 98, 99, 100, 101, 102, 104, 108, 117 reserves, 108 resistance, 11, 18, 62, 64, 65, 67, 73, 78, 79, 80, 81 resources, 40 respiratory failure, 99 response, 7, 8, 10, 14, 15, 27, 30, 34, 38, 39, 40, 41, 44, 50, 63, 65, 101 rhythm, 114 risk, vii, 2, 5, 9, 11, 17, 27, 35, 37, 39, 40, 41, 49, 50, 53, 62, 63, 64, 65, 66, 67, 68, 70, 75, 76, 78, 79, 80, 82, 83, 84, 88, 89, 97, 98, 99, 100, 102, 103, 109, 110, 111, 113, 117, 118, 119, 120 risk assessment, 109 risk factors, 17, 64, 68, 70, 78, 80, 83, 88, 99, 103, 109, 111, 118 risks, 17, 50, 89, 113 risperidone, 120 S SA node, 108 safety, 18, 97 scaling, 13 science, 32 scope, 118 secrete, 63 secretin, 8 secretion, 10, 37, 39 sedatives, 15, 110, 111 selective estrogen receptor modulator, 41 self-reports, 20 semi-structured interviews, 13 senescence, 10, 63, 80 senility, 94 sensation, 9, 13, 119 sensitivity, 65, 81, 108, 119

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Index serotonin, 17 sertraline, 17, 31 serum, 27, 64, 111 serum albumin, 111 services, iv, 49, 51 sex, 81, 83 shape, 70 showing, 97 side effects, 16, 30, 46, 49, 53, 85, 87 signaling pathway, 65 signs, 27, 41, 113, 119 Singapore, viii, 94, 107 skeletal muscle, 10, 28, 65, 81 smoking, 62, 66, 67, 68, 72, 73, 75, 76, 78, 80, 81, 109 smoking cessation, 109 social resources, 40 social support, 51, 117 Spain, 35 specialists, 38, 87 squamous cell carcinoma, 83, 84, 96, 104 stability, 34 stabilization, 44 state, 12, 32, 51, 65, 66, 98 states, 10, 13, 65, 66 statistics, vii, 35 stenosis, 92 steroids, 10, 15, 65, 70 stimulant, 16 stoma, 117 stratification, 98, 99, 100, 102, 109, 111 stress, 19, 108, 109 stressors, 113 stroke, 65, 66, 112 subjective experience, 3 subjectivity, 92 Sun, 56, 80 supervision, 16 suppression, 63 surgical intervention, 110, 113 surgical resection, 104 surgical technique, 100, 103 surveillance, 63

129 survival, viii, 16, 17, 31, 33, 34, 39, 40, 42, 45, 46, 47, 48, 49, 51, 52, 53, 54, 57, 59, 89, 96, 97, 98, 100, 101, 102, 104, 108, 117 survival rate, viii, 96, 97, 100, 101, 108 survivors, 1, 4, 16, 25, 28, 32, 57 susceptibility, 81 symptoms, vii, 1, 2, 4, 5, 9, 13, 16, 19, 25, 27, 28, 31, 41, 67, 119, 120 syndrome, 9, 31, 65, 66, 79, 80, 81, 82, 83, 84, 88 synthesis, 10, 39 systemic risk, 68 T T cell, 8, 27 tachycardia, 119 tamoxifen, 34, 39, 41, 44, 47, 50, 52, 53, 56, 59 target, 94 techniques, 38, 100, 113 testing, 29 TGF, 37, 39 therapeutics, 9 therapy, 7, 14, 19, 29, 30, 32, 34, 37, 38, 39, 40, 41, 42, 45, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 66, 81, 82, 83, 86, 87, 93, 96, 101, 102, 109, 117 thoracotomy, 100 thrombocytopenia, 19 thrombosis, 17, 23 thyroid, 9, 67, 69, 79, 83 thyroiditis, 69, 78 tibialis anterior, 14 tissue, viii, 7, 8, 63, 80, 86, 119 tissue homeostasis, 63 TNF, 7, 8 TNF-α, 7, 8 tobacco, 62, 64, 67, 70, 72, 73 toxicity, 40, 41, 50, 91 training, 19, 81, 117 transformation, 64 transforming growth factor, 37 transmission, 11

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Index

130

transplantation, 112 trauma, 7, 8, 119 treatment, vii, viii, 1, 2, 3, 4, 5, 7, 14, 15, 16, 17, 18, 19, 20, 23, 24, 25, 26, 30, 31, 32, 33, 34, 36, 38, 39, 40, 41, 42, 44, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 85, 87, 88, 89, 90, 91, 92, 96, 99, 100, 102, 104, 108, 110, 111, 113, 117 trial, 16, 17, 18, 30, 31, 32, 55, 58, 82, 91, 94, 100, 101, 104, 121 TSH, 27, 69 tumor, 30, 31, 36, 37, 38, 39, 41, 43, 49, 51, 52, 57, 62, 63, 67, 68, 69, 70, 71, 72, 73, 75, 76, 78, 80, 96, 97, 100, 101, 108 tumor growth, 36, 37, 39, 73 tumor necrosis factor, 31 tumor-free female controls, 75 tumors, vii, 35, 37, 40, 43, 49, 50, 52, 62, 66, 70, 72, 73, 78, 81, 84, 89, 101 tumours, 3, 7, 8, 18

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U UK, 56 uniform, 14 United, viii, 24, 29, 86, 97, 102, 107 United States, viii, 24, 29, 86, 97, 102, 107 urinary retention, 120

V validation, 24, 29, 94, 121 variables, 42 varieties, 38 virus infection, 64 vision, 36, 93, 110 vomiting, 2, 16, 120 vulnerability, 65, 113 W walking, 18, 113 water, 110 weakness, 3, 6, 7, 12, 15, 67 weight gain, 17, 67 weight loss, 111, 112, 113 WHO, vii, 35 withdrawal, 46 worldwide, 62 wound healing, 109 wound infection, 118 Y young adults, 15, 67 young people, 83 young women, 66, 79 Z Zoloft, 31

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