Challenge of Managing Cancer-Related Fatigue

Fatigue is the most common, and one of the most devastating, symptoms in patients with cancer. 1 It has been defined as "a distressing, persistent, subjective sense of tiredness or exhaustion related to cancer or cancer treatments that is not proportional to recent activity and interferes with usual functions." This is partly because fatigue is a complex, multidimensional syndrome. In recent years, there has been a much better understanding of the multiple mechanisms contributing to the expression of fatigue by patients with cancer. Tumor byproducts and host cytokines, direct effects of radiation therapy and chemotherapy, cachexia, deconditioning, opioids and other drugs, hypogonadism, metabolic abnormalities, chronic infection, mood abnormalities such as anxiety and depression, cognitive changes, and severe anemia are all contributors to the intensity of fatigue in patients with cancer. In a given patient, it is quite likely that multiple mechanisms coexist at any given time and that the main contributors change as the disease progresses or as patients reach the completion of therapy. ltimately, fatigue is a symptom, and therefore, it is perceived in the brain. For this reason, centrally acting agents have been among the most commonly tried for the management of fatigue. A recent systematic review concluded that methylphenidate was the agent for which the most research and supportive evidence exists. In this issue of Journal of Clinical Oncology, Moraska et al 7 publish the results of a randomized, controlled trial, comparing a long-acting methylphenidate preparation versus a placebo in patients with cancer-related fatigue (CRF). The authors found no significant differences in usual fatigue, current fatigue, or worse fatigue during the course of the 4-week study. They did observe that patients with more advanced disease showed a significant response to methylphenidate as well as a trend for patients with more severe fatigue to improve more when receiving methylphenidate than when receiving placebo. Our group recently conducted a secondary review of patients who received methylphenidate in our clinical trials. Consistent with the results reported by Moraska et al, we observed that higher levels of fatigue were predictors of response to methylphenidate in patients with advanced cancer. he results of this study are consistent with those of a previous randomized, controlled trial by our group using an immediate-release methylphenidate preparation. 9 However, there are some differences in the findings between our study and that of Moraska et al. Our study found a dramatic improvement in fatigue in both the methylphenidate and placebo groups, with no significant difference between the two arms. 8 Moraska et al 7 saw a less dramatic improvement in fatigue