Ginseng, Donepezil, and Modafinil for Fatigue in Cancer Patients

Zosia Chustecka

June 04, 2007

June 4, 2007 (Chicago) — Some of the new studies with ginseng, donepezil, and modafinil for the treatment of fatigue in cancer patients presented here at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO) show a glimmer of promise, but so far there is not enough evidence to support any pharmacological treatment, and the only consistent evidence of benefit is from exercise programs. This was the conclusion of Ian Tannock, MD, PhD, from Princess Margaret Hospital, University of Toronto, Ontario, who was discussing the new studies.

Dr. Tannock praised the research efforts in this area but said that more work was urgently needed. Fatigue is the number-one symptom that cancer patients complain about, and yet doctors frequently do not even ask about it, he said. A survey of more than 1000 cancer patients reported in the Annals of Oncology found that 58% complained of fatigue, more than double the patients who complained about pain (22%) or about nausea and vomiting (18%) (Stone P et al. Ann Oncol. 2000;11;971-975.)

Promising Results With Ginseng

The most positive study was the study investigating ginseng, which was highlighted at an ASCO press briefing. Lead author Debra Barton, PhD, an associate professor of oncology at the Mayo Clinic in Rochester, MN, commented that ginseng is one of the most popular supplements and is already used by many cancer patients. Long used in traditional Chinese medicine, it is known as an "adaptogen" and is said to help the body adapt to and overcome stress. Preclinical studies have suggested that it has an antifatigue effect (eg, improved aerobic swimming ability in rats), and a previous trial reported at the 2003 ASCO meeting with Asian ginseng suggested a benefit in cancer survivors.

The product used in the current study was 4-year-old root American ginseng from the Ginseng Board of Wisconsin, which donated the product. It was assayed by an independent company, and funding for the study was provided by National Cancer Institute Community Oncology Program.

The study tested 3 doses of ginseng (750 mg, 1000 mg, and 2000 mg) against placebo in 282 patients with a variety of cancers and a life-expectancy of at least 6 months. About half of the patients were receiving chemotherapy. There was no difference between any of the study groups in the rate of adverse effects reported or in the number withdrawing from the study due to adverse effects, and the product appears to be "tolerable," Dr. Barton said.

After 8 weeks, responses on the Brief Fatigue Inventory (BFI) and on the vitality subscale of the SF-36 quality-of-life questionnaire showed an improvement over placebo for the 2 higher doses of ginseng, Dr. Barton reported. In addition, 25% of patients taking 1000 mg of ginseng and 27% of patients taking 2000 mg reported feeling "moderately better" or "much better," compared with only 10% of patients in both the placebo and the 750-mg-ginseng groups.

"There appears to be some activity at the higher doses," Dr. Barton concluded, adding that "this may be noise, but there is too much signal to ignore." At the press conference, she described the results as "very promising" and noted that her group is now planning a larger trial.

"This study is provocative; there is a hint of something there," commented Bruce Cheson, MD, from the Lombardi Comprehensive Cancer Center and Georgetown University Hospital, in Washington, DC, who was moderating the press conference. However, both he and Dr. Barton said there was not enough evidence yet to recommend the use of ginseng to patients; at present, evidencesupports only exercise as an intervention that benefits fatigue, they emphasized. Nevertheless, patients are free to take whatever supplement they wish and often choose to do so, Dr. Cheson continued. "The only thing that I would say is please stop when we start therapy, as we never know whether the supplement may interfere with treatment."

Modafinil Effect on Cognitive Impairment?

Another hint of a positive effect comes from a study in breast cancer patients using modafinil (Provigil, Cephalon), a wakefulness-promoting agent that is approved for use in narcolepsy. The study has reportedly shown a positive effect of modafinil on fatigue, and the results are due to be published soon by the principal investigator, Gary Marrow, MD, from the University of Rochester, in New York.

At the ASCO meeting, however, only 1 part of this study was reported, the results of a secondary analysis, which suggested that modafinil had a positive effect on some aspects of cognitive functioning. Sadhna Kohli, PhD, from the James P. Wilmot Cancer Center, in Rochester, New York, explained that the study consisted of 2 parts — an open-label 4 weeks in which all patients took modafinil, after which only those who reported a beneficial effect on fatigue (68/76 patients) were randomized to receive modafinil or placebo for a further 8 weeks. The secondary analysis found a significant improvement in attention and speed of memory, and Dr. Kohli suggested that the positive results warrant further testing of modafinil in breast cancer patients who report cognitive impairment after chemotherapy, sometimes referred to as "chemofog" or "chemobrain."

However, the third study presented at the meeting, looking at donepezil in fatigue, was negative. Dr. Eduardo Bruera, MD, from the MD Anderson Cancer Center, in Houston, Texas, explained that donepezil is an anticholinesterase inhibitor and is marketed as Aricept (Eisai) for use in Alzheimer's disease. An earlier open-label pilot study by his group, reported at ASCO in 2003, had found a significant improvement in fatigue in cancer patients on opioids. However, the current study was placebo-controlled and found no difference between the 2 groups. "Donepezil was not superior to placebo in the treatment of cancer-related fatigue," Dr. Bruera concluded. The study involved 142 cancer patients, donepezil was used at a dose of 5 mg daily, and assessments were made after 1 week.

The last 2 aspects of this trial may have contributed to the negative finding, 1 delegate in the audience suggested. Edward Shaw, MD, from Wake Forest University, in Winston-Salem, North Carolina, commented that his own group found a positive effect of donepezil on fatigue in a phase 2 study in irradiated brain tumor patients published last year (Shaw EG et al. J Clin Oncol. 2006; 24;1415-1420), but they used the higher dose of 10-mg donepezil and made their assessments at 24 weeks. "We saw a continued reduction in fatigue with time," he said, adding that 1 week is too short a time to expect an effect on a chronic symptom such as fatigue. Dr. Shaw and colleagues are now planning a phase 3 trial of donepezil in cancer-related fatigue.

American Society of Clinical Oncology 43rd Annual Meeting: Abstracts 9001, 9003, and 9004. Presented June 3, 2007.

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