Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section H – Special Populations


Chapter 67 – Cancer in the Elderly: Biology, Prevention, and Treatment

Lodovico Balducci,
Claudia Beghé

SUMMARY OF KEY POINTS

Incidence

  

   

Cancer in the older person is increasingly common.

  

   

Data on prevention and management of cancer in the older person are limited.

Epidemiology of Aging and Cancer

  

   

The older population continues to expand as a result of reduced mortality and birth rates. Currently, 60% of all malignancies occur in persons aged 65 and older, and this proportion is expected to rise to 70% by the year 2030. Although cancer-related mortality is declining among younger persons, it is increasing among the oldest ones.

  

   

Of special interest, cancer appears to affect mainly older persons who are otherwise healthy and would have lived longer were it not for the cancer.

Aging and Carcinogenesis

The association of cancer and age may be explained by three mechanisms that are not mutually exclusive:

  

1.   

Carcinogenesis is a time-consuming process, the end-product of which, cancer, is more likely to develop at an advanced age.

  

2.   

Aging is associated with molecular changes that mimic carcinogenesis; older cells are primed to the effects of environmental carcinogens.

  

3.   

Aging is associated with environmental phenomena such as immune senescence or proliferative senescence that favor the development of cancer.

Aging and Cancer Biology

The biology of common malignancies such as breast cancer, ovarian cancer, non-Hodgkin's lymphoma, and acute myelogenous leukemia (AML) may change with age. In some cases, the tumor may become more indolent, whereas in others, it becomes more aggressive. Two mechanisms underlie these changes:

  

1.   

The biology of the tumor cells (e.g., the prevalence of MDR1 in AML increases after age 60, associated with a worse prognosis).

  

2.   

The aging of the patient: An age-related increase in circulating concentrations of interleukin-6 (IL-6) may favor the growth of lymphomas, whereas hormonal senescence may inhibit the growth of breast cancer.

Assessment of the Older Person

  

   

Aging involves a progressive shortening of life expectancy and reduction in the functional reserve of multiple organ systems.

  

   

Personal and social resources to cope with stress may become more limited.

  

   

Reduced life expectancy and reduced stress tolerance lessen the benefits and enhance the risks of medical intervention.

  

   

A comprehensive geriatric assessment (CGA), evaluating the patient's function, comorbidity, cognition, nutrition, medications, and living resources, is a currently available, reliable instrument for predicting life expectancy and the risk of treatment-related complications.

  

   

The CGA may unveil pre-existing situations or conditions such as undiagnosed disease, poor nutrition, depression, or lack of adequate social support that are remediable and may influence the outcome of treatment.

  

   

A number of laboratory tests, including assays of circulating levels of IL-6 and D-dimer, and tests of physical performance may complement the CGA.

Cancer Prevention

  

   

Older persons may be primary candidates for chemoprevention of cancer, but none of the current chemopreventive agents have demonstrated efficacy definitively.

  

   

Screening asymptomatic patients for cancer of the breast and of the large bowel appears to be reasonable when the life expectancy is 5 years or longer.

Cancer Treatment

  

   

Surgery: Age by itself, up to 100 years, does not appear to increase the surgical mortality rate, although the risk of surgical complications and length of postoperative hospitalization increase with age. Age is a definitive risk factor for death related to emergency surgery.

  

   

Radiation therapy: Tolerance for radiation therapy seems to remain high, even for persons aged 80 and older.

  

   

Cytotoxic chemotherapy: The main pharmacologic changes of age include decreased excretion of drugs and of their active metabolites from the kidneys; decreased volume of distribution of water-soluble drugs, which may in part be accounted for by anemia; increased susceptibility to myelodepression, mucositis, and peripheral and central neuropathy; and cardiomyopathy. The National Cancer Center Network (NCCN) has issued the following guidelines for the management of older cancer patients:

  

1.   

Dose adjustment according to the individual patient's glomerular filtration rate (GFR), for persons aged 65 and older

  

2.   

Prophylactic use of filgrastim or pegfilgrastim for patients aged 65 and older treated with combination chemotherapy of dose intensity comparable to that of the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) regimen

  

3.   

Maintenance of hemoglobin levels of 12 g/dL or greater

INTRODUCTION

The progressive aging of the population is an epidemiologic hallmark of our times. People 65 years of age and older represented 12% of the U.S. population in 1990; the percentage in this age group is expected to grow to 20% by 2030.[1] The segment of the older population undergoing the most rapid growth is that older than 85, the so-called oldest old.

Aging is the most important risk factor for cancer. The incidence of common malignancies increases with age—in fact, currently more than 60% of all neoplasms occur in persons aged 65 and older[2] ( Fig. 67-1 ), and this proportion is expected to increase to 70% by 2030. Today, cancer is the main cause of death among persons up to the age of 85.[2] Clearly, improved cancer control involves effective management of cancer in older adults.

 
 

Figure 67-1  Incidence of different neoplasms with age. A, Men. B, Women.

 

 

This chapter explores the association between cancer and aging, the influence of aging on cancer biology, and prevention and treatment of cancer in older persons, after reviewing the biologic and clinical aspects of aging. This information is presented as a frame of reference allowing the practitioner to estimate risks and benefits of preventive and therapeutic interventions in each patient.

BIOLOGY OF AGING

Molecular and Cellular Biology

Cellular aging observed in vitro (in the culture plate or test tube) is associated with a number of molecular events, of which some may favor and others may inhibit the development of cancer. Formation of DNA adducts, DNA hypermethylation, and point mutation[3] mimic the early stages of carcinogenesis, are associated with activation of oncogenes and inhibition of antiproliferative genes, and may prime the aging cell to the effects of environmental carcinogens, which explains, in part, the association between cancer and age. Other changes, including a progressive reduction in telomere length and telomerase activity[4] and activation of the P14 antiproliferative gene, encoding the CDK16 inhibitor, are contrary to those observed in neoplastic cells.[5] Of special interest are age-related abnormalities in protein synthesis, with reduced activity of DNA-repairing and drug-metabolizing enzymes, which may both accelerate carcinogenesis and enhance the complications of cytotoxic chemotherapy in normal tissues.[6]

Paradoxically, proliferative senescence may enhance the risk of cancer, because the senescent cells lose the ability not only to replicate themselves but also to undergo apoptosis—thereby acquiring immortality and its inherent risks. [7] [8] Proliferative senescence also is associated with the production of tumor growth factors and of proteolytic enzymes that may favor metastatic spread. [7] [8]

Physiology of Aging

Aging involves a progressive reduction in the functional reserve of multiple organ systems, with reduced tolerance of stress, including cancer and cancer treatment. The mechanisms may include increased prevalence of chronic diseases[9]; progressive accumulation of catabolic cytokines, including the interleukins IL-6 and IL-10 and tumor necrosis factor in the circulation[10]; and reduction in the stem cell reserve of different tissues.[11] Catabolic cytokines appear to be pivotal in physiologic aging: Their accumulation is associated with increased prevalence of geriatric syndromes,[12] increased risk of mortality and functional decline,[11] and a generalized catabolic status.[13]

From the standpoint of cancer treatment, the most significant changes include gastrointestinal, renal, hepatic, hematopoietic, and mucosal changes, which may alter the pharmacokinetics of antineoplastic agents and may increase the risk of complications from cancer treatment.

BIOLOGIC INTERACTIONS OF CANCER AND AGING

Aging may affect tumor biology at two levels: carcinogenesis and tumor growth.

Aging and Carcinogenesis

The association of aging with carcinogenesis may be explained by at least three mechanisms: duration of carcinogenesis, increased susceptibility of aging tissues to environmental carcinogens,[3] and changes in body environment, including proliferative senescence[7] and immune senescence.[14] Both experimental and epidemiologic findings support the theory that aging tissues are more susceptible to environmental carcinogens. Several murine tissues, including cutaneous, hepatic, lymphatic, and nervous tissues, have been found to be more likely to develop cancer after exposure to carcinogens if they are obtained from older animals.[3] In humans, the incidence of some cancers, such as nonmelanomatous skin cancer and prostate cancer, increases geometrically with age, suggesting enhanced carcinogenesis.[2] In addition, the incidence of some neoplasms, including non-Hodgkin's lymphomas,[15] anaplastic astrocytomas, and glioblastoma multiforme,[16] has increased several-fold among older adults during the past 30 years, suggesting that older persons may be more susceptible than younger ones to new environmental carcinogens. In the Italian city of Trieste, Barbone and coworkers found that the incidence of lung cancer after exposure to environmental pollutants increased in relation to the patient's age at the time of exposure.[17] The increased susceptibility of older people to environmental carcinogens indicates that primary cancer prevention, including elimination of environmental carcinogens and chemoprevention, may be particularly effective in this population. This is a new concept, directly opposed to common wisdom, which has held that preventive interventions are less efficacious for older persons.

Aging and Tumor Growth

Aging may influence tumor growth at two levels, the neoplastic cell itself and the host environment in which the tumor grows. It is reasonable to expect a concentration of more indolent tumors among older persons ( Fig. 67-2 ), by a process of natural selection. This is certainly the case with breast cancer, because the prevalence of well-differentiated, hormone receptor-rich tumors increases with age.[18]

 
 

Figure 67-2  The prevalence of more indolent tumors may increase with age for a process of natural selection. In this diagram, two persons start developing cancer, both at the age of 35 years. One cancer (A) is very aggressive and will manifest at age 37 and cause death at age 39. The other (B) is very indolent, will not manifest until age 65, and will not cause the patient's death until age 75. By a process of natural selection, by which the bearers of more aggressive tumors die earlier, a higher prevalence of indolent tumors can be expected among older persons.

 

 

The influence of the tumor host on cancer growth was demonstrated in a now-classic experiment by Ershler and coworkers, who demonstrated that the same loads of Lewis lung carcinoma and of B16 melanoma were associated with shorter survival and higher incidence of metastasis in younger animals than in older animals.[19] In successive studies, these investigators demonstrated that the tumor growth rate seemed to decrease for poorly immunogenic and increase for highly immunogenic tumors as the host age increased, highlighting the influence of immune senescence on tumor growth. In humans, Kurtz and colleagues demonstrated a reduction in the growth rate of primary breast cancer among older women, related directly to the degree of mononuclear cell reactions.[20] This observation suggested that immune senescence may mitigate tumor growth in poorly immunogenic tumors.

The clinical behavior of several human malignancies may change with the age of the patient.[21] Table 67-1 reveals that the biology of both the tumor cell and the tumor host may influence the change in prognosis. Another important observation is that in some instances, the prognosis becomes worse with age, in contrast with the generally held view. In any case, age by itself should not be considered a prognostic factor. If it is true that approximately 80% of breast cancers in women aged 70 and older are rich in hormone receptors, the converse also is true: 20% of cancers in women in this age group are not rich in hormone receptors, and appropriate treatment may require the use of cytotoxic chemotherapy. If MDR1 is present in 67% of patients older than 60 years with AML, it also is true that 33% of these patients have a disease responsive to chemotherapy and potentially curable. Each case should be treated on its own merits on the basis of an estimate of risks and benefits.


Table 67-1   -- Age and Changes in Cancer Prognosis

Neoplasm

Age-Related Changes in Prognosis

Mechanism(s)

Acute myelogenous leukemia[73]

  

 

Worse with age

  

 

Increased resistance to chemotherapy

  

 

Increased mortality during induction

  

 

Neoplastic cell

  

 

Increased prevalence of MDR1-expressing cells

  

 

Increased prevalence of stem cell leukemia

Non-Hodgkin's lymphoma[21]

  

 

Worse with age

  

 

Decreased duration of complete remission

  

 

Tumor host

  

 

Increased circulating concentration of interleukin-6

Breast cancer[20]

More indolent disease

  

 

Neoplastic cell

  

 

Increased prevalence of hormone receptor-rich, well-differentiated tumors

 

 

  

 

Tumor host

  

 

Decreased production of sex hormones

  

 

Immune senescence

Celomic ovarian cancer[21]

  

 

Worse with age

  

 

Decreased remission duration

  

 

Decreased survival

Unknown

Non-small cell lung cancer[21]

  

 

Better prognosis with age

  

 

Presentation at an earlier stage

Unknown

 

 

CLINICAL EVALUATION OF THE OLDER PATIENT

The benefit of cancer prevention and cancer treatment may be reduced and the risk enhanced in the older person, owing to a simultaneous reduction in life expectancy and in the tolerance of medical interventions. The basic questions of geriatric oncology include the following:

  

   

Is the patient going to die with cancer or of cancer?

  

   

Is the patient going to suffer the consequence of cancer during his or her lifetime?

  

   

Is the patient able to tolerate cancer treatment?

  

   

What are the long-term consequences of cancer and cancer treatment in older persons?

The issue of long-term consequences has become highly relevant as the percentage of older cancer survivors has increased. For example, the Cancer Acute Leukemia Group B (CALGB) recently reported that the risk of adjuvant chemotherapy-related acute leukemia increases with age and may be as high as 1.7% for women 65 and older.[22]

The life expectancy and functional reserve of the older person may be estimated with a comprehensive geriatric assessment (CGA; Table 67-2 ) to determine the patient's level of functioning and to identify any coexisting medical conditions (e.g., comorbidity, geriatric syndromes, polypharmacy, malnutrition) and the social resources available to ensure compliance with and safety of cancer treatment.[23] In addition, the CGA may unearth unsuspected conditions that interfere with the treatment of cancer, including malnutrition, polypharmacy, cognitive and emotional disturbances, and inadequate social support. [23] [24] [25]


Table 67-2   -- Comprehensive Geriatric Assessment and Clinical Implications

Assessment Component

Clinical Implication(s)

Functional status

 

 Activities of daily living (ADLs) and instrumental activities of daily living (IADLs)

Relation to life expectancy, functional dependence, and tolerance of stress

Comorbidity

 

 Number of comorbid conditions and comorbidity indices

Relation to life expectancy and tolerance of stress

Mental status

 

 Folstein Mini-Mental Status

Relation to life expectancy and functional dependence

 Examination

 

Emotional condition

 

 Geriatric Depression Scale (GDS)

Relation to life expectancy; may indicate motivation to receive treatment

Nutritional status

 

 Mini Nutritional Assessment (MNA)

Reversible condition; possible relationship to survival

Polypharmacy

Risk of drug interactions

Geriatric syndromes

 

 Delirium, dementia, depression, falls, incontinence, spontaneous bone fractures, neglect and abuse, failure to thrive, vertigo

Relation to survival and functional dependence

 

 

General Principles of Geriatric Assessment

In general geriatrics, the CGA has succeeded in reducing the rates of functional dependence and of admission to the hospital and to adult living facilities. [23] [24] In geriatric oncology, the CGA may unearth conditions that may compromise cancer treatment. In a pilot study involving 15 women aged 70 and older with early breast cancer, the performance of the CGA resulted in, on average, an additional 17.2 interventions per patient.[26] Three studies exploring the effects of CGA in older cancer patients demonstrated some degree of functional dependence in approximately 70% of those patients; some degree of comorbidity in more than 70%; and dementia, malnutrition, and depression in approximately 20%. [27] [28] [29]

The CGA also helps the practitioner to make a gross estimate of the patient's life expectancy and expected tolerance of treatment. Life expectancy declines with the degree of functional dependence and also with the seriousness of comorbid conditions and geriatric syndromes. [30] [31] One group of researchers have devised a “frailty index,” based on functional deficit, comorbidity, and social support, from which they calculate the functional rather than chronologic age of each patient.[32] This instrument may become particularly useful for the classification of older patients with cancer enrolled in clinical theapy trials. Two studies demonstrated that the risk of chemotherapy-induced myelosuppression increased for patients who were dependent in some instrumental activities of daily living (IADLs). [33] [34]

Thus, the CGA provides a common language for use in the classification of older patients undergoing cancer treatment or enrolled in clinical trials. A recurrent term that needs clarification is frailty, which commonly is associated with aging. At a recent consensus conference supported by the National Institute on Aging and the American Geriatrics Society, frailty was defined as a syndrome with multiple causes and involving multiple organ systems, characterized by increased vulnerability to stress and associated with sarcopenia, increased concentration of inflammatory cytokines in the circulation, and decreased motility and decreased ability to perform complex movements.[35] The conference recognized the existence of multiple signs of frailty and agreed to adopt for the time being the definition of the frail phenotype that emerged in the Cardiovascular Health Study (CHS).[36] On the basis of five parameters: weight loss of at least 10 pounds over 6 months, reduced energy levels, difficulty in initiating movements, reduced gait speed, and decreased strength of the hands, the CHS recognized three phenotypes with different life expectancy and risk of functional dependence. These phenotypes are (1) fit, with no abnormalities; (2) pre-frail, with one or two abnormalities; and (3) frail, with three or more abnormalities. It is worthy of emphasis that the definition of frailty will evolve with better insight in the biology of this syndrome. In the meantime, the CHS classification also may be helpful for classification of patients enrolled in clinical trials.

CLINICAL ASPECTS OF GERIATRIC ASSESSMENT

Function

Function is assessed on the basis of performance status (PS), activities of daily living (ADLs), and IADLs. The ADLs include transferring, bathing, dressing, eating, toileting, and continence; dependence in one or more of these functional areas, with the exception of continence, is associated with a 2-year mortality rate of approximately 40%. [23] [24] [25] [37] The IADLs are those activities necessary to maintain an independent life, including use of transportation, shopping, and the ability to take medications, to provide one's own meals, to use the telephone, to manage personal finances, and to take care of laundry and housecleaning. Dependence in one or more IADLs (with the exceptions of laundry and housecleaning) is associated with a 2-year mortality rate of 16% [23] [24] [25] [37] and a 50% risk of developing dementia within 2 years.[38] In addition, dependence in IADLs is associated with increased risk of neutropenia from cytotoxic chemotherapy. [33] [34] In two prospective studies, functional dependence and PS appeared poorly correlated; consequently, it is recommended that they be evaluated independently. [27] [28]

Comorbidity

Comorbidity is an independent cause of mortality for older patients with cancer[9] and may be associated with reduced tolerance of cancer treatment. The best way to assess comorbidity is still being investigated. Satariano and Ragland identified seven conditions associated with reduced life expectancy and demonstrated that the risk of mortality increased with the number of comorbid conditions.[39]Other investigators have devised comorbidity scales that take into account the degree of severity of each condition. Of these, the Cumulative Index of Related Symptoms–Geriatrics (CIRS-G) proved in some studies to be the most sensitive.[40] Another advantage of the CIRS-G is that its final score may be translated into the score of another scale in common use in epidemiologic studies, Charlson's scale.

Anemia is of special interest among the comorbid conditions[41] because its incidence and prevalence increase with age. Anemia is an independent risk factor for death and for myelosuppression from cytotoxic chemotherapy,[42] is a main cause of fatigue and functional dependence,[41] and may be associated with congestive heart failure and dementia.[41] An unsolved question is what level of hemoglobin defines anemia. Of special interest is the finding by the Women's Health and Aging Study that hemoglobin levels lower than 13.4 g/dL were an independent risk factor for death among 556 home-dwelling women aged 65 and older, evaluated on a prospective basis for a period of 8 years.[43] Similar findings were reported in the CHS.[44] In patients with cancer, anemia was associated with reduced survival and increased risk of functional dependence.[45]

Geriatric Syndromes

Geriatric syndromes include a number of conditions typical, if not specific, of aging, such as dementia, depression, delirium, incontinence, vertigo, falls, spontaneous bone fractures, failure to thrive, and neglect and abuse. Geriatric syndromes are associated with reduced life expectancy. [23] [24] [25] To be considered a geriatric syndrome, the condition must interfere with the affected person's daily life. Dementia must be moderate to severe; delirium must occur as a result of medications or organic diseases that do not commonly affect the central nervous system (e.g., urinary or upper respiratory infections); incontinence must be complete and irreversible; and falls must occur at least three times a month, or the fear of falling must prevent regular activities such as walking. Depression is of special interest because it is associated with decreased life expectancy, even when it is subclinical.[46] Depression also interferes with treatment compliance and in many cases may be fully reversible by medication. A simple 15-item questionnaire, the Geriatric Depression Scale 15 (GDS 15), speedily and reliably identifies persons with subclinical depression and is part of the CGA.[46]

Social Resources

Pivotal among the social resources ideally available to the older patient is the home caregiver. The ideal caregiver should be able to recognize and manage emergencies, to support the patient physically and emotionally, to mediate conflicts among family members, and to act as spokesperson for the family with the health care provider.[47] Under the best circumstances, the caregiver is the practitioner's best ally in ensuring compliance with treatment and smooth interactions with the patient. For this reason, it behooves the practitioner to participate in the selection, training, and support of the caregiver. In reality, the caregiver of an older person often is an older spouse with health problems of his or her own, or a married daughter who needs to balance her caregiving duties with other family and work responsibilities.

Nutrition

The prevalence of protein-calorie malnutrition increases with age. Isolation, depression, economic restriction, and reduced appreciation of hunger may all contribute to insufficient food intake, and chronic diseases and inflammatory cytokines may impede the synthesis of new proteins.[35] The Mini Nutritional Assessment (MNA) is a simple nutritional screening test used worldwide that identifies patients who are malnourished and those at risk of becoming malnourished, thereby permitting the prevention and early reversal of malnutrition.[48]

Polypharmacy

The prevalence of polypharmacy increases with age and, among cancer patients aged 70 and older, has been found to be as high as 41%. [23] [24] [25] The problem of polypharmacy exemplifies a common problem of elderly patients in developed countries: the absence of a primary care provider.[49] According to a recent study, more than 50% of people 70 years of age and older in the United States, Canada, and Israel, although attending multiple specialty clinics, lacked a primary care physician.

Other Forms of Geriatric Assessment

The CGA is the standard form of geriatric assessment, but it may be complemented by laboratory data and by so-called proofs of physical performance levels ( Box 67-1 ).

Box 67-1 

ASSESSMENT OF OLDER PERSONS: SCREENING TESTS

The comprehensive geriatric assessment (CGA) is time-consuming. A number of provisions that save office time may render its use more cost-effective. Proposed strategies include the following:

  

   

Home assessment, in which questionnaires are mailed to the patient at home and completed before the office visit. The advantage is reduction of the visit time. Disadvantages include dependence on self-reported function and comorbidity, inability to self-assess cognition, and, in a significant proportion of patients, inability to complete the questionnaire.

  

   

Administration of screening tests before the visit, with a more complete CGA then performed for patients for whom screening gives a positive result. The Vulnerable Elderly Survey 13 (VES 13), one of the best-validated screeing tests, can be completed in less than 1 minute. This is our favorite approach because it saves time and has been validated with functional and survival outcomes. Potential disadvantages include disagreement among clinicians on a cutoff score above which the result is considered positive and lack of a way to provide information about comorbidity, nutrition, cognition, and emotional disorders.

  

   

Use of laboratory tests or physical performance tests to identify patients at risk for death and disability. This approach is promising but needs validation and should be considered at present to be in clinical trials.

  

   

An additional issue is the age at which screening should begin. We have selected the age of 70 years, because previous studies have shown that the steepest increase in prevalence of age-related changes is seen between the ages of 70 and 75.

Laboratory Markers of Aging

The recognition that the concentration of catabolic cytokines in the circulation increases with age and usually is correlated with the presence of geriatric syndromes prompted a number of studies aimed at establishing whether these substances may predict functional dependence and decreased survival. In a recent study, Cohen and coworkers demonstrated that increased concentrations of either IL-6 or D-dimer were associated with a 50% increase in the risk of functional dependence and death.[50] When the concentration of both substances was elevated (with values in the upper quartile), however, the risk increased more than threefold.

Tests of Physical Performance

Difficulty in performing some activities is considered a predictor of functional dependence and disability. Of particular interest, a study has shown that the risk of mortality and functional dependence in older persons can be predicted by the “get up and go” test.[51] In this test, the patient is asked to get up from an armchair and walk 10 feet forward and then back to the chair. Both inability to get up without using the chair arms and requiring more than 10 seconds to walk the distance are highly predictive of functional decline.

Issues Related to Geriatric Assessment

A number of issues related to the application of the CGA in clinical practice merit further study. Among these are the questions of which patients should undergo a CGA, who should perform the test, and whether the complete test is always necessary.

Who should undergo a CGA? In three prospective studies of patients with cancer aged 70 and older, the CGA unearthed a number of conditions that were reversible and could interfere with cancer treatment. [27] [28] [29] On the basis of these findings, the NCCN recommended some form of CGA for all patients with cancer aged 70 and older.[25]

Who should perform the CGA? Ideally, the CGA should be performed by a primary care provider at periodic intervals, and the results should be part of the patient's permanent record. Any physician involved in the management of older patients should be familiar with the principles of CGA and its interpretation.

Is a full CGA necessary in all patients? Because the CGA is time-consuming, more cost-effective alternatives have been explored. Their value has not yet been determined. These include the use of a screening instrument to identify patients at high risk for functional dependence,[25] including questionnaires and tests of physical functioning.[1] The problem with both of these, however, is that they do not provide any direct assessment of comorbidity, depression, cognition, and social resources. Another interesting approach, proposed by Ingram and coworkers, involved sending to the patient's home a package including questionnaires about function, comorbidity, depression, and social resources.[29] The CHS assessment appears to be one of the most suitable ways to classify older patients involved in clinical trials: It is simple to execute, time-saving, and widely accepted and has been validated in a population of 8500 subjects.[37] For persons classified as pre-frail and frail, a more in-depth assessment may be in order.

CANCER PREVENTION IN OLDER PERSONS

Some aspects of aging favor and others interfere with cancer prevention. Because the incidence of cancer increases with age, the elderly presumably would be the population most likely to benefit from cancer prevention. At the same time, reduced life expectancy and decreased tolerance of chemopreventive therapy may lessen the benefits of some types of prevention. The study of cancer prevention in older persons is complicated by a lack of general agreement on what represents a meaningful endpoint: Should it be reduction in cancer-related mortality, as commonly accepted in prevention trials, or should it instead be an improvement in quality of life, in view of the limited life expectancy for this population?[52] This section provides a brief review of the evidence supporting chemoprevention and early detection of cancer among older persons.

Chemoprevention

At least three groups of substances, the selective estrogen receptor modulators (SERMs), the retinoids, and the nonsteroidal anti-inflammatory drugs (NSAIDs), have demonstrated cancer preventive activity in randomized clinical trials,[53] but these substances are used to only a limited degree in current clinical practice for cancer prevention. The SERM tamoxifen has a number of potential adverse side effects, including endometrial cancer, deep vein thrombosis, strokes, and vasomotor and genitourinary manifestations of menopause, the incidence of which increases with age.[53] In a decision analysis, Gail and coworkers calculated that tamoxifen may be beneficial for women aged 70 if their risk of developing breast cancer over 5 years is as high as 7% and if they do not present other contraindications to the drug; the threshold of risk at which this agent may be beneficial increases with the age of the patient.[54] Recently it was shown that raloxifen was as effective as tamoxifen in preventing breast cancer and had fewer side effects.[55]

Older persons may be ideal candidates for inclusion in future studies of chemoprevention in view of their increased risk of cancer, but none of the current options for chemoprevention appear to be optimal.

Screening and Early Detection

Because the prevalence of common cancers increases with age, the positive predictive value of screening tests might be expected to increase as well.[52] At the same time, older persons have in general undergone screening for common cancers earlier in life. Previous examinations may have eliminated all prevalence cases and minimized the diagnostic yield of subsequent examinations.

Breast Cancer

Most of the randomized controlled studies on breast cancer detection have established that serial mammograms reduce by 20% to 30% the cancer-related mortality rate among women aged 50 to 70.[56] The benefits of mammography after age 70 have been suggested by three reports. A historically controlled cohort study, the Nijmegen study, showed a reduction in cancer-related mortality up to age 75[57]; a retrospective study of the Survey Epidemiology and End Results (SEER) data showed a more than twofold decrement of breast cancer-related mortality for women aged 70 to 79 who had undergone at least two mammograms after age 70[58]; and another retrospective analysis of the same data showed that women older than 70 who had not undergone screening mammography presented with breast cancer at a more advanced stage than that typical for women who had been screened.[59]

An important question is the role of clinical examination of the breast (CBE). The Canadian study suggested that CBE may be as effective as screening mammography in women aged 50 to 60,[60] and the Breast Cancer Detection Demonstration Project (BCCDP) showed that mammography was superior to CBE only in the diagnosis of ductal carcinoma in situ (DCIS).[61] The CBE appears particularly attractive for older women who undergo multiple clinic visits in the course of the year, because it may be performed with no additional cost and inconvenience.

Colorectal Cancer

Early detection of cancer of the large bowel reduces cancer-related mortality among persons aged 50 to 80, but controversy lingers concerning the most appropriate screening strategy.[52] According to a decision analysis by Frazier and associates, full colonoscopy every 10 years is more cost-effective than yearly examination of the stool for fecal occult blood or more frequent flexible rectosigmoidoscopy.[62] A more recent decision analysis by Lin and colleagues[63] claiming that colonoscopy in persons aged 80 and older has negligible benefit may be misleading: These researchers failed to take into account individual life expectancy and functional reserves, which are highly diverse at that age. Virtual colonoscopy, which appears to be as sensitive as endoscopy, may be a more comfortable alternative for older persons.

Prostate Cancer

The value of screening asymptomatic men for prostate cancer with serial determinations of prostate-specific antigen (PSA) level, and the most cost-effective screening strategies, are controversial.[53] If screening is instituted, it should be continued up to age 75, because a Swedish study has demonstrated that radical prostatectomy reduces prostate cancer-related mortality in men up to age 75.[64]

Other Cancers

No benefits of screening women older than 60 for cervical cancer have been recognized if the women have undergone regular Papanicolaou examinations of the cervix earlier in life[53] and have had normal results. Interest in screening ex-smokers for lung cancer has been renewed by the demonstration that helical (spiral) computed tomography is able to detect small and curable cancers.[52] This approach remains controversial but may be of particular interest in older persons, because the incidence of lung cancer is increasing after age 80, probably because smoking cessation has resulted in a decrease in early coronary deaths and an increase in indolent lung cancers.[65]

Clearly, early detection of breast and colorectal cancer may reduce mortality among older persons and may improve their quality of life. It appears reasonable to institute some form of screening for persons whose life expectancy is 5 years or longer, because the initial benefits of screening are seen after 5 years.

CANCER TREATMENT

Surgery

Although surgical mortality and the risk of other surgical complications increase with the age of the patient, elective surgery appears to be safe in general, even in patients older than 80 years.[66] Persons 70 years of age and older are substantially more vulnerable to the complications of emergency surgery, especially surgery related to the digestive tract. In this population, regular screening for colorectal cancer may minimize the incidence of emergency surgery. A number of recent advances in surgery and anesthesia have rendered cancer surgery even safer for older persons. These include more limited surgical excisions (e.g., transanal resection of rectal cancer) and the use of anesthetic agents with a shorter half-life and minimal respiratory suppression.[67]

Radiation Therapy

Two large patient series from Europe and one from the United States attest to the feasibility and safety of radiation therapy in patients of all ages. [68] [69] [70] Combined chemotherapy and radiation therapy in the management of cancers of the head and neck, the esophagus, the bladder, and the lung also appear to be well tolerated up to the age of 80 at least. Among the newer radiation techniques, brachytherapy and high-dose intraoperative irradiation are of special interest for treatment in older patients: Brachytherapy minimizes the risk of complications to normal tissues, and intraoperative radiation eliminates the inconvenience of serial visits. Data on use of hyperfractionated radiation in older patients are wanted. Among the complications of radiation therapy, mucositis is of special concern in older patients, because age is associated with a more limited reserve of mucosal stem cells and increased proliferation of epithelial superficial cells[71]—two conditions that predispose older persons to more prolonged and severe mucositis. With cancer of the upper airway or upper digestive tract, in which the risk of mucositis is highest, nutritional management is essential and may involve prophylactic insertion of a percutaneous endoscopic gastrostomy tube.[70]

Cytotoxic Chemotherapy

Age is associated with changes in the pharmacokinetics and pharmacodynamics of cytotoxic drugs and increased susceptibility of certain organ systems to therapeutic complications.[71] The pharmacokinetic changes of major interest involve absorption, renal excretion, and volume of distribution of drugs.

The intestinal absorption of nutrients decreases with age, secondary to a reduction in the absorbing surface area, in the splanchnic circulation, and in gastric motility and secretions,[72] but the bioavailability of oral agents (e.g., capecitabine) does not appear to be compromised. Oral drugs are particularly appropriate for older patients because of the convenience of administration and adjustability of doses.

A progressive reduction in GFR is an almost universal consequence of aging, and it may lead to a more prolonged half-life of medications that are excreted from the kidneys (e.g., methotrexate, bleomycin, carboplatin) and of active and toxic metabolites of drugs excreted through other avenues.[71] These metabolites include daunorubicinol and idarubicinol, responsible for approximately 80% of the activity of the parent compounds,[71] and arauridine, responsible for the cerebellar toxicity of high-dose cytarabine.[71] Dose adjustment of these agents to the patient's GFR may improve tolerability.

The volume of distribution (Vd) of a drug is determined by the body composition and the concentrations of serum albumin and of hemoglobin.[71] Hemoglobin is important because most antineoplasticagents are bound to red blood cells. In the presence of anemia, the free concentration in plasma and toxicity of these substances in the circulation increase.[43] Correction of anemia may then ameliorate the toxicity of chemotherapy. Among the pharmacodynamic changes associated with age, the most significant are the increased prevalence of multidrug resistance, abnormal intracellular metabolisms of drugs, and abnormal repair of DNA damage. Multidrug resistance may be caused by increased expression of the MDR1 gene, as is the case in acute myelogenous leukemia[73]; increased prevalence of anoxic tumor cells; and resistance to apoptosis.[71] Abnormal drug metabolism and delay in DNA repair may enhance the toxicity of these agents.[6]

Myelosuppression and mucositis are particularly common and severe complications of cytotoxic chemotherapy. The risk of neutropenia and neutropenic infections with moderately toxic chemotherapy (such as the CHOP regimen—cyclophosphamide, doxorubicin, vincristine, and prednisone) increases with age and appears to be particularly marked after age 70; fortunately, hematopoietic growth factors in pharmacologic doses prevent this complication in 50% to 75% of people older than 70 years of age.[74] Neutropenic infection is potentially fatal and may occur after the first course of treatment—a fact that prompted the recommendations to use growth factors prophylactically in patients aged 65 and older.[75]

The risk of mucositis also increases with age, and this complication may be fatal if not treated promptly.[76] A keratinocyte growth factor, undergoing clinical trials, appears promising for the prevention of mucositis.[77] Other interventions to ameliorate this complication include substitution for intravenous fluorinated pyrimidines by capecitabine, which is associated with a lower risk of mucositis, and ensuring adequate hydration for older people in whom diarrhea or severe dysphagia develops.

Targeted Treatment

Treatments targeted to specific tumor components or tumor functions have substantially reduced the risk of therapeutic complications in older patients with cancer.[78] Some words of caution are in order, however:

  

   

In many cases, these compounds are more a complement of than an alternative to cytotoxic chemotherapy. The most noticeable exceptions to this rule are imatinib, desatinib, and nilatinib.

  

   

A number of complications of these agents may be particularly burdensome to older patients, including the risk of hypertension with bevacizumab; the risk of skin reactions with cetuximab, panitumab, and most small molecule inhibitors of receptor tyrosine kinase; and the risk of myelotoxicity related to lenalidomide and radioimmunotherapy.

Hormonal Treatment

Overall, hormonal treatment of cancer is considered much safer than cytotoxic chemotherapy, and the ongoing tendency is to institute chemical castration for PSA “relapses” in prostate cancer. This approach, however, may have a multiple unwanted effects in older men, including osteoporosis, bone fractures,[79] fatigue, anemia, diabetes, and coronary artery disease.[80]

PRACTICAL DECISIONS RELATED TO THE MANAGEMENT OF OLDER PATIENTS

Informed decision making is the key to effective and safe treatment of older patients with cancer. Any oncologic decision has two components: the person and the neoplasm. For example, cytotoxic chemotherapy is rarely indicated in a woman aged 90 or older with stage 1 or 2 breast cancer, in view of the negligible benefit and the substantial risk of treatment. Extermann and coworkers demonstrated that adjuvant chemotherapy is beneficial to an 80-year-old woman when her chances of dying of breast cancer are only about 30%, if a 1% reduction in breast cancer-related mortality is desirable; in a 90-year-old woman, however, the risk of dying of breast cancer must be close to 70% to justify the use of chemotherapy.[81] Chemotherapy seems definitively indicated if the same patient has a chemotherapy-responsive disease that may shorten her survival, such as large cell non-Hodgkin's lymphoma. The algorithm presented in Figure 67-3 depicts a useful frame of reference for the use of chemotherapy in older patients. The two points that deserve emphasis are (1) the rapidly evolving classification of older patients with cancer and (2) the likelihood that chemotherapy may represent the best option for palliation in frail patients. Several agents with minimal toxicity, including capecitabine at low doses, weekly taxanes, gemcitabine, and vinorelbine, may be used safely in these patients.[35]

 
 

Figure 67-3  Treatment algorithm for the use of chemotherapy in older persons with cancer.

 

 

NATIONAL AND INTERNATIONAL INITIATIVES RELATED TO CANCER AND AGE

The issues of cancer in the older person have been well recognized throughout the Western world and have prompted a number of important responses.

Governmental Responses

The National Cancer Institute, in cooperation with the National Institute on Aging, has held a number of conferences related to cancer and aging. As a consequence of these conferences, six to eight program grants (P20) for the development of geriatric programs within comprehensive cancer centers have been offered. In addition, a number of requests for proposals for the study of management of cancer in the older person have been offered.

All major cooperative groups in the United States and Europe now have a committee or subcommittee whose aim is promotion of enrollment of older patients with cancer into existing clinical trials and promotion of clinical trials devoted to older persons.

Professional Associations and Private Foundations

The American Association for Cancer Research (AACR), the American Society of Clinical Oncology (ASCO), and the European Society of Medical Oncology (ESMO) have dedicated special scientific and educational sessions to the issues of cancer and aging. ASCO also has developed a special curriculum on cancer and age. Of the private foundations, the Hartford Foundation merits special mention: This body has founded, through ASCO, 12 3-year fellowships for special training in geriatric oncology.

A number of industry-funded cooperative efforts for studying the management of cancer in the elderly also have been developed, including the Geriatric Oncology Consortium in the United States, the Geriatric Radiation Oncology Group (GROG) in Italy, and the Italian Group of Geriatric Oncology (GioGER), which, although it originated in Italy, incorporates the effort of several European countries.

Practice Guidelines

In 1999 the NCCN established a panel for the issuance of guidelines for the management of older patients with cancer. The first set of guidelines ( Table 67-3 ) was published in 2000.[52] These guidelines are based on the available clinical evidence, reviewed in this chapter, and are intended to be used as a frame of reference for clinical practice and as a building block to accommodate emerging data. Other associations, including the EORTC and the Canadian Cancer Institute, are preparing their own guidelines.


Table 67-3   -- Guidelines for Management of the Older Person with Cancer Established by the National Cancer Center Network

  

1.   

All patients aged 65 and older should undergo some form of geriatric assessment before institution of treatment.

  

2.   

With compounds that are excreted through the kidneys, or that give origin to active and toxic metabolites excreted through the kidneys, the dose should be adjusted to individual GFRs in persons aged 65 and older. Dose escalation can begin if no evidence of toxicity is encountered.

  

3.   

Patients aged 65 and older undergoing moderately toxic chemotherapy (of dose intensity comparable to that of CHOP) should receive prophylactic growth factors (G-CSF or pegylated G-CSF).

  

4.   

Hemoglobin levels should be maintained at 12 g/dL or greater with epoietin.

  

5.   

Patients aged 65 and older experiencing grade 3 or 4 mucositis should be hospitalized for aggressive fluid resuscitation.

CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; G-CSF, granulocyte colony stimulating factor; GFR, glomerular filtration rate.

 

 

 

CONCLUSIONS

The scope of geriatric oncology includes changes in tumor and patient biology as well as comprehensive evaluation of the older person aimed at establishing life expectancy, treatment tolerance, risk of cancer-related complication, and need for rehabilitative intervention. Biologic changes and CGA are the two poles of preventive and therapeutic interventions. Treatment-related guidelines may help establish a uniform approach to older cancer patients and thus facilitate the interpretation of clinical data. A number of initiatives developed during the past 5 years promote clinical research in older patients with cancer and promise to fill the current gaps in clinical evidence. In no circumstances does age alone represent a contraindication to effective cancer treatment.

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