Mr. D is an 80-year-old man who has been diagnosed with stage IV prostate cancer, with metastatic disease to the bones. He has a history of chronic arthritis and diabetes. His blood sugar is not optimally controlled, and he has had two recent visits to the emergency department for uncontrolled blood glucose. Over the years, as a result of his uncontrolled diabetes, Mr. D gradually developed diabetic peripheral neuropathy, and he uses a walker to help with ambulation. The neuropathy has interfered significantly with his functional status, and he relies on a niece who lives close by to shop for food and everyday essentials. His wife died six months ago, and he admits that he is still mourning his loss. He also reports that he is “exhausted,” “tired to the bone,” and is just “worn out.” Mr. D has agreed to participate in a clinical trial testing a new chemotherapy to treat his prostate cancer.
This case study illustrates the multiple factors influencing cancer fatigue in the elderly. Cancer is a disease affecting predominantly older persons, with incidence and prevalence increasing with age. In addition to cancer, many older persons have comorbid medical conditions (e.g., cardiomyopathies, diabetes, depression) rendering them more susceptible to illness and treatment and limiting their functional capacities. Fatigue from cancer and/or its treatment is the most commonly reported symptom by older cancer patients and affects 70% to 100% of those receiving treatment for cancer. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning. This chapter discusses the current evidence regarding cancer-related fatigue in the elderly and provides recommendations for the assessment and management of this distressing symptom in the elderly cancer population.
Etiology of Cancer-Related Fatigue
To date, the mechanisms and pathophysiology of CRF are largely unknown, although many studies have attempted to describe possible etiology and mechanisms related to its manifestation in cancer patients. Possible CRF mechanisms include cytokine production (i.e., IL-6), abnormal serotonin regulation, neuromuscular dysfunction, and abnormal levels of muscle metabolites. CRF may also be caused by treatments such as chemotherapy, radiation therapy, bone marrow transplantation, biological response modifiers, or contributing factors such as pain, emotional distress, anemia, altered nutritional status, sleep disturbance, decreased activity, and comorbidities. CRF is thought to have peripheral as well as central components as its biologic basis. Peripheral components are those factors that cause negative energy balance that result in fatigue. Factors that contribute to this negative energy balance include cancer, cancer treatments, systemic infections, hypothyroidism, anemia, malnutrition, metabolic abnormalities, sleep disorders, and psychological factors (depression, anxiety). Central components include hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, and increases in immunologic factors and cytokines (T lymphocytes, IL-1 antagonists, tumor necrosis factor receptor II). All of these potential components of CRF are important in elderly cancer patients, and may contribute to the etiology of CRF in this older population.
Cancer-Related Fatigue Across the Domains of Quality of Life
CRF affects all aspects of the patient’s quality of life (QOL) and can persist 5 to 10 years after completion of treatment. The impact on the patient’s physical functioning is exceptionally distressing and has been reported as being more distressing than pain or nausea.
CRF affects physical functioning and can be very debilitating. For the general geriatric population, the need for assistance with activities of daily living (ADLs) and instrumental activities of daily living (IADLs) is an independent predictor of morbidity and mortality. The older cancer patient is more likely to have functional limitations in ADLs than the general elderly population. For many patients, physical activity levels decrease during and after treatment, with some patients not returning to prior treatment levels. This can lead to a cycle of declining physical activity leading to increased fatigue, which leads to further decreased conditioning, and increased weakness and fatigue during any physical activity.
Luciani and colleagues conducted a retrospective cross-sectional study of 214 patients aged 70 or older, seen over the course of 3 months in their Senior Adult Oncology Program. Patients were screened with a questionnaire assessing ADLs, IADLs, performance status (PS), cognitive impairment, depression, and malnutrition. In addition, each patient was assessed for fatigue using the Fatigue Symptom Inventory that measures four aspects of fatigue: severity, frequency, daily patterns of fatigue, and interference with daily activities; complete blood counts and chemical panels were also obtained. Eighty-one percent of the patients reported fatigue and the interference score of fatigue was a probable mediator for dependencies in ADLs (p < 0.001) and IADLs (p < 0.001), and poorer PS (p < 0.001). Data revealed a correlation between severity, interference, and frequency of fatigue and depression, but only hemoglobin level partially correlated with fatigue. Anemia correlated with decreased functional status. All fatigue dimensions were significantly associated with ADL and IADL dependencies and with the Geriatric Depression Scale. The authors concluded that fatigue in the elderly could represent a long-term complication of cancer and cancer treatment that may accelerate functional decline.
Comorbid conditions in the older cancer patient are also causes of morbidity and mortality, affecting life expectancy, tolerance to treatment, and quality of life. Those older than 65 years have an average of three comorbidities, with the most common being cardiovascular disease, hypertension, COPD, arthritis, and depression. Comorbidities were found to be a prevailing issue among 867 elderly patients with newly diagnosed breast, prostate, lung, or colorectal cancer. Kozachik and Bandeen-Roche conducted a secondary analysis on this population and followed the patients at four points in time (6 to 8 weeks, 12 to 16 weeks, 24 weeks, and 52 weeks) during the year after their diagnosis. The patients also completed a demographic questionnaire, the Comorbidity Index, and the Patient Symptom Experience. The researchers sought to determine whether the patient’s sex, age, comorbidity status, cancer site, stage of disease, or treatment regimen predicted patterns of pain, fatigue, and insomnia over time. The mean patient age was 72.6 years, 54% were men, and reported a mean of more than two comorbidities. Twenty-seven percent reported four or more comorbidities. The top four comorbid conditions reported were heart problems (31%), arthritis (20%), high blood pressure (50%), and chronic lung disease (16%). Results revealed that advanced age was not significantly associated with increased patterns of pain, fatigue, and insomnia. Comorbidities were correlated with pain, fatigue, and insomnia only at wave 1 and 4 observation times. Sex was associated with significant risks of reporting fatigue and insomnia or fatigue and pain, with women reporting the most fatigue and sleep disturbance. Treatment modality was associated with significantly increased risks of pain, fatigue, and insomnia. Having late-stage lung cancer and reporting pain, fatigue, and insomnia at wave 2, 3, and 4 observation times were significantly associated with death.
The psychological impact of CRF in older cancer patients can greatly diminish their quality of life. CRF affects the patient’s social activities, leisure time, and responsibilities. There is debate as to whether a correlation exists between fatigue and depression. However, depression occurs in approximately 20% to 50% of patients with cancer. It is the most common psychiatric disorder among cancer patients and yet is frequently undiagnosed because of the oftentimes coexistent symptoms from cancer and/or cancer treatment, such as fatigue, pain, and appetite loss. As in the aforementioned case study, depression and grief for this elderly patient are important considerations in a plan of care.
Hwang, Chang, Rue, and Kasimis assessed multidimensional independent predictors of cancer-related fatigue and found that dyspnea, pain, lack of appetite, feeling drowsy, feeling sad, and feeling irritable predicted fatigue independently. Physical and psychological symptoms predict fatigue independently in the multidimensional model and superseded laboratory data. Liao and Ferrell assessed fatigue in the elderly and found a significant relationship between fatigue and depression, pain, number of medications, and physical function. Respini and colleagues found that fatigue correlated with depression in older cancer patients to a degree comparable to that in younger patients. This study assessed the prevalence and correlates of fatigue in 77 cancer patients aged 60 or older during outpatient treatment with chemotherapy or pamidronate. An older study conducted by Hickie and colleagues examined the prevalence and sociodemographic and psychiatric correlates of prolonged fatigue syndromes of 1593 patients attending four general primary care practice settings. Twenty-five percent reported prolonged fatigue and 37% had a psychological disorder. Of the 25% with fatigue, 70% had both fatigue and psychological disorder, while 30% had fatigue only. Data revealed that patients with fatigue were more likely to also have a depressive disorder. The literature clearly shows the interrelationship between fatigue and psychological disorders.
Fatigue Assessment
Mr. D comes to the clinic today for his third course of treatment and reports that he has been “very tired” for the past week, and that he is unable to perform some activities of daily living, such as buying groceries and cooking. When asked to rate his fatigue intensity over the past 7 days, he reports that it is a 6 out of 10. According to Mr. D’s subjective rating, he is currently suffering from moderate fatigue. His oncologist initiated a more focused fatigue history and examination in addition to a comprehensive geriatric assessment. Mr. D was queried about the onset, pattern, and duration of his fatigue over the past 7 days. While conducting a thorough assessment of treatable contributing factors, his oncologist focused on Mr. D’s two comorbidities: chronic arthritis and diabetes, as well as bereavement from his wife’s recent death. On the basis of this medical history, the oncologist focused his queries around factors related to the comorbidities that may be contributing or exacerbating Mr. D’s CRF: uncontrolled pain from his chronic arthritis and neuropathy, his activity level, his nutritional status, possible depression secondary to complicated bereavement, and possible anemia secondary to three courses of clinical trial treatment. Mr. D admits that the pain related to his chronic arthritis has been flaring recently, and that his activity level has been low. He also reports that he has been unable to sleep at night because of the arthritis flare-ups.
An essential component of managing CRF in the elderly is a thorough assessment. First, comorbidities need to be assessed and addressed to determine other factors that may be contributing to fatigue related to cancer treatments. Elderly patients with a history of diabetes or other comorbidities may be at higher risk for experiencing debilitating fatigue if treatment is planned. After assessing for comorbidities, patients should be asked to rate their fatigue level on a numerical analog scale (0-10). The NCCN guidelines recommend the following cut-offs for fatigue severity: 0 to 3 for “none to mild,” 4 to 6 for “moderate,” and 7 to 10 for “severe.” The guidelines recommend that all patients with a reported fatigue severity of moderate to severe intensity should be assessed using a focused history and examination to pinpoint treatable causes. Treatable causes include anemia, pain, insomnia, malnutrition, and emotional distress. Finally, any referrals made to supportive care experts such as a dietician, rehabilitation, social work, psychology/psychiatry, or support groups should be documented. The NCCN guidelines recommend using an interdisciplinary model for managing CRF.
Mr. D comes to the clinic today for his third course of treatment and reports that he has been “very tired” for the past week, and that he is unable to perform some activities of daily living, such as buying groceries and cooking. When asked to rate his fatigue intensity over the past 7 days, he reports that it is a 6 out of 10. According to Mr. D’s subjective rating, he is currently suffering from moderate fatigue. His oncologist initiated a more focused fatigue history and examination in addition to a comprehensive geriatric assessment. Mr. D was queried about the onset, pattern, and duration of his fatigue over the past 7 days. While conducting a thorough assessment of treatable contributing factors, his oncologist focused on Mr. D’s two comorbidities: chronic arthritis and diabetes, as well as bereavement from his wife’s recent death. On the basis of this medical history, the oncologist focused his queries around factors related to the comorbidities that may be contributing or exacerbating Mr. D’s CRF: uncontrolled pain from his chronic arthritis and neuropathy, his activity level, his nutritional status, possible depression secondary to complicated bereavement, and possible anemia secondary to three courses of clinical trial treatment. Mr. D admits that the pain related to his chronic arthritis has been flaring recently, and that his activity level has been low. He also reports that he has been unable to sleep at night because of the arthritis flare-ups.
Fatigue Management
On the basis of Mr. D’s CRF assessment, referrals to supportive care experts such as a dietician, physical therapist, psychologist, social worker, and pain specialist were considered in order to manage the treatable causes. An endocrinologist was also consulted to assess whether Mr. D’s diabetes continues to be poorly controlled. Mr. D was given patient education materials that included information about CRF and its management. His nurse discussed the education material, including strategies of fatigue management such as energy conservation and physical activity. His oncologist also discussed the use of medications such as Ritalin to manage his CRF, but Mr. D declines because he doesn’t want to have to take another “pill.”
Pharmacologic
A number of pharmacologic agents have been evaluated for the treatment of cancer-related fatigue. The class of pharmacologic agents that shows the most promise in managing cancer-related fatigue is psychostimulants, which are known to increase level of alertness and motivation. Methylphenidate has been evaluated in HIV patients and advanced cancer patients. In a pilot study by Bruera and colleagues, an improvement was shown in general well-being and depression, as well as in fatigue scores as measured by the FACIT-F. Because of the rapid onset of action and short half-life of methylphenidate, a subsequent double-blind, randomized, placebo-controlled trial by Bruera and colleagues tested a patient-controlled methylphenidate protocol for patients with a self-reported fatigue intensity of 4 or more as measured by the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F). The dosage tested in this study was methylphenidate 5 mg or placebo every 2 hours as needed, up to four tablets per day, with fatigue assessment at day 8, 15, and 36. Fatigue intensity decreased significantly at day 8 in both groups, but there was no significant difference in fatigue improvement. However, in the open-label phase, a significant improvement in fatigue was found between groups, and was sustained through days 15 and 36. It was unclear whether the extended improvement during the open-label phase was an independent result or due to placebo effect. Although there is evidence on a preliminary level to support the effectiveness of psychostimulants for the treatment of cancer-related fatigue, some caution needs to be taken, particularly for geriatric oncology patients. Because of the rapid onset of these agents, as well as their behavioral effects and tolerance issues, there is an increased risk for side effects. The most common side effects of psychostimulants include agitation and insomnia, which may cause more harm than benefit for elderly cancer patients. Cardiovascular side effects such as hypertension, palpitations, arrhythmias, as well as confusion, psychosis, and tremors are rare side effects, but again may be potentially dangerous for elderly cancer patients. These common and potential side effects limit the use of this class of agents for elderly cancer patients because of contraindications for cardiovascular and other comorbid conditions.
Modafinil has been tested as a fatigue treatment option. In a study of breast cancer survivors, Morrow and colleagues reported an 86% reduction of fatigue intensity with a modafinil dosage of 200 mg per day. Donepezil, an agent used in the treatment of Alzheimer dementia, was evaluated by Bruera and colleagues in a double-blind placebo-controlled trial of donepezil 5 mg per day compared to placebo. The study results were negative, with no statistically significant difference shown between groups. Toxicities are also a problem for this drug including nausea, vomiting, diarrhea, muscle and abdominal cramps, and anorexia, which may limit its use in the geriatric oncology setting. Studies exploring the use of antidepressants as a possible mechanism for managing fatigue demonstrated no differences in fatigue scores.
Nonpharmacologic
A number of systematic reviews and one Cochrane review have been undertaken to examine the efficacy of nonpharmacologic strategies, such as exercise, in fatigue management. A detailed assessment by a rehabilitation expert such as a physical therapist should be accessed, if available, in order to prescribe a comprehensive and safe exercise regimen. The prescribed exercise regimen should be initiated gradually and at a pace based on the individual’s capabilities. Table 17-1 provides an outline of key concepts to be included in patient education for CRF. The outline includes education points on what fatigue is, common causes of fatigue, common words used to describe fatigue, what patients should tell their clinicians about fatigue, energy conservation principles, and the principles of exercise.
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There are several treatable causes that have an impact on CRF. Nutrition is one that is of particular importance for the elderly cancer patient. Geriatric patients in general may also be at higher risk for malnutrition. Potential reasons include more difficulty accessing healthy food items, poorly fitted dentures, or inability to prepare healthy meals secondary to functional limits. Geriatric oncology patients may be particularly at risk because of gastrointestinal side effects (nausea, diarrhea) and poor appetite secondary to cancer treatment. It is important in oncology to stress the importance of optimizing nutrition, particularly in relation to fatigue management. Patients should be provided with adequate information on potential side effects so they are aware of what to expect during treatment. If unable to eat regularly, patients can be advised to switch their eating habits from three large meals per day to six smaller meals spread throughout the day. The importance of maintaining adequate fluid intake should be emphasized, unless contraindicated. Finally, if available, referrals to nutrition experts such as dieticians should be initiated to aid elderly patients with optimizing their nutrition as a strategy for fatigue management.
Another treatable cause that may aggravate CRF is sleep deprivation. As a result of the natural course of aging, the length and quality of REM sleep decreases as the aging process continues. Elderly cancer patients may be at higher risk for greater sleep disturbance. Patients can be instructed on the principles of sleep hygiene. These principles include the avoidance of caffeinated drinks or intense exercises before going to bed. Maintaining a dark, cool, and quiet sleep environment may help with inducing and enhancing sleep. If possible, patients should be strongly encouraged to limit their daily nap times to no more than two 60-minute naps per day. This strategy will help in maintaining the quality of nighttime sleep. Relaxation or sleep-inducing strategies, such as warm baths, milk, or soothing music, can be used.
Stress-management strategies, such as meditation, massage, or muscle relaxation, may also be used to manage cancer-related fatigue. Any contributing factors, such as anxiety, should be addressed by supportive care experts and assessed as a possible contributor to sleep disturbance. Patients should be assessed for any other symptoms, such as uncontrolled pain, that may be interfering with the quality of sleep. Maintaining physical activity during the day may help with promoting sleep at night, and patients should be encouraged to remain as active as possible. Finally, if pharmacologic intervention is warranted, clinicians can discuss the various options available either over the counter or prescribed and, together with the patient, a pharmacologic agent should be chosen that will provide the greatest benefit without debilitating side effects.
On the basis of Mr. D’s CRF assessment, referrals to supportive care experts such as a dietician, physical therapist, psychologist, social worker, and pain specialist were considered in order to manage the treatable causes. An endocrinologist was also consulted to assess whether Mr. D’s diabetes continues to be poorly controlled. Mr. D was given patient education materials that included information about CRF and its management. His nurse discussed the education material, including strategies of fatigue management such as energy conservation and physical activity. His oncologist also discussed the use of medications such as Ritalin to manage his CRF, but Mr. D declines because he doesn’t want to have to take another “pill.”
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