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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
A state-of-the-art, multidisciplinary approach to cancer and aging With the majority of cancers occurring in individuals over the age of 65 against a backdrop of an expanding aging population, there is an urgent need to integrate the areas of clinical oncology and geriatric care. This timely work tackles these issues head-on, presenting a truly multidisciplinary and international perspective on cancer and aging from world-renowned experts in geriatrics, oncology, behavioral science, psychology, gerontology, and public health. Unlike other books on geriatric oncology that focus mainly on treatment, Cancer and Aging Handbook: Research and Practice examines all phases of the cancer care continuum, from prevention through evidence-based diagnosis and treatment to end-of-life care. Detailed clinical and research information helps guide readers on effective patient care as well as caregiver training, research, and intervention. Coverage includes: * Epidemiology of cancer in older adults, plus the unique physical, mental, and social issues involved * Strategies and guidelines for prevention, screening, and treatment of older individuals with cancer * The most common cancers in the elderly, including breast, colorectal, lung, prostate, and ovarian cancer * Cancer survivorship in older adults as well as the all-critical issues of palliative care and pain management * Emerging topics such as caregiver and family issues, different models of care, and cost considerations An essential resource for clinicians and caregivers as well as researchers interested in this evolving field, Cancer and Aging Handbook is also useful for public health professionals and policymakers who need to formulate services and allocate resources for the growing population of older cancer patients.
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Veröffentlichungsjahr: 2012
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Table of Contents
Copyright
Title Page
Foreword
References
Preface
References
Contributors
Part I: Cancer and Aging in Context
Chapter 1: Epidemiology of Cancer in the Older-Aged Person
1.1 Introduction
1.2 Age and Cancer Biology
1.3 Conclusions
References
Chapter 2: Biological Aspects of Aging and Cancer
2.1 Introduction
2.2 Normal Aging
2.3 Theories of Aging
2.4 Aging and Cancer
2.5 Conclusions
References
Chapter 3: Physiological, Psychological, and Social Aspects of Aging
3.1 Introduction and Background
3.2 Physiological Aspects of Aging
3.3 Psychological Aspects of Aging
3.4 Social Aspects of Aging
3.5 Summary
References
Part II: Strategies for Cancer Prevention in Older Adults
Chapter 4: Overview of Cancer Prevention Strategies in Older Adults
4.1 Introduction
4.2 Cancer Prevention Strategies in Older Adults
4.3 Other Issues for Cancer Prevention in Older Adults
4.4 The Future of Cancer Prevention in Older Adults
References
Chapter 5: Breast Cancer Prevention
5.1 Introduction
5.2 Lifestyle Modification
5.3 Pharmacologic Prevention
5.4 Surgical Prevention
5.5 Conclusions
Acknowledgment
References
Chapter 6: Colorectal Cancer Prevention and Aging
6.1 Introduction
6.2 Colorectal Carcinogensis
6.3 Evaluation of Potential Preventive Measures
6.4 Conclusions
References
Chapter 7: Prostate Cancer Prevention
7.1 Introduction
7.2 Rationale for Prevention
7.3 PSA Screening Trials
7.4 Conclusion
References
Chapter 8: Lung Cancer Prevention
8.1 Introduction
8.2 Lung Cancer Epidemiology
8.3 Smoking Prevention and Cessation
8.4 Chemoprevention
8.5 Lung Cancer Chemoprevention Challenges
8.6 Conclusions
References
Part III: Cancer Screening Guidelines for Older Adults
Chapter 9: Cancer in Older People: To Screen or Not to Screen?
9.1 Introduction
9.2 Cancer Types
9.3 Balance Between Benefits and Risks of Screening in Elderly People
9.4 Perspectives
References
Chapter 10: Breast Cancer Screening
10.1 Introduction
10.2 Risk Assessment
10.3 Recommendations for High-Risk Women
10.4 Screening Approaches
10.5 Conclusions
References
Chapter 11: Colorectal Cancer Screening
11.1 Introduction
11.2 Development, Characteristics, and Treatment of Colorectal Cancer
11.3 Screening
11.4 Conclusions
11.5 Summary
References
Chapter 12: Prostate Cancer Screening
12.1 Introduction
12.2 Prostate Cancer Screening Methods
12.3 Discussion
Acknowledgments
References
Chapter 13: Other Screening Opportunities for the Future
13.1 Introduction
13.2 Current Cancer Screening Procedures for the Elderly
13.3 Common Cancers for Which Future Screening Opportunities may be Available
13.4 Applicability of Current Cancer Screening Results to Elderly People
13.5 Guidelines for Screening of the Elderly
13.6 Future Screening Prospects
13.7 Conclusions
References
Part IV: Cancer Treatment
Chapter 14: General Principles in Older Adults with Cancer
14.1 Introduction
14.2 General Guidelines
14.3 The Two-Step Approach
14.4 Proactive Supportive Care
14.5 Conclusions
References
Chapter 15: Surgery for Older Adults with Cancer
15.1 Introduction
15.2 Disease-Site-Specific Variance in Surgical Practice with Older Age
15.3 Advances in Surgical Practice
15.4 Summary
Acknowledgment
References
Chapter 16: Chemotherapy in Older Adults with Cancer
16.1 Introduction
16.2 General Pharmacological Issues Related to Chemotherapy in Elderly Cancer Patients
16.3 Pharmacology and Side Effects of Specific Anticancer Drugs in Elderly Individuals
16.4 General Side Effects of Chemotherapy in Older Adults with Cancer
16.5 Practical Recommendations
16.6 Conclusions and Future Perspectives
Acknowledgment
References
Chapter 17: Radiotherapy in Older Adults with Cancer
17.1 Introduction
17.2 Clinical Assessment of Older Patients in Radiation Oncology
17.3 Technological Advances in Radiation Oncology
17.4 Modification of Standard Radiotherapy in Older Patients
17.5 Summary and Conclusions
References
Part V: Common Cancers in the Elderly
Chapter 18: Breast Cancer
18.1 Introduction
18.2 General Aspects of Breast Cancer
18.3 Surgery
18.4 Alternative Approaches in Patients with Restricted Life Expectancy
18.5 Treatment of Metastatic Breast Cancer
18.6 Conclusions
References
Chapter 19: Colon Cancer
19.1 Introduction
19.2 Surgery for CRC in Older Patients
19.3 Radiotherapy in the Treatment of Rectal Cancer in Older Patients
19.4 Adjuvant Chemotherapy
19.5 Metastatic Setting
19.6 Conclusion
References
Chapter 20: Lung Cancer
20.1 Introduction
20.2 Definition of Target Population
20.3 Epidemiology
20.4 Etiology
20.5 Histology
20.6 Molecular Biology
20.7 Classification and Staging
20.8 Prognosis
20.9 Prevention and Early Diagnosis
20.10 Clinical Presentation
20.11 Diagnostic Testing
20.12 Comprehensive Geriatric Assessment
20.13 Comorbidity
20.14 Treatment Options
20.15 Surgery
20.16 Radiotherapy
20.17 Medical Treatment
20.18 Molecular Defined Targets
20.19 Special Lung Cancer Patients
20.20 Conclusions and Palliative Care
References
Chapter 21: Prostate Cancer
21.1 Introduction
21.2 Clinical Presentation
21.3 Diagnosis, Staging, and Prognostic Factors
21.4 Health Status Evaluation in Elderly Prostate Cancer Patients
21.5 Treatment of Localized Disease
21.6 Treatment of Advanced Disease
21.7 Practical Guidelines
21.8 Conclusion
Acknowledgments
References
Chapter 22: Ovarian Cancer
22.1 Introduction
22.2 Demographics
22.3 Treatment Strategies
22.4 Toward Crosstalk between Oncological and Geriatric Assessments
22.5 Conclusion
References
Part VI: Cancer Survivorship and Aging
Chapter 23: Theoretical Perspectives from Gerontology and Lifespan Development
23.1 Introduction
23.2 An Overarching Perspective
23.3 Basic Approaches and Concepts of Lifespan Developmental Psychology and Lifecourse Perspectives
23.4 Definitional Issues and Case Examples
23.5 A Matrix of Factors Influencing Well-Being of Older Cancer Patients and Survivors
23.6 Overview of Relevant Theories and Concepts
23.7 Lessons and Implications for Professionals
23.8 Conclusions
References
Chapter 24: Adaptation and Adjustment to Cancer in Later Life: A Conceptual Model
24.1 Introduction
24.2 Adjustment and Adaptation to Cancer
24.3 A Conceptual Model of Adjustment to Cancer
24.4 Stressors
24.5 Quality-of-Life Outcomes as Indicators of Adjustment to Cancer
24.6 Summary and Implications for Future Research
Acknowledgment
References
Chapter 25: Long-Term and Late Physical and Psychosocial Effects of Cancer in Older Adults
25.1 Introduction
25.2 Physical Late and Long-Term Cancer Effects
25.3 Long-Term and Late Psychosocial Effects
25.4 Age-Related Complications
25.5 Prevention and Management of Long-Term and Late Effects
25.6 Conclusions
References
Part VII: End-of-Life Care
Chapter 26: Palliative Care for Cancer Patients and Their Families
26.1 Introduction
26.2 Whole-Patient Assessment
26.3 Communication
26.4 Advance care Planning
26.5 Roles of Family and Caregiver in Palliative Care
26.6 Symptom Management
26.7 The Terminal Phase
26.8 Hospice Care
26.9 Summary
References
Chapter 27: Pain Management
27.1 Introduction
27.2 The Importance of Cancer Pain Management in the Elderly
27.3 Epidemiology of Pain in Cancer Patients
27.4 Assessment of Pain in the Geriatric Cancer Patient
27.5 Pain Treatment Timeline
27.6 Other Analgesic Agents and their use and Potential Side Effects
27.7 Complementary Therapies
27.8 Conclusions
References
Part VIII: Emerging Issues
Chapter 28: Caregiver Knowledge and Skills
28.1 Introduction
28.2 Assessing Cancer Care Needs in the Home
28.3 Helping Caregivers Meet Patient Needs
28.4 Implications and Conclusions
References
Chapter 29: Comprehensive Geriatric Assessment
29.1 Introduction
29.2 Definition of Comprehensive Geriatric Assessment
29.3 Comprehensive Geriatric Assessment in Oncology
29.4 CGA and Outcomes in Clinical Oncology
29.5 Conclusions
References
Chapter 30: Economic Cost of Treating Older Adults with Cancer
30.1 Introduction
30.2 Overall Cost of Cancer Care
30.3 Cost of Cancer Treatment by Tumor and Treatment Characteristics
30.4 Unique Healthcare Needs in the Elderly
30.5 Emerging Therapies
30.6 Conclusions
References
Chapter 31: Multidisciplinary Models of Care
31.1 Introduction
31.2 The Importance of Multidisciplinary Care
31.3 Geriatric Assessment
31.4 Multidisciplinary Approaches
31.5 Conclusions
References
Index
Copyright © 2012 by Wiley-Blackwell. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data:
Bellizzi, Keith M.
Cancer and aging handbook: research and practice / Keith M. Bellizzi and Margot A. Gosney
p. cm.
Includes bibliographical references and index.
ISBN 978-0-470-87442-4 (cloth)
Foreword
You may open the window
And fail to see the fields and the river;
Even if you are not blind
You may be unable to enjoy the view of trees and flowers!
These verses of Fernando Pessoa are engraved on his monumental tomb in the Lisboa cathedral. They crystallize more eloquently than any scientific paper the urgency to study geriatric oncology. Diversity is a hallmark of aging. Individuals of the same chronologic age may differ substantially in life expectancy and tolerance of stress. When it comes to older individuals, the art of medicine consists in identifying those patients who are more likely to benefit from an aggressive treatment and those that are more likely to be harmed by it. In addition, the goals of treatment may change from patient to patient according to one's physical stamina and one's lifetime priorities. To a large extent, the management of an older individual is a social issue, involving the home caregiver and all the persons connected with the caregiver. It behooves the practitioner to ensure that the caregiver is appropriate for the patient's need and that caregiving does not disrupt the caregiver's family life.
The management of older individuals, including older cancer patients, involves a wisdom developed over a lifetime, thanks to time-consuming listening and painstaking collection and interpretation of clinical details. Only a practitioner willing to invest the time necessary to these endeavors will be able to provide safe and effective care to the older patient. In the management of older individuals with cancer, the practitioner needs to feel comfortable with uncertainty; to enjoy being creative in novel situations; to think outside the box; and to enrich with his/her own experience the dictates of medical textbooks, treatment guidelines, and clinical pathways. The best source of clinical evidence, the randomized clinical trials, are not very helpful for personalized care, because they cannot encompass the variety of conditions encountered in older individuals. A prominent geriatrician from the UK has defined evidence-based medicine as “evidence-biased medicine” [1], as the controlled conditions of clinical trials are rarely, if ever, reproducible in the practice arena.
There are other reasons for studying geriatric oncology beside the uniqueness of each cancer patient. They include the biological interactions of aging and cancer. Aging is a risk factor for carcinogenesis. This statement is confirmed by the association of smoking cessation with an epidemic of lung cancer in the elderly (people who no longer die of a coronary attack live long enough to develop lung cancer) [2] and that age is a risk factor for chemotherapy-induced acute myelogenous leukemia [3]. Also, the behavior of neoplasias may change with aging. For example, the prevalence of adverse prognostic factors increases with the age of patients with acute myelogenous leukemia [4], whereas breast cancer may become more indolent in the elderly [5]. The tumor host interactions represent a fascinating and largely unknown subject.
The problems of geriatric oncology are becoming everyday problems in the practice of oncology, given the rapid expansion of the aging population [6]. By the year 2000 50% of all malignancies occurred in the 12% of the population aged 65 and over; by the year 2030 it is predicted that individuals 65 and over will account for 20% of the population and 70% of all cancers in the United States [6]. This book, which gathers the contributions of some of the world's best known experts in the field, could not be more timely.
Perhaps more than any other field of medicine, geriatric oncology is rapidly evolving. Nobody will be able to provide a final word, during our lifetimes, at least. This book should be considered as an important foundation supporting both the practitioner of oncology and the clinical and basic investigators in the area. It is necessary, every so often, to summarize where we are and to decide where we should be going. By providing such a beacon, the book will have fulfilled this goal.
In one of his first novels, Love and Pedagogy, Miguel de Unamuno stated: “The truth is the worst of all lies.” This paradox certainly applies to a medicine carved in stone rather than lived as an ongoing journey and a fascinating adventure. This book provides a current guide to practitioners and scientists involved in the journey.
LODOVICO BALDUCCI
References
1. Evans GG. Evidence based and evidence-biased medicine. Age Ageing 1995;24:461–463.
2. Peto J. The lung cancer incidence falls in ex-smokers: misconception 2. Br J Cancer 2011;104:389.
3. Lyman GH, Dale DC, Wolff DA, et al. Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony stimulating factor. A systematic review. J Clin Oncol 2010;28:2914–2924.
4. Lugar SM. Treating the elderly patients with acute myelogenous leukemia. Am Soc Hematol Educ Program 2010;62–69.
5. Spazzapan S, Crivellari D, Bedard P, et al. Therapeutic management of breast cancer in the elderly. Expert Opin Pharmacother 2011;12:945–960.
6. Balducci L, Ershler WB. Cancer and aging: A nexus at several levels. Natl Rev Cancer 2005;5:655–662
Preface
Since the 1980s there has been an unprecedented increase in the attention being paid to the topic of cancer and aging. This is reflected by a 2007 Institute of Medicine workshop on cancer in the elderly and several special journal issues on this topic [1–3]. This response is the direct result of three converging forces: the aging of the population, the age-sensitive nature of cancer, and innovations in medical care. The confluence of these factors represents a significant public health challenge for the future. This challenge is further complicated by a potential shortage of oncologists, geriatricians, and nurses due to the projected exponential increase in incidence and prevalence of cancer in older adults coupled with a reduction in healthcare professionals entering into these fields [4, 5].
These trends provide both challenges and opportunities. A central challenge is building the evidence base from epidemiologic, clinical trial, and behavioral research focusing on care for older adults across the cancer care continuum. Unfortunately the science of cancer care in the elderly population lags far behind what is known in children and other adults with cancer. Therefore, much of what is being practiced is extrapolated from studies of younger cohorts or based on clinical judgment. Another challenge is our capacity to respond to the complex healthcare needs of older adults given the projected shortages of geriatric/gerontology-trained healthcare workers. We believe that the answer to this question is multifaceted and will require thinking “outside the box” to (1) test new models of cancer care: (2) encourage new physicians to pursue geriatric fellowships: (3) provide broader geriatric and gerontology training for primary-care physicians and nurses: and (4) foster research and clinical collaboration among geriatricians, gerontologists, adult oncologists, and behavioral scientists. This latter endeavor is important as each of these disciplines contributes different perspectives, all essential to providing quality care to the growing population of older adults.
With challenges come opportunities. As we age, we become more heterogeneous in terms of physical and psychosocial health as a result of our previous lifestyles, environmental exposure, and genetic composition. Cancer care for older adults will likely be based on individualized approaches that account for this heterogeneity as well as the needs and preferences of the individual. This will likely require a paradigm shift from population-based medical care and healthcare to patient-centered care, which, we believe, will ultimately result in the highest-quality and most cost-effective care.
This multidisciplinary book was written by some of the most prominent international experts in the field of cancer and aging. The chapters in this book provide a synthesis of findings from current epidemiologic, behavioral, and clinical trial research across the entire continuum of cancer care, from prevention and screening, to treatment and survivorship, to end-of-life care. This book also includes a section on emerging issues in cancer care for older adults, including chapters focusing on caregivers, comprehensive geriatric assessment, the economic cost of treating older adults with cancer, and finally a discussion of multidisciplinary models of care. For some topics in this book, the evidence is still nascent, and the authors were challenged to provide recommendations for future research in these areas. In doing so, they raise some interesting questions about the complex issues facing older adults before, during, or after the diagnosis of cancer.
We believe that this book will demonstrate that the answer to addressing one of the biggest public health challenges of our time does not rest within any one discipline and that a broader knowledge and multidisciplinary approach is required to care for older adults at risk for, or living with, cancer. Our hope is that this information will be useful for healthcare providers, medical students, public health professionals, and policymakers who care for, or make policies that pertain to, the health of older adults.
KEITH M. BELLIZZI
MARGOT A. GOSNEY
References
1. Institute of Medicine. Cancer in Elderly People: Workshop Proceedings, Washington, DC, 2007.
2. Lichtman SM, Balducci L, Aapro M. Geriatric oncology: A field coming of age. J Clin Oncol 2007;25:1821–1823.
3. Bellizzi KM, Mustian KM, Bowen DJ, Resnick B, Miller SM. Aging in the context of cancer prevention and control: Perspectives from behavioral medicine. Cancer 2008;113:3479–3483.
4. Erikson C, Salsberg E, Forte G, Bruinooge S, Goldstein M. Future supply and demand for oncologists: challenges to assuring access to oncology services. Journal of Oncology Practice. 2007;3(2):79–86.
5. Association of Directors of Geriatric Academic Programs. Geriatric medicine: A clinical imperative for an aging population, Part I. Ann Long-Term Care 2005;13:18–22.
Contributors
Part I
Cancer and Aging in Context
Chapter 1
Epidemiology of Cancer in the Older-Aged Person
Lodovico Balducci
Senior Adult Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
1.1 Introduction
Age is a risk factor for most cancers. In the United States 50% of all malignancies occur in men and women over the age of 65, which represents 12% of the population. With the current growth rate of the older population, it is estimated that 70% of all cancers will occur in the elderly by the year 2030 [1, 2]. This finding is a call to face incoming cancer epidemics in a population that has been grossly understudied. As in other fields of geriatrics [3], clinical epidemiology will have a critical role in determining the best cancer care in older heterogeneous adults.
In this chapter we will examine how clinical epidemiology may help us to gain insight into the biology and the management of cancer in the older person. In closing we will explore new epidemiological approaches to determine benefits and risk of cancer treatment in older individuals.
1.2 Age and Cancer Biology
Clinical epidemiology helps us understand the interaction of aging with carcinogenesis and tumor behavior. The study of the incidence of cancer in advanced age may shed light on age-related factors that favor cancer development. Likewise, comparison of the natural history of cancer in younger and older individuals indicates that some cancers may become more aggressive and others more indolent with aging.
1.2.1 Aging and Carcinogenesis
The increased incidence of cancer in the older person may be due to three not necessarily mutually exclusive mechanisms. These include duration of carcinogenesis, increased susceptibility of older tissues to environmental carcinogens, and changes in body environment (chronic inflammation, increased resistance to insulin) [4].
The changing epidemiology of lung cancer supports the fact that aging is associated with cancer because carcinogenesis is a time-consuming process. As of 2005 the median age of lung cancer was around 71 years, up from 55 years in the mid-1970s [5]. This shift is arguably due to smoking cessation that is associated with a rapid decline in cardiovascular mortality. Ex-smokers now do live long enough to develop lung cancer [6, 7]. Indeed, ex-smokers or never smokers account for an increasing proportion of newly diagnosed lung cancer [8]. Figure 1.1 summarizes the age-related changes in lung cancer mortality over a 20-year period.
Figure 1.1 Changes in lung-cancer-related mortality [5].
A number of experimental studies have shown that some older tissues are primed to the action of environmental carcinogens and are more likely to undergo malignant transformation than younger tissues when exposed to the same dose of carcinogens [4]. Clinical epidemiology suggests that this is the case in older humans as well for the following reasons:
The incidence of some cancers, such as prostate and colon cancer, increases more rapidly with age. This finding suggests that older tissues are more susceptible to environmental carcinogens. In support of this theory, the rate of malignant transformation of adenomatous polyps becomes more rapid with the age of the patient [2].
Since the 1970s there has been a dramatic increase in the incidence of certain tumors, such as non-Hodgkin's lymphoma and malignant brain tumors in older individuals [9, 10]. This finding suggests the possibility that older people develop cancer more quickly than younger ones when exposed to new environmental carcinogens.
Age is a risk factor for the development of myelodysplasia and acute myelogenous leukemia after anthracycline-based adjuvant chemotherapy of breast cancer or after treatment for lymphoma [11, 12].
In a more recent longitudinal study of the population of Bruneck, Italy, individuals with shortest leukocyte telomeres had more than a threefold increase in the risk of cancer with respect to those with the longest telomeres [13]. According to a number of studies, summarized in Reference 14, telomere length is a mirror of the functional age of a person.
There is no convincing epidemiologic evidence supporting the association of cancer with changes in body environment, including immune-senescence, endocrine senescence, and proliferative senescence of fibroblasts. This possibility is suggested by the increased incidence of lymphatic tumors in presence of immune suppression and increased incidence of colon cancer in the presence of obesity [15].
Epidemiology has also produced some hypothesis-generating information related to the prevention of cancer in older individuals. This includes reduced incidence of cancer of the large bowel with regular use of aspirin [16] and reduced incidence of breast cancer in patients treated with selective estrogen receptor modulators (SERMs) or aromatase inhibitors for the adjuvant treatment of breast cancer.
1.2.2 Aging and Tumor Behavior
The clinical behavior of some tumors changes with the age of the patient (Table 1.1) [17]. The table highlights two important facts, emerging from clinical epidemiology:
Table 1.1 Clinical Behavior of Tumors Change with Age
Clinical Behavior
Cancer
in the Aged
Mechanism
Acute myelogenous leukemia
More resistant to treatment
Increased prevalence of unfavorable genomic changes and of resistance to chemotherapy
Non-Hodgkin's lymphoma
Age is a poor prognostic factor
Increased circulating concentrations of interleukin 6 and increased risk of undertreatment
Breast cancer
More indolent
Increased prevalence of hormone-receptor-rich tumors; endocrine senescence
Ovarian cancer
More lethal
Unknown
Malignant brain tumors
More lethal
Increased prevalence of unfavorable genomic changes
It has always been known that age is a poor prognostic factor for acute myelogenous leukemia (AML), due to changes in the biology of the disease, which include higher prevalence of multidrug resistance, of unfavorable cytogenetics, and of NPM1 unmutated and flt3 mutated tumors [18]. At least in part, these changes may be explained by the fact that AML in older patients is preceded by myelodysplasia, a disease that affects the early hematopoietic progenitors.
Age is a poor prognostic factor for both aggressive and indolent non-Hodgkin's lymphomas [19]. Increased circulating concentrations of interleukin 6 (IL6), a powerful stimulator of lymphocyte replication, may, in part, explain, this finding [20]. In the case of large cell lymphomas, clinical epidemiology suggests another important possibility: inadequate doses of chemotherapy. A systematic review demonstrated that individuals 60 and older had the same outcome as did younger adults if they received the same dose intensity of chemotherapy [21]. The review does not address the important question as to whether the undertreatment of the aged was justified by comorbidity and poor functional reserve, but it underlines the possibility that undertreatment may be responsible for some of the age-related prognostic changes in cancer, such as decreased survival in patients 60 and over with large cell lymphoma.
It is well established that metastatic breast cancer is associated with a more indolent course in older women, which include higher prevalence of bone and skin metastases in lieu of visceral and brain metastases. This finding may be due to increased prevalence of well-differentiated, hormone-receptor-rich tumors, endocrine senescence that disfavor the growth of hormone sensitive cancer, and availability of several forms of endocrine treatment [22]. Nevertheless, despite a more indolent course, breast cancer is still a lethal disease in older women and should be treated aggressively. Also, not all breast cancers in older women are indolent. Even in the oldest ages at least 20% of tumors are hormone receptor poor and very aggressive. Age is a risk factor for early death in glyoblastoma multiformis and malignant astrocytoma [9].
Epidemiological observations have identified important age-related differences in tumor behavior that have led to the discovery of underlying molecular or physiologic mechanisms. In addition, clinical epidemiology has revealed that inadequate treatment might have been responsible for poorer outcomes among older patients.
1.2.3 Age and Clinical Presentation of Cancer
Heterogeneity in terms of function and life expectancy is a hallmark of aging [23, 24]. The practitioner managing older patients is faced with a number of issues, including whether (1) cancer screening and cancer treatment may reduce cancer-related mortality in patients with limited life expectancy and (2) older individuals are able to tolerate aggressive cancer treatment. Clinical epidemiology has given important insights into these issues.
A number of older studies summarized in Goodwin et al. [25] demonstrate that the majority of cancers were diagnosed at a more advanced stage in older compared with younger adults. The reasons for delayed diagnosis are poorly understood and may involve decreased awareness of early symptoms of cancer in the aging population and their providers. It is possible that symptoms such as pain, constipation, malaise, or weight loss be mistakenly ascribed to preexisting diseases or even to age itself. Another potential cause of delayed diagnosis is limited access to healthcare. One reversible cause of delayed diagnosis is reduced utilization of effective screening interventions such as mammography or colonoscopy by older individuals [26]. Disturbingly, lack of physician recommendations might have been the major cause of underutilization of these life-saving procedures by the elderly. Thus, public and professional education may reduce the cancer-related mortality of older individuals.
Multiple Malignancies
As aging is a risk factor for cancer, it should not be unexpected for older cancer patients to present with more than one malignant disease. Excluding non-melanomatous skin cancer, approximately 20% of cancer patients 70 and older have more than one neoplasm in their lifetime [27]. This association may be explained by several factors, such as:
The phenomenon of
field carcinogenesis
, which explains how patients who experience a previous cancer are susceptible to a second neoplasm in the same organ, as all cells of that organ have been exposed to the same carcinogen
More frequent clinical monitoring of individuals with previous history of cancer (e.g., frequent utilization of CT scans or MRI may explain the association between lymphoma and renal cell carcinoma)
Carcinogenic effects of previous cancer treatment, including chemotherapy-induced AML in patients who received adjuvant chemotherapy from previous cancers [11, 12].
Increased prevalence of indolent malignancies, including prostate cancer and chronic lymphocytic leukemia in older individuals
At present there is no evidence of a special genetic profile that renders certain older individuals more susceptible to multiple neoplasms requiring more intense monitoring. Also, a history of multiple neoplasms does not appear to increase the risk of an older patient to die of cancer [27].
1.2.4 Clinical Profile of the Older Cancer Patient
At least three studies have explored function and comorbidity of older cancer patients and have revealed that 70% of individuals over 70 years of age reported dependence in one or more instrumental activities of daily living (IADL) and that significant comorbidity was present in 40–90% of patients [28–30]. The prevalence of memory disorders, malnutrition, and dependence in one or more basic activity of daily living was present in as many as 20% of patients [28–30]. These studies revealed that the majority of older cancer patients needed some assistance in receiving and managing cancer treatment. When compared with an age-matched population without cancer, older cancer patients appeared to be in better health, but with reduced number of comorbid conditions and reduced prevalence of functional dependence. The impression that cancer may be a disease of “healthy elderly” is reinforced by the low prevalence of neoplastic diseases among patients living in institutions [31]. Thus, clinical epidemiology suggests that the majority of older individuals with cancer may benefit from cancer treatment if they have adequate medical and social support.
A study in 2000 was particularly provocative as it showed that women 80 and older diagnosed with breast cancer have a longer life expectancy than do women of the same age without breast cancer, according to SEER data [32]. These data may be misleading, however, because in the majority of the patients with breast cancer, the cancer was diagnosed at mammography. It is reasonable to expect that only the healthiest octogenarians might have been chosen to undergo mammography.
1.2.5 Age and Cancer Management
Diversity is a hallmark of the aged population [23, 24]. The influence and the interactions of comorbidity, polypharmacy, geriatric syndromes, and social support on cancer diagnosis and outcome are best studied in large databases where this information is prospectively collected. So far the main source of information related to the prevention and treatment of cancer in older people has been the Surveillance, Epidemiology, and End Results (SEER) program. SEER is the US National Cancer Institute–funded cancer registry representing four main geographic areas of the United States and includes information on cancer in approximately 21% of the US population [32]. When coupled with the Medicare data, SEER allows us to study the benefits and risks of cancer treatment in individuals 65 and older.
Indeed, SEER has been the source of important, albeit inadequate, information. Through SEER we have learned that
Women aged 70–79 had a twofold reduction in breast cancer mortality if they underwent at least two mammographic examinations [33–35]. The benefit was present even in women with moderate comorbidity [35].
Androgen deprivation in older men was associated with increased risk of bone fractures when the treatment was protracted longer than one year [36]. Androgen deprivation was also associated with increased risk of diabetes and myocardial infarction.
Age was a risk factor for chemotherapy-induced acute leukemia, and this effect was enhanced by the use of hemopoietic growth factors [11, 12].
Age was a risk factor for anthracycline-induced chronic cardiomyopathy [37].
In other areas, however, the information provided by SEER has been inconclusive, as is the issue of whether cancer chemotherapy is a cause of dementia in older breast cancer patients [38, 39]. The main limitation of the SEER data is the absence of information related to the function, severity of comorbidity, cognition, social support, and geriatric syndromes. This information is crucial to the advancement of geriatric oncology for several reasons: (1) function, comorbidity, and geriatric syndromes determine the so-called active life expectancy that is as important as survival and disease-free survival as treatment outcome in the older population [17]; (2) this information predicts the risk of mortality of older individuals [23, 24]; and (3) a number of more recent and yet largely unpublished studies showed that function, cognition, comorbidity, risk of falls, and other geriatric syndromes may be used to predict the risk of complications from cancer treatment in older individuals [40, 41]. Only by collecting a host of pretreatment information may we be able to fine-tune our predictions and decide for which patients cancer treatment may be beneficial or detrimental. New tumor registries, including the Endhoven registry in the Netheralands, have made a concerted effort to collect this prospective information.
1.3 Conclusions
Clinical epidemiology has a unique role in the study of older cancer patients. In the case of carcinogenesis and cancer behavior, clinical epidemiology has been the dictionary allowing us to translate bench findings into clinical data. It has demonstrated that older individuals are more susceptible to carcinogens than younger ones, and that the clinical behavior of cancer changes with age, due to a combination of “seed and soil” factors.
From a clinical standpoint, clinical epidemiology has demonstrated that older cancer patients are generally healthier than older individuals without cancer, and that age is a risk factor for delayed diagnosis and undertreatment of cancer. Clinical epidemiology is the best available approach to establish whether cancer treatment benefit older patients in terms of active life expectancy and which age-related factors may influence the treatment toxicity and the disease outcome. For this purpose it is important to have a prospective collection of data related to function, comorbidity, geriatric syndromes, and social support.
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Chapter 2
Biological Aspects of Aging and Cancer
Gabriel Tinoco
Mya Thein
William B. Ershler
Department of Internal Medicine,Harbor Hospital,Baltimore MD
Hematology/Immunology Unit, National Institute on Aging, Baltimore MD
Division of Hematology/Oncology, Institute for Advanced Studies in Aging, Gaithersburg MD
2.1 Introduction
Cancer incidence increases with each decade of adult life [1, 2], and with the current public interest and emphasis on both healthcare and aging, there is an expanding interest in geriatric oncology [3–11]. In addition to the clinical and policy issues relevant to the dramatic increase in the number of older patients with cancer, there remain the very important questions of why and how aging predisposes to cancer. Understanding this association may provide fundamental clues to the biological underpinnings of both processes. In this chapter we attempt to establish a framework around themes in aging biology that are relevant to the development and progression of cancer.
2.2 Normal Aging
It is a central gerontologic principle that aging is not a disease. The gradual functional declines that accompany normal aging have been well characterized in the literature (see Ref. 12 for a review), but under normal circumstances do not account for symptoms of disease. For example, kidney function declines with age [13]. and, in fact, has proved to be a useful biological marker of aging (see discussion below). Yet, clinical consequences of this change in renal function, in the absence of a disease or the exposure to an exogenous nephrotoxic agent, are not observed. Similarly, bone marrow changes with age. Although there are stem cell changes reported with age (see below), hematopoietic function is basically intact. For example, even when bone marrow is donated from a 65-year-old person to an human leukocyte antigen (HLA)-matched younger recipient, the transferred marrow supports hematopoiesis for the life of the recipient, a finding that confirms similar studies in laboratory animals [14].
Unlike the commonly held notion that stem cell compartments diminish in either number or function with age ultimately resulting in an inability to meet homeostatic demands, age-related hematopoietic stem cell (HSC) changes appear to be an exception, at least for murine species in which this issue has been most directly addressed. Early work demonstrated that marrow serially transplanted could reconstitute hematopoietic function for an estimated 15–20 lifespans [15]. Furthermore, the capacity for old marrow to reconstitute proved superior to that of young marrow [16]. Subsequently, a number of investigators using a variety of techniques have concluded that HSC concentration in old mice is approximately twice that found in young mice [17–20]. Some evidence suggests that the intrinsic function of HSC changes somewhat with age, most notably with a shift in lineage potential from lymphoid to myeloid development. This may contribute to an observed relative increase in neutrophils and decrease in lymphocytes in the peripheral blood of older people [21].
Although marrow stem cell numbers are preserved, the proliferative potential of progenitor cells is less [14, 18]. In addition, erythropoietin responses are blunted with advancing age even in the absence of clinical disease [22, 23], and low levels of anemia are commonly observed in otherwise healthy older people [22–24]. The diminished bone marrow reserve is also of clinical importance in considering cytotoxic chemotherapy for myelotoxicity is clearly greater in older cancer patients [25–27].
Distinct changes in measurable immune functions have been described with age, reviewed elsewhere [28], but the clinical consequences of these are minimal or even nonexistent in the absence of disease (see discussion below). Whether these changes contribute to a heightened susceptibility to infection remains a subject of debate.
Thus, aging is not a disease, but the consequences of aging may render an individual susceptible to disease. For example, there are age-associated changes described in immune functions and, although not of sufficient magnitude to pose primary problems, these alterations may render an individual susceptible to reactivation of tuberculosis [29, 30] or herpes zoster [31] and less capable of responding to influenza vaccine with protective titers of antibody [32, 33]. The immune decline, however, is not of sufficient magnitude or duration to account for the increased incidence of cancer in old people [34]. In fact, findings in experimental animals, have led some researchers to postulate that immune senescence may contribute to the observed reduced tumor growth and spread in a variety of tumors (discussed below).
2.2.1 Life Expectancy, Lifespan, and Maximum Survival
From the perspective of those who study aging, there is an important distinction made between median (life expectancy) and maximum lifespan. Over the past several decades, with the advent of modern sanitation, refrigeration, and other public health measures including vaccination and antibiotics, there has been a dramatic increase in median survival [35]. Early deaths have been diminished and more individuals are reaching old age. In the United States today, life expectancy for bot genders approaches 80 years [36]. Median survival is what concerns public health officials and healthcare providers, but for those studying the biology of aging, it is maximum survival that is the focus of greatest attention. Significantly, it has been estimated that if atherosclerosis and cancer were eliminated from the population as a cause of death, about 10 years would be added to the average human lifespan, yet there would be no change in maximum lifespan [37].
The oldest human being alive today (i.e., early 2012) is approximately 120 years old. What is intriguing is that the record has remained stable, unchanged by the public health initiatives mentioned above. In fact, some more recent data indicate that the maximum survival is actually declining in the United States [38, 39]. In the laboratory, similar limits have been established for a variety of species. Drosophila, free of predators, can live for 30 days, whereas C57BL/6 mice maintained in a laboratory environment on a healthy diet ad libitum may survive for 40 months. What is interesting is that, unlike the public health initiatives in humans, experimental interventions in lower species have been associated with a prolongation of maximum survival. In drosophila, for example, transgenic offspring producing extra copies of the free-radical scavenging enzymes superoxide dismutase and catalase survived about 33% longer than controls [40]. However, there has been some criticism of this work, based on the claim that the controls were unusually shortlived. In mammalian species, the only experimental intervention that characteristically prolongs maximum survival is the restriction of caloric intake. In fact, dietary restriction (DR) has become a common experimental paradigm exploited in the investigation of primary processes of aging [41].
2.2.2 Cellular versus Organismal Aging
There has been much written about cellular senescence and the events that lead up to cell death [42, 43]. After a finite number of divisions, normal somatic cells invariably enter a state of irreversibly arrested growth, a process termed replicative senescence [44]. In fact, it has been proposed that escape from the regulators of senescence is the antecedent of malignant transformation. However, the role of replicative senescence as an explanation of organismal aging remains the subject of vigorous debate. The controversy relates, in part, to the fact that certain organisms (e.g., drosophila, Caenorhabditis elegans) undergo an aging process, yet all of their adult cells are postreplicative.
What is clear is that the loss of proliferative capacity of human cells in culture is intrinsic to the cells and not dependent on environmental factors or even culture conditions [44]. Unless transformation occurs, cells age with each successive division. The number of divisions turns out to be more important than the actual amount of time passed. Thus, cells held in a quiescent state for months, when allowed back into a proliferative environment, will continue to undergo approximately the same number of divisions as those that were allowed to proliferate without a quiescent period [45].
The question remains whether this in vitro phenomenon is relevant to animal aging. One theory is that fibroblasts cultured from samples of old skin undergo fewer cycles of replication than those from young [46]. Furthermore, when various species are compared, replicative potential is directly and significantly related to lifespan [47]. An unusual β-galactosidase with activity peaks at pH 6 has proved to be a useful biomarker of in vitro senescence because it is expressed by senescent but not presenescent or quiescent fibroblasts [48]. This particular β-galactosidase isoform was found to have the predicted pattern of expression in skin from young and old donors with measurably increased levels in dermal fibroblasts and epidermal keratinocytes with advancing age [48]. The nature of the expression of this in vivo biomarker of aging in other tissues will be important to discern.
2.3 Theories of Aging
Providing a rational, unifying explanation for the aging process has been the subject of a great number of theoretical expositions. Yet, no single proposal suffices to account for the complexities observed (Table 2.1). The fact that genetic controls are involved seems obvious when one considers that lifespan is highly species-specific. For example, mice generally live for about 30 months and humans about 90 years. However, the aging phenomenon is not necessarily a direct consequence of primary DNA sequence. For example, mice and bats have 0.25% difference in their primary DNA sequence, but bats live for 25 years, 10 times longer than mice. Thus, regulation of gene expression seems likely to be the source of species longevity differences.
Table 2.1 Theories of Aging
Intrinsic stochastic
Somatic mutation; intrinsic mutagenesis; impaired DNA repair; error catastrophe
Extrinsic stochastic
Ionizing radiation; free-radical damage
Genetically determined
Neuroendocrine; immune
Although there is considerable intraspecies (within-species) variation in longevity, this variability is much lower with inbred strains or among monozygotic twins, than with dizygotic twins or nontwin siblings. Also, various genetically determined syndromes have remarkable (albeit incomplete) features of accelerated aging. These include Hutchison–Guilford syndrome (early-onset progeria), Werner's syndrome (adult-onset progeria), and Down's syndrome [49]. Although no progeria syndrome manifests a complete phenotype of advanced age, identification of the genes responsible for these particular syndromes is beginning to pay dividends by providing clues to the molecular mechanisms involved in the aging process. For example, Werner's syndrome is now known to be caused by mutations in a single gene on chromosome 8 that encodes a protein containing a helicase domain [50, 51]. Similarly, a mutation in the lamin A (LMNA) gene localized to chromosome 1 has been demonstrated to be the cause of the Hutchison-Guilford syndrome [52]. The future functional characterization of these specific proteins will, no doubt, increase our level of understanding of the aging process (Table 2.2). Examination of aging in yeast has also been informative with regard to the genetic controls of aging. These single-cell organisms follow the replicative limits of mammalian cells, and it has been observed that lifespan is related to silencing large chromosomal regions. Mutations in these silencing genes lead to increased longevity [53]. Thus, if there are certain genes that regulate normal aging, or at least are associated with the development of an aged phenotype, it stands to reason that acquired damage to those genes might influence the rate of aging. Over the years several theories have been proposed that relate to this supposition. In general, they hypothesize a random or stochastic accumulation of damage to either DNA or protein that eventually leads to dysfunctional cells, cell death and subsequent organ dysfunction, and ultimately organism death. Prominent among these is the somatic mutation theory [54], which predicts that genetic damage from background radiation, for example, accumulates and produces mutations and results in functional decline. A variety of refinements have been suggested to this theory invoking the importance of mutational interactions [55], transposable elements [56], and changes in DNA methylation status [57].
Table 2.2 Progeria-Related Disorders
A related hypothesis is Burnet's intrinsic mutagenesis theory [58], which proposes that spontaneous or endogenous mutations occur at different rates in different species and that this accounts for the variability observed in lifespan. Closely related to this notion is the
