Modafinil Fails to Improve Fatigue in Cancer Patients

Roxanne Nelson

May 08, 2014

The psychostimulant drug modafinil (Provigil, Cephalon, Inc) failed to significantly improve fatigue in lung cancer patients in a small study published online in the Journal of Clinical Oncology. The improvement in symptoms for patients who received the active drug was similar to those who received placebo.

Maybe it is now time to "lay the idea to rest" that modafinil and other psychostimulants are useful in the treatment of cancer-related fatigue, suggests an accompanying editorial.

Results Similar to Placebo

The study was conducted by Anna Spathis, of Addenbrookes Hospital in Cambridge, United Kingdom, and colleagues in 208 patients with stage IIIa-IV non–small cell lung cancer or recurrent disease after surgery or radiation therapy.

Patients were randomly assigned to modafinil (100 mg on days 1 to 14; 200 mg on days 15 to 28) or placebo, and of this group, 160 patients (modafinil, n = 75; placebo, n=85) completed questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis.

Modafinil and placebo both led to a clinically significant improvement in fatigue scores. Scores from the Functional Assessment of Chronic Illness Therapy–Fatigue assessment scale improved from baseline to day 28 (mean score change: modafinil, 5.29; placebo, 5.09), with little difference between the 2 groups.

Patients were also asked to rate the treatments on a 4-point verbal rating scale; 47% of the modafinil group and 23% of the placebo group reported that the intervention was not helpful (P = .13).

"We argue that the clinically significant benefit seen in both arms is likely related to the placebo effect," Dr. Spathis and colleagues comment. "There is insufficient evidence to prescribe modafinil for patients with cancer-related fatigue outside of a clinical trial context. Future trials need to have sufficient power to evaluate the effect in those patients with severe fatigue and could incorporate a placebo wash-in period to minimize the influence of the placebo effect."

Modafinil is a novel central nervous system stimulant that is approved by the US Food and Drug Administration for the treatment of narcolepsy, shift-work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.

As compared with other psychostimulants stimulants, such as methylphenidate, the authors note, it has a relatively selective site of action in the brain, with resultant fewer adverse effects and lower potential for abuse. Thus, it is popular among persons such as pilots for its ability to enhance mood and cognitive effects.

Studies in cancer fatigue have produced mixed results. Several open-label studies have reported significant benefit from modafinil use. But the only randomized, controlled trial of modafinil in this patient population showed a small effect on fatigue in a subgroup of patients who had severe fatigue at baseline (Cancer. 2010:116;3513-3520.).

End of the Road for Stimulants?

So is this the end of the road for psychostimulants in the treatment of cancer-related fatigue? This is the question posed in the accompanying editorial by Kathryn J. Ruddy, MD, and Charles L. Loprinzi, MD, from the Mayo Clinic, Rochester, Minnesota, and Debra Barton, RN, PhD, from the University of Michigan, Ann Arbor. It has been repeatedly hypothesized over the years that stimulants could improve fatigue in cancer patient, but overall, studies have not given support to the premise, they comment.

Even though this latest study by Dr. Spathis and colleagues 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," they note.

Other types of pharmacologic agents are currently being studied for cancer-related fatigue, including ginseng. Although more research is needed, the editorialists point out, American ginseng (Panax quinquefolius) appears to reduce cancer-related fatigue.

But more importantly, there are safe and reasonable options for symptom relief, aside from pharmacologic agents. A number of studies have looked at aerobic exercise, mindfulness-based exercise, such as yoga, and psychosocial interventions, such cognitive-behavioral therapy. More study is needed as to the frequency and duration of the nonpharmacologic interventions, as well as the cancer type and treatment, but they appear to be safe and helpful, Dr. Ruddy and colleagues note.

ASCO Guidelines of Fatigue in Cancer Survivors

The American Society of Clinical Oncology (ASCO) has recently issued guidelines that address fatigue in cancer survivors. The article offers recommendations on treatment that echo the suggestions made by the editorialists.

ASCO recommends that all cancer survivors be evaluated for symptoms of fatigue after they complete their treatment, and that they be offered strategies for fatigue management. Medical and treatable factors that may be contributing to fatigue should also be addressed. In terms of treatment strategies, ASCO points to evidence indicating that physical activity interventions, psychosocial interventions, and mind-body interventions may reduce cancer-related fatigue in this population. They also note that there is limited evidence for use of psychostimulants in the management of fatigue in patients who are disease free after active treatment.

The study was supported by a Supportive and Palliative Care Research grant from the National Cancer Research Institute and an extension grant from Sobell House Hospice Charity, Oxford, United Kingdom. The authors of the study and Dr. Ruddy have disclosed no relevant financial relationships. Dr. Barton and Dr. Loprinzi have received research funding from the Ginseng Board of Wisconsin and Ortho-McNeil-Janssen Scientific Affairs.

J Clin Oncol. Published online May 5, 2014. Abstract, Editorial

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