Tuesday, July 17, 2007

Sertraline is not good for what ails you; Palliative care & ALS

Lancet Oncology has a couple of articles to note:

First is a randomized controlled trial of sertraline in advanced cancer patients suggesting it's not good for what ails you. This was a randomized, placebo controlled trial of 189 patients with advanced cancer who weren't feeling great (had some symptoms of depression, fatigue, anxiety, etc.) but who weren't felt to be actually depressed. What was meant by that last phrase - it's a little tricky - the patients had to score 4/10 on scales of self reported depression, anxiety, or fatigue - but who didn't have 'major depression' by the assessment of the 'responsible' clinician. That is, the patients weren't formally assessed for major depression, meaning that probably some of them indeed had major depression given how depression is notoriously under-diagnosed in cancer patients (on the other hand this does replicate 'real life' insofar as these weren't patients the treating clinician would have likely treated anyway). Patients were given 50mg of sertraline or placebo and primary analyses were at 4 & 8 weeks (although it seems patients were followed longer). Numerous assessment scales were employed.

Most patients were over 60 and had ECOG scores of 1. Sertraline did not come out looking good: basically no benefit on any of the many measures they took of depressive symptoms, fatigue, quality of life, etc.; it was discontinued earlier and more often than placebo due to adverse effects; and the study was actually stopped early because it looked like the sertraline patients had higher mortality than placebo (this wasn't significant in the final analysis however and was probably a statistical event and not a clinical one).

Prior to seeing this study I hadn't been aware people had been suggesting SSRI's for advanced cancer patients without a clear indication for them as a "quality of life booster" or a preventive measure against future depression and this study will likely squelch further investigation of this. I wonder though if further investigation is needed and that's to see if sertraline is effective for at all 'true' major depression in advanced cancer patients particularly given than some of these patients certainly had major depression and pretty much all of them had depressive symptoms. This, I think, is the true implication of this study. I would need to do a literature review here, and maybe a reader could help out, but my impression was that there are a handful of quality studies looking at antidepressants in cancer that were generally positive. What I'm unsure of is how many of these studies were of advanced cancer patients as that may make a world of difference.

I'll also briefly mention a trial of radium-223 in hormone-refractory prostate cancer with painful bone mets. Radium-223 is beginning to be studied in humans as a novel radionucleotide (similar to strontium or samarium) and this was a phase II study in which it (or placebo injection) was given to patients undergoing concurrent external beam radiation. It only involved ~60 patients and the main outcomes were tolerability (it was well tolerated) and markers of bone turnover (alkaline phosphatase). Tantalizingly their results suggested an antineoplastic effect of the radium (slowed down PSA rise and the patients who received it lived longer) although the study wasn't really designed or powered to show this. Pain/analgesia and quality of life weren't measured at all. One assumes that these will be looked at in phase III trials and I hope these outcomes don't get lost as people get excited over this as an antineoplastic agent.

JAMA has a couple pieces recently as well.

First is a another installment of JAMA's 'perspectives on care at the close of life' series - this one on palliative care for patients with ALS. Like the rest of the series it is a comprehensive review based around a case and patient/family/clinician interviews. One of the most interesting aspects of the article to me was its discussion of tracheostomy and long term mechanical ventilation and that there's some evidence to suggest that many patients who receive this do so under emergency circumstances and without their explicit consent. Yikes.

Last is a 'coda' to their recent one on management of fatigue at the close of life. I really appreciated these lines. This is July, the time when fresh palliative care fellows are starting their training, and understanding this perspective is key to their education:

"I am deeply humbled by my experience in caring for Mrs D. She taught me much about balancing "cure" and "care" in patients facing chronic and progressive illness. She reminded me that the challenge of providing genuine "patient-centered" care—care is fundamentally grounded in a patient's goals and preferences—especially within the context of great uncertainty.

Mrs D also taught me much about managing fatigue in elderly persons with progressive illness. Although I seemed to achieve temporary success with treatments like antidepressants, exercise, and appetite stimulants, I truly believe my most important intervention was a willingness and commitment to listen to her frustrations, fears, and hopes around this troubling and refractory symptom. My treatment attempts, regardless of their efficacy, seemed to at least validate her illness experience."

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