June 12, 2008 (Chicago, Illinois) — A drug used to treat narcolepsy might have another use, researchers say, in the treatment of cancer-related fatigue. Modafinil, sold by Cephalon under the brand name Provigil, could play a role in treating this debilitating effect of cancer. Reporting here at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting, investigators found that the eugeroic agent was especially useful for patients with severe baseline fatigue.

"Although this drug did not have a positive effect for everyone, until now there was nothing reliable to prescribe for people who are most severely fatigued," lead investigator Gary Morrow, PhD, from the University of Rochester, in New York, told reporters.

Eugeroic agents are stimulants that are said to improve wakefulness without interfering with sleep or causing addiction because they clear from the body in about 12 hours. The US Food and Drug Administration approved modafinil for the treatment of narcolepsy, sleep apnea, and other sleep-related disorders.

Researchers are also exploring the potential benefits of modafinil in the treatment of so-called chemo brain and other chemotherapy-related cognitive disorders. But the drug has been linked to cases of serious rash, hypersensitivity reactions, and psychiatric symptoms. As reported by Medscape Oncology at the time, safety labeling for modafinil was changed in October 2007 to reflect these concerns.

Linked to Serious Rash, Hypersensitivity, and Psychiatric Symptoms

The drug has also been involved in controversies related to public misuse of the product. Some people have abused modafinil in the hope of benefiting from perceived cognition-enhancing effects.

This latest trial found that patients taking modafinil reported a significant overall effect of the drug on fatigue (P =.03). In the randomized phase 3 trial, investigators studied 642 patients who were receiving chemotherapy for a variety of cancers. Patients were asked to complete a survey on 2 occasions during the study.

Researchers used a standard scale, similar to that used to measure pain, and asked patients to rate their level of fatigue from 0 (none) to 10 (as bad as it can be). Anyone who reported a fatigue value greater than 2 was randomly assigned to receive either 200 mg daily of modafinil or an identical-looking placebo.

A total of 320 patients were randomized to the modafinil group and 322 to the placebo group. Researchers found that patients who had the most severe fatigue at the beginning of the study showed the most significant improvement after taking the drug. Patients with mild or moderate fatigue showed no significant improvement.

Drug Appears to Work Best in Severely Fatigued Patients

At the meeting, Dr. Morrow said his team does not yet understand why modafinil appears to work best in the most severely fatigued patients. But, he noted, "if you think about it in the context of severe nausea or a pounding headache, any amount of relief is going to be noticeable."

During the discussion period after the presentation, Edward Shaw, MD, from the Wake Forest Comprehensive Cancer Center, in Winston-Salem, North Carolina, asked Dr. Morrow whether in future studies he would restrict the protocol to patients with severe fatigue or whether he would pursue a range of fatigue levels, as in this study.

Dr. Morrow responded that he could build a case either way. Jamie Von Roenn, MD, from Northwestern University, in Chicago, Illinois, who was discussant for the session, suggested that investigators continue to study all patients, including those with low levels of fatigue.

Dr. Von Roenn said the current trial was well conceived and well implemented and confirms that the current dose of modafinil is well tolerated.

A cancer patient from Seattle participating in the discussion period raised concerns about the researchers' use of a measure similar to the pain scale. "I very respectfully suggest that this might not be an ideal measure because patients really struggle with these."

The patient said that she has found it more useful to jot down the number of good high-energy hours she experienced during the day and the number of not-so-great low-energy hours. She said this is easier to do than trying to quantify the problem on a fairly random 1-to-10 scale.

A Reported 80% to 85% of Cancer Patients Struggle with Fatigue

In previous studies, Dr. Morrow and his team showed that 80% to 85% of patients receiving chemotherapy report fatigue. At last year's ASCO meeting, Ian Tannock, MD, from the University of Toronto, in Ontario, said that fatigue is the number 1 symptom that cancer patients complain about. Yet, he said, doctors frequently do not even ask about it. Some have suggested that fatigue is even more prevalent than pain, nausea, and vomiting.

Dr. Morrow said that this new study adds credence to the argument that fatigue and depression are very different, because his group found that modafinil had no effect on depression.

"We've also tested antidepressants such as Paxil with cancer patients and, as expected, it helped their depression but did nothing for fatigue," he said. Paroxetine (Paxil, GlaxoSmithKline) is a selective serotonin-reuptake inhibitor that has been on the market in the United States since 1992.

Dr. Von Roenn added: "It's gratifying that there are more papers on patient care at this year's ASCO meeting than ever before. I feel better about that and we are moving in the right direction."

The researchers have disclosed no relevant financial relationships. The National Cancer Institute funded the research, and Cephalon, the maker of modafinil, provided the drug and placebo for the study.

American Society of Clinical Oncology (ASCO) 44th Annual Meeting: Abstract 1012. Presented June 2, 2008.

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