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Originally published as JCO Early Release 10.1200/JCO.2005.04.7324 on February 27 2006 © 2006 American Society of Clinical Oncology. Phase III Comparison of Depomedroxyprogesterone Acetate to Venlafaxine for Managing Hot Flashes: North Central Cancer Treatment Group Trial N99C7
From the Mayo Clinic and Mayo Foundation, Rochester; Duluth CCOP, Duluth, MN; Meritcare Hospital Community Clinical Oncology Program (CCOP), Fargo, ND; Wichita Community Clinical Oncology Program, Wichita, KS; Upstate Carolina CCOP, Spartanburg, SC; Missouri Valley Cancer Consortium, Omaha, NE; Sioux Community Cancer Consortium, Sioux Falls, SD; Scottsdale CCOP, Scottsdale, AZ; and Illinois Oncology Research Association CCOP, Peoria, IL Address reprint requests to and reprints requests to Charles Loprinzi, MD, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; e-mail: cloprinzi{at}mayo.edu
PURPOSE: Vasomotor hot flashes are a common problem in menopausal women. Given concerns regarding estrogen and/or combined hormonal therapy, other treatment options are desired. Prior trials have confirmed that progestational agents and newer antidepressants effectively reduce hot flashes. This current trial compared a single intramuscular dose of medroxyprogesterone acetate (MPA), depot preparation, versus daily oral venlafaxine as treatment for hot flashes. METHODS: Women with bothersome hot flashes were entered onto this trial, were randomly assigned to treatment, and then had a baseline week where hot flash scores were recorded without treatment. They were then treated and observed for 6 weeks; daily diaries were used to measure hot flash frequencies and severities. There were 109 patients per each arm randomly assigned to receive MPA 400 mg intramuscularly for a single dose versus venlafaxine 37.5 mg per day for a week, then 75 mg per day. RESULTS: During the sixth week after random assignment, hot flash scores were reduced by 55% in the venlafaxine arm versus 79% in the MPA arm (P < .0001). In an intention-to-treat analysis, 46% of venlafaxine patients (50 of 109) compared with 74% of the MPA patients (81 of 109) had a decrease in hot flashes by more than 50% from baseline (P < .0001). Less toxicity was reported in the MPA arm. CONCLUSION: A single MPA dose seems to be well tolerated and more effectively reduces hot flashes than does venlafaxine.
Hot flashes are a major problem in many women as they approach menopausal years. Estrogen-based therapy has been the mainstay for treating hot flashes for many years, resulting in an 80% to 90% reduction in hot flashes. Nonetheless, new data have raised concerns with regard to estrogen, with or without progesterone, increasing the risk of breast cancer, cardiovascular disease, and/or cognitive dysfunction.1,2 Thus, alternative therapies for hot flashes are desired. Newer antidepressants have been established as an alternative means of alleviating hot flashes. A double-blind, placebo-controlled, randomized, dose-finding clinical trial, published in 2000, demonstrated that venlafaxine relieved hot flashes significantly more than did a placebo.3 Venlafaxine 37.5 mg per day for a week and then 75 mg per day reduced hot flashes by approximately 60% from baseline, during 4 weeks. Progestational agents represent another nonestrogenic means of treating hot flashes. A double-blind, randomized, cross-over, placebo-controlled clinical trial demonstrated that low doses of daily oral megestrol acetate decreased hot flashes to a degree similar to that seen with estrogen therapy.4 An alternative progestational agent is medroxyprogesterone acetate (MPA). In a randomized, controlled trial, short-term use of intramuscular MPA was comparable or better than low-dose megestrol acetate (40 mg per day for 6 weeks) for relieving hot flashes.5 In addition, a placebo-controlled trial demonstrated that MPA 20 mg daily moderately decreased hot flashes.6 There have been no published reports regarding the comparison of newer antidepressant drugs versus hormonal therapy for the treatment of hot flashes. This current trial was developed to address this question.
Patients eligible for this clinical trial were women who had reported bothersome hot flashes, defined by their reported occurrence of at least 14 times per week for at least 1 month before study entry and of a sufficient severity to make them desire therapeutic intervention. Although tamoxifen, raloxifene, and aromatase inhibitors were allowed as long as they were started at least 4 weeks before study entry and were planned to be continued throughout the following 6 weeks, treatment with antineoplastic chemotherapy, androgens, and/or estrogens was not allowed. Patients were also not allowed to have received prior progestational therapy within the last year unless it was part of hormone replacement therapy, in which case it must have been discontinued at least 3 months before study entry. Patients who were pregnant or nursing were not eligible for this clinical trial. Patients could not have used antidepressants within the last year. They must not have been using other agents for treatment of hot flashes for at least 2 weeks before study entry. Patients with prior thromboembolic disease were not eligible. In addition, eligible patients must not have had uncontrolled hypertension. Informed written consent was required from all patients per US federal guidelines.
After a baseline history and physical examination, patients were stratified by age (18 to 49 v > 50), current tamoxifen use, current raloxifene use, duration of hot flash symptoms (< 9 v At study initiation, patients were randomly assigned onto one of three treatment groups: venlafaxine 37.5 mg per day for 1 week and then 75 mg per day continuously, MPA 400 mg intramuscularly (IM) for one dose, or MPA 500 mg IM at 2-week intervals for three total doses. The MPA injectable suspension (USP) 400 mg MPA/mL was supplied as Depo-Provera (Pharmacia & Upjohn Co, a division of Pfizer Inc). Accrual initially was slower than was desirable, thus it was decided to discontinue the multidose MPA arm after only nine patients were accrued to this arm. The following analysis primarily refers to the two major study arms, venlafaxine and single-dose MPA. After random assignment of patients, but before the institution of any protocol treatment, patients underwent a baseline week whereby they were asked to complete a daily hot flash diary questionnaire. The daily hot flash questionnaire asked patients to record how many mild, moderate, severe, and very severe hot flashes they had each day. They were provided with descriptions of hot flash severities as provided by women from a prior hot flash trial, as a way to judge the severity of each of their hot flashes.8 Patients also completed a general well-being scale9 and a Uniscale quality-of-life instrument, previously validated for this purpose,10,11 at the end of the baseline week and at the end of the sixth treatment week. Patients were contacted by study nurses every other week during the study period. In addition to completing the daily hot flash diary questionnaire, patients completed a symptom experience diary weekly after the baseline week and after each of the first 6 weeks of study treatment, inquiring about appetite changes, fatigue, nausea, dizziness, mouth dryness, constipation, vaginal bleeding/spotting, vaginal dryness/dyspareunia, mood changes, nervousness, sleeping troubles, abnormal sweating, libido, and difficulty achieving orgasm. Each item was scored numerically from 0 to 10 corresponding with absent to very prominent symptoms. After the 6-week treatment period, patients were contacted by the study nurse to ascertain whether their questionnaires were completed. The patient was asked how satisfied she was with her hot flash control. If the patient was satisfied, then she continued with the same treatment she was receiving (daily venlafaxine orally in the venlafaxine arm or no further treatment if they had received MPA). Patients who were satisfied with their treatment after 6 weeks were called monthly for the next 5 months and then every other month for the next 6 months to inquire about whether they were still having hot flashes. If they were, patients were asked the average number of mild, moderate, severe, and very severe hot flashes they were having per day. From this information, hot flash scores could be calculated.
Statistical Methods Missing data were handled in several ways as a sensitivity analysis of the robustness of results in relation to missing data.14-16 Less than 15% of possible data were missing, and the treatment comparison results were consistent across a series of analyses by various imputation methods. A two-sided comparison of the primary end points with 100 patients per treatment group had the required 82% power and 2.5% type I error rate to detect a difference of 0.45 standard deviations or 0.9 hot flashes per day, 2.25 units of hot-flash score, or a decrease of 16% from the baseline score. The 2.5% type I error rate was used to correct for the correlated tests for the two primary end points.17
Patient Characteristics A total of 227 patients were randomly assigned onto this study between June 18, 2002 and August 13, 2004. Figure 1 provides a trial profile. Baseline characteristics for the study arms were well balanced for all of the issues of interest, with no statistically significant differences between the study arms (Table 1).
Efficacy Hot flash efficacy between the study treatment arms is illustrated in Figure 2, demonstrating a significant advantage for MPA compared with venlafaxine (mean reductions of 79% and 55% of baseline hot-flash scores at 6 weeks, respectively; P  .0001). Virtually identical results are seen when hot flash frequencies are plotted.
As listed in Table 2, 86% of the 94 assessable patients randomly assigned to MPA 400 mg reported greater than a 50% reduction in hot flash scores during the sixth follow-up treatment week compared with 53% of the 94 assessable patients randomly assigned to receive venlafaxine (P < .0001). If the denominators are changed to include all patients randomly assigned to MPA 400 mg and venlafaxine (109 patients per arm), similar differences are seen (74% v 46%; P < .0001). During the sixth treatment week, 23% of patients receiving MPA 400 mg (22 patients) reported no hot flashes compared with 1% in the venlafaxine arm (one patient; P < .0001). Again, if the denominators are changed to include all 109 patients randomly assigned to each MPA 400 mg and venlafaxine, similar differences are seen (P < .0001).
Treatment efficacy in patients receiving tamoxifen was similar to that observed in patients who were not taking tamoxifen. Likewise, treatment efficacy in patients with a history of breast cancer versus no history of breast cancer was similar, as were treatment efficacies in women grouped by tertiles of baseline hot flash scores. Data from this study provided information from monthly nurse phone calls regarding long-term hot flash control for some of the patients who entered onto this trial. Of the 74 patients initially randomly assigned to MPA 400 mg who did not subsequently receive other hot flash therapy, 50 reported hot flash data 6 months after random assignment. Of these 50 patients, 60% (30 patients, or 27% of the 109 patients originally randomly assigned to receive MPA 400 mg) reported hot flash scores at 6 months that had decreased by more than 90% from baseline. Of the 68 patients initially randomly assigned to venlafaxine who did not subsequently receive other hot flash therapy, 33 reported hot flash data 6 months after randomly assigned. Of these 33 patients, 33% (11 patients; 10% of the 109 randomly assigned patients) reported hot flash scores at 6 months that had decreased by more than 90% from baseline. The data from the nine patients randomly assigned to receive the higher dose of MPA (500 mg IM every 2 weeks for three doses) in this trial were numerically better than was seen with the single-dose MPA arm, but are not presented because of the small patient numbers.
Toxicity
In terms of overall well-being on global quality-of-life measurements, results were virtually equivalent. Overall quality of life increased by 1.8 and 4.2 points, respectively, for patients taking MPA 400 mg and venlafaxine (P = .11). The overall General Well-Being Scale indicated an average improvement of 8.6 and 10.3, respectively (P = .14). None of the individual items were statistically different between the two arms.
This trial did support the prestudy hypothesis that a single dose of MPA would more substantially alleviate hot flashes than would the nonhormonal agent, venlafaxine. This was seen clearly during the initial 6 weeks of this trial, representing the primary study end point. Understanding that the study methodology was less stout for the time after 6 weeks (data were collected by phone calls as opposed to questionnaires and a higher rate of patient dropout was observed), this improved hot flash benefit seemed to last for at least 6 months after a single MPA dose, with almost three times as many patients still reporting a 90% hot flash reduction after MPA versus venlafaxine (27% v 10%; P = .003). This long-term effect of the single dose of this depot preparation of MPA is similar to that seen with short-term MPA IM used in another trial,5 and is likely related to its long half-life, which is approximately 50 days. Although 400 mg of MPA IM might be considered by some to be a high dose, it is a small dose when compared with how this drug has been used to treat breast cancer. In this latter situation, MPA doses of 500 mg IM daily for 28 days18 and 500 mg/d orally for many months19 have been used. This treatment has been well tolerated overall, with the exception of weight gain.19 Although both venlafaxine and MPA seemed to be well tolerated by the majority of patients in this trial, short-term toxicity incidences favored the MPA treatment. Regarding convenience, a single injection of MPA might be favored by many women, compared with taking daily capsules for weeks to months. This approach is also less expensive; the cost of a 400-mg MPA injection is estimated to cost approximately $100, whereas a 3-month prescription of venlafaxine 75 mg per day currently is estimated to cost three to four times as much. Given the hot flash reduction efficacy, toxicity, convenience, and economic issues discussed, MPA would seem to be the recommended drug, without reservation, for treatment of hot flashes in women without a history of thrombophlebitis. Nonetheless, another major factor, dealing with the long-term safety of MPA (particularly as it relates to breast cancer), weighs in on this decision. Given that there are no data to address this question definitively, it is necessary to rely on available circumstantial evidence to shed light on this topic. Regarding circumstantial evidence that might be deemed to be negative with regard to MPA safety, MPA is a hormone, albeit a progestational agent rather than an estrogenic agent. Comfort with the administration of hormones has markedly declined in recent years with the publication of the Women’s Health Initiative trials1,2 reporting that combined estrogen plus progesterone therapy increased the risk of thromboembolic disease, breast cancer, and heart disease, and negatively affected cognition. Blame for progesterone as a part of this problem is supported by the recognition that the estrogen plus progesterone treatment was associated with an increased breast cancer incidence that was not observed in patients receiving estrogen treatment alone. In addition, there are laboratory-based data to suggest that transient exposure to progesterone can stimulate breast cancer growth, although these data are balanced by conflicting laboratory-derived data, suggesting that progesterone can inhibit breast cancer growth,20 including data that MPA blocks the stimulation of growth in hormone receptor–positive breast cancer cell lines.21 There is additional circumstantial evidence supporting that a single dose of MPA, given without estrogen, is safe. First, a Breast Cancer Detection Demonstration Project cohort study, conducted from 1980 to 1995 and involving 46,355 postmenopausal women, provides some informative data.22 Although this report mainly relates to estrogen and estrogen-progestin combinations, data regarding 3,048 women who were receiving progestin treatment alone showed that their relative risk of being diagnosed with breast cancer was 0.9 (11 occurrences of 3,048). This is partially balanced, however, by a smaller sample involving data from the Nurses Health Study, in which in 1,983 women taking progestin alone, 12 developed breast cancer, for a multivariate adjusted relative risk of 2.24.23 In another report from the Nurses Health Study, a one-time blood draw was performed. For the highest quartile of endogenous progesterone concentrations, the relative risk of developing invasive breast cancer was 0.8 to 0.9.24 Adding to the circumstantial evidence to suggest that MPA is safe are data demonstrating that MPA, and other progestational agents, can be used for treating metastatic breast cancer.25 A recent report also provided additional data supporting the safety of MPA, with regard to breast cancer, by indicating that it elevated the expression of a breast cancer metastasis suppressor gene.26 In addition, it is generally accepted that short-term use of hormonal therapy is quite safe, and a single injection of MPA, even if it is a depot preparation, would certainly qualify as short-term treatment. Thus, although there are valid concerns regarding the use of estrogen and progesterone therapy together,27 it has to be accepted that there is no definitive answer regarding the safety of a single 400-mg dose of MPA. Given that it has taken decades of study involving tens of thousands of women for us to think we understand the safety of estrogen or combined hormonal therapy, additional definitive data regarding a single MPA dose is not likely to become available in the foreseeable future. Therefore, decisions regarding whether to use MPA for hot flashes will need to be made with less than definitive data. In summary, the data from this trial demonstrate that MPA reduces hot flashes to a more substantial degree than does venlafaxine.
Additional participating institutions include: Iowa Oncology Research Association CCOP, Des Moines, IA 50314 (Roscoe F. Morton, MD); Rapid City Regional Oncology Group, Rapid City, SD 59709 (Larry P. Ebbert, MD); Mayo Clinic Scottsdale CCOP, Scottsdale, AZ 85259 (Robert F. Marschke Jr, MD); CentraCare Clinic, St Cloud, MN 56301 (Harold E. Windschitl, MD); Geisinger Clinical Oncology Program, Danville, PA 17822 (Albert M. Bernath Jr, MD); Grand Forks Clinic Ltd, Grand Forks, ND 58201 (John A. Laurie, MD); Metro-Minnesota Community Clinical Oncology Program (Patrick J. Flynn, MD); Quain and Ramstad Clinic, Bismarck, ND 58506 (Ferdinand Addo, MD); Meritcare Hospital CCOP, Fargo, ND 58122 (Ralph Levitt, MD); Saskatchewan Cancer Foundation, Saskatoon, Saskatchewan, Canada S7N 4H4 (Maria Tria Tirona, MD); Sioux Community Cancer Consortium, Sioux Falls, SD 57105 (Loren K. Tschetter, MD).
The authors indicated no potential conflicts of interest.
The pharmaceutical sponsors reviewed and provided input into the initial study design, but did not have any input into the writing of this manuscript. The manuscript was submitted to them before submission for publication, but no revisions were made based on comments.
Supported by the National Cancer Institute and in part by Public Health Service Grants No. CA-25224, CA-37404, CA-35103, CA-63849, CA-63848, CA-35195, CA-35272, CA-35269, CA-35101, CA-60276, CA-52352, CA-37417, CA-35448 for the collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic. Venlafaxine was provided by Wyeth Ayerst. Medroxyprogesterone acetate was purchased by an unrestricted grant provided by Upjohn. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
9 months), and the mean patient-reported frequency of hot flashes per day at study entry (two to three v four to nine v more). Patients were then randomly assigned centrally by the North Central Cancer Treatment Group Randomization Office by a method of dynamic allocation that balanced the marginal distributions.
