Cancer Chemotherapy in the Elderly Patient
Cancer Chemotherapy in the Elderly Patient
The management of older patients with cancer is historically challenging because of a lack of prospective data regarding the appropriate management of this population. In this review, we address some of the issues and challenges surrounding the treatment of older cancer patients, including the withholding of medically appropriate treatment based on chronologic age, the historical omission of elderly from clinical trials, and the impact of geriatric assessment, and age-related changes in pharmacokinetics and pharmacodynamics. Finally, we conclude by discussing the existing evidence related to cancer treatment in the elderly, focusing primarily on the malignancies most commonly seen in older patients, and making general treatment recommendations where applicable.
Geriatric Oncology, the systematic examination of the treatment of elderly patients with cancer, is a relatively new field of study. Before the National Cancer Institute and the National Institute on Aging released the sentinel document “Perspectives on Prevention and Treatment of Cancer in the Elderly” in 1983, most of the patient populations in clinical trials were relatively young and healthy, and older patients were frequently excluded.[2,3] Cancer is a disease that disproportionately affects older patients. However, it is important to draw the distinction between chronologic and biologic age in order to provide the best care for individual patients.
A number of retrospective data and clinical trials focusing on treatment and supportive care of older patients with cancer are ongoing or have been completed. Some differences in pharmacokinetics and natural history of disease do exist between older and younger patients, but for the most part, healthy elderly patients, with minimal comorbidities, like their younger counterparts, benefit from and are able to tolerate standard chemotherapeutic regimens across a broad spectrum of malignancies. In this review, we discuss the unique challenges and the many opportunities associated with the treatment of elderly cancer patients.
Cancer Burden in the Elderly
The population of the United States continues to age: 12.3% of the population was aged 65 or older in 2008, and by 2030, this figure will be over 20%. Between 2002 and 2006, 54.7% of newly diagnosed cancers and 69.7% of all deaths from cancer occurred in patients aged 65 or older. Across various types of cancer, older persons remain more likely to develop and die from cancer (see Figures 1 and 2). Estimated costs for cancer care in the US in 2004 were over $72 billion.[6,7] The staggering cost of cancer care underscores the importance of developing evidence-based guidelines for treating older cancer patients.
Chronologic vs Biologic Age: Evaluation of the Elderly Cancer Patient
Traditionally, age 65 years and above has been used as a cutoff to define the elderly. However, it is increasingly recognized that biologic age is more important than chronologic age alone in predicting the tolerance and efficacy of standard chemotherapy in the elderly. Thus, there is a shift toward further risk stratification of elderly cancer patients based on their functional status and the presence or absence of comorbidities. Extensive efforts have been made to develop assessment tools for predicting the efficacy:toxicity ratio of chemotherapy in the elderly.
The Comprehensive Geriatric Assessment (CGA) is a valuable tool in the assessment of older patients and focuses on several domains, including functional status, comorbidity, cognitive function, nutrition, psychological and social support, and medications. The results of a CGA are useful in directing care and identifying needs in this population.[8,9] When evaluating an elderly cancer patient, other than the standard Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky scales, the Charlson Comorbidity Index (CCI, Table 1) and the Cumulative Illness Rating Scale-Geriatrics (CIRS-G) are examples of tools that may be incorporated into the routine evaluation of elderly patients.
An exhaustive discussion of these tools is beyond the scope of this review. However, it is clear that a CGA, although useful, is time-consuming and only indicated in select patients.[8,9] Furthermore, advanced age alone does not portend a poor outcome. Much more sensitive predictors of outcome include the functional status of the patient, the presence of organ dysfunction, and the presence of other comorbidities.
The National Comprehensive Cancer Network (NCCN) has developed useful guidelines for managing older cancer patients, and these can be readily accessed at http://www.nccn.org. Nevertheless, some of the challenges that remain are (1) developing and validating low burden–high frequency instruments that can be administered more frequently during the treatment course, and (2) developing and validating biomarkers of occult hematopoietic and renal dysfunction.
Pharmacokinetics and Pharmacodynamics of Anticancer Agents in the Elderly
A comprehensive review of the pharmacokinetics of anticancer agents in the elderly has been the subject of several recent excellent articles, and is beyond the scope of this review.[10-12] In general, most of the data in the elderly have been derived from a few prospective studies (eg, in taxanes) and a large number of retrospective analyses.
A solid theoretical basis exists for abnormal pharmacokinetics for both oral and intravenous agents in the elderly. Potential factors include decreased absorption because of delayed gastric emptying and reduced gastrointestinal motility; changes in body composition resulting from increased fat content, decreased water content, and increase in volume of distribution; decreased metabolism caused by changes in liver blood flow; decreased excretion resulting from age- and disease-related decline in glomerular filtration rate; and the potential for drug-drug interactions caused by polypharmacy. However, prospective studies of young and elderly cancer patients with normal organ function have shown no appreciable differences in pharmacokinetics for taxanes and platinum agents. The age-related differences in pharmacokinetics, when observed, are subtle and characterized by extreme heterogeneity.
Most of the age-related differences in cancer patients are in the realm of pharmacodynamics, and manifest as decrements in end-organ function, which in turn leads to either dose reductions or a delay in administration of chemotherapy, changing the risk-benefit ratio in treating elderly cancer patients. Thus, the principal challenge in addressing the efficacy-tolerance balance of treatment in the elderly is the development and validation of biomarkers predictive of renal and hematopoietic dysfunction in the setting of cytotoxic chemotherapy.[13,14]
Inclusion of Elderly Patients in Clinical Trials
One of the major barriers to determining the appropriate treatment for older patients is the lack of prospective clinical data focusing on older patients. Elderly patients are often underrepresented in clinical trials.[2,7] In addition, few clinical trials are designed to focus specifically on older patients. Furthermore, older patients are much more likely to be undertreated than their younger counterparts. Much of the data that do exist are extrapolated from unplanned retrospective or pooled analyses. The National Institutes of Health and other organizations have specifically identified the need to increase the participation of older patients in clinical trials.
One area in which these issues have been closely examined is breast cancer. Despite a 5-fold increase in incidence and 10-fold increase in mortality in patients with breast cancer over the age of 65, these patients are often undertreated and underrepresented in clinical trials. One study found that the proportion of patients age 65 and older, age 70 and older, and age 75 and older among all patients with breast cancer was 60%, 45%, and 31%, respectively. The proportion of patients in these three age groups included in clinical trials was 36%, 20%, and 9%, respectively, suggesting that older patients were routinely excluded from participation. Another study showed women over the age of 70 with early-stage, node-negative invasive breast cancer were less likely to receive both definitive locoregional therapy and adjuvant chemotherapy, compared with women aged 50 to 69. Multivariate analysis also shows that an age of 75 years or older was independently associated with treatment that deviated from accepted guidelines, even after adjusting for comorbidities, marital status, race, educational background, tumor characteristics, and clinical stage.