Laying to Rest Psychostimulants for Cancer-Related Fatigue?

Patients with cancer frequently suffer from fatigue as a result of chemotherapy, radiation, and/or the disease itself. Psychosocial distress (eg, from depression, anxiety, relationship problems, employment disruption, and financial problems) can contribute to this fatigue, as can comorbid conditions (eg, anemia, deconditioning, thyroid disease, malnutrition, infection, renal disease, cardiovascular disease, and pulmonary disease). In hospitalized patients with advanced cancer, fatigue is nearly universal; fatigue also affects approximately a third of disease-free cancer survivors. Treating cancer-related fatigue is difficult, and increasing sleep is often not adequate. Over the years, it has been repeatedly hypothesized that psychostimulants could improve cancer-related fatigue. Most investigations have focused on methylphenidate, a dopamine and norepinephrine reuptake inhibitor approved for the treatment of attention deficit hyperactivity disorder and narcolepsy. Because methylphenidate can increase wakefulness, it began to be tested as an antidote to narcoticassociated sedation in the late 1980s. In the 1990s, methylphenidate was evaluated as a treatment for mood and cognitive problems in patients with cancer as well as other populations. However, despite initial enthusiasm, and some evidence of benefit even within the last 5 years, most recent randomized controlled trials have argued against the efficacy of methylphenidate for cancer-related fatigue. About a decade ago, interest in methylphenidate, administered on an as-needed basis, was fueled when a small (N 31) single-arm study was published supporting a substantial reduction in cancer-related fatigue with this approach. However, subsequent larger (N 112, N 141) placebo-controlled randomized trials by the same group were negative. In the first of these two randomized trials, all patients received daily phone calls from nurses, leading the investigators to posit that the absence of methylphenidate effect might have been due to benefit from the nursing intervention superseding any benefit from the methylphenidate. However, their second randomized trial did not show any difference between those who received a telephone-based nursing intervention and those who did not, and again, methylphenidate was not found to be superior to placebo. Likewise, another study (N 148) found no greater improvement in cancer-related fatigue with long-acting methylphenidate compared with placebo, and patients who received long-acting methylphenidate experienced more nervousness and appetite loss. One recent placebo-controlled cross-over study did suggest that methylphenidate improved cognition and ability to work, but did not appear to help with fatigue. In the past decade, attention has turned to modafinil and armodafinil, both US Food and Drug Administration approved to treat excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work disorder, as potential treatments for cancer-related fatigue; initial pilot studies were mildly encouraging. The Spathis et al article that accompanies this editorial reports on a study of modafinil for the treatment of fatigue in patients with lung cancer. This nicely reported double-blind trial showed no greater improvement in fatigue for patients with stages 3 and 4 disease who received the active drug than for those who received placebo. In fact, 47% of the modafinil group and 23% of the placebo group stated that the study treatment was not helpful. Although this study involved a relatively small number of patients, its methodology appears sound, and its findings are consistent with those from multiple prior negative studies of psychostimulants for cancer-related fatigue, including another large randomized trial that evaluated modafinil. National Comprehensive Cancer Network guidelines currently recommend energy conservation, optimization of physical activity, psychosocial interventions, consideration of psychostimulants, and management of comorbidities (eg, pain, insomnia, depression). Provider-directed National Cancer Institute recommendations also include the use of psychostimulants along with treatment of anemia, exercise, cognitive-behavioral therapy (CBT), and rest. Based on the Spathis et al data and similar results from other studies, it could be argued that these guidelines should be re-evaluated and modified; it may well be that psychostimulants such as methylphenidate, modafinil, and armodafinil should no longer be recommended for management of cancer-related fatigue outside of a clinical trial, unless new research evidence better demonstrates value from them. Nevertheless, it is important to note that select patients with cancer may still benefit from psychostimulants for treatment of conditions other than cancer-related fatigue, such as narcotic-induced fatigue and depression. Further research is needed to clarify when a potential therapeutic benefit might outweigh the risk of known JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 18 JUNE 2