Provigil for Cancer Fatigue – pro

NCCN recommends psychostimulants for some cases of severe cancer related fatigue. Provigil was not designed for cancer patients, it is used mainly to treat people with narcolepsy. It has some troublesome side effects. In a clinical trial for narcolepsy, 74 of the 934 patients (8%) who received PROVIGIL dropped out compared to 3% of patients that received placebo. The most frequent reasons for stopping Provigil were headache, nausea, anxiety, dizziness, insomnia, chest pain and nervousness. NCCN recommends psychostimulants for some cases of severe cancer related fatigue. Provigil is of a different class than other psychostimulants. It appears to be so supported especially for the fatigue of brain cancer.

I reviewed the literature and performed a literature search. I identified two prospective open-label studies of modafinil(Provigil). One study showed positive effects on fatigue that had persisted for an average of 2 years following breast cancer treatment. For these patients, fatigue severity and other measures of quality of life were significantly improved following 1 month of treatment with modafinil. Another recent study of 30 patients with malignant and benign brain tumors who were treated with surgery, radiotherapy, and/or chemotherapy found that modafinil was associated with significant improvements in fatigue scores. The most commonly reported adverse effects of modafinil treatment were headache, infection, nausea, nervousness, anxiety, and insomnia, all of which were generally mild. Randomized clinical trials of modafinil are under way to investigate its effect on cancer related fatigue in patients receiving chemotherapy and those who have completed chemotherapy or radiation therapy.

A phase III trial was presented at the 2008 meeting of the American Society of Clinical Oncology in Chicago, May 30-June 2. It included 642 patients with cancer-related fatigue who were undergoing chemotherapy for a variety of cancers. Patients were randomized to receive Provigil (n=320) or placebo (n=322) and were evaluated for fatigue, sleepiness, and depression at two different time points. Patients with severe baseline fatigue had significant improvement on Provigil compared with placebo (p=0.017). However, patients with mild to moderate fatigue did not show improvement. All patients in the study appeared to have less “sleepiness” than in the control group (p=0.002). Provigil had no effect on depression. The authors concluded that Provigil could be of benefit in treating severe cancer-related fatigue.

The subject was favorably discussed at ASCO educational meeting in 2010. A 2009 review by Cooper et al found 2 prospective open-label studies, one randomized double-blind, dose-controlled trial with an open-label extension, and one Phase 3 randomized, placebo-controlled, double-blind trial. It concluded that the studies were too disparate to be able to provide definitive recommendations; however, if traditional therapies have failed or are intolerable, modafinil can be considered a treatment option.

Similarly, the 2013 Cochrane guideline says: “There is increasing evidence that psychostimulant trials provide evidence for improvement in CRF at a clinically meaningful level. There is still a requirement for a large scale RCT of methylphenidate to confirm the preliminary results from this review.” More recent studies question whether such is the case. For example,  in a study presented at ASCO on June 8, 2013, 208 patients with lung cancer were randomly assigned in a 1:1 fashion to modafinil or placebo in a recent study. Enrollees were given modafinil at a dose of 100 mg for 14 days, followed by 200 mg for 14 days. At 28 days, those assigned to the modafinil group (104 patients) demonstrated a change of 5.28 points in fatigue score compared to 5.11 in the placebo group (104 patients; Fig. 1). Adverse events, including headache, nausea/vomiting, and anxiety—symptoms commonly associated with modafinil—were equal between groups.

K. Fife, A multicenter, randomized, double-blinded, placebo-controlled trial of modafinil for lung cancer-related fatigue: Dose response and patient satisfaction data. J Clin Oncol 31, 2013 (suppl; abstr 9503)

Minton O, Richardson A, Sharpe M, et al. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev 2010; :CD006704.


Morrow GR, Jean-Pierre P, Roscoe JA, et al. A phase III randomized, placebo-controlled, double-blind trial of a eugeroic agent in 642 cancer patients reporting fatigue during chemotherapy: a URCC CCOP Study. Journal of Clinical Oncology. 2008;26:abstract 9512

Kaleita TA, Wellisch DK, Graham CA et al. Pilot study of modafinil for treatment of neurobehavioral dysfunction and fatigue in adult patients with brain tumors. J Clin Oncol 2006 ASCO Meeting Abstract 1503.

Morrow GR, Gillies LJ, Hickok JT et al. The positive effect of the psycho-stimulant modafinil on fatigue from cancer that persists after treatment is completed. J Clin Oncol 2005 ASCO Meeting Abstract 8012.

Carr D, Goudas L, Lawrence D et al. Management of Cancer Symptoms: Pain, Depression, and Fatigue. Evidence Report/Technology Assessment No. 61. Prepared by the New England Center Evidence-Based Practice Center. Contract No. 290-97-0019. AHRQ Publication No. 02-E032. Rockville, MD: Agency for Healthcare Research and Quality, July 2002.

Maryann R Cooper, Heather M Bird, and Michael Steinberg Efficacy and Safety of Modafinil in the Treatment of Cancer-Related Fatigue
The Annals of Pharmacotherapy 2009; 43:721-725


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