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Phase III Randomized Placebo-Controlled Trial of Two Doses of Megestrol Acetate as Treatment for Menopausal Symptoms in Women With Breast Cancer: Southwest Oncology Group Study 9626

J. Wendall Goodwin, Stephanie J. Green, Carol M. Moinpour, James D. Bearden, III, Jeffrey K. Giguere, Caroline S. Jiang, Scott M. Lippman, Silvana Martino, Kathy S. Albain

From the Ozarks Regional Community Clinical Oncology Program, Springfield, MO; Pfizer Inc, New London, CT; Southwest Oncology Group Statistical Center, Seattle, WA; Upstate Carolina Community Clinical Oncology Program, Spartanburg; Greenville Community Clinical Oncology Program, Greenville, SC; Department of Medicine, University of Hawai’i, John A. Burns School of Medicine and The Queen's Medical Center, Honolulu, HI; The University of Texas M.D. Anderson Cancer Center, Houston, TX; The Angeles Clinic and Research Institute, Santa Monica, CA; and the Loyola University Chicago Stritch School of Medicine, Maywood, IL

Corresponding author: J. Wendall Goodwin, MD, Cancer Research for the Ozarks, 1730 E Republic Rd, Suite V, Springfield, MO 65804; e-mail: jgoodwin{at}sprg.mercy.net

	ABSTRACT

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Purpose Prior progestin studies treating hot flashes in women have been short duration and single dose. This study tests the progestin megesterol acetate (MA) at two doses versus placebo over 6 months.

Patients and Methods Patients with T1-3, N0-1, M0 breast cancer were eligible after completion of surgery and chemotherapy and at least 4 months of tamoxifen (if prescribed). Women were required to have at least 10 hot flashes of any severity or at least five severe episodes per week. Patients were randomly assigned to placebo, MA 20 mg, or MA 40 mg for 3 months. Success at 3 months was defined as completion of treatment with a 75% reduction in hot flashes from baseline. If success was achieved, drug treatment for another 3 months was given on the same blinded arm; if not, open-label MA 20 mg was added to blinded study drug and continued for 3 months. Other menopausal symptoms were also assessed.

Results Two hundred eighty eight eligible women were randomly assigned (286 eligible), of whom 85% were on tamoxifen, 40% had over 63 hot flashes/week, and 75% had vasomotor symptoms for 6 months. Success at 3 months was 14% on placebo, 65% on 20 mg, and 48% on 40 mg (both MA doses superior to placebo; P < .0001). Most successes at 3 months were maintained at 6 months (77% on 20 mg and 81% on 40 mg).

Conclusion MA significantly reduced vasomotor symptoms with durable benefit over 6 months. MA 20 mg/d is the preferred dose. There was no significant impact on other menopausal symptoms.

	INTRODUCTION

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Symptoms from ovarian failure (eg, vasomotor symptoms) can interfere with day-to-day functioning of breast cancer survivors.¹ Estrogen replacement therapy alleviates symptoms, but may be contraindicated for some survivors of breast cancer due to the possibility of activating latent cancer cells or causing contralateral breast cancer.²

Caution dictates that we evaluate alternative methods to treat these symptoms.³ Although the addition of progestin to estrogen does not provide additional benefit in reducing vasomotor symptoms over estrogen alone,⁴ various studies have demonstrated that progestin alone will also reduce the number and intensity of hot flashes.^5,6 Loprinzi et al⁷ reported a randomized placebo-controlled trial in 97 women and 66 men with cancer treated with 40 mg of megestrol acetate (MA) for 4 weeks for vasomotor symptoms. There was a 20% reduction in hot flashes on the placebo arm compared with 80% on the MA arm. The present study, conducted at Southwest Oncology Group (SWOG) institutions, was designed to confirm these results with a larger sample size and over a longer duration of treatment and to investigate whether decreasing the MA dose to 20 mg would be equivalent to the higher dose.

	PATIENTS AND METHODS

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Patients
Patients were required to have stage T1-3, N0-1, M0 infiltrating breast cancer with appropriate local and regional therapy. Surgery and chemotherapy must have been completed while tamoxifen was allowed on study, provided it was started at least 4 months before registration. Other prior hormones and steroids had to be discontinued before registration. Prior megestrol acetate for hot flashes was allowed only if discontinued at least 6 months prior. Other ongoing medications for hot flashes were allowed. Patients were ineligible if they were pregnant or lactating, had a history of deep vein thrombosis, or, if postmenopausal, had recurrent or persistent vaginal bleeding. Postmenopausal patients with any bleeding within the previous year were required to have a normal endometrial biopsy before registration. Prior malignancies were not allowed except for adequately treated basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer or stage I or II cancer, or for other cancers from which the patient was disease free for 5 years. All patients signed written informed consent in accordance with institutional and federal guidelines.

Menopausal status was collected on the standard Southwest Oncology Group Breast Cancer Prestudy Form: Postmenopausal (prior bilateral ovariectomy OR > 12 months since last menstrual period with no prior hysterectomy OR age 50 and other definitions of pre/post do not apply); Premenopausal (< 6 months since last menstrual period with no prior bilateral ovariectomy and not on estrogen replacement or age < 50 and other definitions of pre/post do not apply).

For the initial registration patients were required to complete a 7-day Patient Daily Log of Hot Flashes documenting either 10 or more hot flashes of any severity or five or more severe or very severe hot flashes. For reregistration at 3 months, patients must have completed the Month 3 Patient Report of Menopausal Symptoms, with registration occurring 90-104 days after start of treatment.

Study Design
Patients were randomly assigned to receive placebo, 20 mg MA (MA20), or 40 mg MA (MA40) daily according to a dynamic allocation scheme.⁸ Protocol-specified stratification factors were tamoxifen status (not on v > 4 months), number of hot flashes per week (5 to 34 v 35 to 63 v > 63), and duration of hot flashes (< 6 months v 6 months); these variables were based on those used by Loprinzi et al.⁷ Patients were given two bottles and took one pill from each bottle daily. Depending on the randomization, the two bottles distributed were either two bottles of placebos identical to the study drug; one bottle with placebo and one bottle with MA20; or both bottles with MA20. Study drugs were blinded to patients and investigators. Response evaluation using the Daily Log of Hot Flashes was conducted at 6 months. Failure was defined as less than 75% reduction in hot flash episodes compared with baseline or discontinuation of treatment before 3 months, while success was defined as its complement.^5-7 Patients were reregistered after response determination. Those considered a success continued on blinded study drug for an additional 3 months. Patients who did not achieve a success received one open-label MA20 tablet in addition to blinded study drug for an additional 3 months. A final response evaluation was conducted at 6 months, after which time the patient's treatment was unblinded, and subsequent treatment occurred at the discretion of the treating physician. Patients also completed a symptom log at baseline, 3 months, and 6 months; an assessment window of 1 week before or after the scheduled date was allowed for these two assessments.

Patients were removed from protocol treatment if hormone replacement therapy (HRT) or tamoxifen was started after entry, if disease recurred or symptoms progressed, if toxicity was unacceptable, or if severe vaginal bleeding lasted for more than 2 weeks.

Instruments
The Patient Report of Menopausal Symptoms utilized was based on a hot flash log developed by Loprinzi et al.^7,9 The number and severity of hot flashes were recorded daily for 1 week; four severity categories ranged from "mild" to "very severe" and were defined on the form (C.L. Loprinzi, personal communication, September 1997). The study Symptom Log, an adaptation of a Symptom Checklist used in previous trials,^10-12,14 addressed frequency and bothersomeness of vaginal dryness plus symptoms associated with menopause such as fatigue, feeling downhearted and blue, and frequency of intercourse and pain with intercourse (if applicable). Physicians rated depression toxicity according to the functional definitions of Common Toxicity Criteria (CTC) version 2. Grade 1 was worsening from baseline, but not interfering with function; grade 2 was interfering with function, but not activities of daily living; and grade 3 was interfering with activities of daily living. The fatigue toxicity scale was also functional, with grade 1 being increase from baseline, but not altering normal activities; grade 2 being a decrease of one in Eastern Cooperative Oncology Group performance status or difficultly performing normal activities; and grade 3 being a decrease of 2 or more in performance status or loss of ability to perform some activities.

Statistical Methods
Primary end points. A planned sample size of 279 eligible patients (93 per arm) allowed detection of differences in probability of hot flash success for three comparisons: placebo versus low dose, placebo versus high dose, and low dose versus high dose. These primary comparisons were planned at the one-sided .017 level to correct for multiple testing. One-sided tests were used for the primary comparisons because inferior performance of either MA20 or MA40 compared with placebo was not of interest; however, P values for two sided are also provided. Each comparison had power of at least 0.9 to detect a difference of 0.25. All eligible patients were analyzed according to the assigned arm, regardless of deviations from protocol-specified procedures.

Standard ² tests for contingency tables were used to test differences in proportions. P values for one-sided tests are half the ² P value if the difference is in the hypothesized direction. Primary treatment arm comparisons occurred at 3 months.

Secondary end points. Exploratory, descriptive analyses were conducted for several secondary end points: 6-month durability of the response, treatment arm comparisons for other menopausal symptoms with respect to frequency, and control.

The study was not designed to evaluate breast cancer relapse as an end point. The sample size was too small to have statistical power to detect an increase in breast cancer relapses or second breast cancers. All data was monitored by the data monitoring and safety committee.

	RESULTS

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Accrual and Patient Characteristics
Between April 1998 and May 2000, 288 patients were randomly assigned (Table 1), with 286 eligible. There were 101 eligible patients registered to the placebo arm, 92 patients to the MA20, and 93 patients to the MA40 arm. Two patients were deemed ineligible: one patient completed the Symptom Checklist more than 10 days before registration; the other patient did not complete a Hot Flash Log 7 days before registration.

Two hundred forty-one patients eligible at the first registration were reregistered to the second part of the trial. Of these, 16 patients were ineligible, with 15 patients due to reregistration outside of the 3-month window, and one patient due to inadequate 3-month assessment. All patients completing 3 months of treatment also completed the 3-month hot flash log. Log compliance at 6 months was also excellent among patients who completed an additional 3 months of treatment (all but three completed logs; Fig 1).

View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient flow chart.

Fourteen percent of patients randomly assigned to placebo achieved success as defined by the protocol, compared with 65% on MA20 and 48% on MA40.

The tests of placebo versus MA20 and placebo versus MA40 are highly significant (P < .001 for each, both one- and two-sided). Since the MA20 versus MA40 comparison was specified as one-sided, the test is nonsignificant (P = .989). The two-sided P value is .022. The 98.3% CI (corresponding to the two-sided 0.17 level test) for the difference in probability of success (MA40–MA20) is from -.32 to -.01, suggesting possible inferiority of MA40 compared with MA20 instead of the hypothesized superiority. By arm distributions of change from baseline to 3 months for the placebo and MA20 arms indicate more benefit for MA20, even among those with a protocol-defined "nonsuccess."

Secondary End Points
Age and tamoxifen subsets. Success by treatment within age and tamoxifen subsets, as well as by number and duration of hot flashes at baseline, are presented in Table 2. None were associated with response overall. Treatment differences do not vary substantially across subsets for the most part. However, there is a suggestion of treatment-age interaction, with patients older than 50 years possibly receiving more benefit from MA than younger patients (interaction P = .07).

Among patients who had a success at 3 months, most (64%, 77%, 81%, respectively, on placebo, MA20, and MA40) were continued successes (completing an additional 3 months of treatment and maintaining a reduction of at least 75% below baseline). An additional 7%, 11%, and 14%, respectively, changed to worse than 75% below baseline, but the increase was two hot flashes or less per day compared with the 3-month count. All patients who completed treatment completed a 6-month hot flash log.

Among patients who did not achieve a success at 3 months, addition of 20 mg of MA resulted in 30 out of 64 (47%) successes in patients who had been on placebo, but was not useful in patients who had been on active drug. Ten patients who were missing either logs or had not completed 6 months of treatment were conservatively considered nonresponders.

	DISCUSSION

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Megestrol acetate was highly successful in alleviating vasomotor symptoms in breast cancer survivors with durable results at 6 months. Success at 3 months was 14% on placebo, 65% on MA20, and 48% on MA40 (both superior to placebo, P < .0001). Most successes at 3 months were maintained at 6 months (77% on MA20 and 81% on MA40). Since the MA40 is (1) not superior to the MA20 with respect to the primary end point and is (2) not superior with respect to secondary end points or toxicity, MA20 is the preferred dose.

At the time of design of this study, longer-term follow-up was not available on the patients from the initial Loprinzi et al study.⁷ However, since then, a follow-up study reported that 45% of patients contacted retrospectively continued to use MA approximately 3 years after registration on study.¹⁵ An additional 9% had discontinued MA after resolution of hot flashes. Our study confirms the short-term effectiveness of MA in the treatment of hot flashes in women with breast cancer as well as longer-term (6 month) benefit. Our study also confirms a substantial placebo response(14% at 3 months).

The results from our study and that of Quella et al¹⁵ suggest that megestrol acetate retains its effectiveness in controlling flushing episodes with long-term use. Neither study was designed to evaluate long-term toxicity or relapses with long-term use. Few adverse events were reported in the current study. Despite lack of data concerning breast cancer recurrence from our study and the longer follow-up of the Quella et al study, there is still a concern about the use of progestins in women with a history of invasive breast cancer. Progesterone is a mitogen to breast epithelium, and mitotic activity reaches its peak during the luteal phase of the menstrual cycle when progesterone levels are highest, suggesting that progesterone may influence the risk of breast cancer in the presence of estrogen.¹⁶ Studies both in vitro and in vivo have demonstrated both stimulating and inhibitory properties of progestins on breast epithelium.^17,18 Data from the Woman's Health Initiative study and review reports^19-22 demonstrate an increased risk of breast cancer from estrogen plus progesterone as compared with estrogen alone in HRT. These data would suggest caution when using progestins in women with a history of invasive breast cancer. The Woman's Health Initiative population, however, differs from the current study population who received megestrol acetate plus tamoxifen or megestrol acetate alone. Conclusive evidence of increased rate of relapse or increased rate of breast cancer induction with the use of progestins plus antiestrogen is lacking. Data from the breast cancer detection demonstration project indicates a cohort who took only progestins alone for HRT and had a relative risk of developing breast cancer of 0.9.²³ This was partially balanced, however, by a smaller sample from the nurse's health study where there was an adjusted relative risk of 2.24 when progesterones alone were used as HRT.²⁴

In this study, MA did not impact favorably on menopausal symptoms other than hot flashes. Based on physician ratings, this study found more weight gain on both the placebo and the MA40 arm. In this trial, there was also no significant improvement in pain with intercourse or vaginal dryness. This is not an unexpected finding since the closely related drug medroxyprogesterone acetate does not have an effect on vaginal cells.²⁵

Other interventions in addition to pharmacologic agents may be helpful. Ganz et al found significant improvements in hot flushes by nonpharmacologic interventions including education, counseling, and individually tailored programs.⁶

Since the present study was designed, Sloan et al²⁷ reported on methods used to measure hot flashes in cancer survivors. The authors supported the reliability and validity of their hot flash measure. In addition, the authors noted that conclusions about efficacy did not differ for a "frequency only" outcome compared with a variable that incorporated both frequency and severity. Although the authors suggested using a composite measure, their data also support the use of the frequency only measure as used in this study.

A variety of agents have been used for the treatment of hot flashes in women with a history of breast cancer. They could be classified as high efficacy (hormones) with a potential for breast cancer influence, moderate efficacy, modest efficacy, and mixed or no efficacy.²⁸ Those agents with moderate efficacy decreased the baseline flushing approximately 50% to 60% and include the selective serotonin reuptake inhibitor fluoxetine²⁹venlafaxine³⁰ and paroxetine³¹ and have no breast cancer influence. Gabapentin has also been found to have a moderate efficacy.³² Clonidine has modest efficacy, but has toxicity limitations.³³ Soy phytoestrogens,^34,35 black cohosh,³⁶ and vitamin E³⁷ have marginal or no efficacy with a concern about adverse breast cancer influence from the phytoestrogens. Recently, Loprinzi demonstrated the superiority of one intramuscular injection (400 milligrams) of medroxyprogesterone acetate over venlafaxine (75 milligrams daily) for hot flash reduction.³⁸

In conclusion, this study demonstrates MA significantly reduces vasomotor symptoms with a durable benefit throughout 6 months in women with a history of invasive breast cancer. The recommended dose is 20 mg per day. This treatment could be considered in women refractory to nonhormonal therapies whose symptom status is impaired by the vasomotor symptoms and who have been informed of the risk and benefit of such treatment by their physician.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Kathy S. Albain, Bristol Myers Squibb Stock: N/A Honoraria: Kathy S. Albain, Bristol Myers Squibb Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: J. Wendall Goodwin, Carol M. Moinpour, Scott M. Lippman, Silvana Martino, Kathy S. Albain

Administrative support: Carol M. Moinpour, Scott M. Lippman

Provision of study materials or patients: James D. Bearden III, Silvana Martino, Kathy S. Albain

Collection and assembly of data: J. Wendall Goodwin, Stephanie J. Green, Jeffrey K. Giguere, Caroline S. Jiang

Data analysis and interpretation: J. Wendall Goodwin, Stephanie J. Green, Carol M. Moinpour, Caroline S. Jiang, Silvana Martino, Kathy S. Albain

Manuscript writing: J. Wendall Goodwin, Stephanie J. Green, Carol M. Moinpour, Scott M. Lippman, Silvana Martino, Kathy S. Albain

Final approval of manuscript: J. Wendall Goodwin, Stephanie J. Green, Carol M. Moinpour, James D. Bearden III, Caroline S. Jiang, Scott M. Lippman, Silvana Martino, Kathy S. Albain

	Appendix

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View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. (A) Histogram of percent hot flash reduction at 3 months—placebo arm. Percent reduction in hot flashes at 3 months from baseline for those patients who submitted both the baseline and 3-Month Menopausal Symptoms Questionnaire on Placebo. Negative numbers on the x-axis indicate that an increase in hot flashes was observed. Also includes observations for five patients in the placebo group who had forms submitted despite going off treatment early. (B) Histogram of percent hot flash reduction at 3 months—MA20. Percent reduction in hot flashes at 3 months from baseline for those patients who submitted both the baseline and 3-Month Menopausal Symptoms Questionnaire on MA20. Negative numbers on the x-axis indicate that an increase in hot flashes was observed. Also includes observations for two patients in the 20 mg/d group who had forms submitted despite going off treatment early. (C) Histogram of percent hot flash reduction at 3 months—MA40. Percent reduction in hot flashes at 3 months from baseline for those patients who submitted both the baseline and 3-Month Menopausal Symptoms Questionnaire on MA40. Negative numbers on the x-axis indicate that an increase in hot flashes was observed.

	ACKNOWLEDGMENTS

 
We acknowledge contributions of patients who submitted symptom forms and Clinical Research Associates who collected and monitored submission of forms; statistical (Danika Lew) and administrative assistance (Pat Stokes, Lisa Luce, Mark Blitzer, and Linda Massey) was helpful in manuscript preparation; and input from Charles Loprinzi, MD.

	NOTES

 
Supported in part by the following Public Health Service Cooperative Agreement grant numbers awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA35119, CA67663, CA45807, CA46441, CA76447, CA20319, CA35431, CA45377, CA58348, CA35281, CA67575, CA14028, CA58416, CA12213, CA35192, CA76132, CA46282, CA45808, CA35178, CA37981, CA04919, CA45450, CA03096, CA13612, CA42777, CA63844, CA12644, CA58882, CA76448, CA58658, CA22433, CA74647, CA76429, CA46136, CA63848, CA35262; and also by Bristol-Myers Squibb for active and placebo agents, as well as funding for distribution of study drug to participating institutions.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted January 19, 2007; accepted December 13, 2007.

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