Provigil does NOT alleviate fatigue in most patients treated with docetaxel chemotherapy

It has been suggested on and off that taking a drug called modafinil (Provigil) with chemotherapy can help to alleviate the tiredness and fatigue felt by some patients who are receiving docetaxel-based chemotherapy (for prostate cancer and for other forms of cancer).

Modafinil is a drug that is approved here in the USA to “improve wakefulness in adults who experience excessive sleepiness … due to one of the following diagnosed sleep disorders: obstructive sleep apnea …, shift work sleep disorder, also known as shift work disorder, or narcolepsy.”

While it is certainly possible that there is a subset of patients who may benefit from treatment with modafinil (or its “second-generation cousin” amodafinil, marketed as Nuvigil), a small, randomized, Australian trial seems to have shown that this is neither a wise nor a viable strategy for the majority of men with prostate cancer who need docetaxel-based chemotherapy.

The relevant data have recently been published by Hovey et al. in Supportive Care in Cancer (which is probably not a journal read by most medical oncologists).

The authors describe data from 83 patients with breast or prostate cancer enrolled in a small, multi-center, randomized, double-blind, placebo-controlled trial. All patients were receiving docetaxel-based chemotherapy (with a minimum dose of docetaxel of 50 mg/m2, given every 3 weeks). Patients with significant docetaxel-associated fatigue (at the start of their third of subsequent cycle of chemotherapy) were randomized to also receive either modafinil 200 mg/day or a placebo for 15 days. The docetaxel-based chemotherapy was continued for up to four further cycles.

A similar, small trial appears to be ongoing at the University of Rochester here in the USA, and there are a bunch of other trials testing the hypothesis that modafinil and amodafinil may be used to manage fatigue in cancer patients of differing types.

Here is a summary of the findings reported by Hovey et al.:

  • 65/83 evaluable patients had prostate cancer.
  • There was no significant difference between the two treatment arms with regard to effect on fatigue.
  • The occurrence of low-grade nausea and vomiting (≤ Grade 2) was nearly twice as high among patients receiving modafinil:
    • 25.0 percent among the patients receiving the placebo
    • 45.4 percent among the patients receiving modafinil

The authors also state that “Overall toxicity was comparable between treatment groups” and that “there was a modest but consistent trend towards improvement of docetaxel-related fatigue in those treated with modafinil.” What seems quite clear to The “New” Prostate Cancer InfoLink is that such a modest improvement was probably completely obliterated by the increase in risk for nausea and vomiting as a side effect!

Furthermore, on the basis of these data — at least with respect to the management of prostate cancer — we can’t see the justification for the authors’ proposition that, “Larger, longer term, randomized, controlled studies are required to clarify the exact role of modafinil in the treatment of docetaxel-related fatigue.” Primum non nocere!

If modafinil and amodafinil are to have a real value in the management of fatigue among cancer patients, we need to be able to identify patients who really will be likely to benefit, and understand how to select for those patients with accuracy. Then we can conduct trials to see if we can find out how much they really do benefit.

6 Responses


    I too don’t see much sense in just repeating what this trial did in a larger study population.

    However, I’m impressed that there was a modest decrease in fatigue. Taking off from Sitemaster’s point that that advantage was likely mostly erased by the increase in nausea and vomiting, I’m thinking that the advantage in decreased fatigue would likely be amplified if the nausea and vomiting in some patients could be better controlled. There are drugs that are effective in reducing nausea and vomiting in the chemo setting.

    Therefore, why would it not be useful to do a trial where, as part of the protocol, patients experiencing bothersome nausea and vomiting (probably Grade 2 rather than including Grade 1) were treated with one of the countermeasures for those side effects? Now that nausea and vomiting have been observed as side effects, it would be meaningful to get a handle on how well those side effects could be countered, with the benefit of getting a better handle on the anti-fatigue impact of the drug.

    Provigil has been recommended as a possible answer to fatigue for men on ADT (see, for example, the late Brad Guess’s article “Preventing and treating the side effects of testosterone deprivation therapy in men with prostate cancer – a guide for patients and physicians” (I do not have personal experience with it, partly because I have essentially not experienced fatigue while on ADT, probably because I’ve kept up aerobic and strength exercise over the past 14 years since my diagnosis. I believe that exercise is the best approach for fatigue for those of us who can manage to do it.)

  2. Dear Jim:

    Adding yet another prescription drug to control the side effects caused by Provigil in men who are already on ADT and chemotherapy (and maybe other medications too), are often elderly, etc., would not generally considered to be good medicine when the hypothetical clinical benefits of Provigil are as small as this (i.e., not statistically significant). The drugs that work well to control nausea and vomiting also come with their own spectrum of side effects, so one would be adding known risk again along with what is still only a hypothetical benefit from a small Phase II study.

    If this trial had shown a large, statistically significant benefit, the situation would be different, but that’s exactky what it did not show.

  3. I appreciate your comment, but from a patient’s perspective I’m thinking added research could benefit enough people to be worth while.

    Some fatigue is just a nuisance, but for some of us it can profoundly decrease quality of life. My wife suffered a stroke last summer and for months was burdened with great fatigue, which worked in concert with other effects to depress her and greatly reduce her activity. While I had experienced about a month of fatigue from radiation that was easily addressed by a nap, as well as fatigue from low-dose thalidomide that was also resolved with pleasant naps, what she was enduring was far beyond that.

    This experience leads me to think that there is likely a subset of chemo patients for whom a shot at reducing fatigue would be worthwhile, even if it meant the burden and risk of additional drugs to counter the side effects of the anti-fatigue drug. At least it would be encouraging to have the option and be able to check it out. This reminds me of the use of ADT. Some of us can’t stand it, even after countermeasures, often drugs but also lifestyle tactics, for the common side effects. However, most of us will do fine, provided we use countermeasures as needed.

    To me, this leaves no convincing case for additional research but no compelling case against it either.

  4. I do not have much to say about fatigue, except that I have it, or have had it, or whatever. So as a public service, here is the most comprehensive and versatile post on cancer-related fatigue that I could find.

  5. Thanks, George. As you noted, the article is comprehensive, and it is also actively maintained and authoritative. It is notable that the authors judge that there is a lot of room for more research and understanding before we have a good grasp of what is causing fatigue for an individual patient.

  6. My pleasure, Jim Waldenfels.

    I was lucky, as I knew about chronic fatigue before I got it. I had it a bit while under treatment, but figured it was just a bother due to all that the doctors threw at me. I am retired, so if I felt “tired”, I just rested. But about 3 years ago, friends in the UK told me about how it got classified as a purely psychiatric phenomenon, as an excuse for the British incapacity system not to compensate with benefits. I read enough about it to fully understand the science and politics. So when fatigue really cut in, 3 months after the treatment was finished, I knew what it was. Then I looked on line and found the text I posted.

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