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For Cancer-Related Fatigue, Modafinil Is Put to the Test, but Fails to Show Benefit over Placebo

Apr 28, 2014

        Key Points: 
  • This clinical trial evaluated the effectiveness of modafinil versus placebo in treating cancer-related fatigue.

  • 208 patients with advanced non-small cell lung cancer were randomized to receive modafinil, a central nervous system stimulant, or a placebo over a 28-day period. A questionnaire on days 1, 14, and 28 assessed fatigue, depression, daytime sleepiness and quality of life.

  • Both the treatment and placebo groups experienced some improvement in fatigue, however, no significant differences were observed between the two groups along all variables.

  • The authors concluded that modafinil should no longer be prescribed outside a clinical trial setting.

  • The study findings challenge the current National Comprehensive Cancer Network guidelines which recommend considering central nervous system stimulants for cancer patients with fatigue, where other causes of fatigue have been ruled out. 


By Shira Klapper, Senior Writer/Editor

Fatigue continues to be the most prevalent—and among one of the most distressing—of symptoms experienced by patients with cancer. In an attempt to ameliorate the effects of this debilitating condition, several studies over the past few years have put their hopes in a class of drugs called central nervous (CNS) stimulants, which are widely used to target sleepiness. However, those studies found only weak evidence supporting the medications’ effectiveness.

Now, a new study in the Journal of Clinical Oncology (JCO) online ahead of print (April 28, 2014), adds to the less-than-encouraging data: The study—in which the CNS stimulant modafinil was given to patients with cancer-related fatigue (CRF)— showed the drug to have no benefit over placebo, although interestingly, both treatments brought about clinically significant changes in CRF. 

The JCO study, “Modafinil for the Treatment of Fatigue in Lung Cancer: Results of a Placebo-Controlled Double-Blind, Randomised Trial,” was carried out by a UK-based team led by Bee Wee, MD, PhD, Senior Lecturer in Palliative Medicine at the University of Oxford and Visiting Professor at Oxford Brookes University.

Lead author, Anna Spathis, MSc, MD, stated that her interest in cancer-related fatigue arose from her firsthand experience watching patients struggle with the loss of energy. 

“I see patients all the time who say that fatigue is the single thing that is having the worse effect on their lives,” said Dr. Spathis. “They have a sense of not being able to function. It differs from the fatigue that we’re all used to because of its severity and also that it’s not relieved by resting.”

CRF, which can stop people in their tracks, is especially devastating for patients who are given a prognosis of only a few weeks to months to live.

“Fatigue stops people from getting on with their lives, from doing things they want to do,” said Dr. Spathis. “In the case of advanced cancer, this is particularly problematic because time may be short.” 

Putting modafinil to the test

To test the effectiveness of modafinil for CRF, the research team undertook a rigorously designed placebo-controlled, double blind, randomized-controlled trial (RCT) with a patient-sample large enough to conclude statistical significance. To date, there is only one other study that used an RCT to evaluate the effectiveness of modafinil for cancer-related fatigue.

In the current study, 208 patients with non-small cell lung cancer (NSCLC) from 24 hospitals across the UK were assigned to either the modafinil or the placebo group. Patients were eligible if they had stage 3a, 3b or 4 NSCLC or recurrent disease after surgery or radiotherapy, a WHO performance status of 0-2, and a fatigue level of 5 or greater on a scale of 1 to 10. At the beginning of the study and then again after 28 days, patients completed a questionnaire assessing depression, daytime sleepiness, and quality of life.

Analysis of the data showed that both modafinil and placebo brought about clinically significant changes in fatigue. However, the difference between the two treatment arms was not significant, leading the research team to conclude that any benefits observed among patients were due to the experience of being in a study and receiving a pill, aka “the placebo effect.”

The study also found that those in the modafinil group experienced a significantly greater withdrawal rate due to death, disease progression, and adverse events (AEs). Commenting on the higher rate of AEs observed in the treatment group, Dr. Spathis stated, “Most likely it’s a chance event, but we have not been able to show modafinil is safe in this patient group.”

Based on the study’s results, the research team concluded that modafinil “should not be prescribed outside a clinical trial setting.” This conclusion has implications for the National Comprehensive Cancer Network, whose current guidelines recommend that modafinil and the CNS stimulant methylphenidate be considered when reversible causes of fatigue have been excluded. 

Strong evidence for nonpharmacologic treatment of CRF

For now, Dr. Spathis noted, doctors would do best treating CRF with such nonpharmacologic treatments as exercise, education, and self-care techniques.

“The best evidence so far is for nonpharmacologic interventions, “said Dr. Spathis, pointing out that exercise, in particular, is effective because it can break a vicious cycle in which fatigue leads to less physical activity, which in turn causes loss of fitness, leading to greater fatigue, and so on.

Additional insight into caring for patients with CRF might also come from taking a closer look at the strong placebo effect observed in this study.

“In our RCT, we found a clinically significant placebo effect,” said Dr. Spathis. “Maybe that placebo effect comes from patients knowing they’ve been given a drug that may be helpful. Or maybe it’s simply that talking to somebody who understands what the problem of fatigue is, who acknowledges the issue, has an impact.”

Anna Spathis, MSc, is a Consultant in Palliative Medicine at Cambridge University Hospitals NHS Foundation Trust. She is a member of the research team led by Bee Wee, PhD. Dr. Wee is a Consultant in Palliative Medicine at Sir Michael Sobell House in Oxford, a Senior Lecturer in Palliative Medicine at the University of Oxford, and Visiting Professor at Oxford Brookes University.



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Spathis, A, Fife, K, Blackhall, F, et al. Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled double-blind, randomised trial. J Clin Oncol. 2014; Published online ahead of print 4.28.2014.


The Exclusive Coverage series on ASCO.org highlights selected research from JCO with additional perspective provided by the lead or corresponding author.

@ 2014 American Society of Clinical Oncology

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