Cancer risk, incidence, and mortality increase dramatically with age. Approximately 60% of all cancers and 70% of deaths from cancer occur in adults age 65 and older (Yancik & Ries, 2000). With the rapid expansion of the older population and subsequent increase in cancer incidence, health care providers will see a significant increase in the number of older people with cancer (B.D. Smith, Smith, Hurria, Hortobagyi, & Buchholz, 2009). In light of this increase, the care and treatment of older adults with cancer becomes an important issue not only for oncology nurses but also for gerontological nurses and others who provide care for this population. This article will examine the impact of physiological aging on cancer treatment decision making and treatment-related toxicities.
Aging is associated with a decrease in functional reserve capacity in multiple tissue and organ systems. The diminished reserve capacity results in impaired homeostasis and an altered response to stressors. Physiological processes in almost all body systems decline gradually over time. The rate of decline is highly individualized and is determined by environmental, lifestyle, and genetic factors (Adams & White, 2004). Significant heterogeneity exists in physiological and functional reserve capacity among older adults. Until recently, chronological age had been used as a primary factor in cancer treatment decision making. However, chronological age does not adequately predict or reflect the extent of age-related physiological changes in an individual. Thus, parameters of physiological and functional capacity, rather than just chronological age, need to be considered in determining and tailoring cancer treatment in older adults.
The decision to treat cancer in older adults is based not only on the type and stage of cancer but also on the patient’s ability to tolerate treatment. Age alone should not prevent appropriate cancer treatment in older adults. Standard cancer treatment regimens, including surgery, chemotherapy, and radiation therapy, can be used safely and effectively in older adults and can enhance quality of life and improve survival (Extermann, 2004; Saltzstein & Behling, 2002). Toxicity associated with cancer treatment in older adults can be minimized with timely and appropriate supportive care and with increased monitoring and follow up.
Implications for Treatment Decision Making
An evaluation of physiological and functional reserve is needed to determine which older adults will tolerate and benefit from cancer treatment. This evaluation enables clinicians to estimate life expectancy and whether the person is most likely to die from the cancer or another condition. Primary components of the evaluation include the presence and severity of comorbid medical conditions and the functional status of the older adult. Comorbidity and functional status are independent factors in older adults with cancer; therefore, they need to be assessed independently (Extermann, Overcash, Lyman, Parr, & Balducci, 1998). In addition, other components of comprehensive geriatric assessment (CGA) can help identify patients at risk for poor treatment tolerance and adverse outcomes (Chen et al., 2003; Freyer et al., 2005; Maione et al., 2005). Alterations in drug pharmacokinetics resulting from age-related physiological changes also need to be considered in treatment decision making.
Comorbid medical conditions such as diabetes, heart disease, hypertension, arthritis, and lung disease are prevalent in older adults with cancer, and the number of comorbidities increases with age (Yancik et al., 1998). In Yancik et al.’s (1998) study, patients ages 55 to 64 had an average of 2.9 comorbidities, and those age 75 and older had an average of 4.2 comorbidities. Comorbidity limits treatment options, negatively affects treatment tolerance, and influences the presence and severity of symptoms and other complications (Frasci et al., 2000). Comorbidity is also associated with poorer survival, increasing both cancer and non-cancer mortality (Firat, Bousamra, Gore, & Byhardt, 2002; Piccirillo, Tierney, Costas, Grove, & Spitznagel, 2004).
Comorbidity adds to the complexity of caring for older adults with cancer. The treatment of comorbid conditions during cancer treatment may result in an increased likelihood of drug interactions. In addition, cancer treatments, including chemotherapy, radiation therapy, and other supportive care drugs, may exacerbate comorbid conditions. For example, corticosteroids used to prevent nausea and allergic reactions may cause hyperglycemia in diabetic patients. In addition, angiogenesis inhibitors such as bevacizumab (Avastin®) and tyrosine kinase inhibitors (e.g., sunitinib [Sutent®], sorafenib [Nexavar®]) contribute to treatment-related hypertension in patients with preexisting hypertension and those at risk (Kurtin, 2009).
Functional status in older adults with cancer is a significant consideration in treatment decision making. Specific components of functional status include activities of daily living (ADLs) and instrumental ADLs (IADLs). ADLs include bathing, dressing, ambulating, using the toilet, maintaining continence, and feeding oneself. IADLs are skills needed to maintain one’s independence in the community, such as the ability to use a telephone, travel, shop, prepare meals, do housework or yardwork, take medications, and manage finances. Physical functioning prior to diagnosis (Stommel, Given, & Given, 2002) and pretreatment IADL function (Maione et al., 2005) have been associated with survival in cancer patients following treatment.
Comprehensive Geriatric Assessment
CGA involves a multidimensional evaluation to determine the overall health status of an older adult. Table 1 lists the components of the CGA. In oncology practice, CGA helps clinicians better understand the patient’s physiological age and identify older patients at risk for functional decline and treatment toxicity (Extermann, 2003; Extermann et al., 2005). CGA can be used to guide treatment planning and decision making in older adults with cancer. In other words, CGA helps determine which patients may benefit from and tolerate standard cancer treatment and which patients may benefit most from a palliative treatment approach. CGA also helps identify potentially reversible problems that could be better managed to facilitate cancer treatment.
Table 1: Components of Comprehensive Geriatric Assessment
CGA, using an interdisciplinary team approach, is time consuming and labor intensive. Thus, it is often not feasible in the busy outpatient oncology setting. The National Comprehensive Cancer Network’s (NCCN) (2009c) senior adult oncology guidelines propose screening to determine which patients may need a more comprehensive assessment. CGA, using a self-report format, has been conducted in outpatient cancer populations (Hurria et al., 2007; Ingram et al., 2002). Overcash, Beckstead, Moody, Extermann, and Cobb (2006) have proposed an abbreviated CGA. When problems are identified, patients undergo more extensive assessments in these areas.
Alterations in Pharmacokinetics
Multiple age-related physiological changes affect the pharmacokinetic properties of chemotherapeutic agents and other drugs. Alterations in drug absorption, distribution, metabolism, and excretion may affect treatment tolerance and result in greater toxicities in older adults with cancer (Lichtman et al., 2007). Age-related physiological changes that affect drug pharmacokinetics must be taken into account when determining drug regimens for cancer treatment, as well as when prescribing drugs to manage treatment side effects and other chronic and acute medical problems.
Absorption. Drug absorption is affected by age-related changes in the gastrointestinal system, such as increased gastric acid secretion, decreased gastrointestinal motility, mucosal atrophy, reduced absorptive surface area, and reduced splanchnic circulation (Lichtman, 2003; Sawhney, Sehl, & Naeim, 2005). These changes result in reduced absorption of drugs and nutrients. Until recently, most chemotherapy drugs were given parenterally, so absorption was not a significant issue in cancer treatment. With the increased use of oral chemotherapeutic drugs, alterations in drug absorption become more important (Skirvin & Lichtman, 2002).
Distribution. Aging is associated with changes in body composition, including reductions in total body water, protein stores, and lean body mass and an increase in total body fat (Elmadfa & Meyer, 2008). These changes alter the distribution of chemotherapeutic agents and other drugs in older adults. The reduction in total body water decreases the distribution of drugs that are water soluble, while the increase in total body fat increases the distribution of lipid-soluble drugs. Decreases in serum albumin and hemoglobin concentration in older adults increase the distribution of drugs that bind to albumin and hemoglobin (Lichtman, 2003).
Metabolism. Drug metabolism refers to the metabolic breakdown of a drug. The liver is one of the most common sites of drug metabolism. Age-related changes in the liver, including decreased liver size, reduction in hepatic blood flow, and impairments in hepatic oxidative pathways and the cytochrome P-450 enzyme system, result in an overall reduction in the metabolic capacity of the liver (Lichtman, 2003; Sawhney et al., 2005). Several chemotherapy agents, including taxanes, cyclophosphamide (Cytoxan®), and vinca alkaloid drugs, are metabolized by cytochrome P-450 enzymes (Lichtman & Boparai, 2008). Treatment with these drugs may be affected by the concurrent use of commonly prescribed drugs and other substances that induce the cytochrome P-450 system (e.g., phenytoin [Dilantin®], phenobarbital, carbamazepine [Equetro®, Tegretol®], omeprazole [Prilosec®], St. John’s wort, cigarette smoke) or those that inhibit the system (e.g., cimetidine [Tagamet®], diltiazem [Cardizem LA®, Dilacor XR®, Tiazac®], verapamil [Calan®, Covera-HS®, Isoptin SR®, Verelan PM®], fluoxetine [Prozac®], sertraline [Zoloft®], paroxetine [Paxil®], grapefruit juice), making dosage adjustments necessary (Lichtman, 2003; Reuben et al., 2009).
Excretion. The decline in renal function that occurs with aging affects drug excretion. A reduction in renal mass leads to a decrease in functional nephrons and a decline in glo-merular filtration rate. The kidneys’ ability to appropriately concentrate or dilute urine and excrete water and electrolytes is also impaired (Luckey & Parsa, 2003; Sawhney et al., 2005). Serum creatinine level has limited usefulness for evaluating renal function in older adults due to reduction in muscle mass. Thus, creatinine clearance should be calculated and used to guide drug dosing. Many chemotherapy drugs, including platinum compounds, alkylating agents, capecitabine [Xeloda®], purine analogues, antimetabolites, camptothecins, and etoposide [Etopophos®], have significant renal excretion (Lichtman & Boparai, 2008). When these drugs are used in older adults, renal function must be evaluated carefully, and dosages reduced accordingly. The concurrent use of other nephrotoxic drugs should be avoided.
Implications for Managing Treatment Toxicities
Treatment tolerance and toxicity are significant concerns in treating older adults with cancer. Age-related physiological changes alter the effects of cancer treatment and make older adults more susceptible to the toxic effects of treatment. Treatment toxicities of particular concern when caring for older adults with cancer are myelotoxicty, mucosal toxicity, cardiotoxicity, neurotoxicity, and musculoskeletal toxicity. These are reviewed below and summarized in Table 2.
Myelotoxicity is a common effect of chemotherapy treatment. It often results in treatment delay and dosage reduction. Age-related changes in the bone marrow and hematopoiesis, including an increase in bone marrow fat, a reduction in stem cell mass and mobilization, and an increase in cytokines that inhibit hematopoiesis, contribute to greater myelosuppression and delayed recovery after chemotherapy in older adults (Balducci, Hardy, & Lyman, 2000). The manifestations of chemotherapy-induced myelotoxicity include neutropenia, anemia, and thrombocytopenia.
Neutropenia. Neutropenia is the primary dosage-limiting myelotoxicity. Depending on the treatment regimen, neutropenia often develops 1 to 2 weeks after the administration of chemotherapy. Neutropenia in older adults increases the risks of infectious complications and treatment-related mortality (Balducci & Repetto, 2004). Neutropenia in older adults is often more severe and more prolonged (Dees et al., 2000) and frequently results in hospitalizations and increased costs among older adults with cancer (Crawford, Dale, & Lyman, 2004).
While it is important to monitor for febrile neutropenia, older adults who are neutropenic may not exhibit common signs of infection, such as fever (Crighton & Puppione, 2006). They must be monitored for atypical signs of infection, including altered mental status or delirium, increased fatigue, loss of appetite, and changes in activity level. The routine use of prophylactic antibiotic agents is controversial because of concern about promoting antibiotic resistance; however, fluoroquinolone prophylaxis is recommended in high-risk patients with afebrile neutropenia following chemotherapy (Zitella et al., 2006). Good hand washing and minimizing exposure to potentially infectious people are the most effective ways to prevent infection. The effectiveness of the neutropenic diet or protective isolation in preventing infection has not been established (Crighton & Puppione, 2006; Zitella et al., 2006).
The NCCN (2009c) guidelines for senior adult oncology recommend the prophylactic use of colony stimulating factors (CSFs) with dosage-dense chemotherapy regimens in older adults. In addition, the NCCN (2009b) guidelines for myeloid growth factors and the most recent American Society of Clinical Oncology guidelines (T.J. Smith et al., 2006) suggest that CSFs should be used when the risk of developing febrile neutropenia is greater than 20%. The risk of developing febrile neutropenia is estimated by considering the chemotherapy regimen and dosage and patient factors, including older age, prior chemotherapy treatment, prior treatment-related neutropenia, bone marrow involvement, poor performance status, and renal or liver dysfunction (NCCN, 2009b).
Anemia. Anemia is a common problem in older adults with cancer (Penninx, Cohen, & Woodman, 2007). If anemia is present prior to starting therapy, it should be evaluated thoroughly and corrected because chemotherapeutic agents dramatically increase the incidence of anemia (Capo & Waltzman, 2004). Moreover, a reduction in red blood cells affects the pharmacokinetics of chemotherapy agents that bind with and are transported by hemoglobin, including taxanes and anthracyclines (Schrijvers, Highley, De Bruyn, Van Oosterom, & Vermorken, 1999). Mild to moderate anemia in older adults with cancer can contribute to symptoms that negatively affect quality of life.
The NCCN (2009c) guidelines for senior adult oncology recommend maintaining a hemoglobin of 12 g/dL to minimize toxicity and related symptoms. Because of increased risks for thrombosis and mortality, erythropoiesis-stimulating agents (ESAs) should not be used to correct anemia in cancer patients receiving curative treatment; rather, blood transfusions should be used to treat symptomatic anemia (NCCN, 2009a). In cancer patients receiving palliative chemotherapy treatment, the benefits and risks associated with ESAs and blood transfusions should be weighed and discussed with the patient. ESAs should not be used in cancer patients who are not receiving chemotherapy (NCCN, 2009a).
Thrombocytopenia. Thrombocytopenia also occurs following treatment with chemotherapy. The risk of spontaneous bleeding is low in patients being treated for solid tumor cancers (Capo & Waltzman, 2004). Patients with or at risk for thrombocytopenia should be instructed to monitor for and report signs and symptoms of bleeding, including petechia, bruising, nosebleeds, and blood in urine, stool, or emesis. Patients with thrombocytopenia should limit the use of drugs that affect platelet function or bleeding such as nonsteroidal anti-inflammatory drugs and aspirin. If uncontrolled bleeding occurs, platelet transfusions are required.
Mucositis, an inflammation of the mucosal lining of the oral cavity and gastrointestinal (GI) tract, is a common toxicity of chemotherapy and radiation therapy. Age-related changes in the mucosa make older adults more susceptible to mucosal injury and mucositis. Diminished renal and hepatic elimination of chemotherapy agents, poor dentition, impaired nutrition, and vitamin deficiencies also contribute to mucositis in older adults (Sonis, 2004). Mucositis occurs more frequently and may be more severe and more prolonged in older adults (Crivellari et al., 2000). Mucositis places older adults at greater risk for poor outcomes including increased hospital admissions, dosage reductions or delays, greater risk of infection, severe pain requiring opioid analgesic agents, and increased treatment costs (Elting et al., 2003; Murphy, 2007).
Oral mucositis often impairs swallowing and limits nutritional and fluid intake. Oral intake may need to be supplemented by enteral or parenteral nutrition. Decreased fluid intake, nausea and vomiting, and diarrhea associated with oral and GI mucositis can rapidly lead to dehydration. In older adults, mucositis that inhibits fluid intake or results in severe diarrhea must be managed aggressively. Intravenous fluids may be needed to prevent and treat dehydration (Bond, 2006).
The increased prevalence of cardiac disease and cardiovascular changes associated with aging places older adults with cancer at risk for treatment-related cardiotoxicity. Cardiomyopathy with congestive heart failure (CHF) is a common cardiotoxic effect, but myocardial infarction, myocarditis, pericarditis, arrhythmias, and other electrocardiographic changes can occur (Chanan-Khan, Srinivasan, & Czuczman, 2004). Cardiotoxicity is an established complication associated with anthracycline agents, including doxorubicin (Adriamycin PFS®), daunorubicin (Cerubidine®), idarubicin (Idamycin®), and epirubicin (Ellence®). Other chemotherapeutic and biological agents, including mytomycin (Mutamycin®), cyclophosphamide (Cytoxan®), fluorouracil (Adrucil®), interferons, interleukin-2, and monoclonal antibodies (e.g., trastuzumab [Herceptin®]), also have been associated with cardiotoxicities (Meinardi et al., 2000; Suter et al., 2007; Viale & Yamamoto, 2008).
Cardiotoxicity may develop acutely during treatment or it may develop as a long-term treatment side effect (Meinardi et al., 2000). The risk of treatment-induced CHF increases with age (Pinder, Duan, Goodwin, Hortobagyi, & Giordano, 2007; Swain, Whaley, & Ewer, 2003; Tan-Chiu et al., 2005). In Pinder et al.’s (2007) study, rates of CHF in the sample increased over the 10 years of follow up. Older patients with cardiovascular risk factors and those receiving cardiotoxic agents should be monitored for cardiotoxicities during and after treatment. Baseline cardiac function should be established prior to treatment with anthracyclines and trastuzumab. Patients should be monitored for signs and symptoms of early CHF including weight gain, shortness of breath, orthopnea, and pedal edema. After it develops, CHF is treated symptomatically with pharmacological agents, including diuretic agents, angiotensin-converting enzyme inhibitors, beta blockers, and digoxin [Lanoxin®]. Healthy lifestyle behaviors (e.g., physical activity, smoking cessation, weight management, dietary modifications) are also integral in the management of CHF (Chanan-Khan et al., 2004; Viale & Yamamoto, 2008).
Aging is associated with anatomical and physiological changes in the central and peripheral nervous systems. Neuronal loss results in a decrease in brain volume and enlargement of the cerebral ventricles. Cerebral blood flow and glucose and oxygen metabolism in the brain are reduced. The level and functioning of neurotransmitters also change (Sullivan & Pfefferbaum, 2007). Age-related changes in the central nervous system contribute to deficits in multiple cognitive processes, including memory, attention, processing speed, and executive function (Myers, 2008). Age-related nervous system changes also contribute to impairments in sensation, balance, coordination, and movement.
Delirium and Cognitive Impairment. Older adults with cancer may have baseline cognitive deficits that put them at greater risk for delirium during treatment and for long-term cognitive impairment after treatment (Extermann, 2005). In addition, multiple chemotherapy agents and radiation therapy involving the brain and adjacent areas have been associated with acute and chronic cognitive changes (Abayomi, 2002; Plotkin & Wen, 2003).
In older adults it is important to establish a baseline level of cognitive functioning before treatment and to conduct ongoing assessments during treatment to identify changes in cognitive functioning. Polypharmacy, especially the use of anticholinergic drugs and benzodiazepines, should be minimized. The lowest possible dosage should be used for necessary medications. When opioids are needed for pain control, the starting dosage should be low and the dosage should be titrated slowly. The concurrent use of adjuvant pain medications may allow the opioid dosage to be minimized. If cognitive changes occur with a particular opioid, the health care provider can consider switching to another opioid. Fluid and electrolyte imbalances can contribute to delirium and alterations in cognitive functioning. It is important to monitor for and correct electrolyte abnormalities and to prevent and aggressively treat dehydration (Bond, 2009).
Peripheral Neuropathy. Peripheral neuropathy is a common, dosage-limiting toxicity of many chemotherapy agents, including platinum compounds, taxanes, vinca alkaloid agents, thalidomide (Thalomid®), and bortezomib (Velcade®). Age-related changes in the peripheral nervous system, including a reduction in peripheral nerve myelin and the presence of comorbid diseases that affect peripheral nerves, may place older adults with cancer at risk for chemotherapy-induced peripheral neuropathy. The degree of nerve damage associated with chemotherapy depends not only on the drug and total cumulative dosage, but also on preexisting nerve damage from diabetic, alcohol, or inherited neuropathies (Quasthoff & Hartung, 2002).
Chemotherapy-induced peripheral neuropathy may have sensory, sensorimotor, or autonomic components. Sensory alterations include pain, numbness and tingling, dysesthesias, paresthesias, allodynia, and diminished or absent sensation or proprioception. Motor deficits include weakness, gait disturbance, altered balance, and impaired fine motor skills. Autonomic symptoms may include postural hypotension, constipation, urinary retention, and sexual dysfunction (Visovsky, Collins, Abbott, Ashenbrenner, & Hart, 2007). Peripheral neuropathy interferes with ADL and IADL function and negatively affects quality of life. In older adults, peripheral neuropathy may be disabling and contribute to impaired mobility and falls (Wickham, 2007).
There are no treatments to reverse neuropathy, but there are measures to prevent or reduce its occurrence (Armstrong, Almadrones, & Gilbert, 2005). Prior to starting therapy, it is important to identify patients who are at risk for developing neuropathy. Peripheral neuropathy may be prevented by minimizing the use of neurotoxic agents and by avoiding combinations of neurotoxic agents. Patients should be taught signs and symptoms of peripheral neuropathy and instructed to contact their health care provider if any are noted. Health care providers should perform a baseline assessment and ongoing assessments of sensation and motor function (Marrs & Newton, 2003). If neuropathy develops and progresses, it is important to consider discontinuation of the neurotoxic agents. The treatment of peripheral neuropathy focuses on the symptomatic relief of pain and other dysesthias and paresthesias. Patients must also be taught strategies to promote their safety and prevent further complications (Armstrong et al., 2005; Marrs & Newton, 2003; Quasthoff & Hartung, 2002; Visovsky et al., 2007).
Osteoporosis and osteoarthritis are common age-related conditions. In addition, cancer treatments contribute to the progression of osteoporosis and development of other musculoskeletal complications. Together these toxicities increase the risk for falls and fracture, and negatively affect quality of life in older adults with cancer. They may also lead to treatment discontinuation.
Osteoporosis. Hormonal therapies, including aromatase inhibitors (AIs) in postmenopausal women with breast cancer and androgen deprivation therapy in men with prostate cancer, decrease circulating levels of estrogen and testosterone. This reduction in hormones accelerates bone loss and contributes to the development and more rapid progression of osteoporosis. Glucocorticoids and other chemotherapy agents used in cancer treatment may also contribute to accelerated bone loss (Pfeilschifter & Diel, 2000).
Preventive strategies and treatments for osteoporosis are most effective when started early. Older adults receiving hormonal therapies and other cancer treatments that cause bone loss should undergo a baseline bone density assessment using dual-energy absorptiometry before starting treatment. Follow-up assessments should be conducted annually (Hillner et al., 2003) Calcium and vitamin D supplementation should be implemented unless there is a contraindication (e.g., hypercalcemia). The pharmacological treatment for osteoporosis includes using oral or intravenous bisphosphonates, selective estrogen receptor modifiers (e.g., tamoxifen [Nolvadex®], raloxifen [Evista®]), and calcitonin (van London, Taxel, & Van Poznak, 2008. Other lifestyle changes, such as smoking cessation, moderate alcohol use, limited caffeine intake, and engagement in weight-bearing exercise and resistance training, promote bone health and slow bone loss (Limburg, 2007; Maxwell & Viale, 2005).
Aromatase Inhibitor-Induced Arthralgias. Increasingly, AIs are being used in postmenopausal women with estrogen receptor-positive breast cancer. Women taking AIs for breast cancer treatment experience musculoskeletal side effects, including joint pain and stiffness (Altundag, Dede, Harputluoglu, & Gullu, 2007; Crew et al., 2007). AI arthralgias can affect the hands, knees, hips, lower back, and shoulders. Women previously treated with taxanes are more likely to experience musculoskeletal symptoms. Joint symptoms contribute to nonadherence and discontinuation of AIs. Anti-inflammatory drugs and opioid analgesics may be used to treat arthralgias. Adjuvant treatments, such as heat and ice or acupuncture, should be considered. Exercise is commonly used to treat osteoarthritis. Regular exercise and weight control may be helpful in managing arthralgias related to AIs (Winters, Habin, & Gallagher, 2007).