The Hospice Clinician Blog

Megestrol acetate (MA) is a progestin that has been used
as an appetite stimulant and weight loss remedy in variety of
clinical conditions. Many are more familiar with the highly
recognizable brand-name, Megace. Although the weight
loss indication for MA is only approved for treatment of
anorexia and cachexia in patients with AIDS, it has been widely
used for the treatment of weight loss in cancer patients, frail
nursing home residents, dementia patients, and frail elderly
patients in the community with non-cancerous serious
chronic health conditions.

Studies in patients with cancer and AIDS have shown MA to be an effective appetite stimulant that is associated with weight gain (1-4). Alternatively, studies in geriatric patients including mostly nursing home residents have failed to demonstrate similar consistent benefits (1,2,5,6,13). Reports on the clinical significance of MA induced weight gain vary considerably. Some clinicians believe that the weight gains that have been achieved with MA are not related to reversing the catabolic state of advanced disease, but reflect only increased body fat or water retention (12).

There has been widespread use of MA for treatment of weight loss in elderly nursing home residents in the past several years. This has been fueled by intense pressure on skilled nursing facilities to prevent and aggressively treat “unintended weight loss”. This pressure on the nursing homes is the result of scrutiny from both State and Federal regulatory agencies to monitor weight loss and potentially levy monetary penalties on facilities for deficiencies in this area. A dramatic increase in the utilization of MA for weight loss became very apparent starting in 2000 to 2001, coinciding with increased regulatory focus on weight loss in the nursing home industry.

The high cost of this drug coupled with the high volume of use in non-approved applications stimulated numerous clinical reviews and research reports regarding its effectiveness for treatment of weight loss and its adverse effects potential during the past few years. The majority of these studies have been conducted in geriatric patients. To date, the reports in the medical literature indicate only modest benefits at best and a potential for serious adverse events (6).

A retrospective study by Bodenner, et al. in The American Journal of Geriatric Pharmacology (June 2007), concluded that megestrol acetate was associated with an increase in death among elderly nursing home residents being treated for weight loss. A statistical analysis by the authors demonstrated that the survival time of those patients receiving MA was on average 7.3 months less than case matched cohorts who did not receive MA and this was
determined to be highly significant. Furthermore their results found no significant increase in weight for their study population of 709 nursing home residents.

Deep venous thrombosis (DVT) is another potentially devastating adverse effect that has been associated with the use of MA for treatment of weight loss in elderly patients. In a 2003 article by Kropsky, et al, reported a 4.9% incidence of DVT in elderly nursing home residents receiving MA for treatment of weight loss (7). The average age of the patients was 87 and the average duration of therapy was 183 days. DVT has been identified as a significant risk of MA therapy in geriatric patients by other researchers as early as 2000 in the Journal of the American Medical Directors Association and again in a 2003 review of cases by Marshall, et al (8,9).

Megestrol induced hormonal influences have also been reported including: adrenal suppression; and suppression of testosterone levels in men resulting in loss of lean muscle mass (10,11). Depressed testosterone levels may be one reason MA does not produce weight gains in men as well as it does in women (10, 11, 13). Doses used for the treatment of weight loss are usually in the range to 400mg to 800mg per day in single or divided doses. Doses above 800mg per day have not been shown to have any additional benefit. Reports on MA efficacy in the treatment of weight loss have yielded conflicting results with study participants both gaining or losing weight on MA therapy. A 2002 study of 152 elderly California nursing home residents found that only 28% of patients achieved a 5% weight gain after an average duration of treatment of nearly 4 months with MA. (13). A retrospective study of elderly patients at a Florida VA Medical Center in 2005 demonstrated mixed results. In this study of 57 patients treated with MA; 40% of the patients gained weight, 49% lost weight, and 11% had no change over a 12 month period.

Identification of particular patient characteristics which could predict a positive response to MA would be beneficial, however, more research is needed to shed some light on this. There is sufficient evidence to formulate some guidelines about which patients are at high-risk for potentially serious MA adverse effects. MA therapy should be considered very cautiously, if at
all in the following types of patients due to serious risks outweighing potential benefits:

• History of thromboembolic disease
• Bed-bound, or otherwise immobile
• Heart failure
• Elderly nursing home residents

Alternative pharmacologic interventions for appetite stimulation and treatment of weight loss have included various agents from different pharmacologic classes: the steroid dexamethasone (Decadron); the cannabinoid dronabinol (Marinol); the antidepressant mirtazapine (Remeron); and the antihistamine cyproheptadine (Periactin). None of these drugs have been proven to be more effective than megestrol acetate and all have potential side effects of varying significance, however, none have been associated with an increased risk of death in the elderly or increased risk of DVT.

Dexamethasone has been shown to be equally efficacious as MA when used as an appetite stimulant, however, it is associated with more potential for side effects. Dronabinol was not as effective as MA for appetite stimulation or weight gain and has been associated with adverse effects upon the central nervous system which may be especially problematic in the elderly. Mirtazapine has been shown to result in significant weight gains in patients treated for depression and may have the lowest side effect potential of all the drugs mentioned in this article. Cyproheptadine is a less potent appetite stimulant with the potential for sedation, delirium, and anticholinergic side effects which are especially problematic in the elderly.

In conclusion, MA has been shown to increase the appetite and induce weight gain in non-geriatric adult patients with cancer or AIDS. The weight gain may be due to increased fat production or water retention. At this time megestrol acetate should not be given to geriatric patients or patients with an underlying predisposition to thromboembolic events because the risks for serious adverse events do not outweigh the potential benefits of therapy.

References:
1. Farrar AIDS Patient Care 1999;13:149-51
2. Cochrane Database Syst Rev 2005;(2):CD004310
3. Karcic, etal J Nutr Health Aging 2002;6:191-200
4. Ottery, et al Semin Oncol 1998;25(2 Suppl 6):35-44
5. Yeh et al. J Amer Geriatr Soc 2000;48:485-92
6. Bodenner, et al. The American Journal of Geriatric Pharmacology 2007;5(2):137-146
7. Kropsky, eta al. Journal of the American Medical Directors Association 2003;4:255-256
8. Bolen, et al Jouranal of the American Medical Directors Association 2000;48:248-52
9. Marshall, LL The Consultant Pharmacist 2003;18:764-63
10. Goodman, Cagliero European Journal of Gynecology & Oncology 2000;21:1117-118
11. Morley, Thomas Annals of Long Term Care 2003:6s:1-11
12. Lambert, et al. J. Clin. Endocrinol. Metab. 2002;87:2100-2106
13. Joyner, et al. ASCP Annual Meeting 2002; Poster presentation

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