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.
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.
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.
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.
Elements of a Comprehensive Geriatric Assessment
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.
Frailty Criteria According to the Cardiovascular Health Study
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?
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.
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.
Numerous pharmacokinetic and pharmacodynamic changes associated with aging must be considered in patients receiving antineoplastic treatment.
Pharmacokinetic Changes of Aging and Their Consequences
The most important pharmacokinetic changes of aging are listed in Table 3.[2,23]
The absorption of nutrients decreases with age. It is reasonable to assume that the absorption of drugs may be reduced as well. This change may be especially consequential given the rapid development of new oral antineoplastic agents. The issue may be addressed by phase II studies of new oral agents in individuals aged 70 and older, aimed at establishing bioavailability and efficacy.
The decline in glomerular filtration rate GFR is almost universal with aging. This change will affect numerous agents, including
• Drugs whose parent compound is primarily eliminated from the kidney (eg, methotrexate, bleomycin, carboplatin)
• Drugs that give rise to active metabolites excreted by the kidneys (eg, idarubicinol, daunorubicinol). These include opioids, which are commonly used to manage cancer pain. The 6-glucuronide metabolite of morphine is 10 times as potent as the parent compound and is entirely eliminated renally.
• Drugs that give origin to toxic metabolites excreted from the kidney (eg, the ara-uridine metabolite of high-dose cytarabine, which is toxic to the cerebellum).
The decline in GFR may not affect the pharmacokinetics of drugs that are only partially eliminated by the kidney (eg, fludarabine, etoposide, gemcitabine [Gemzar]), as the activity of other excretory mechanisms may be increased to compensate for reduced renal elimination. The dose of chemotherapy may be adjusted according to individual GFR, utilizing the formula of Kintzel and Dorr. Among several formulas available to assess individual GFR, that proposed by Wright appears to be most suitable, as it is the most precise in estimating low GFR values.
The volume of distribution of hydrosoluble agents is determined by total body water, the concentration of drug-binding proteins, and the hemoglobin concentration, as a number of agents, including the anthracyclines, the epipodophyllotoxins, and the camptothecins, are heavily bound to red blood cells. In the presence of anemia, the toxicity of these agents is increased.[27-29]
A number of changes in hepatic size and circulation reduce the ability to extract and metabolize drugs. Phase I reactions, responsible for activation and deactivation of drugs through oxidoreduction, appear particularly affected, whereas phase II reactions, responsible for glucuronation and acetylation, appear to maintain their activity with aging. Phase I reactions are also affected by drug interactions, which are particularly common in the elderly due to polypharmacy.[30,31]
The pharmacodynamic changes of aging may alter both the effectiveness and toxicity of antineoplastic treatment.
It is clear that the biology of some tumors changes with age, and these changes may influence treatment effectiveness.[32-36] For example, the prevalence of multidrug-resistant acute myelogenous leukemia increases with age. The biology of breast cancer may become more indolent with age, which may lead to reduced sensitivity to cytotoxic gents and increased sensitivity to hormonal therapy.
The susceptibility of numerous organs and systems to the complications of treatment increases with age. Of special interest are myelotoxicity, mucositis, cardiomyopathy, nervous toxicity, bone toxicity, vascular toxicity, and skin toxicity.
• Neutropenia-The risk of neutropenia and neutropenic infections increases with age, and so does infection-related mortality.[37-42] The duration of hospitalization is approximately 25% longer for individuals aged 65 and over experiencing a neutropenic infection than it is for younger patients, with associated increased risks of hospital complications and deconditioning. Prevention of neutropenic infections is extremely important to prevent the complications of myelotoxicity and to be able to deliver adequate doses of chemotherapy. A recent study demonstrated that only 40% of patients with large-cell lymphoma received a relative dose intensity of CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone) ≥ 85%, which is essential to obtaining the highest cure rate.
Several studies have shown that filgrastim (granulocyte colony-stimulating factor, Neupogen), pegfilgrastrim (Neulasta), and lenograstim are effective in reducing (by 50%) the risk of neutropenia and neutropenic infections in older individuals and in allowing the administration of chemotherapy at full dose intensity in the majority of patients.[37-43] A meta-analysis of these studies indicated that the use of myelopoietic growth factors significantly reduced infectious mortality in patients of all ages and particularly in the oldest individuals.[37,38] To be effective, these agents should be administered prophylactically, beginning with the first course of chemotherapy, because the majority of neutropenic infections occur after the first and second courses of treatment.
• Anemia-Anemia is another complication of myelosuppressive chemotherapy, and is of particular concern in older individuals. The prevalence of anemia in general increases with age, and anemia is associated with increased risk of functional dependence, dementia, cardiovascular diseases, and chemotherapy-related toxicity.[45,46] In about 50% of older individuals, the causes of anemia preexisting chemotherapy include nutritional deficiency of iron or cobalamine, and absolute or relative erythropoietin deficiency.
The management of anemia involves investigation of its possible causes. Chemotherapy-induced anemia is improved by erythropoiesis-stimulating agents (ESAs) in approximately 60% of cases. Controversy lingers about the use of ESAs in cancer patients.[44,47] A number of recent studies have suggested that ESAs may shorten the survival of cancer patients by stimulating tumor growth, in addition to causing an increased incidence of deep-vein thrombosis and hypertension. An in-depth review of these studies is beyond the scope of this article. Suffice it to say that no clinical trials in which hemoglobin levels were kept ≤ 12 g/dL have shown an adverse effect of ESAs on survival or tumor growth. In addition, a Cochrane meta-analysis showed that the use of ESAs was associated with a reduction in blood transfusions. Given the negative effects of anemia on the function of older individuals, it appears prudent and safe to maintain the hemoglobin of these patients at around 12 g/dL, at least during chemotherapy administration.
• Thrombocytopenia-The risk of thrombocytopenia also increases with age. Currently, the only antidote to this complication is oprelvekin (Neumega), which is toxic and of minimal benefit. A megakaryocyte-stimulating factor is undergoing clinical trials and may become available in the next couple of years.
Mucositis is more common and more severe in older individuals. The major causes include fluorinated pyrimidines, methotrexate, and anthracyclines. Two age-related factors may lead to the pathogenesis of mucositis: increased proliferation of mucosal cells, making them more susceptible to cycle-active chemotherapy, and reduced reserve of mucosal stem cells, which slows recovery after chemotherapy. The combination of diarrhea and dysphagia may be deadly for older individuals, who are particularly susceptible to fluid depletion.
Currently, no antidote to mucositis has proven efficacious in older cancer patients. Aggressive fluid resuscitation is necessary for patients unable to drink, to prevent lethal fluid depletion. When indicated, the substitution of the prodrug capecitabine (Xeloda) for intravenous fluorinated pyrimidines may prevent mucositis. Since capecitabine is activated in the neoplastic tissue, the exposure of normal tissue to the active compound is minimized.
The anthracyclines and the monoclonal antibody trastuzumab (Herceptin) may compromise cardiac function, and age is a risk factor for this complication. Anthracycline-related cardiomyopathy is generally irreversible as is associated with damage to the myocardium. Older individuals receiving these drugs should undergo sequential monitoring of ejection fraction, and treatment should be discontinued for declines of 14% or higher. This complication is uncommon when the total dose of doxorubicin (or epirubicin) can be maintained below 300 mg/m2.
Other interventions that reduce the risk of cardiomyopathy include administration of doxorubicin by continuous infusion and simultaneous administration of doxorubicin and dexrazoxane. Dexrazoxane, however, may increase the risk of mucositis and myelotoxicity and may reduce the response of the tumor to chemotherapy. Thus, it has not gained wide acceptance. Pegylated liposomal doxorubicin (Doxil) has reduced cardiotoxicity compared to conventional doxorubicin, and may be substituted in patients with metastatic breast cancer, ovarian cancer, or multiple myeloma. Liposomal doxorubicin is also effective in large-cell lymphoma, but has never been compared with doxorubicin in this disease.
Trastuzumab seems to interfere with myocardial trophism, and exposure to the drug may freeze the myocardium. Trastuzumab-induced myocardial dysfunction does not appear to be associated with morphologic or molecular alterations of the myocardium, so this complication is generally reversible. As age is a risk factor for such toxicity, serial monitoring of cardiac function in older patients receiving trastuzumab appears prudent, with discontinuance of the drug in the presence of a drop in ejection fraction. In patients with cardiac dysfunction, the tyrosine kinase inhibitor lapatinib (Tykerb) may safely substitute for trastuzumab, although it is not clear whether the effectiveness of these two agents is comparable.
Age is a risk factor for peripheral neuropathy, a complication of alkaloids, epipodophyllotoxins, taxanes, epothilones, and platinum derivatives. Peripheral neuropathy may compromise ADLs and IADLs, and may increase the risk of falls in older individuals. There are no antidotes to this complication. The use of docetaxel (Taxotere) in lieu of paclitaxel, carboplatin in lieu of cisplatin, or vinorelbine in lieu of vinblastine may ameliorate the risk of this complication. The simultaneous infusion of calcium and magnesium may prevent oxaliplatin (Eloxatin)-related neuropathy.
Two forms of hormonal treatment-the aromatase inhibitors for breast cancer and the luteinizing hormone-releasing hormone (LHRH) analogs for prostate cancer-are particularly prone to causing this complication. The use of LHRH analogs for longer than 1 year has resulted in a greater than 50% increase in bone fractures. In the adjuvant treatment of postmenopausal women, aromatase inhibitors have also caused an increased in fractures, compared with tamoxifen. Older individuals of both sexes are particularly at risk for fractures, because they are prone to falls.
Osteopenia and osteoporosis may be reversed with bisphosphonates. Indeed, administration of zoledronate at the beginning of treatment has reduced the risk of these complications.[57,58] Given the potential risks associated with zoledronate, including osteonecrosis of the jaw and renal insufficiency, this approach should not be sanctioned as standard therapy until two questions are addressed:
(1) Are less powerful (and less toxic ) bisphosphonates as effective as zoledronate in preventing osteopenia and osteoporosis?
(2) Is it necessary to treat all patients ab initio or would it suffice to just treat patients who already have osteopenia or develop osteopenia during treatment?
Age is a risk factor for hypertension, thrombosis, and hemorrhage resulting from treatment with angiogenesis inhibitors. Of these, the most powerful is bevacizumab (Avastin), a monoclonal antibody to the vascular endothelial growth factor (VEGF). Similar complications may be observed with oral inhibitors of VEGF receptor–bound tyrosine kinase (eg, sunitinib [Sutent], sorafenib [Nexavar]) and with other antiangiogenic preparations undergoing clinical trials.
Individuals of all ages treated with bevacizumab should undergo serial monitoring of blood pressure and urine analysis (looking for proteinuria). Adequate blood pressure control may ideally be obtained through the cooperation of the oncologist and the patient’s primary care physician, who should be alerted to potential treatment complications.
The inhibition of the receptor-bound tyrosine kinase with small molecules or with anti–epidermal growth factor receptor (EGFR) antibodies has been associated with a number of cutaneous complications whose pathogenesis is not clear. The most serious of these is necrolytic dermatitis, which may be lethal. The most common complication is eczema, which often becomes infected. The incidence and severity of cutaneous complications increases with age. As in younger individuals, treatment in older patients involves skin emollients, clindamycin ointment, and oral tetracyclines when superinfection is present.
Aging appears to be a risk factor for complications that may occur 5 to 10 years after the administration of chemotherapy. These include the following conditions:
• Acute Myelogenous Leukemia and Myelodysplasia-The incidence of this complication of breast cancer adjuvant chemotherapy increases with age and may be as high as 1.5% in women aged 65 and older.[61-65] The use of anthracyclines and especially of mitoxantrone is a major risk factor. The role of myelopoietic growth factors in the pathogenesis of this complication is controversial.[62,63] In addition to considering a very careful balance of benefits and risks of adjuvant chemotherapy in older women, for whom the treatment benefit is marginal, this complication should dissuade clinicians from the use of anthracyclines that may be advantageous only in tumors that overexpress topoisomerase II.
• Chronic Cardiomyopathy-Approximately one-fifth of patients treated with anthracyclines seem to experience a progressive cardiac dysfunction years later.[67-70] The risk of this complication increases with age. The number of people experiencing clinically relevant cardiomyopathy seems to increase with time. As the incidence of symptomatic cardiomyopathy is small, this risk should not prevent the use of anthracyclines when these drugs may be lifesaving, as in cases of large-cell lymphoma. The use of safer alternatives to anthracyclines-such as liposomal doxorubicin-should be explored, especially in older individuals.
Clearly, the management of older individuals with systemic cancer treatment presents unique issues, which have been outlined in this brief review. In addition, a number of questions need to be addressed in future clinical trials.
NCCN Guidelines for the Management of Cancer in Older Individuals
The decision to treat older individuals with systemic cancer therapy involves the assessment of individual life expectancy, treatment tolerance, and social support, prevention of the most common complications of treatment, and minimization of toxicity. This approach has been summarized in the National Comprehensive Cancer Network (NCCN) guidelines shown in Table 4. In addition to providing an estimate of life expectancy, functional reserve, and social support, the geriatric assessment may unearth conditions that may interfere with the effectiveness of treatment (eg, unknown comorbidity, polypharmacy, risk of malnutrition, early memory disorders, subclinical depression, polypharmacy).
The recommendation to maintain hemoglobin levels at around 12 g/dL may be debated in view of the potential ESA risks. Irrespective of the ESA controversy, however, this recommendation emphasizes that anemia-even mild anemia-may compromise the survival and functioning of older cancer patients and may increase the risk of complications of cytotoxic chemotherapy. As anemia may have reversible causes in more than 50% of cases (eg, iron and cobalamine deficiency, low erythropoietin production secondary to renal insufficiency), the causes of anemia should be thoroughly investigated.
The next revision of the NCCN guidelines will also include recommendations for the use of targeted therapy, for the assessment of comorbidity and polypharmacy, and for the prevention of bone complications.
A number of important issues need to be addressed in future clinical trials, including:
• Determining the long-term effects of cancer and cancer treatment on independent living. Prolongation of active life expectancy is one of the treatment goals in the elderly, but no organized effort has been made so far to gauge this outcome;
• Fine-tuning of the clinical definition of frailty, aimed to improve its positive predictive value for the risk of deconditioning after minor stress. This may occur with the addition of physical and laboratory findings; the determination of circulating inflammatory cytokines appears particularly promising to this end.
• Phase II studies of new agents in individuals aged 70 and older, to establish both effectiveness and toxicity.
• Interaction of comorbidity and polypharmacy with cancer and cancer treatment. The scope of this investigation includes all areas of health care, not just oncology, and implies a strict cooperation of geriatricians, primary care physicians, and specialists. Bevacizumab-induced hypertension represents an excellent paradigm for the development of this investigation.
• Support of the home caregiver of the older cancer patient. The caregiver is an essential player in the effective delivery of care, and is subject to emotional and medical complications of caregiving. Preservation of the health of the caregiver is necessary to improve the outcome of cancer in the older person.
• Adoption of a common language in the classification of older patients that would allow long-term investigation of the outcome of cancer and cancer treatment. Given the diversity of the older population, retrospective analysis of outcomes in large populations will be essential to encompass all the individual variations that cannot be included in clinical trials.
Financial Disclosure: Dr. Balducci is a consultant for Amgen and Millennium and a speaker for Amgen, Novartis, Millennium, and Sanofi-Aventis.
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