Pharmacology of Antineoplastic Agents in Older Cancer Patients
Pharmacology of Antineoplastic Agents in Older Cancer Patients
ABSTRACT: The fastest growing segment of the US population is the group over the age of 65 years. In the next 30 years, this group will comprise over 20% of the population. Because 60% of all cancers occur in this age group, there will be an expected rise in the total cancer burden. Emerging data will better guide the use of chemotherapy in older patients. Studies will be presented discussing the pharmacokinetics of a number of chemotherapeutic agents, with an emphasis on those that have come into use over the past few years. Many of these agents seem to have a beneficial therapeutic index, particularly in regard to elderly patients. There has also been a rising trend in the use of oral chemotherapy. This change was fueled by patient preferences, quality-of-life issues, and the need to decrease the cost of chemotherapy administration. Factors that must be taken into consideration with oral administration of chemotherapy include limitations of the saturability of absorption, patient compliance, and the pharmacokinetic and pharmacodynamic changes that occur in elderly patients. Interpatient variability and drug metabolism, particularly age-related changes in drug metabolism, have been studied. The cytochrome P450 system is particularly important in this context. Safe administration of chemotherapy requires careful attention to the physiologic changes occurring with age and dose adjustments to compensate for end-organ (ie, renal and hepatic) dysfunction. These adjustments will be discussed for specific drugs. Complementary and alternative therapies will also be presented. [ONCOLOGY 14(12): 1743-1763, 2000]
Approximately 60% of all cancers occur in persons over the age of 65 years. Increasing age is directly associated with increasing rates of cancer, corresponding to an 11-fold greater incidence in persons over the age of 65 years vs those under 65. Consequently, the older population comprises a majority of cancer patients. Persons 65 years of age and older are the fastest-growing segment of the US population and will account for an estimated 20% of Americans by the year 2030. The over-75-year-old group will triple by 2030, and the over-85-year-old group will double in the same period. The average life expectancy of a 75-year-old person is currently 10 years, and of an 85-year-old, 6 years.[3-6] Together, these statistics outline a population that, in the future, will increasingly require specific management for various cancers.
The definition of "elderly" or "geriatric" patient groups is arbitrary and does not necessarily reflect the underlying health status of an individual. Following Medicare and Social Security regulations, the definition of "elderly" is most often based on an age over 65 years. Investigators have recently begun isolating the over-75 population for data analysis as well.[7,8] A special group, the "frail elderly" patient, is characterized by an age of 85 years or older, mild impairment of activities of daily living, significant comorbidity, and the presence of a geriatric syndrome.
Treatment decisions change significantly with increasing patient age.[9,10] Older patients are more likely to be undertreated with chemotherapy because of physician fear of toxicity and lack of data supporting efficacy in this population.[11,12] Studies that have addressed chemotherapy toxicity in older patients have shown that they can tolerate such regimens as well as younger patients.[13-20] Lack of data on older persons has been a serious concern for physicians in their decision-making process. Future studies will need to incorporate more elderly patients, in order to yield meaningful data that will support evidence-based decisions. As the elderly population continues to grow, there will be an increasing need for studies, physician education, and therapies for this group. This article will review the differences and similarities of older and younger populations with respect to pharmacology, toxicity, and management.
As practitioners treat more older patients, the question of whether pharmacokinetic data from patients in their 60s can be applied to patients in their 70s or 80s will become a more important issue. Throughout their lifetime, individuals experience subtle and gradual age-related changes that are difficult to identify. Older persons, compared to younger populations, typically have more disease states, take more medications, experience more adverse effects and drug interactions, and have more variability in nutritional status and underlying chronic health status that may contribute to pharmacokinetic differences.[22-24] Pharmacokinetic data on older patients are limited because only a small number of these individuals are included in studies with a wide range of patient ages. Consequently, the majority of data are inferred from the small number of older patients enrolled in trials that are not specifically targeted at an older age group.[25-27]
The pharmacokinetic and pharmacodynamic properties of various drugs may differ significantly between older and younger patients, as the result of physical, biochemical, and nutritional factors. Absorption may be affected by treatment toxicities as well by prior therapies such as surgery, radiation, and chemotherapy. The distribution of agents may be affected by differences in body fat, muscle, and protein and by fluid differences seen most often with aging, cancer cachexia syndromes, obesity, ascites, or pleural effusions. Protein binding may be altered by hypoalbuminemia, leading to an increase in free fractions of agents. The metabolism of agents may also be affected by changes in hepatic or renal function.[22-27]
Aging, cancer, other disease states, or other medications may alter renal and hepatic metabolism and the elimination of chemotherapy agents in the elderly. Renal function typically declines in a steady fashion. Studies of hepatic drug metabolizing enzyme activity, particularly the cytochrome P450 microsomal system, show a decline in activity of approximately 30% among healthy elderly men and women, compared with younger individuals. Cytochrome P450 1A2 also shows a decline in activity of 20% to 25% in healthy elderly subjects.[28,29] Due to the large metabolic capacity of the liver, age-related changes and their clinical significance are difficult to measure.
Decreases in the glomerular filtration rate (GFR) of approximately 1 mL/min for every year over age 40 are well known. The age-related decrease in GFR correlates with pharmacokinetic alterations of drugs that are excreted renally. Due to the physiologic decline in renal function with age, chemotherapeutic agents, which are primarily excreted renally, must be used with extreme care in the elderly. Dose adjustments may be needed, particularly in the frail elderly, in whom chemotherapy is often contraindicated. Dosing modifications for these declines have been suggested (Table 1).[8,31,32]