Background   Cachexia occurs in up to 80% of cancer patients.  Abnormal weight loss (more than 5-10% of pre-morbid weight) results in significant physical and psychological morbidity and is an independent risk factor for early mortality.  Attempts to treat anorexia with enteral or parenteral feedings (see Fast Fact #190) have demonstrated limited efficacy, at the price of increased morbidity.  This Fast Fact discusses megestrol acetate (MA), a synthetic progestin, as an appetite stimulant.

Outcome Data   Overall, data suggests that approximately one in four patients taking MA will have an increase in their appetite, and one in twelve will have an increase in their weight. Clinical trials have also demonstrated that MA is:

• Equally efficacious to dexamethasone as an appetite stimulant.
• Associated with fewer long-term side effects than corticosteroids.
• Superior to dronabinol (see Fast Fact #93) in appetite stimulation and non-fluid weight gain.
• Effective when used concurrently with radiation therapy in lung or head and neck cancer to reduce treatment associated weight loss.

Despite these apparent benefits, most weight gain attributed from MA in clinical studies is largely adipose tissue and not lean muscle. Furthermore, no clear benefit to quality of life has been demonstrated, nor has any study shown a survival advantage from MA therapy. 

Dosing   The optimal timing to initiate treatment with MA (prophylactic or therapeutic) and the optimal duration of therapy are unknown. MA is typically dosed orally, once daily. There is an increasing dose/response curve from 160 to 800 mg/day; doses above 800 mg/day have no additional benefit.  Different strategies include beginning at 400 mg per day and titrating for effect to 800 mg/day; or initiating treatment at 800 mg/day.  Generally, MA is dosed in the elixir form both for patient convenience and cost (see below).  MA is 60-80% excreted in urine; no guidelines are available for dosing in renal impairment.

Costs (AWP = average wholesale price)

• Tablet:  20 mg (AWP = $69.20/100 pills); 40 tablets = 800 mg = $27.68/day.  40 mg (AWP = $123/100 pills); 20 tablets = 800 mg = $24.60/day
• Elixir:  40 mg/ml (AWP = $143.95/240 ml) = 20ml = 800 mg = $11.90/day.  625 mg/5 ml (AWP = $883.80/150 ml) = 5 ml = 625 mg = $29.46/day.

Adverse Effects   Multiple adverse effects have been reported including thromboembolic events (use with caution in patients with history thromboembolism), nausea, diarrhea, impotence, peripheral edema, hypertension, hyperglycemia, breakthrough uterine bleeding, and skin photosensitivity. MA can precipitate adrenal insufficiency via suppression of the hypothalamus-pituitary-adrenal axis.

Future Considerations

• Early investigational studies combining the use of MA with formoterol fumarate clinically significant improvement in muscle mass and/or function in cancer patients. More controlled trials are needed to determine if this combination is more effective than MA alone.
• Studies combining the use of carnitine and celecoxib suggest equal efficacy to using MA alone and may be an alternative for patients with contraindications to MA use.
• A recent clinical trial has suggested that the use of MA in children with cancer can be safe and associated with significant weight gain. However, more studies are needed to corroborate the safety and efficacy of pediatric MA therapy.

References

1. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin. 2002; 52:72-91.
2. Jatoi A. On appetite and its loss.  J Clin Oncol. 2003; 21(9, Suppl):S79-S81.
3. Jatoi A. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol, 2002; 20:567-73.
4. McQuellon RP. Supportive use of megestrol acetate with head/neck and lung cancer patients receiving radiation therapy. Int J Radiat Oncol Biol Phys. 2002; 52:1180-5.
5. Tisdale MJ. Biology of Cachexia. J Natl Cancer Inst. 1997; 89:1763-73.
6. Ronga I, Gallucci F, et al. Anorexia-cachexia syndrome in pancreatic cancer: recent advances and new pharmacological approach. Adv Med Sci. 2014; 59(1):1-6.
7. Ruiz Garcia V, Lopez-Briz E, et al. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database of Syst Rev. 2013.
8. Megestrol acetate: Drug information. In: Post TW (Ed), UpToDate, Waltham, MA. www.uptodate.com . Accessed on January 31, 2016.
9. Argiles, JM, Anguera A, Stemmler B. A new look at an old drug for treatment of cancer cachexia: megestrol acetate. Clin Nutr. 2013; 32(3):319-24.
10. Yaylali GF, Dogu GG, et al. Effects of megestrol acetate on adrenal function and survival in cancer patients. Endocrine Abstracts. In: www.endocrine-abstracts.org. 2015.
11. Greig CA, Johns N, et al. Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy. Support Care Cancer. 2014; 22(5):1269-75.
12. Madeddu C, Dessi M, et al. Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib +/- megestrol acetate for patients with cancer-related anorexia/cachexia syndrome. Clin Nutr.  2012; 31(2):176-82.
13. Cuvelier GD, Baker TJ, et al. A randomized, double-blind, placebo-controlled clinical trial of megestrol acetate as an appetite stimulant in children with weight loss due to cancer and/or cancer therapy. Pediatr Blood Cancer. 2014; 61(4):672-9

Version History:  This Fast Fact was originally edited by David E Weissman MD and published in October 2003. Re-copy-edited in April 2009; and copy-edited again by Dr. Renee Foutz in January 2016.