Thursday, August 9, 2007

Donepezil for cancer fatigue; Phase I trials; Cachexia

Two from the latest Journal of Clinical Oncology & one from Lancet Oncology.

First is a randomized controlled trial of donepezil for cancer fatigue. I briefly mentioned these results as they were presented at ASCO, but will look at them closer here. The trial involved ~110 advanced cancer patients (average age 56 years, women with breast cancer predominated, median ECOG performance status 2, median fatigue 7/10) who reported fatigue of at least 4/10 on a 0-10 scale; they were randomized to 5mg of donepezil daily for 7 days. Results: patients improved modestly after a week with both placebo and active treatment - there were no differences between the groups for any outcome as well as side effects. Highlighting the power of the placebo effect (or perhaps these patients' desperation to feel better) almost all patients in both groups elected to continue donepezil in an open labeled fashion at the end of the trial.

As a side note this study was a pleasure to read and I wish more trials were presented like this: succinct intro & discussion, straightforward assessment scales, results focus on the primary outcome and don't present 5 tables of difficult to interpret secondary outcomes. One doesn't have to slog through 2 pages of results to figure out what's important - many papers seem to present every scrap of data (tabulated different ways) and are annoying to read.

The one major concern I have with the findings are that one week and 5mg may not be sufficient. While doubtful, it's conceivable that 10mg daily for 3 weeks would be effective - in using donepezil for dementia it can take some time to determine efficacy. Anyone out there using this (I'm not)?

This study was from the MD Anderson palliative group & this is the second controlled trial they've published in as many years that found negative results for interventions which looked good in open-labeled trials. It reminds me of link #3 below about cancer cachexia research moving slowly - part of the reason there may be a perception that the field is moving so slowly is because there are dozens of open-labeled "trials" which have exciting, "promising" results which don't stand up to the rigors of randomization and control. All hype, no pay-off.

There's also a study looking at cancer patients' attitudes towards potential conflicts of interest in their physicians (while in phase I trials). It involves survey results of adults receiving chemotherapy trials at the University of Chicago and was interesting to me for a couple of reasons. The main findings - patients care about both financial and intrinsic (the researcher's career, peer respect, etc.) conflicts of interest and generally feel they should be disclosed but also generally feel that this wouldn't change their decision to enroll in a trial - seem pretty straight-forward.

What was notable was the patients' general perceptions of research: nearly half believed patients in research received better medical care and nearly a quarter believed their physician cared more about the research than them! You could interpret this in a lot of ways but one wonders if there's a subset of patients enrolling in trials because they feel they'll get better/more attentive care (the ugly flip side of this being their fear their doctor won't provide proper care for them if they disappoint him or her by not enrolling). Is this the case? I don't know, although it seems reasonable to think that fear drives people to enroll in phase I trials (particularly the first-in-humans ones) as much as hope or a desire to help others by furthering science....

(And for you fellow armchair EBM pundits there's also an all too believable article about how common underpowered research is presented at meetings, usually without comment.)

Lancet Oncology has a news article about why progress in treating cancer cachexia has been so slow. It reviews the dismal state of the science now and summarizes in a manner much more eloquently that I've been able to on this blog my thoughts about megestrol:

"The only other choices we currently have are megestrol acetate or glucocorticoids”, says Marks. Both drugs improve appetite and energy intake but have severe toxic effects. Furthermore they do not restore muscle mass, so any effect on quality of life is short lived. In fact, they both increase muscle proteolysis, and any weight gain is caused by accumulation of fat or oedema. As Tisdale observes, “megestrol acetate is the most used approach to clinical management and therapy for cachexia, not because it works, but because there is nothing else”.

...As well as some of the barriers to cachexia research (including a general lack of funding in supportive cancer research in general).

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