1Medical Oncology, S.Croce General Hospital, Cuneo; 2National Cancer Institute, Genova; 3Gynecological Oncology, University of Torino, Torino; 4Medical Oncology, City Hospital, Massa; 5Medical Oncology, City Hospital, Alba; 6Medical Oncology, S. Andrea Hospital, La Spezia, Italy
Received 2 July 2001; revised 15 October 2001; accepted 14 December 2001.
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Abstract |
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Hot flashes are frequent in postmenopausal breast cancer patients, especially when treated with tamoxifen. Estrogen replacement therapy is the most effective treatment for hot flashes, but its use is controversial in breast cancer survivors. Progestins may offer a good alternative for the control of hot flashes in this setting; in particular, oral megestrol acetate has been proven effective in a randomized, placebo-controlled clinical trial. With the aim of further improving these results, we have designed a randomized study comparing oral megestrol acetate with depot intramuscular (i.m.) medroxyprogesterone acetate (MPA) for the control of hot flashes in postmenopausal patients with a history of breast cancer.
Patients and methods
Seventy-one postmenopausal patients were randomized to receive an i.m. injection of depot MPA 500 mg on days 1, 14 and 28, or oral megestrol acetate 40 mg daily for 6 weeks. Patients recorded daily the number and severity of their hot flashes; response was defined as a 50% decrease in the number and severity of hot flashes.
Results
At week 6, hot flashes were reduced by 86% on average in the whole group of patients, without significant differences between the two progestins. Response was obtained by 75 and 67% of patients receiving MPA or megestrol, respectively (P = 0.5). Responders were followed to assess maintenance of response (without further treatment), which was significantly better with i.m. MPA: in this group, 89% of responders still showed a benefit at week 24, compared with 45% in the megestrol group (P = 0.03).
Conclusions
Our study shows that a short cycle of i.m. depot MPA injections provides significant and long-lasting relief from postmenopausal hot flashes in patients with a history of breast cancer, offering an alternative to estrogen replacement therapy or prolonged administration of oral megestrol.
Key words: breast cancer, hot flashes, medroxyprogesterone acetate, megestrol acetate, postmenopausal symptoms, tamoxifen
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Introduction |
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Estrogen replacement therapy is considered the most effective treatment for postmenopausal hot flashes; however, the prescription of estrogens in breast cancer survivors is avoided by many clinicians because of a theoretical increased risk of relapse associated with their use.
The administration of progestational agents is a possible alternative to estrogens, offering good control of hot flashes in most patients. In a placebo-controlled, double-blind randomized study, megestrol acetate reduced hot flashes by 85% in a group of breast and prostate cancer patients when administered at a dose of 40 mg/day orally for 4 weeks [4]. The study did not evaluate the duration of response obtained with megestrol acetate; however, the results of a follow-up investigation showed that some patients chose to keep on taking this medication for up to 3 years [5]. This may be interpreted as indirect evidence that long-term treatment with megestrol is necessary to maintain the initial benefit.
Another progestin, medroxyprogesterone acetate (MPA), has been in use for many years for the treatment of hot flashes in healthy postmenopausal women [6]. Intramuscular administration of a depot formulation of MPA has been shown to be effective against hot flashes in randomized, placebo-controlled studies [7, 8]. An interesting characteristic of depot MPA is its long duration of action, due to the fact that progestin is released slowly from the muscle after the injection [9]. In our experience, some breast cancer patients benefit from a dramatic and prolonged reduction of their hot flashes after a short initial cycle of depot MPA injections. Based on these encouraging observations, we designed a randomized trial to compare this treatment modality with oral megestrol acetate in a group of breast cancer survivors.
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Patients and methods |
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Patients were randomized to one of two groups: group 1 received intramuscular (i.m.) depot MPA (500 mg i.m. on days 1, 14 and 28); group 2 received oral megestrol acetate (40 mg p.o. once daily from day 1 to day 42). Treatment allocation was not double blinded because this would have required the administration of i.m. placebo in group 2, which was judged impractical.
The frequency and severity of hot flashes in the participating patients were monitored through a self-compiled diary, which was started 7 days before the beginning of treatment (to provide baseline data) and continued for 6 weeks thereafter. The diary had columns for each day of the week and rows labeled mild, moderate, severe and very severe. Patients were asked to record every day the number of hot flashes that they had suffered and their severity, assigning them to one of the four grades detailed above. Choice of grade was subjectiveno definition of mild, severe or very severe was given to the patients, who were only asked to be consistent over the duration of the study. At the end of each week, patients were also asked to record in their diary all postmenopausal symptoms, other than hot flashes, or side effects of therapy encountered during the last 7 days. Patients could choose items from a list which included insomnia, fatigue, mood instability, vaginal discharge, dizziness, appetite increase, appetite decrease, dry mouth and fluid retention.
Three main efficacy parameters were evaluated at the end of the sixth week from the start of treatment (i.e. after 6 weeks of daily oral treatment with megestrol acetate or 2 weeks after the last of three i.m. injections of depot MPA), using the average values recorded for that week in comparison to baseline values calculated during the initial week with no treatment. For each group, changes in average number of hot flashes per day and average daily hot-flash score were analyzed using values recorded in the first week (with no treatment) as a baseline. The average daily hot-flash score for each patient was calculated by adding the 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 in a week, and then dividing the sum by seven. The third parameter was the proportion of patients who obtained a 50% reduction in the frequency of hot flashes and hot-flash score, as compared with baseline values. This value was arbitrarily chosen as a threshold for a clinically significant result, and was used to define responding patients. All patients who achieved a <50% reduction, or who did not complete the treatment for any reason, including side effects or refusal, were defined as treatment failures and withdrawn from the study. Off-study patients, who returned for their normal clinical follow-up, were only asked to report late side effects of treatment such as withdrawal bleeding. Responding patients were asked to continue their diaries for up to a total of 24 weeks from the start of treatment. No maintenance treatment was given in responding patients, who were visited at 2-monthly intervals. When hot flash frequency or score returned to >50% of baseline values, the patient was considered to have lost the initial response and was withdrawn from the study.
Statistical analysis
The primary end point of the study was the proportion of responding patients 6 weeks after the planned start of treatment (7 weeks after randomization). A patient was classified as a responder if she achieved a 50% reduction in the frequency of hot flashes and hot-flash score. Sample size was calculated assuming a proportion of responders in group 2 (receiving megestrol acetate) of 70%, and that the treatment with MPA was associated with a 25% absolute increase in the proportion of responders (from 70 to 95%). For an 80% power and a two-sided 5% significance, 90 subjects were planned to detect such a difference. The study was stopped after 71 patients had been randomized over a period of 2 years because of difficulties encountered during patient enrollment.
The proportion of responders was compared by means of the chi-square test [10]. Confidence limits for proportions were estimated according to Fleiss [10].
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Results |
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Reduction of hot flashes
Figure 1 shows changes in the number of daily hot flashes and the daily hot-flash score calculated from diary recordings during the baseline week and the following 24 weeks. The curves are based on all available diary recordings, which were provided by 65 patients (91%) at baseline and 53 (75%) at week 6. The mean number of hot flashes and hot-flash score at baseline did not differ significantly between the two groups. At week 6, the mean number of hot flashes per day was 1.21 [95% confidence interval (CI) 0.651.77] in group 1 and 1.42 (95% CI 0.671.17) in group 2; the mean scores were 2.08 (range 1.043.12) and 2.34 (range 0.993.7), respectively. Differences between the two groups at week 6 were not statistically significant. To assess the relative reduction in the number of hot flashes and the hot-flash score between baseline and week 6, we considered the 53 patients who provided complete diary recordings at baseline and at week 6. Overall, the average daily number of hot flashes was reduced by 87.5 ± 16.7% (range 28.6100) as compared with baseline values, and the average daily hot-flash score was reduced by 89.6 ± 17.1% (range 6.9100). The differences between the two groups were not significant. Good control of hot flashes by both treatments is also apparent in the reduction of the frequency of related symptoms, such as insomnia, mood instability and fatigue, as compared with baseline values (Table 2).
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Tolerability
Although the treatment in both arms was generally well tolerated, more patients in the megestrol group experienced adverse effects, which in six women (16.6%) led to early discontinuation of therapy (no patient in the MPA group interrupted treatment). Reasons for interruption were skin rashes in two patients (5.9%), dyspnoea in two patients (5.9%), gastric pain in one patient (2.9%) and increased arterial blood pressure in one patient (2.9%). Table 4 shows the other side effects reported during treatment. Withdrawal bleeding after the end of treatment was experienced by two patients (5.4%) in the MPA group and seven (18.9%) in the megestrol group.
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Discussion |
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Another progestational agent, MPA, has been in use for some years in healthy postmenopausal women with hot flashes; oral and parenteral formulations have been evaluated in controlled clinical trials [68]. To our knowledge, our study is the first were depot i.m. MPA was used for hot flashes in breast cancer survivors, many of whom were concurrently receiving the antiestrogen tamoxifen. Dosages and schedule of MPA in this study were based on previous empirical observations of long-term relief of hot flashes after a short cycle of i.m. injections in some of our patients. Although no definitive conclusions can be drawn from the comparison with oral megestrol, due to the small number of patients recruited and the difficulty in obtaining valid diary recordings from all subjects during treatment and follow-up, our results suggest that depot MPA can be expected to abrogate or substantially reduce hot flashes in most breast cancer patients. Moreover, nearly 90% of patients responding to MPA in our study maintained the initial benefits of treatment for 6 months without further treatment. Thus, when considering progestin therapy for the control of hot flashes in breast cancer survivors, depot MPA can be regarded as a reasonable treatment option. Occasionally a patient does not respond to progestins; in this case, other treatments should be offered with the aim of obtaining satisfactory control of the symptom. Encouraging results have recently been reported with low-dose antidepressants, such as paroxetine [14] and venlafaxine [15], suggesting that they may play an important role in this field.
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Acknowledgements |
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Footnotes |
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References |
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