Fighting Cancer Fatigue

Although cancer-related fatigue is a common problem, it is still not well understood, say the experts interviewed for this article. Cancer fatigue is multifactorial, encompassing anemia, cachexia, and other disease-related and treatment-related factors, as well as depression, anger, and anxiety. Investigators are just beginning to tease out the various mechanisms involved in fatigue, and there is no consensus on how to assess or treat fatigue. “Assessment of fatigue is variable, practice patterns among oncologists who treat fatigue are variable, and we have a long way to go until we have standard treatment and assessment,” stated Michael Fisch, MD, Assistant Professor in the Department of Palliative Care and Rehabilitation Medicine at the University of Texas M.D. Anderson Cancer Center.Figure: Michael Fisch, MD: “Fatigue is often the ‘card’ that symptomatic cancer patients play initially while they are trying to find trust in their providers and preserve their dignity.”Another investigator emphasized that physical factors could be causing fatigue—i.e., reduced red blood cell count, lowered thyroid hormone, and impaired kidney and liver function: “When treating a patient with fatigue, the patient should be assessed to exclude these or other medical conditions that could be causing the fatigue,” said Fernando Dimeo, MD, a sports physician with the Institute of Sports Medicine at Charite University Hospital in Berlin, Germany. “There is no doubt that fatigue is more profound than just correcting anemia. Anemia is one factor in a multifactorial model of fatigue,” stated Eduardo Bruera, MD, Professor and Chair of the Department of Palliative Care and Rehabilitation Medicine at M.D. Anderson Cancer Center. Assessment, Assessment, Assessment A common theme to emerge in interviews for this article was the need for a thorough assessment to rule out other factors that might be causing fatigue. Dr. Fisch proposed the notion that sometimes a “symptom masquerade” occurs where the expressed symptom is fatigue, but the significant underlying problem is some other specific symptom such as pain or anxiety. For example, continued Dr. Fisch, an older patient with prostate cancer and widespread bone metastases is taking no analgesic medications and reports that he does not have any pain but says he has overwhelming fatigue. On testing, his hemoglobin (Hb) is in the normal range. “In this situation, the patient is reluctant to be stigmatized as ‘wimpy’ or depressed, but fatigue is an acceptable way for him to discuss his distress,” Dr. Fisch said. “Fatigue is often the ‘card’ that symptomatic cancer patients play initially while they are trying to find trust in their providers and preserve their dignity.” In situations like the one Dr. Fisch described, he will explain to the patient that medications commonly used for pain control may help resolve this kind of severe fatigue. He might say, “I think I can help you with this prescription. Let's give it a short-term trial and see if it helps your energy level.” “Often, you see dramatic improvement in fatigue in this circumstance,” he noted. Symptom masquerade may contribute to the variation in results of studies of treatment approaches to fatigue, he continued. This underscores the need for thorough assessment of fatigue. “Assess them, assess them, and assess them more,” Dr. Fisch emphasized. Aside from pain, a number of factors could be operative, including guilt, depression, anxiety, change in body image, and illness-related physical factors. Preliminary research is under way at several centers to try to identify which factors are operative in cancer-related fatigue. A study by a group in Copenhagen has utilized a multidimensional instrument to characterize different aspects of fatigue, including physical and mental fatigue, reduced motivation, and reduced activity in patients admitted to specialized palliative care. Although the details are not yet available, the study is expected to be published soon. Lead investigator Mogens Groenvold, MD, of the Department of Palliative Medicine at Bispebjerg University Hospital, said that it is important to find out which kinds of fatigue characterize different groups of patients. “For example, even though the intensity of fatigue may be the same, the nature of fatigue following chemotherapy and radiation may be different,” he explained. “The same is the case for newly diagnosed patients undergoing intensive treatment versus patients with fatigue mainly resulting from advanced disease. Taking the nature of the patient's fatigue into account when planning treatment has the potential to improve the outcome.” Depression, Fatigue, or Both? Assessment of the patient with cancer-related fatigue should include a differential diagnosis of depression, a distinction that has important treatment implications, said William Breitbart, MD, Chief of the Psychiatry Service at Memorial Sloan-Kettering Cancer Center. “The problem is that both depression and fatigue share symptoms, and fatigue can be a symptom of depression. Most people think of fatigue as being physically tired. Cancer-related fatigue encompasses mental exhaustion and symptoms such as irritability, moodiness, and ‘feeling down.’ It can be difficult to differentiate between cancer-related fatigue with symptoms related to attention/concentration and mood or depression with fatigue as a symptom.” Both fatigue and depression are common complications of cancer and cancer treatment, and both increase as the disease progresses. “They may coexist, which complicates therapy,” Dr. Breitbart noted. Antidepressants will not help cancer-related fatigue, but they will help cancer-related depression. Fatigue is more common than depression, occurring in about 40% of patients with all stages of cancer. Depression, occurring in about 15% of cancer patients, is more likely to be found in patients with a past history of depression. Check Sleeping Patterns Dr. Breitbart said it is helpful to evaluate sleeping patterns in patients who present with fatigue and depression. Patients can be tired from sleeping too much or too little. Antidepressants plus a stimulant such as methylphenidate or modafinil are useful in the former group, and antidepressants and a drug to target insomnia, such as zolpidem tartrate, may be helpful in the latter group, he noted. Also, methylphenidate and modafinil are “good antidepressants and sometimes work in both depression and fatigue.” The take-home message, he said, is to make an accurate diagnosis in patients who present with fatigue: “Depression can be treated. Differentiation of fatigue from depression can guide therapy. When you can't differentiate between the two, psychostimulants can be useful for both.” Ongoing Study of Fatigue in Prostate Cancer Patients Treated with Hormone Therapy Dr. Breitbart and colleagues are currently conducting an NCI-sponsored study in patients with prostate cancer treated with hormone therapy who have cancer-related fatigue. Patients with depression, as diagnosed by SCID (Structured Interview for Depression), were excluded from participation. Three different interventions are being compared as treatment of cancer-related fatigue: methylphenidate versus modafinil versus placebo. “Modafinil is a drug that promotes wakefulness. It may be more acceptable to oncologists than methylphenidate because it is safer, does not result in dependence, does not increase heart rate and blood pressure, and you don't need a triplicate prescription for it,” he explained. The same group of investigators previously studied methylphenidate versus pemoline versus placebo for AIDS-related fatigue. Results showed that both active agents significantly improved fatigue, functional ability, quality of life, and cognition. The study excluded patients with a diagnosis of depression. Benefits of Exercise Oncologists don't routinely prescribe exercise for cancer-related fatigue. This is partly because on the surface it would seem like rest should help fatigue and that exercise might exhaust patients even further. However, a growing body of evidence suggests that exercise in fact reduces cancer-related fatigue and may have additional benefits. For example, Dr. Dimeo and colleagues have conducted six studies of endurance training in cancer patients, which consists of 20 to 30 minutes or more of aerobic exercise using large muscle groups in a rhythmical way. Most of the studies have utilized the treadmill, controlled for speed and heart rate at different settings.Figure: William Breitbart, MD: “It can be difficult to differentiate between cancer-related fatigue with symptoms related to attention/concentration and mood or depression with fatigue as a symptom.”The first pilot study included patients who had undergone bone marrow transplantation, and the second included cancer patients with chronic fatigue. The same group of investigators also conducted four randomized controlled trials of endurance training with fatigue as the primary endpoint (three in patients after high-dose autologous blood stem cell transplantation and one in patients with solid tumors):Figure: Kerry S. Courneya, PhD, said that with the results of studies supporting the role of exercise in cancer-related fatigue, he hopes that the information will filter down to those working with cancer patients on the front lines of therapy, such as physical therapists and nutritionists. ONS, he noted, has recognized the importance of exercise in reducing fatigue, and he said he hopes that oncologists will become aware of the studies and advise their patients with fatigue to exercise. ▪ The first compared physical activity versus placebo. ▪ The second compared physical activity versus relaxation techniques. ▪ An ongoing study is comparing physical activity versus behavioral psychotherapy. Other endpoints of the randomized controlled trials include bone marrow regeneration following chemotherapy and heart function and the incidence of complications following high-dose chemotherapy. The randomized trials and the pilot trials included a total of 200 patients; the patient populations included leukemia and lymphoma patients post bone marrow transplantation; patients with solid tumors post-surgery; and cancer patients with diverse diagnoses suffering from chronic fatigue. “We observed that most outcomes were better following exercise training,” Dr. Dimeo said. “There was a faster reconstitution of bone marrow function after chemotherapy, and less chemotherapy-related complications, including pain, diarrhea, and need for platelet transfusions.” These results imply that exercise not only reduces fatigue but also may have beneficial effects that extend beyond fatigue. “I don't want to be too optimistic. Let's just say there is growing evidence that cancer patients, during and after therapy, should not avoid physical activity,” he said. “Exercise is contraindicated in very few situations, such as bone instability or pain, and if physical activity is not contraindicated, patients should exercise regularly. Our studies suggest that the effects of exercise are not limited to just physical performance, but may also reduce treatment-related complications.” Additional Evidence for Exercise “The positive results of exercise are counterintuitive,” noted Kerry S. Courneya, PhD, Professor and CIHR Investigator at the University of Alberta in Edmonton, Canada, who is also involved in studies of exercise in cancer patients. He is lead author of one study and coauthor of a second showing that aerobic exercise reduces cancer-related fatigue after and during treatment, respectively (J Clin Oncol 2003 May 1;21:1660–1668; and Segal et al: J Clin Oncol 2003; May 1;21:1653–1659). The first study included 53 breast cancer survivors who completed chemotherapy and/or radiation prior to entering the study. Patients were randomized to either an aerobic intervention (i.e., stationary bike exercise for 20 minutes three days a week at 60% of maximum heart rate) or rest for 15 weeks. In the intervention group, exercise was intensified over the course of the study to 45-minute sessions three times a week conducted at 75% of maximum heart rate. Improvement in fatigue was assessed using the FACT (Functional Assessment of Cancer Therapy) self-report scale. Each item on the scale is scored 0–4, with 0 signifying not at all tired and 4 meaning very tired. Patients who exercised reported a median seven-point improvement in fatigue, whereas no change in fatigue was observed in the control group. A three-point change in score is regarded as clinically important, noted Dr. Courneya, so this was a robust result. The second study included 155 patients with prostate cancer who were undergoing hormone therapy at the time of the study. Patients were randomized to either a weight-training program three times a week for 12 weeks consisting of nine different exercises for large and small muscle groups or no exercise. Dr. Courneya noted that prostate cancer patients with bone metastasis often have muscle wasting and that is why he and his colleagues chose to study weight training in these patients. The group who exercised had a median three-point change on the FACT fatigue scale, whereas no change in fatigue was observed in the control group. “The three-point change was not as robust as the change in the breast cancer patients, but it is definitely clinically important,” Dr. Courneya said. “We are not sure why the magnitude of change was smaller in the prostate cancer study. But these were two different cancer populations, different interventions were used, and one study included patients who were off treatment while the other included those on treatment.”Figure: Charles Loprinzi, MD: “Out of 15 to 20 randomized, placebo-controlled trials, virtually all have shown that corticosteroids or progestational agents can benefit patients with cancer anorexia/cachexia by stimulating appetite. Nonetheless, these drugs do not work as well or for as long as is desirable and they are thus less than optimal therapies. The search for better therapies for this clinical problem continues.”“It was a surprise to see that exercise improved fatigue. In both studies, the primary endpoint was quality of life. We were hoping to show that exercise does not increase fatigue but does improve quality of life. The results showed actual reductions in fatigue.” With the results of these two studies, as well as other recent studies to support the role of exercise in cancer-related fatigue, Dr. Courneya is hopeful that this information will “filter down to people working with cancer patients on the front lines of therapy, like physical therapists and nutritionists.” The Oncology Nursing Society, he noted, has recognized the importance of exercise in reducing fatigue, and he said he hopes that oncologists will become aware of these studies and advise their patients with fatigue to exercise. Cachexia & Fatigue Cachexia is one of several factors that are associated with fatigue in patients with advanced cancer, noted Charles Loprinzi, MD, Professor of Oncology at the Mayo Clinic and Principal Investigator of the North Central Cancer Treatment Group Community Cancer Oncology Program Research Base. “The question is: If we reverse cachexia, will that reverse fatigue?” Out of 15 to 20 randomized, placebo-controlled trials, virtually all of them have shown that corticosteroids (such as dexamethasone) or progestational agents (such as megestrol or medroxyprogesterone) can be of benefit in patients with cancer anorexia/cachexia by stimulating patients' appetites, Dr. Loprinzi commented. “Nonetheless, these drugs do not work as well or for as long as is desirable and they are thus less than optimal therapies. The search for better therapies for this clinical problem continues.” Furthermore, it is not known whether these treatments for anorexia/cachexia actually improve fatigue, he added. Total parenteral nutrition (TPN) is another treatment that has been studied in cachexia, but results have been disappointing in most patients and suggest that this approach can cause more harm than benefit in most patients with anorexia/cachexia, he said. In support of this contention are randomized controlled trials of TPN that failed to show any improvement in survival and quality of life with this treatment, but rather have demonstrated a tendency for poorer outcomes in these patients, he said. Ginseng as a Potential Antidote A small placebo-controlled study presented at last year's ASCO Annual Meeting suggested that ginseng can improve fatigue in cancer patients. Dr. Charles Loprinzi said the study encouraged North Central Cancer Treatment Group investigators to sponsor a larger, more definitive, placebo-controlled trial of ginseng for treatment of cancer-related fatigue. The NCI has approved this study concept, and he hopes that patient accrual to the trial will be able to start sometime this year. Erythropoietin & Fatigue Studies have shown that erythropoietin is effective for cancer-related anemia in patients on myelosuppressive chemotherapy; in these studies, quality of life and fatigue also improved with erythropoietin, although these were not primary endpoints. Other evidence suggests that when hemoglobin is increased, fatigue improves, Dr. Michael Fisch said. “Some oncologists are using erythropoietin to treat fatigue [as distinct from anemia], because there is clinically evident subjective improvement in patients, but one could be skeptical about this practice.” It is not known whether erythropoietin actually improves fatigue in patients who are not taking myelosuppressive chemotherapy. To explore this question, he and Dr. Eduardo Bruera are currently conducting a preliminary community-based study through the M.D. Anderson Community Clinical Oncology Program (CCOP) to compare erythropoietin with placebo in patients with cancer-related fatigue who are not taking myelosuppressive chemotherapy. “No research has been conducted so far with fatigue as the primary endpoint in studies of erythropoietin,” Dr. Fisch explained. Guidelines from ASCO and ASH in 2002 stated that the evidence for use of erythropoietin to treat cancer-related fatigue is weak, which is one of the reasons Dr. Fisch and colleagues are conducting their study. Planned enrollment is 128 patients, and this is not a registration trial for a new indication for erythropoietin therapy, he said. “If these results are positive, further research with a larger sample of patients may be worthwhile.” Fatigue, the primary endpoint of this study, will be assessed by the LASA (Linear Analog Scale Assessment), an instrument that evaluates quality of life. Results will show the proportion of patients whose energy level and quality of life is significantly improved as a result of erythropoietin. The study population will include cancer patients who have bothersome fatigue by self-report and Hb in a range of 8.5 to 11 g/dl. Patients with solid tumors of Stage III or IV, but who are not undergoing chemotherapy or radiotherapy, will be treated with either 60,000 IU erythropoietin per week or placebo. Shortly after accrual was begun, reports of venous thromboembolism in some patients treated with erythropoietin necessitated stopping the study and amending the dosing protocol to set more conservative parameters about the rate of rise and the upper boundary of Hb level, Dr. Fisch noted. The new protocol states that if Hb goes above 13 g/dl the drug will be withheld until Hb drops to 11 (the upper limit in the previous protocol was Hb 15). The rate at which Hb rises is changed as well; if Hb greater than 1g in a two-week period, the dose will be reduced to 40,000 IU per week. Patients will be treated for six weeks and assessed weekly by LASA and questionnaire items about pain, fatigue, depression, and other symptoms, as well as a few assessments that involve verbal descriptors related to fatigue, depressed mood, and anhedonia. If no response is observed, open-label erythropoietin will be given for another six weeks. “This is a fairness issue,” Dr. Fisch said. “We think people whose fatigue has not improved should get the opportunity to receive open-label treatment with erythropoietin [rather than the possibility of placebo treatment] if they so desire.” Because the study is blinded, patients who don't improve won't know if they were in the placebo or treated group. Thus, some non-responding patients may receive erythropoietin for the initial six weeks and then for another six weeks in the open-label portion of the study. Accrual should be complete in the next 18 to 24 months, he said, and results should provide information about whether there is improvement in fatigue with a generous dose of erythropoietin as well as the safety of this agent. “The results of this study, whether positive or negative, will help us determine the next step in the direction of this research,” Dr. Fisch said.—A.G.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.