In addition to the CGA, other forms of assessing physiological age are noteworthy. The frailty index is calculated by summing the functional deficits in an aging person.11 Physiological age is assessed based on the average number of deficits accumulated by a person of that chronological age. For example, if a 75-year-old woman has the number of deficits that correspond to an average 61-year-old, the woman’s physiological age is assessed as 61 years. However, determining the frailty index is too laborious for clinical applications because it requires the clinician to evaluate 70 conditions11; in addition, it is not clear whether the index predicts mortality risks and tolerance of stress.
Numerous laboratory tests have been proposed for the assessment of physiological aging. Of these, the assessment of inflammatory markers in the circulation12 and the length of leukocyte telomeres13 bear a relation to mortality risk. Telomere length also predicts the risk of adverse events from cytotoxic chemotherapy.14 Although these tests are of interest, they have not been validated. The determination of inflammatory markers lacks adequate sensitivity; moreover, the telomere length varies among different persons, thus making the comparison of physiological age based on telomere length problematic.
Influence of Aging on Cancer Treatment
Factors related to aging that may influence cancer treatment include cancer biology, which may be different among younger and older patients; decreased life expectancy of the older person, which may reduce the benefits of cancer treatment; and increased vulnerability to complications due to cancer therapies.
Biology of Cancer and Aging
Cancer growth and aggressiveness are influenced by 2 factors, namely, the tumor cell and the tumor host. For example, acute myeloid leukemia is less susceptible to treatment in the elderly patient population, and this is due — at least in part — to the higher prevalence of unfavorable prognostic factors, including complex cytogenetic changes, MDR-1 gene expression, and the involvement of the early multipotential hemopoietic progenitors.15 By contrast, in the setting of breast cancer, the prevalence of favorable prognostic factors, such as hormone receptor concentration and good cellular differentiation, increases with age.16 Genomic and proteomic analysis may help account for these factors in clinical trials.
Assessment of patient-related factors is difficult. Such factors may include immunosenescence, endocrine senescence, proliferative senescence, and chronic inflammation.17 Animal data suggest that immunosenescence may have different effects on the growth of various neoplasms; for example, immunosenescence may enhance the growth of highly immunogenic neoplasms, while disfavoring the growth of poorly immunogenic neoplasms. Decreased production of sexual hormones may inhibit hormone-dependent cancers, such as breast and prostate cancers.
Age is associated with increased insulin resistance, which results in an increased concentration of insulin, a powerful growth factor for several tumors, in the circulation.18 The aging of stromal tissues involves the proliferative senescence of fibroblasts, facilitating neoplastic growth with the production of tumor growth factors and enzymes that dissolve basal membranes.19 Age is also associated with progressive and chronic inflammation, which may contribute to immunosenescence and tumor growth.17
Polypharmacy is another patient-related factor among the older population because the number of medications used and the prevalence of polypharmacy increase with age.8 For example, the use of metformin, a drug that decreases insulin resistance and, consequently, circulating levels of insulin, is associated with prolonged survival in patients with prostate or breast cancer.20,21 As mentioned previously, polymorbidity may also affect cancer growth. For example, the prognosis of breast, prostate, or large bowel cancer is worse in individuals with diabetes than in those without diabetes.8 At present, these factors cannot be accounted for in randomized clinical trials.
The risk–benefit ratio of antineoplastic treatment may be reduced in the majority of older individuals. The expected benefits are lower in this population due to a progressive decline in life expectancy. Even in the most fit of older persons, individual age is a risk factor for some complications of chemotherapy, including myelosuppression, mucositis, cardiomyopathy, and peripheral neuropathy.22 The risk of such complications increases in individuals with compromised function and multiple morbidities.
It is reasonable to aim for a cure when facing a rapidly lethal but curable disease, such as large B-cell lymphoma or acute leukemia, despite the high risk of serious complications. Currently, it is reasonable not to submit older individuals with limited life expectancies and a chronic, but not life-threatening disease, such as chronic lymphocytic leukemia, to the toxicity of fludarabine, cyclophosphamide, and rituximab,23 which may add a few months of survival at a time when most patients might have died of a disease other than cancer.
Cure, prolongation of survival, and symptom management are the main goals of treatment; however, the preservation of function and active life expectancy should also be goals for older patients.24 Active life expectancy is a period of time during which a person remains functionally independent. Loss of functional independency is a significant threat to the quality of life of older individuals.24
Barriers to Treatment
Numerous social factors may preclude cancer treatment in older patients, including accessibility (eg, many older individuals may not be able to negotiate their way alone to a treatment center), difficulty with finances (recipients of Medicare may have to pay unaffordable co-payments for cancer treatment), and inadequate home support. However, it is important to remember that ageism can be a hindrance to the reception of adequate cancer treatment.25
A study conducted by the Cancer and Leukemia Group B (CALGB) demonstrated that the main obstacle to clinical trial participation of older patients with breast cancer was the reluctance of physicians to offer experimental treatment to older individuals.25 Clinical studies of cancer treatment among older patients must account for the factors outlined in this brief review, including a poor understanding of the interaction between tumor and patient, a reduced risk–benefit ratio, the increased risk of treatment complications, the inclusion of active life expectancy among the treatment goals, and the socioeconomic barriers to treatment.
Clinical Trials in Older Patients With Cancer
Aging may be associated with a number of pharmacological changes that render the study of new drugs in the older population necessary (Table 2).22 Data on drug absorption are wanted, but the bioavailability of oral drugs is expected to decrease with age. Decreased total body water content is associated with a decreased volume of distribution and an increased level of water-soluble drugs in the circulation, which may purportedly increase toxicity. Renal excretion and hepatic metabolism of drugs are universally decreased with age. Although the decline in the glomerular filtration rate may be accounted for by calculating the level of creatinine clearance, a clinical test of hepatic metabolism is still needed. As already mentioned, numerous age-related changes in target organs may be associated with increased hemopoietic, mucosal, cardiac, and neurological toxicities. The question of whether a new agent is effective and safe in both the younger and older patient populations must be addressed in appropriate clinical trials.
Advanced age should never be a criterion to exclude older individuals from participating in clinical trials designed for adults. Rather, as clinicians, we must ask whether certain clinical trials should be exclusively dedicated to older individuals.