Monday, August 20, 2007

Celecoxib & cachexia; QOL & research; CPR; EBM

Cancer cachexia and then several things in brief...

Head & Neck has an interesting trial of celecoxib for cancer cachexia. This was a small, randomized, placebo-controlled, and blinded trial of 11 patients with recently diagnosed head/neck/or upper GI cancers, 5% unintentional weight loss, no mechanical GI obstruction, and who were awaiting curative-intent cancer treatment (despite the fact that most of the patients had stage IV disease??); none were on other appetite modulators or anti-inflammatories (glucocorticoids, megestrol, NSAIDs etc.). They received 200mg bid of celecoxib or placebo for 3 weeks and a bunch of metabolic, inflammatory, and nutritional parameters were measured.

Despite the fact that that only 11 patients were involved & the study only lasted 21 days, celecoxib actually appeared to have some measurable and statistically significant effects: mean weight and body mass index increased (by 1kg and 0.3kg/m^2 in the treatment group - weight decreased by 1.3kg in the placebo group), health-related QOL improved a little in the treatment group as well. Laboratory measures of inflammation (CRP, IL-6, etc.) and other things like resting energy expenditure and lean body mass didn't differ between groups. Usually it's a good thing when small (but randomized and controlled) trials show treatment benefit (it's an indication that the effect is pretty robust if you only need 50-100 people to show an effect exists as opposed to, say, 10,000 patients in a hormone replacement therapy trial). This one, with so few people, however seems to swing in the opposite direction and one wonders if this is all chance - that the 4 (yes, 4) people who happened to get celecoxib were unique in some unmeasured way.

On the other hand we have a small, brief, trial of a drug with a well-defined risk profile which showed an effect that isn't anything to sneeze at: 2.3kg difference in just 3 weeks. And unlike the seeming hundreds of uncontrolled open-label trials out there this one can't be as easily dismissed. Longer term trials with many more people are obviously needed - do these trajectories in weight gain/loss continue for longer than a few weeks? Is lean body mass gained/preserved or (like with megestrol) is just fat gained? And does any of this translate into people feeling better or living longer? (Recent post on cachexia research here.)

Annals of Oncology has a review on the use of quality of life/symptom control as end points in advanced cancer trials (of chemotherapy and other anti-cancer treatments). Symptoms and QOL as primary endpoints was rare; few studies discussed powering for QOL/symptoms; methodologic quality (choice of instruments, measuring patient compliance with QOL/symptom measurement, etc.) was poor but, notably, improving since 2000. Most interesting were the authors recommendations for improving symptom/QOL measurement and reporting in such trials, particularly with and eye to helping clinicians better understand and communicate QOL risks/benefits of a treatment:

"More than 80% of the studies reported changes [in symptoms or QOL scores] in group means or medians, with an average determined at baseline for each group, and then at one or more pre-defined times of follow-up. This strategy is sub-optimal for assessment of QoL or symptoms in clinical trials. QoL is the property of an individual and not of a group; it will improve in some patients and decline in others, and will do so at variable rates, so that average values may have little meaning. A strategy that leads to marked improvement in QoL in 50% of patients with an advanced malignancy, while QoL declines in the other 50% due to progression of disease, would represent substantial therapeutic effect, but a comparison of mean QoL scores with baseline might show no difference. Also, some patients will drop out (usually those who are doing poorly), and comparison of a reduced sample at varying times on treatment with the whole sample at baseline, or with the averaged score at baseline for the patients that remain on study, leads to bias that confounds interpretation. The above problems can be overcome by defining criteria for ‘palliative response’ for individual patients and determining the proportion of patients that satisfy it."

Annals of Internal Medicine has a review on new CPR guidelines which looks at some of the debates in the field as well as reviews the evidence which underlies the current recommendations. Despite general acknowledgment of the dismal outcomes for most people suffering cardiac arrests there is zero mention in the paper about cessation of resuscitative efforts, let alone not beginning them, or medical decision making of any form outside of the treatment protocols themselves.

For fellow EBM nerds out there JAMA had a recent commentary on EBM and practice (particularly institution-wide) change. I learned a new acronym (actually this includes elements both of an acronym and an abbreviation): "EBMgt" for evidence based management. (If anyone knows a linguist or similar such person please comment and let us know what such hybrid foreshortenings are called.) I read the commentary and wondered to myself 'well what does this have to do with palliative care?' as most of it was about beta blockers for heart failure etc. However the standardization of evidence based practices is a reality now and demands to 'EB' everything we do will continue. The provision of palliative care services will likely not be exempted from proving such services benefit patients (or, to be cynical, saves someone money) and it's in our benefit to make sure this happens in a reasonable way (see similar concerns in my last post).

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