This article by Dr. Groopman, a world famous humanitarian and clinical investigator of AIDS and hematologic support growth factors, describes the problem of fatigue in AIDS and cancer patients. Dr. Groopman also summarizes the insidious and understudied aspects of this problem. His statements regarding the disability caused by fatigue and its adverse effects on patients self-confidence, social relationships, employment, and self-care abilities are profound and insightful.
Fatigue does, in fact, affect between 60% and 100% of cancer patients undergoing active chemotherapy. The ability of radiation to induce fatigue is often underestimated by both physicians and patients. In fact, my own experience suggests that radiation produces fatigue virtually 100% of the time. Whether fatigue accompanies the lymphocytopenia of radiation, or whether lymphocytopenia is a marker for fatigue, has not been well analyzed.
Other biomarkers for the presence of fatigue include the sedimentation rate and perhaps loss of the diurnal cortisol rhythm. Such biomarkers of fatigue must be prospectively identified.
Causes of and Treatments for Fatigue
In Table 1, Dr. Groopman lists the causes of fatigue in cancer patients, but he does not include the immunosuppressive effects of cancer and/or HIV. Although the immune hyporeactivity of cancer patients cannot currently be reversed, use of protease inhibitors in AIDS patients may allow for recovery of the immune system, which, in turn, may correlate with an improvement in fatigue.
Likewise, my extensive personal experience with the use of interleukin-2 (Proleukin)-based therapy for renal carcinoma suggests that patients develop severe fatigue during active immunotherapy. In sharp contrast, during the rebound and recovery period of immune function, there is an immediate loss of the sense of fatigue. Again, prospective studies must be performed to track these potential immune markers of fatigue.
The authors Table 2, which outlines a treatment algorithm for the use of erythropoietin(Drug information on erythropoietin) (epoetin alfa [Epogen, Procrit]) in anemic cancer patients, is a table that I personally use as well. Although my initial experience with erythropoietin in cancer patients was negative, that may well have been due to the low doses (5,000 units three times per week) that I was using. My current practice is identical to the algorithm given in Table 2. The value of increasing erythropoetin dose to 20,000 units three times per week is somewhat controversial and is not yet fully supported by prospective data.
Table 1 lists interventions for the treatment of fatigue; these are certainly important for oncologists to carefully review. The most noticeable recommendation is the use of exercise and fitness training. In the article, Dr. Groopman describes the mistaken advice that cancer patients commonly receive to rest and limit their activities. However, such restriction of activities further worsens muscular wasting and reduces functional capacity.
Rather, patients must be placed into rigorous physical rehabilitation programs, if at all feasible, once pain and other complications of cancer therapy are controlled. In fact, Dr. Victoria Mock of Johns Hopkins randomized 50 early-stage breast cancer patients to an exercise program or usual care. In a presentation at the Oncology Nursing Societys 22nd annual meeting, Dr. Mock reported that those randomized to the exercise program had statistically significant improvements in physical and emotional functioning, including less fatigue.
Scale to Prospectively Assess Fatigue
Fatigue can be effectively assessed prospectively in clinical trials using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale recently developed and published by Dr. David Cellas group. As a clinical trialist, I would recommend that this tool be incorporated prospectively into secondary end points in a variety of clinical trials. The value of secondary end point assessments has been demonstrated in the Eastern Cooperative Oncology Group (ECOG) trial of chemotherapy for advanced lung cancer (of which Dr. Philip Bonomi is principal investigator.)
Cella and colleagues demonstrated that changing quality-of-life measures were more important predictors of survival than the chemotherapy itself. The value of the quality-of-life component was recognized in a plenary session at the 1997 annual meeting of the American Society of Clinical Oncology.
Role of Neuroactive Drugs
Lastly, the potential for relieving fatigue prospectively with currently available neuroactive drugs should not be ignored. To my knowledge, there are no prospective, placebo-controlled, phase III trials looking at antidepressants or antianxiety agents as treatment for fatigue/depression in cancer patients. The widespread availability of safe, effective antidepressants may well lead to new insights into the treatment of fatigue in cancer patients.
Certainly, the depression, stress, and anxiety that occur in virtually all patients diagnosed with advanced malignancy are remarkably undertreated, just as in the past, pain was remarkably undertreated. Pain was assumed to be something that patients would have to tolerate. We have learned to challenge that medieval idea. Now, the concept that fatigue is something that must be lived with may be the next medieval idea that needs to be challenged and altered.