Pharmacology of Antineoplastic Medications in Older Cancer Patients
Pharmacology of Antineoplastic Medications in Older Cancer Patients
ABSTRACT: Older patients are more susceptible to the complications of chemotherapy, and may be less equipped to react to these complications. After an introduction to the basic principles of geriatric medicine, this article explores the treatment of older cancer patients with systemic chemotherapy, including discussions of the pharmacology of aging, the effectiveness and toxicity of antineoplastic treatment in this population, and issues that need to be addressed in future clinical trials.
Aging is associated with a progressive decline of function, increased prevalence of comorbidity, slower cognition, and progressive sensorial deprivation. Together, these changes lead to decreased functional reserve of multiple organ systems, which influences the pharmacokinetics and pharmacodynamics of drugs. The likelihood of drug interaction increases as well, due to a high prevalence of polypharmacy in these individuals. In addition, aging may be associated with more limited resources and social support.
Older individuals are not only more susceptible to complications of chemotherapy; they are also less equipped to react to these complications. For example, in the absence of a home caregiver, an older patient may not be able to reach the hospital for the management of a severe neutropenic infection, and sometimes may not even be able to reach the phone and call for help. The decision to treat an older individual with cytotoxic drugs should take into account social support.
In this review, we will examine the pharmacokinetics and pharmacodynamics of antineoplastic agents after a brief introduction to geriatric medicine, as a framework of reference for clinical decisions. We will conclude with the outline of a research agenda specific for older cancer patients.
Basic Principles of Geriatrics
This section explores the influence of age on medical decisions in older cancer patients. To this end, it considers the definition of age, its clinical assessment, the goals of cancer treatment in the older aged person, and aging of specific organs and systems.
Definition of Age
lammation, as the accumulation of cellular oxidative damage, as a loss of entropy and “fractality,” and as a loss of the plasticity of tissue stem cells. To a large extent, these definitions represent different faces of the same event and describe interwoven phenomena. The construct of age as chronic inflammation is the most useful from a clinical standpoint, because the inflammatory status of a person may be correlated with life expectancy, function, and the prevalence of typical manifestations of aging called “geriatric syndromes.” Several studies have demonstrated a correlation between the concentration of inflammatory cytokines in the circulation and the risk of death, disability, dementia, delirium, osteoporosis, and failure to thrive.[5,9-12]
Aging is universal but highly individualized. Chronologic age does not reflect physiologic age. Rather, it represents a landmark, located around age 70. That is, the majority of physiologically old individuals are older than 70. This does not mean, however, that all individuals older than 70 are physiologically old. It only means that the determination of physiologic age is indicated for the population aged 70 and over. In addition to age 70, there may be another landmark, between age 90 and 95, beyond which the majority of people are physiologically old. This second landmark has not been clearly identified, however.
Clinical Assessment of Age
Physiologic age is reflected in a person’s independent living, life expectancy, and frailty. Independent living and life expectancy may be estimated with a comprehensive geriatric assessment, or CGA (Table 1). The survival of a person dependent in one or more instrumental activities of daily living (IADLs) depends on someone else compensating for the inability to perform a specific activity, such as a driver who provides transportation or a carrier who brings the groceries home. A person dependent in activities of daily living (ADLs) or with a geriatric syndrome may need a home caregiver or admission to an assisted-living facility.
Function, comorbidity, and geriatric syndromes may be factored in a formula that predicts the 4-year risk of mortality for individuals aged 70 and older.[14,15] Canadian investigators have estimated a person’s physiologic age based on 90 parameters, but this system is too cumbersome for use in a busy clinic. Polypharmacy is both an expression of comorbidity and a risk factor for medication-related complications. Malnutrition may be a sign of inadequate social support or depression, and is itself a risk factor for mortality, functional decline, and therapeutic complications. As already mentioned, social support is essential to the survival and thriving of individuals dependent in one or more IADLs or ADLs.
Functional impairment or disability do not necessarily imply that a person cannot live independently. A functional impairment (eg, weakness of an extremity) becomes a disability when it affects a function (eg, paraplegia may keep a person from walking). Appropriate environmental changes may prevent a disability from becoming a handicap. For example, a paraplegic who has access to a wheelchair may still be independent in transferring.
The construct of frailty has long-term clinical implications. While it is considered germane to aging, frailty still needs a consensus definition. Most gerontologists subscribe to the definition that emerged from a recent conference of experts, who portrayed frailty as a condition of extreme susceptibility to stress. A frail person may lose his or her independence when exposed to a minor stress, such as elective surgery or cytotoxic chemotherapy. The recognition of frailty may play a part in the decision to treat older cancer patients.
Currently, the diagnosis of frailty is based on five criteria derived from the Cardiovascular Health Study (CHS), as outlined in Table 2. The CHS investigators were able to identify three groups of individuals associated with differences in survival duration, risk of hospitalization, and risk of admission to assisted living over an 8-year follow-up period. These three groups were characterized as follows: (1) fit individuals are normal in all parameters; (2) prefrail individuals present with one or two abnormalities; (3) frail individuals present with three or more abnormalities.
The CHS definition represents both an instrument for screening older individuals for frailty, and a frame of reference for future studies of frailty. As an instrument, it is rather rudimentary. While it is very sensitive to frailty, it lacks specificity. After an 8-year follow-up, approximately 60% of the so-called frail individuals and 75% of the prefrail were still alive, and about half of the survivors still enjoyed independent living. This instrument may be fine-tuned by the introduction of additional assessments including, for example, the concentration of inflammatory cytokines in the circulation.
General agreement exists that frailty is a syndrome resulting from multiple pathogeneses, such as chronic inflammation, sarcopenia, loss of organ function, and the combined effect of drugs and comorbidity. A number of important clinical questions must still be addressed, including:
• Is frailty reversible, at least to some extent?
• Is the recognition of frailty useful to identify individuals at risk for specific stresses (eg, surgical procedures or cancer chemotherapy)?
• Can one grade frailty?
• Does frailty affect the course of cancer and other diseases ?
• How does frailty interact with medications?
Goals of Medical Treatment in the Older Person
The definition of physiologic age suggests the scope of treatment goals. In addition to cure, prolongation of survival, and symptom management, other important aims include preservation of independent living (also referred to as maintenance of active life expectancy) and prevention of frailty.
Aging of Specific Organs and Systems
In the same individuals, different organs and systems may age at different rates. These changes may influence the pharmacokinetics and pharmacodynamics of drugs. Common changes of aging include:
• Decreased total body water and total body proteins, and increased total body fat
• Reduction in glomerular filtration rate and tubular function
• Reduction in splanchnic circulation, liver size, and type 1 (cytochrome P450–mediated) hepatic reaction
• Decreased intestinal mucosal surface and ability to regenerate the mucosa after injury; decreased gastric secretions and gastric motility
• Reduced hematopoiesis
• Reduced cardiac reserve
• Reduced brain volume and peripheral nerve conduction
• Reduced production of sexual hormones and growth hormone, and increased production of adrenal steroids and cathecholamines
• Reduced bone density, osteopenia, and osteoporosis.