Abstract: Anemia is one cause of cancer-related fatigue, but the perception nowadays might be that it is the principal cause of the condition because of numerous recent clinical studies focusing on fatigue due to anemia and the appropriate pharmacological treatment. But fatigue is notoriously multifactorial, and oncologists should also consider the many other elements that might be making their patients' lives unmanageable. Improving sleep hygiene, treating electrolyte imbalance, adjusting pain medication, and promoting exercise are a few of the measures now available. And as research uncovers more of the biochemical causes of fatigue, new treatments will certainly be in the offing. Fatigue is reported to occur in 40 to 84 percent of cancer patients, and in some cases, lasts years after treatment. This went unrecognized, however, for many years until other symptoms such as pain and nausea and vomiting became better controlled. One might say that awareness of cancer-related fatigue is at the stage that cancer-related pain control was five to eight years ago. The Fatigue Coalition, a multidisciplinary group of medical practitioners, researchers, and patient advocates, produced two large studies in recent years that identified fatigue as the overwhelmingly untreated and overwhelmingly important symptom that cancer patients face today. “We found that fatigue is pervasive and profound, and that it far outranks pain, nausea and vomiting, and depression in terms of being the most bothersome and long lasting,” said Fatigue Coalition member Gregory A. Curt, MD, Clinical Director of the National Cancer Institute. The Coalition studies also found that fatigue is rarely discussed by patients and clinicians and is infrequently treated. Half of all patients surveyed said they did not discuss treatment for fatigue with their physicians, and only 27 percent received recommendations about fatigue from their physicians.Figure: Andrea Barsevick, RN, DNScFigure: Gregory A. Curt, MDFigure: Eduardo Bruera, MDEducate First Another fatigue expert, Andrea Barsevick, RN, DNSc, Director of Nursing Research at Fox Chase Cancer Center in Philadelphia, noted that educated patients are more comfortable talking with their physician about fatigue, which means that it is more likely that measures will be taken to intervene as soon as symptoms begin. And by informing patients about fatigue before it becomes a problem, physicians can prepare them for what to expect and potentially avert fatigue associated with stress and anxiety. “Education is the most powerful tool we have right now for the management of fatigue,” Dr. Barsevick said. “We don't understand all the physiological mechanisms or causes, so at this point we need to educate people about what we do know.” Simply recognizing what is going to happen can help patients handle fatigue, said Sharon T. Wilks, MD, a hematology and medical oncology specialist at San Antonio Tumor and Blood Clinic in San Antonio, TX. “If patients expect fatigue and know it is part of the Process, they can adjust and cope with it better.” If fatigue is initially addressed by the physician, the patient is far more likely to bring it up in the conversation as they begin to have symptoms, Dr. Wilks said. But patients are often reluctant to bring it up, she noted. “They worry that fatigue is a sign of recurrence, an untreatable symptom, and so they'll hesitate to talk about it with their physician.” Patients might also assume their fatigue is self-limited, that cancer treatment would be changed or stopped if they complained of fatigue, or that if they complain they would be viewed as making trouble for their caregiver. Assess or Miss Fatigue can be well hidden, so physicians should be ready with some quantifiable, validated means of assessing it. “If you just rely on empathy and use your clinical sense, you are going to miss most of these problems and underestimate how much distress patients are in,” said psychologist Steven Passik, PhD, Director of Oncology Symptom Control Research at Indiana Community Cancer Care in Indianapolis. The fatigue treatment guidelines of the National Comprehensive Cancer Network (NCCN) advise clinicians to screen for fatigue on every initial visit, and periodically thereafter. The first assessment can be as simple as asking patients to rate their fatigue on a scale of 0 to 10, or to describe it as mild, moderate, or severe. When the fatigue is rated 4 and over, or as moderate or severe, the provider should do a more focused history and physical exam. Follow-up assessments can determine whether the fatigue has progressed and whether there have been associated or alleviating factors. According to the NCCN guidelines, it is particularly significant whether fatigue is interfering with daily activities. “The guidelines say that every patient needs to be screened at every encounter with their health care provider,” said Dr. Barsevick, a member of the guidelines panel. “If patients are coming to a radiation therapy department, they should be screened for their fatigue level at every visit. And if they are reporting they are experiencing fatigue, it's up to the practitioner to decide what to do.” In the future, a fatigue assessment might be automated. Dr. Curt noted that much of this work could be done with centralized informatics, with patients entering the data while in the oncologist's waiting room. For a more detailed assessment, Dr. Curt recommends an algorithm developed by Dr. Russell Portenoy of Beth Israel Medical Center in New York City, published in The Oncologist (1999;4:1–10), which determines at the clinical level which common etiologies are involved in the fatigue symptoms and what the best therapeutic approaches might be. As worthy as it might be to do fatigue assessments, some oncologists won't be inclined to find the time, Dr. Curt said. Cancer-related fatigue has baffled many clinicians who have been disappointed trying to control it. At the most recent annual congress of the Oncology Nurse Society, one participant voiced the opinion: “We are all sometimes frustrated by our ‘med/onc’ colleagues who blow off fatigue because they can't fix it.” Dr. Curt agreed with that sentiment. “The reason we don't ask patients about fatigue now, or why I didn't ask a few years ago, is that fatigue was a ‘black box’ diagnosis that had no treatment,” he said. “It was considered a consequence of the disease and the treatment, and we expected that it would go away. But once you get oncologists to ask the question ‘Is fatigue something that is having an impact on your life?,’ and get the patient willing to answer the question because they believe there is something that can be done to alleviate their symptoms, then we will change the whole paradigm.” The proactive approach is applied at the University of Texas MD Anderson Cancer Center in Houston. Eduardo Bruera, MD, Director of the Symptom Control and Palliative Care Center there, said uncomplicated assessments can be done by the patients themselves before entering the doctor's office, and then left in the chart and monitored at each visit. His Care Center uses a multidisciplinary team to assess fatigue and other symptoms for in-patients referred there, but Dr. Bruera said any assessment done by a clinician can be helpful. “Fingers on the hand from one to five or zero to 10, there are very simple ways to assess pain, nausea, lack of appetite, and fatigue that are common in our patients,” he said. “And it can really help out.” Dr. Passik has tested a one-question assessment, asking patients to rate the statement “I get tired for no reason.” “We find it correlates well with the longer measures,” he said. “You might start an assessment with the simplest, fastest measurement, like zero to 10 or a visual analog, and then if someone scores high, you could test the person with one of the better validated scales.” Tumor-Related Fatigue The most common cause of fatigue in the cancer patient may be the tumor itself rather than the therapy, said Daniel D. Von Hoff, MD, Director of the Arizona Cancer Center in Tucson. He said asthenia associated with chemotherapy, biological therapy, or radiation therapy is often blamed for causing severe fatigue, “but contrary to what most doctors would think, studies do not find an association between the weakness and the type of anticancer therapy.” The most likely cancer-related culprit is thought to be the asthenin, a term for any of a number of cytokines that cause fatigue as well as weight loss, loss of muscle function, and anemia. Cachexia is probably also mediated by cytokines secreted from tumors, such as tumor necrosis factor (TNF), interleukins 6 and 8, and C-reactive protein, as well as by the host itself trying to fight the tumor.Figure: Daniel D. Von Hoff, MDFigure: Sharon T. Wilks, MDResearchers in Dr. Von Hoff's laboratory are investigating treatments to stop asthenin production, including Enbrel, a drug used in rheumatoid arthritis, and Remicade, an antibody to TNF. Other researchers are testing thalidomide, the cardiology drug pravastatin, and omega-3-rich fish oil, all of which have effects on cytokines. Available Therapies Removing the tumor would obviously be the best all-around way to cure cancer and tumor-related fatigue, but there are many other causes that can be addressed by prescribing or modifying medications. These include the following: ▪ Opioid pain medications doses can be reduced. ▪ Medications for depression can be reduced or changed. ▪ Proper hydration and nutrition can be maintained. ▪ Acute and chronic infection can be treated. ▪ Abnormalities in blood work, including low sodium and high calcium, can be corrected. Dr. Wilks noted that electrolyte derangement and magnesium and calcium abnormalities due to diarrheal complications or vomiting can be easily detected in a standard blood chemistry panel and corrected in an outpatient visit. “Many times I have found a cancer patient to be hypomagnesemic, and when I could improve that, it helped the fatigue,” she said. ▪ Hemoglobin levels causing weakness can be treated with erythropoietin. Rowena N. Schwartz, PharmD, Coordinator of Pharmacy Services at the University of Pittsburgh Cancer Center, said she does not think of erythropoietin as a treatment for fatigue, but rather as a treatment for anemia that may be causing fatigue. “People assume that erythropoietin is the treatment for fatigue, but people without anemia certainly can be fatigued,” she said. Dr. Wilks added a clinical pearl, noting that since erythropoietin induces red blood cell production, the patient needs to have an adequate level of iron. “Patients can become iron deficient when they are taking Epogen, because the red blood cell production is taking all up the iron stores,” she said. “Sometimes if you see a patient failing to improve on erythropoietin it may be due to acquired iron deficiency.” Attention to Lifestyles Cancer patients may not sleep well because of depression, anxiety, or excessive resting during the day, and this can be changed by modifying sleep habits or with medication, Dr. Wilks said. Choosing a medication to aid sleep depends on the patient's age, as older patients can be more sensitive to sedatives or sleep agents than younger patients. Other changes that can improve fatigue include (1) advising patients to increase their dependence on others for home management, transportation, and other daily needs; (2) educating patients about fatigue and how long it may last; (3) advising patients to balance therapy with valuable activities they enjoy doing; (4) advising patient to have a regular exercise routine; and (5) recommending stress-reduction techniques Other Medications Dr. Bruera listed other medications that can be helpful in relieving fatigue: ▪ Psychostimulants of the methylphenidate amphetamine group (such as Ritalin) can aid patients who are sleepy, especially due to pain medications and to depression. ▪ Corticosteroids can improve the subjective sensation of tiredness and fatigue in patients, but probably not for long periods. ▪ Megestrol acetate has subjective effects on fatigue in patients with cachexia, which has been proven not to be a consequence of the weight gain that produced. ▪ Testosterone: “Hypogonadism is more common in cancer patients than thought, and recent research suggests that pain medications can cause a certain level of hypogonadism,” Dr. Bruera said. “When that is identified, replacement with testosterone and/or estrogens can potentially be useful. Unfortunately no good studies have been done with cancer patients, and you have to be careful about using hormones in a breast or prostate patient, which might aggravate the clinical course of the cancer.” ▪ Depression, psychological distress, or anxiety can be addressed with counseling and medication. Dr. Barsevick believes the vast majority of cancer patients are not depressed, but she said it makes sense to evaluate depression if someone reports symptoms. “With all the medications we have today, a bona fide depression does not need to go untreated.” Some antidepressants may also improve energy levels, so using those before others may be appropriate in treating fatigue. And exercise can improve mood as well as physical well being. Exercise vs Energy Conservation Patients complaining of fatigue have been told for years to refrain from doing tiring things. But lessons learned from treating heart failure, arthritis, and chronic obstructive pulmonary disease show that the opposite may be true. “It makes us [clinicians] feel good to tell patients to conserve their energy, but data from studies in other chronic diseases suggest that when we add inactivity to an already weakened person we further decondition them,” Dr. Bruera said. “Rather than encouraging energy conservation, physicians should promote physical activity. Making people exercise helps them build stamina and might have beneficial effects on their sensation of fatigue.” He said studies are testing the hypothesis that deconditioning of muscles due to inactivity further aggravates that sensation of fatigue and may generate a vicious circle in patients. Long-Term Problem An unexpected finding of the Fatigue Coalition's survey was that the symptoms are long lasting. Former cancer patients who had completed therapy more than two years earlier were still experiencing symptoms of fatigue almost daily, complaining of weakness, trouble concentrating, increased but nonrestorative sleep, a “need to push one's self,” emotional problems attributable to fatigue, and difficulty with memory. These complaints were as common in patients who had completed therapy more than two years before as in those who had completed therapy more recently. Dr. Wilks said she has had patients finish therapy and go into remission, only to return one or two years later saying their energy level was still not what it was before treatment. “What struck me most when I did bone marrow transplants and had the opportunity to see patients annually, was that they would have loss of energy for years after active therapy,” Dr. Wilks said. With nausea and vomiting under control and pain control getting better, fatigue may be the great frontier of supportive care research, Dr. Von Hoff said. That research will be spurred by patients themselves. “Patients brought pain to the forefront, and now they're saying maybe they shouldn't have to put up with fatigue, either,” he said.