Nutrition Support Blog: It's All About the Outcome
July 28, 2011
Large randomized studies have resulted in a number of surprises for medicine and nutrition in the last 30 years. Cardiologists were among the first to receive a jolt of unexpected insight regarding the effects of “obviously beneficial” interventions. Premature ventricular contractions (PVC’s) after an MI are associated with increased mortality, hence providing medications that suppressed PVCs seemed a “slam-dunk” intervention. However, a large multicenter trial demonstrated that suppressing PVCs after an MI significantly increased mortality.1 Intensivists have learned that decreasing tidal volume can be life saving in ARDS, even if it acutely results in worrisome blood gasses.2 The world of nutrition received a shock when it was revealed that β-carotene supplements significantly increased lung cancer incidence in a high risk population, despite all of the epidemiology and animal studies indicating that it may be beneficial.3 There was no clue that there was anything “con” about probiotics until a large randomized trial revealed significantly increased mortality from probiotics provided via a jejunal tube to patients with severe acute pancreatitis.4
Considering how many aspects of care have not yet been thoroughly investigated, it is a bit unsettling to ponder what other interventions that we deem beneficial may actually have unintended, and even negative, consequences.
Recently I was reminded of the limitations of our knowledge in regards to outcomes while preparing a presentation on medications used to stimulate appetite. Megestrol acetate increases appetite and allows weight gain in cancer patients.5 However, because most of the studies are small and relatively short-term, there is minimal data to let us know if the use of megestrol as an appetite stimulant improves overall outcomes such as quality of life and activity level, or if it in fact, has negative consequences. Especially concerning to me was data that megestrol binds to the glucocorticoid receptor, decreases testosterone levels in men, causes adrenal suppression, and that at doses effective for increasing oral intake (400 to 800 mg/day) causes loss of lean muscle mass.6,7 Even treating patients with testosterone during megestrol therapy did not reverse the muscle loss.6 Resistance exercise during megestrol treatment does appear to minimize the loss of lean muscle mass, and it is possible that in some forms of end-stage cancer that megestrol may have anti-cachectic effects beyond appetite enhancement.6,8 However, knowing that megestrol acts as a catabolic agent in most patients and that there is a the lack of data about overall outcomes makes me concerned about it’s routine use, especially in the long-term or elderly patient that is already at risk for skin breakdown and loss of functional capacity. Although increasing food intake may seem like one of those slam-dunk clinical moments, considering what we known about megestrol (and what we have learned from past studies where the treatment can be worse than the initial threat), megestrol may not be the best route. Our bias is that megestrol may be best reserved for more palliative or very selective short-term heme-oncology indications until further data is available.
1. Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. the cardiac arrhythmia suppression trial (CAST) investigators. N Engl J Med 1989;321:406-412
2. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338:347–354.
3. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–1035.
4. Besselink MG, van Santvoort HC, Buskens E, et al.; Dutch Acute Pancreatitis Study Group. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomized, double-blind, placebo-controlled trial. Lancet. 2008;23;371(9613):651-9.
5. Berenstein EG, Ortiz Z. Megestrol acetate for the treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD004310.
6. Lambert CP, Sullivan DH, Freeling SA, Lindquist DM, Evans WJ. Effects of testosterone replacement and/or resistance exercise on the composition of megestrol acetate stimulated weight gain in elderly men: a randomized controlled trial. J Clin Endocrinol Metab. 2002 May;87(5):2100-6.
7. Evans WJ Megestrol Acetate Use for Weight Gain Should Be Carefully Considered J. Clin. Endocrinol. Metab. 2007 92: 420-42.
8. Mantovani G, Macciò A, Lai P, Massa E, Ghiani M, Santona MC. Cytokine involvement in cancer anorexia/cachexia: role of megestrol acetate and medroxyprogesterone acetate on cytokine downregulation and improvement of clinical symptoms. Crit Rev Oncog. 1998;9(2):99-106. Review.
“However beautiful the strategy, you should occasionally look at the results.” - Sir Winston Churchill
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