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Background Vasomotor hot flashes are a common symptom in women during menopause and in men who have undergone androgen-deprivation therapy for prostate cancer. Although treatment with estrogens in women and androgens in men can attenuate these symptoms, these hormones may be contraindicated in women with breast cancer and in men with prostate cancer. Pilot trials have suggested that the progestational agent megestrol acetate can ameliorate hot flashes in both groups of patients.
Methods The patients included 97 women with a history of breast cancer and 66 men with prostate cancer who had undergone androgen-deprivation therapy. All patients had experienced bothersome hot flashes (median number per day at base line, 6.1 for the women and 8.4 for the men). After a one-week pretreatment observation period, the patients received megestrol acetate (20 mg twice daily) for four weeks, followed by placebo for four weeks, or vice versa in a double-blind manner as determined by pretreatment randomization. The patients documented the frequency and severity of hot flashes in daily symptom diaries.
Results After four weeks, hot flashes were reduced by 21 percent in the group receiving placebo first and by 85 percent in the group receiving megestrol acetate first (P<0.001). An intention-to-treat analysis of data for all eligible treated patients showed that 74 percent of the megestrol acetate group, as compared with 20 percent of the placebo group, had a decrease of 50 percent or more in the frequency of hot flashes during the first four weeks (P<0.001). The degree of efficacy was similar in men and women. The only side effect was withdrawal menstrual bleeding in women, generally occurring one to two weeks after the megestrol acetate had been discontinued.
Conclusions Low-dose megestrol acetate is well tolerated and can substantially decrease the frequency of hot flashes in women and men. .
The most common treatment for hot flashes in women is estrogen-replacement therapy, which may eliminate hot flashes altogether. However, many physicians believe that estrogen-replacement therapy is relatively contraindicated in patients with breast cancer because of the concern that it may stimulate growth of the tumor.
Men who have undergone androgen-deprivation therapy (bilateral orchiectomy or treatment with a gonadotropin-releasing-hormone agonist) for metastatic prostate cancer also may have hot flashes3,4,5,6,7,8. Such symptoms can interfere with the quality of life3.
Preliminary data have suggested that megestrol acetate, a progestational agent, can decrease the frequency of hot flashes. A nonblinded study reported that megestrol acetate in daily doses of 20, 40, and 80 mg decreased menopausal hot flashes by 80, 89, and 98 percent, respectively9. Beneficial effects of other progestational agents on menopausal hot flashes have also been reported10,11,12,13,14. A pilot study reported that low doses of a progestational hormone abolished hot flashes in five of seven men (71 percent) who had undergone orchiectomy3.
Our trial was designed to assess the efficacy and short-term toxicity of low-dose megestrol acetate as a treatment for hot flashes in women with breast cancer and in men who had undergone androgen-deprivation therapy for prostate cancer.
Methods
Patient Population
The patients were either women with a history of breast cancer or men who had undergone a surgical bilateral orchiectomy or a so-called medical orchiectomy with the use of a gonadotropin-releasing-hormone agonist. To be eligible for the study, the patients must have had bothersome hot flashes for at least one month. Bothersome hot flashes were defined as hot flashes that occurred at least seven times per week and were sufficiently severe that the patient desired therapeutic intervention. All patients had a life expectancy of six months or more. Current or planned therapy with antineoplastic chemotherapy, androgens, estrogens, progestational agents, or corticosteroids was not allowed. However, the antiestrogen agent tamoxifen (20 mg per day) was permitted. Women who were breast-feeding and those with childbearing potential were excluded from the study.
Study Design
Informed consent was obtained from all the patients, as directed by federal guidelines. All the patients were stratified according to the duration of hot flashes (less than nine months, or nine or more months) and the average daily frequency of hot flashes (1 to 3, 4 to 9, or 10 or more). In addition, the men were stratified according to the type of orchiectomy they had undergone (medical or surgical) and the duration of androgen ablation (less than 4 months, 4 to 12 months, or more than 12 months), and the women were stratified according to age (under 50 years, or 50 years or older) and use of tamoxifen (yes or no). All participants were then randomly assigned in a double-blinded fashion to one of two groups: those receiving megestrol acetate (Megace) first (group 1), who received the drug for four weeks, followed by placebo for four weeks; or those receiving placebo first (group 2), who received placebo for four weeks, followed by megestrol acetate for four weeks.
After randomization, the patients were given a set of questionnaires and two coded, blister-packed medication cards containing an eight-week supply of study medication (20 mg of megestrol acetate or placebo twice daily) labeled with the days and weeks of the study. The patients were instructed not to take any tablets for the first seven days but to document the number and severity of their hot flashes each day on the questionnaire for the first week. For the subsequent eight weeks, they were to take one tablet twice each day, making sure that they were taking the medication for the correct week on the medication card, and to record the number and severity of hot flashes each day on the questionnaire for the corresponding week. The patients were also instructed to record selected toxic effects (appetite changes, fluid retention, or vaginal problems) on a weekly basis. Every two weeks, the patients were either evaluated at the medical center or contacted by telephone by an oncology nurse, who documented compliance, encouraged completion of the questionnaires, and addressed any problems. When they had completed the double-blind medication, the patients were asked to indicate their preference for one study drug or the other on the last page of the questionnaire, then return their questionnaires and medication cards to the medical center.
After the ninth week, the medication code was broken and the patients were allowed to continue to take megestrol acetate in an open-label manner for four weeks, if they wished to do so. During the open-label period of the study, the daily dose of megestrol acetate was titrated from 10 to 80 mg per day, as necessary, to determine the lowest dose that effectively controlled hot flashes. During this titration phase, doses were not to be changed more often than once per week, and the patients were asked to record the number and severity of their hot flashes each day on the corresponding questionnaire for that week.
Statistical Analysis
Since this was a crossover study, the therapeutic effects of megestrol acetate and placebo could be compared in two ways for each measure of efficacy: patients could be used as their own controls in a standard crossover analysis, or alternatively, the values recorded in the first period for the patients taking each study drug could be compared and the second-period values ignored. Since there were substantial carryover effects when megestrol acetate was taken before placebo, the second analysis was more informative in this study. Nonparametric tests15 (Wilcoxon rank-sum, chi-square, and Fisher's exact tests) were used because of the skewed distributions of most of the data on efficacy and toxicity. All P values are two-tailed.
Three variables were used to assess the efficacy of treatment: the average number of hot flashes per day, the average daily hot-flash score during the last week of a given treatment period, and the patient's preference at the end of the study. The average number of hot flashes per day was adjusted by dividing this number by the average number of hot flashes per day at base line. The average daily hot-flash score for each patient was calculated by adding the total number of mild hot flashes plus twice the number of moderate hot flashes plus three times the number of severe hot flashes plus four times the number of very severe hot flashes recorded in a given week and then dividing the sum by the number of days (a minimum of four) on which values were recorded. The average daily hot-flash score was adjusted by dividing it by the average daily hot-flash score at base line.
Results
From May 8, 1992, through May 5, 1993, 100 women and 66 men were enrolled in the trial and randomly assigned to group 1 (megestrol acetate first) or group 2 (placebo first). One woman withdrew from the study before starting any medication, and two women were ineligible. The two groups were well balanced with respect to the stratification factors (Table 1). All 163 patients who could be evaluated provided information for the analysis of toxicity. Approximately 82 percent of the women and 91 percent of the men provided usable data for the analysis of efficacy.
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During the first four-week medication period, megestrol acetate significantly decreased the frequency of hot flashes and the hot-flash scores for both men and women (Table 2). In group 2, there was a 21 percent reduction in the hot-flash score after four weeks of placebo, whereas in group 1, there was an 85 percent reduction in the hot-flash score after four weeks of megestrol acetate (P<0.001).
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Figure 1 shows the course of changes in the hot-flash score after the patients started taking megestrol acetate or placebo. It generally took two to three weeks of megestrol acetate therapy to achieve a maximal effect, and the hot flashes generally did not increase in frequency or severity until two to three weeks after the switch from megestrol acetate to placebo. Figure 1 also shows an unexpected finding: there appeared to be a substantial increase in the women's hot-flash scores for a few days after megestrol acetate was started. This increase occurred in both the women who received megestrol acetate as the initial study medication and those who received it after taking placebo for four weeks. The hot-flash scores did not increase after the women started taking the placebo, nor did the men's scores increase initially with megestrol acetate. After noting this phenomenon, we looked at the group of women who chose to receive open-label megestrol acetate after the double-blind study had been completed. These data, presented in Figure 2, also show a spike in the severity of hot flashes for a few days after the reinitiation of megestrol acetate. With further examination, it became apparent that this temporary increase in the severity of hot flashes occurred only in the women who were concomitantly receiving tamoxifen.
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The crossover analyses had to be ignored because of significantly different carryover effects, reflecting a persistent reduction in hot flashes during the placebo period in the patients who received megestrol acetate first (Figure 1).
Data on side effects were obtained from the weekly questionnaires that the patients completed. The patients were asked whether there had been any change in their appetite during the preceding week or whether they felt they had fluid retention; the women were also asked whether they had any vaginal symptoms, such as dryness, irritation, or discharge. There was no suggestion that megestrol acetate was related to any of these symptoms. We did not specifically inquire about other potential side effects, such as mood changes, migraine headaches, or vaginal bleeding, but we did include a general question about any side effects attributed to the study medication. The only evident toxic effect was vaginal bleeding, which was reported by 15 women (31 percent) who initially received megestrol acetate and had bleeding subsequently while receiving placebo. Vaginal bleeding was reported during the first week after discontinuation of megestrol acetate by 27 percent of the 15 women and during the second, third, and fourth weeks by 53, 13, and 6 percent, respectively. None of the women who initially received placebo reported vaginal bleeding.
On completion of the nine-week protocol, patients were asked which of the two four-week study medications worked better to reduce hot flashes. Of the 67 patients who initially received placebo and answered this question, 87 percent said megestrol acetate worked better, 4 percent said placebo worked better, and 9 percent had no preference (P<0.001). Of the 58 patients who initially received megestrol acetate and answered this question, 45 percent chose megestrol acetate, 40 percent chose placebo, and 16 percent had no preference (P = 0.67). The differences in these percentages were probably related to the delayed effect after the start of megestrol acetate and the prolonged (carryover) effect after its cessation (Figure 1).
Discussion
Our data show that megestrol acetate can markedly diminish hot flashes in both men and women, supporting the conclusions from an uncontrolled pilot trial of this drug9 and other studies involving related progestational agents3,10,11,12,13,14. The specific mechanism for the reduction in hot flashes is not well understood. Medroxyprogesterone acetate does not appear to cause any estrogenic effect on vaginal cells,14 suggesting that progestational hormones do not act by being converted into estrogenic compounds.
Much of the literature on progestational agents as therapy for menopausal symptoms has focused on medroxyprogesterone acetate10,11,12,13,14. This drug is similar to megestrol acetate, and the available data on the two drugs suggest that they have similar effects on hot flashes, although no direct comparison has been undertaken.
It may take two to three weeks before megestrol acetate begins to have a beneficial effect on hot flashes, and the effect may persist for weeks after discontinuation of the drug. This pattern is similar to that seen with estrogen-replacement therapy16. In addition, the effect of megestrol acetate on hot flashes in women (an 83 percent reduction in the hot-flash score) is remarkably similar to that reported with estrogen therapy (an 85 percent reduction in vasomotor hot flashes)16.
The increase in the hot-flash score during the first few days after the start of megestrol acetate treatment was a surprise, since we are unaware of any other report of this phenomenon. It appears to be a real finding rather than an artifact of the analysis, and it apparently occurs only in women taking tamoxifen. The cause of this initial agonist-like effect before a subsequent antagonist-like effect on hot flashes in women is not clear.
This study did not examine the possibility of long-term side effects. On the basis of data from studies using higher doses of megestrol acetate and studies examining the long-term use of low doses of estrogens and progesterone in healthy women, several theoretical side effects should be considered. These include weight gain, thromboembolic disorders, edema, lipid changes, cardiovascular morbidity, and the possible influence of megestrol acetate on bone structure and on hormonally sensitive cancers, such as breast, endometrial, and prostate tumors. In addition, male impotence has been reported with high doses of megestrol acetate,17 but this is not a problem in men who are receiving androgen-deprivation therapy.
On the basis of our data, appetite stimulation and weight gain would not be expected to be serious problems in most patients receiving low-dose megestrol acetate, since there was no suggestion of appetite stimulation with four weeks of therapy. Appetite stimulation with megestrol acetate is dose-dependent when the dose ranges from 160 to 800 mg per day,18 and we used a much lower dose to control hot flashes in our subjects.
To date, thromboembolic toxicity has not been clearly associated with large doses of megestrol acetate in placebo-controlled clinical trials19. Nonetheless, data from some studies suggest an increased risk of thromboembolic disease with high doses of megestrol acetate,19 and preliminary results from one of our placebo-controlled trials indicate an increased incidence of thromboembolic problems when a large dose of megestrol acetate (800 mg per day) is used in conjunction with combination chemotherapy in patients with advanced, incurable lung cancer (unpublished data). Thus, although there are no convincing data one way or the other, it is conceivable that the prolonged use of low doses of megestrol acetate may slightly increase the risk of thromboembolic disease in a manner similar to that suggested with oral contraceptives20,21,22,23. With hormone-replacement therapy, however, there is no clearly discerned relation between thromboembolic problems and treatment with estrogen and progesterone24.
The possible effects of low doses of megestrol acetate on the courses of hormonally sensitive tumors of the breast, endometrium, and prostate are unknown. Although it is possible to hypothesize that low doses of megestrol acetate may stimulate the growth of hormonally sensitive tumors in a manner similar to that of low doses of estrogen in breast and endometrial cancer and low doses of androgens in prostate cancer, it is also plausible that megestrol acetate can inhibit the growth of these cancers. Large doses of megestrol acetate have been reported to have antitumor activity in breast,25 endometrial,26 and prostate27 cancer. The influence of low doses of megestrol acetate on hormonal therapy with drugs such as tamoxifen is also unknown. Thus, at this time there is no substantial evidence to suggest that low doses of megestrol acetate will stimulate (or inhibit) the growth of tumors in humans or influence hormonal treatment with drugs such as tamoxifen, although the possibility of these effects should be the subject of future research.
The influence of low-dose megestrol acetate on cardiovascular disease has not been clarified, but concern has been expressed about the effect of progesterone on lipid levels28. Further data are needed to understand this effect. On a positive note, there are data suggesting that progestational agents can potentiate bone mineralization and thus provide protection against osteoporosis, although the definitive effect of progesterone on bones has not been clarified29,30.
In view of the results of this trial, two questions should be addressed: Are hot flashes a prominent enough symptom to require therapy in men who have undergone androgen-deprivation therapy or in women with breast cancer? If so, what treatment options are available for these patients?
Hot flashes have been reported to occur in over 75 percent of men who have undergone an orchiectomy and to interfere with their quality of life3. Androgens can abolish hot flashes in men,31 but their use would defeat the purpose of androgen-deprivation therapy. Estrogens may decrease hot flashes, but at the risk of gynecomastia, breast tenderness, and increased cardiovascular morbidity32. Cyproterone acetate, an antiandrogen with progestational properties, has been reported to decrease hot flashes after an orchiectomy,33 but this drug is not commercially available in the United States. This leaves megestrol acetate as the recommended treatment for hot flashes in patients with prostate cancer who have undergone androgen-deprivation therapy.
It is well known that hot flashes are a substantial clinical problem in menopausal women, whether or not they have a history of breast cancer. Estrogens are the mainstay of treatment for hot flashes in most menopausal women but have generally been contraindicated in those with a history of breast cancer. The wisdom behind this contraindication is currently a subject of considerable debate, especially in the case of women with small breast tumors and a very high probability of a cure with local therapy alone34. It has been suggested that estrogen treatment combined with tamoxifen is a rational approach,35 although this is not widely accepted. All in all, estrogens are not currently used in most patients with a history of breast cancer. Although several nonhormonal antidotes, such as clonidine, methyldopa, and belladonna alkaloids, have been proposed for treating menopausal hot flashes, none are very effective36,37,38,39. The data from our trial demonstrate that low doses of megestrol acetate can substantially attenuate hot flashes in most women, making this drug a reasonable treatment option for patients with breast cancer who have bothersome hot flashes.
Supported in part by grants (CA-25224, CA-37404, CA-15083, CA-35103, CA-37417, CA-35101, CA-35195, CA-35269, CA-35448, CA-35272, CA-52352, CA-35415, and CA-35113) from the National Cancer Institute.
Source Information
From the Departments of Oncology and Urology, Mayo Clinic and Mayo Foundation, Rochester, Minn. (C.L.L., S.K.Q., J.R.O., A.M.D., J.E.O.); Siouxland Hematology-Oncology Associates, Sioux City, Iowa (J.C.M.); the Carle Cancer Center Community Clinical Oncology Program, Urbana, Ill. (A.K.H.); the Sioux Community Cancer Consortium, Sioux Falls, S.D. (R.A.N.); the Quain and Ramstad Clinic, Bismarck, N.D. (T.F.); the St. Luke's Hospitals Community Clinical Oncology Program, Fargo, N.D. (C.J.); the Grand Forks Clinic, Grand Forks, N.D. (N.E.K.); the Iowa Oncology Research Association Community Clinical Oncology Program, Des Moines (W.W.B.); and the Nebraska Oncology Group, Creighton University and University of Nebraska Medical Center, Omaha (R.M.R.). Additional participating investigators and institutions are listed in the Appendix.
Address reprint requests to Dr. Loprinzi at the Mayo Clinic, 200 First St., SW, Rochester, MN 55905.
References
Additional institutions and investigators participating in the collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic include the Duluth Community Clinical Oncology Program, Duluth, Minn. (J.E. Krook); the Geisinger Clinical Oncology Program, Danville, Pa. (R.M. Goldberg); the Ochsner Community Clinical Oncology Program, New Orleans (C.G. Kardinal); the St. Cloud Clinic of Internal Medicine, St. Cloud, Minn. (H.E. Windschitl); the Cedar Rapids Oncology Project Community Clinical Oncology Program, Cedar Rapids, Iowa (M. Wiesenfeld); the Toledo Community Clinical Oncology Program, Toledo, Ohio (P.L. Schaefer); the Illinois Oncology Research Association Community Clinical Oncology Program, Peoria (J.B. Gerstner); and the Rapid City Regional Oncology Group, Rapid City, S.D. (L.P. Ebbert).
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Full Text
N Engl J Med 1995;
332:64-65, Jan 5, 1995.
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