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© 1999 American Society for Clinical Oncology Randomized Comparison of Megestrol Acetate Versus Dexamethasone Versus Fluoxymesterone for the Treatment of Cancer Anorexia/CachexiaFrom the Mayo Clinic and Mayo Foundation, Rochester, and Duluth Community Clinical Oncology Program (CCOP), Duluth, MN; Illinois Oncology Research Association CCOP, Peoria, and Carle Cancer Center CCOP, Urbana; Missouri Valley Cancer Consortium, Omaha, NE; and Scottsdale CCOP, Scottsdale, AZ. Address reprint requests to Charles L. Loprinzi, MD, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; email loprinzi.charles@ mayo.edu.
PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetites in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0.75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetites and drug toxicities. RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P = .03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P = .06). CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.
CANCER ANOREXIA IS a prominent clinical problem that affects the quality and quantity of life of many patients with advanced cancer. An effective, nontoxic means of alleviating this clinical problem is needed. Corticosteroids were the first drugs to be evaluated in placebo-controlled trials for alleviation of cancer anorexia/cachexia. The first such trial was reported by Moertel et al1 in 1974. Three subsequent placebo-controlled trials confirmed their finding that corticosteroids could result in a temporary improvement in appetite in patients with advanced cancer.2-4 None of these trials reported any beneficial effect of corticosteroids on patient weight. In 1990, the first5 of many6-9 published placebo-controlled trials reported that megestrol acetate was able to stimulate appetite in patients with anorexia/cachexia associated with cancer or acquired immunodeficiency syndrome. A variety of doses had been used in these randomized clinical trials, leading to a dose-response study. This study suggested that a dose of 800 mg/d was optimal for appetite stimulation.10 In addition to demonstrating appetite stimulation in these patients, these trials also demonstrated an improvement in nonfluid weight gain. Some patients on these trials gained 20 to 30 or more pounds without any evidence of fluid accumulation. The above trials suggested that, compared with corticosteroids, megestrol acetate was a more powerful appetite stimulant. When this current trial was developed, clinical experience also suggested that megestrol acetate would be superior to corticosteroids in respect to toxicity. Megestrol acetate was not usually associated with corticosteroid toxicities, such as peptic ulcer disease, cataracts, opportunistic infections, glucose intolerance, or myopathy, and, unlike corticosteroids, did not cause clinically apparent adrenal suppression, which requires the tapering of a drug when it is discontinued. Notably, however, more recent information has suggested that the abrupt withdrawal of megestrol acetate may lead to adrenal insufficiency symptoms in a minority of patients.11,12 These suspected advantages of megestrol acetate over corticosteroids were counterbalanced by the substantially different costs of the medications. Whereas several days worth of corticosteroids could be obtained for less than a dollar, a daily dose of megestrol acetate would cost many dollars per day. After the initial positive North Central Cancer Treatment Group (NCCTG) trial evaluating megestrol acetate,5 an informal poll of NCCTG medical oncologists illustrated approximately equal preferences for initial use of megestrol acetate versus an inexpensive corticosteroid for patients suffering from cancer anorexia/cachexia. In response, we decided to prospectively compare the dexamethasone dose used by Moertel et al1 with a defined dose of megestrol acetate, which was reported almost 20 years later.10 In addition, we decided to concurrently evaluate the use of an anabolic corticosteroid in this clinical situation. Anabolic corticosteroids have been demonstrated to increase muscle mass,13 which has led to their illicit use by athletes to improve muscle bulk and strength. Limited information from a pilot study suggested that an anabolic corticosteroid might be helpful in patients with advanced cancer.14 Thus, we included a third arm in this randomized clinical trial to compare the anabolic corticosteroid, fluoxymesterone, with the other two study agents.
The patient eligibility criteria for this trial were similar to those used in previous NCCTG trials involving patients with cancer anorexia/cachexia.5,10,15,16 Specifically, we enrolled adult patients with advanced incurable cancer (other than breast, prostate, ovarian, or endometrial cancer). Each patient was required to have a history of losing at least 5 pounds within the previous 2 months (excluding perioperative weight loss) or to have had an estimated daily caloric intake of less than 20 cal/kg (estimated by the entering investigator). In addition, the attending physician must have determined that weight gain would be beneficial, and the patient must have perceived weight loss as a problem. Eligible patients were required to have a life expectancy  3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or better. Patients could not have had evidence of ascites and could not be receiving supplementary tube feedings or parenteral nutrition. There could be no known mechanical obstruction of the alimentary tract, malabsorption or intractable vomiting, and no current or planned treatment with adrenal corticosteroids, estrogens, or progestational agents. Patients were not eligible if they had evidence of brain metastases, thromboembolic disease within the previous 6 months, poorly controlled hypertension, or congestive heart failure. Pregnant or nursing women were also ineligible, as were patients with cataracts, patients with a history of diabetes requiring insulin, and patients with a history of peptic ulcer disease or opportunistic infections. Before randomization, patients were stratified by primary disease site, severity of weight loss, sex, ECOG performance status, planned use of concurrent radiation therapy, planned use of concurrent chemotherapy, and physician estimate of survival. Patients were then randomly assigned, according to an adaptive allocation scheme17 to receive megestrol acetate 800 mg every day (five 160-mg tablets), dexamethasone 0.75 mg orally qid, or fluoxymesterone 10 mg orally bid. If intolerable toxic reactions or excessive weight gain were attributed to the medication, then the drug was to be stopped or, alternatively, reduced by approximately 50%, according to protocol guidelines. Before study initiation, and monthly while participating in this protocol, patients were to have a history and physical examination, including weight determination. Patients were to have completed a short questionnaire at each evaluation time to judge appetite, food intake, nausea, vomiting, drug toxicities, and general quality of life (uniscale).18 These measures have been used successfully in a number of NCCTG cancer control clinical trials.15,16,19
Statistical Methods
Between September 1992 and July 1996, 496 patients were randomized onto this three arm phase III clinical trial. After randomization, 10 patients (2%) canceled (before taking any study medications) and 11 (2%) were found to be ineligible, resulting in 475 assessable patients. Baseline characteristics of these 475 patients, listed in Table 1, demonstrate balanced study groups. Baseline questionnaires were available from 455 patients (96%).
To evaluate the effect of the study medications on patients' appetites, 311 (66%) of the patients completed a baseline questionnaire and at least one follow-up questionnaire. The 34% drop out rate was similar to what we have seen in several previous anorexia/cachexia trials5,10,15,16 and probably resulted because these study participants are extremely ill, suffering from substantial cancer anorexia/cachexia along with many comorbid problems relative to advanced cancer. The responses at 1 month to five appetite-related questions are listed in Table 2. This table illustrates a consistent superiority of megestrol acetate over fluoxymesterone, and a similar efficacy for dexamethasone and megestrol acetate. Similar findings were observed when data from the best follow-up questionnaire answers, as opposed to data from the questionnaire at 1 month, are compared with the baseline data. Of note, the table reports that, of the patients receiving megestrol acetate or dexamethasone, approximately 60% to 70% of those answering the questionnaires at 1 month noted an improvement in appetite at that time point. Because an appreciable number of patients did not complete follow-up questionnaires (as always happens in these types of studies), an intent-to-treat analysis was performed by classifying those with missing data as treatment failures. This confirmatory analysis revealed that approximately 30% to 40% of all patients reported an appetite improvement 1 month after treatment initiation. The results comparing efficacy among the treatment groups from the intent-to-treat analysis are consistent with results presented in Table 2.
The O'Brien global test, which combined all questionnaire data, indicated a superiority of megestrol acetate over fluoxymesterone (P = .0004) and a trend for megestrol acetate to be better than dexamethasone (P = .10). An index was constructed that counted the number of variables out of nine possible (Table 3) that showed an improvement at any point after the baseline value. Patients on megestrol acetate and dexamethasone treatments reported a median increase in 4.5 and 4.3 variables (out of nine variables), respectively (P = .45), compared with a median increase of only 3.8 variables for fluoxymesterone (P = .04). More than one-third of patients (35%) receiving megestrol acetate improved on eight or more of the nine variables compared with only 23% of patients receiving dexamethasone (P = .03) and only 16% of patients receiving fluoxymesterone (P = .0001).
For the weight gain analyses, all patients with clinically apparent edema or ascites were censored. As previously mentioned, patients who went off the study without providing follow-up weight data were considered treatment failures in an intent-to-treat analysis manner. Weight gain data are presented in Table 4, suggesting a trend for increased nonfluid weight gains for the megestrol acetate arm compared with both fluoxymesterone and dexamethasone. A subset analysis based on sex did not reveal any substantial sex differences. Figures 1 and 2 present weight gain data as a percentage of baseline weight for each patient over time. Figure 1 compares people on megestrol acetate versus those on fluoxymesterone. The lack of symmetry of the graph (more lines in the upper left and lower right quadrants) indicates that weight gain was greater for patients receiving megestrol acetate than for those receiving fluoxymesterone. Figure 2 shows a greater symmetry, indicating little difference in weight profiles between patients receiving megestrol acetate and dexamethasone.
Toxicity There were nonstatistically significant trends observed for five toxicities, including hirsutism and virilization (women only; with noted incidences in the fluoxymesterone arm of 12% and 9%, respectively), infection (16% on dexamethasone v 8% on fluoxymesterone v 11% on megestrol acetate), and thromboembolic disease (5% on the megestrol acetate arm v 2% on fluoxymesterone v 1% on dexamethasone). No substantial trends existed for the other seven potential toxicities observed, which included acne, stria, nausea, vomiting, edema, ascites, and pleural effusion. However, one other additional toxicity that was not prospectively defined, insomnia, was noted more frequently in the dexamethasone arm (4% v 0% on megestrol acetate v 1% on fluoxymesterone, P = .005). Toxicity information was also collected by patient-completed questionnaires from which 10 potential toxicities were identified. Data from these questionnaires are listed in Table 5. Notable findings included more heartburn with dexamethasone; less abdominal pain with fluoxymesterone; less nausea with megestrol acetate; and no substantial differences among the three hormones for impotence, menstrual changes, or androgenization.
The median times on study for patients receiving megestrol acetate, fluoxymesterone, and dexamethasone were 64, 54, and 57 days, respectively (P = .02). Study removal for toxicity and/or patient refusal to continue the study medications occurred in 25%, 33%, and 36%, respectively (P = .07). There were no statistically significant survival differences among the three study arms, with a median overall survival time of 126 days (Fig 3). As we have observed in a previous study,21 the attending physicians could prognosticate survival across a wide range of tumor types (Fig 4).
The average maximum, general quality-of-life values per patient were 67, 71, and 69 for the megestrol acetate, dexamethasone, and fluoxymesterone arms, respectively. Comparisons between megestrol acetate and the other two arms were nonsignificant. The quality-of-life profiles (zeroes imputed for patients who died) for the three treatments indicate a considerable decrease over time (Fig 5). Although indicative of the sensitivity of the instrument, results show little differences among the three treatments.
We should begin the discussion by addressing the question: Is cancer anorexia/cachexia something that should be treated? It is apparent that, to the best of our knowledge, the prophylactic use of an appetite stimulant in patients at risk for cancer anorexia/cachexia does not improve survival nor does it affect global quality-of-life scores.19 In addition, the treatment of cancer anorexia/cachexia has related costs, just like virtually all drug therapies, both in terms of economics and toxic effects from drug treatment. Nonetheless, most, if not all, of the above costs can also be said regarding the use of narcotics for cancer pain, antitussives for cough, and antiemetics for nausea/vomiting; all three of these treatments are regularly accepted and used. It is clear that anorexia/cachexia is a major symptom in patients with advanced cancer.22,23 Placebo-controlled, double-blind trials have demonstrated agents that can positively impact (although with clearly limited efficacy) cancer anorexia/cachexia.1-10 The trials have also shown that both physicians and patients desire effective treatments for this prominent clinical problem. All in all, the decision to treat a patient with an appetite stimulant needs to be an individual one, based on patient desires and concomitant medical conditions. Assuming it is accepted that cancer anorexia/cachexia is worth treating in selected individuals, let us continue this discussion with the most clear cut conclusion we can make from this current trial; the anabolic corticosteroid, fluoxymesterone, is clearly an inferior drug for appetite stimulation in patients with cancer anorexia/cachexia, at least in the dose and schedule studied here. Fluoxymesterone was clearly associated with less appetite stimulation and its toxicity profile was not better than the other two studied agents. Conclusions from the comparison of megestrol acetate and dexamethasone are not quite as clear because there are advantages and disadvantages related to each treatment. In terms of appetite stimulation, the effects are remarkably similar between these two drugs, with maybe the suggestion of a slight, but not statistically significant, edge for megestrol acetate. For nonfluid weight gain, there seems to be a slight edge for megestrol acetate, but again, this was not statistically significant. Similar findings were reported in a small (52 patients) three-armed randomized trial comparing megestrol acetate (160 mg/d), prednisolone (10 mg tid), and a placebo for patients undergoing pelvic radiation therapy.24 What about toxicity? We saw more corticosteroid-type toxicities with dexamethasone versus megestrol acetate, although maybe not to the magnitude that might have been expected. This is balanced a bit by noting the slightly higher (5% v 1%) incidence of thromboembolic phenomena in the megestrol acetate group, a toxicity that has previously been associated with megestrol acetate.19 However, probably the most telling toxicity result is the higher percentage of patients who stopped the study medication because of toxicity or patient refusal with dexamethasone versus megestrol acetate (36% v 25%, respectively; P = .03). Because of the prominent role of pharmaco-economics in current practice, we should discuss the financial costs of the two therapies. We will limit this to the costs of purchasing the drugs, although it could be appropriately argued that costs of the treatment of differential toxicities could be important (the latter being a significantly complex subject). Costs presented below represent average wholesale prices based on a recent publication.25 Dexamethasone is relatively inexpensive, with the cost of the daily dose used in this trial in the range of $0.60 per day. If dexamethasone was given as a single daily 4-mg dose (as opposed to 0.75 mg orally qid), the cost could be as low as $0.30 per day. In contrast, an 800-mg daily dose of megestrol acetate costs around $20 to $25 per day, if purchased in tablet form (40-mg tablets are the largest tablet strength available in the United States so this would require 20 tablets per day). An 800-mg dose of a liquid formulation of megestrol acetate, however, costs approximately $10.25 per day in the United States. It seems that the megestrol acetate liquid suspension may be more bioavailable than are the megestrol acetate tablets that we used. The rationale for this hypothesis is derived from data that demonstrate that a micronized megestrol acetate tablet preparation is approximately 20% more bioavailable than the traditional megestrol acetate tablet preparation.26 Because the liquid megestrol acetate suspension consists of the micronized megestrol acetate preparation, it may similarly be approximately 20% more bioavailable than the tablet form that we used in this study. If so, a liquid suspension megestrol acetate dose of 640 mg would seem to be equivalently bioavailable to the 800-mg tablet dose that was used in this trial. This 640-mg dose of megestrol acetate suspension has a comparable daily cost of approximately $8.00 per day. Hopefully, data will become available in the near future to evaluate the relative bioavailability of the different megestrol acetate preparations that are available to patients. Given the above, which drug should be used in clinical practice, if it is opted to prescribe a drug for the treatment of cancer anorexia/cachexia? It could be argued that it would be reasonable to choose an inexpensive corticosteroid in selected cases. This might apply to a patient with a poor prognosis, where it might be expected that the patient would only be treated for a short period of time (eg days to a couple of weeks) and where the corticosteroid boost might provide a temporary improvement in energy and/or pain.27 In this setting, the patient might get some short-term appetite stimulation benefits without the toxicities usually related to long-term use of corticosteroids. For planned long-term use (weeks to months), it might be preferable to choose megestrol acetate, given its better patient acceptance (approximately two-thirds as many patients stopping megestrol acetate for toxicity or patient refusal on this study compared with dexamethasone) and its trend toward improved appetite stimulation and nonfluid weight gain. Again, the two concerns of treatment with megestrol acetate are the slightly increased risk of thromboembolic problems and the increased medication cost. As far as the latter is concerned, consideration of using a lower megestrol dose (eg, 160 to 480 mg/d) could be entertained based on positive results previously reported by some investigators using these lower doses.6,7,28
Additional participating institutions include: Cedar Rapids Oncology Project Community Clinical Oncology Program (CCOP), Cedar Rapids, IA (M. Wiesenfeld, MD); Meritcare Hospital CCOP, Fargo, ND (R. Levitt, MD); Toledo Community Hospital Oncology Program CCOP, Toledo, OH (P.L. Schaefer, MD) Ochsner CCOP, New Orleans, LA (C.G. Kardinal, MD); Grand Forks Clinic, Ltd, Grand Forks, ND (D.J. Walsh, MD); CentraCare Clinic, St Cloud, MN (H.E. Windschitl, MD); Geisinger Clinic & Medical Center CCOP, Danville, PA (S. Nair, MD); Siouxland Hematology-Oncology Associates, Sioux City, IA (J.C. Michalak, MD); Iowa Oncology Research Association CCOP, Des Moines, IA (R.F. Morton, MD); Saskatchewan Cancer Foundation, Saskatoon Cancer Centre, Saskatoon, Saskatchewan, Canada; Allan Blair Cancer Centre, Regina, Saskatchewan, Canada (A.W. Maksymiuk, MD); Sioux Community Cancer Consortium, Sioux Falls, SD (L.K. Tschetter, MD); Quain and Ramstad Clinic, Bismarck, ND (D.M. Pfeifle, MD); and Rapid City Regional Oncology Group, Rapid City, SD (L.P. Ebbert, MD).
Conducted as a trial of the North Central Cancer Treatment Group Clinic and supported in part by Public Health Service grants no. CA-25224, CA-37404, CA-15083, CA-63849, CA-35269, CA-35113, CA-35195, CA-60276, CA-52352, CA-37417, CA-35415, CA-35272, CA-35448, CA-35103, and CA-35101 from the National Cancer Institute, Department of Health and Human Services.
1. Moertel CG, Schutt AJ, Reitemeier RJ, et al: Corticosteroid therapy of preterminal gastrointestinal cancer. Cancer33:1607-1609, 1974[Medline] 2. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat Rep69:751-754, 1985[Medline] 3. Popiela T, Lucchi R, Giongo F: Methylprednisolone as an appetite stimulant in patients with cancer. Eur J Cancer Clin Oncol25:1823-1829, 1989[Medline] 4. Wilcox J, Corr J, Shaw J, et al: Prednisolone as an appetite stimulant in patients with cancer. BMJ288:27, 1984
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Von Roenn JH, Armstrong D, Kotler DP, et al: Megestrol acetate in patients with AIDS-related cachexia. Ann Intern Med121:393-399, 1994 10. Loprinzi CL, Michalak JC, Schaid DJ, et al: Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J Clin Oncol11:762-767, 1993[Abstract] 11. Loprinzi CL, Jensen MD, Jiang NS, et al: Effect of megestrol acetate on the human pituitary-adrenal axis. Mayo Clin Proc67:1160-1162, 1992[Medline]
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Leinung MC, Liporace R, Miller CH: Induction of adrenal suppression by megestrol acetate in patients with AIDS. Ann Intern Med122:843-845, 1995 13. Freed DJ, Banks AJ, Longson D, et al: Anabolic steroids in athletics: Crossover double-blind trial on weightlifters. BMJ5:471-473, 1975 14. Chlebowski RT, Herrold J, Ali I, et al: Influence of nadrolone decanoate on weight loss in advanced non-small cell lung cancer. Cancer58:183-186, 1986[Medline] 15. Kardinal CG, Loprinzi CL, Schaid DJ, et al: A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer65:2657-2661, 1990[Medline] 16. Goldberg RM, Loprinzi CL, Mailliard JA, et al: Pentoxifylline for treatment of cancer anorexia/cachexia? A randomized, double-blinded, placebo-controlled trial. J Clin Oncol13:2856-2859, 1995[Abstract] 17. Therneau TM: How many stratification factors are "too many" to use in a randomization plan? Control Clin Trials14:98-108, 1993[Medline] 18. Sloan JA, Loprinzi CL, Kuross SA, et al: A randomized comparison of four tools measuring overall quality of life in patients with advanced cancer. J Clin Oncol16:3662-3673, 1998[Abstract] 19. Rowland KM, Loprinzi CL, Shaw EG, et al: Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer Treatment Group study. J Clin Oncol14:135-141, 1996[Abstract] 20. O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics35:549-556, 1979[Medline] 21. Sloan JA, Loprinzi CL, Laurie J, et al: A simple stratification factor prognostic for survival in advanced cancer: The GBU index. Proc Am Soc Clin Oncol 17:557a, 1998 (abstr 2136) 22. DeWys WD, Begg C, Lavin PT, et al: Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med69:491-497, 1980[Medline] 23. Bruera E, MacDonald RN: Asthenia in patients with advanced cancer. J Pain Symptom Manage3:9-14, 1988[Medline] 24. Lai YL, Fan FM, Yeh CY: Management of anorexic patients in radiotherapy: A prospective randomized comparison of megestrol and prednisolone. J Pain Symptom Manage9:265-268, 1994[Medline] 25. 1998 Drug Topics Red Book. Montvale, NJ, Medical Economics Company, 1998 26. Gaver RC, Pittman KA, Reilly CM, et al: Bioequivalence evaluation of new megestrol acetate formulations in humans. Semin Oncol12:17-19, 1985 (suppl 1) 27. Robertson CL, Marques CB, Gralla RJ, et al: Documenting the rapidity of pain relief and palliation of other lung cancer symptoms with the use of dexamethasone. Proc Am Soc Clin Oncol 16:80a, 1997 (abstr 280) 28. Bruera E, Ernst S, Hagen N, et al: Symptomatic effects of megestrol acetate (MA): A double-blind, crossover study. Proc Am Soc Clin Oncol15:531, 1996 (abstr 1716) Submitted March 5, 1999; accepted June 17, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 and Kruskal-Wallis tests in a similar fashion. O'Brien global tests were used to assess collective differences among the treatments across the various end points.
