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© 2000 American Society for Clinical Oncology Evaluation of Soy Phytoestrogens for the Treatment of Hot Flashes in Breast Cancer Survivors: A North Central Cancer Treatment Group TrialFrom the Mayo Clinic and Mayo Foundation, Rochester; Duluth Community Clinical Oncology Program (CCOP), Duluth, MN; Carle Cancer Center CCOP, Urbana; Illinois Oncology Research Association CCOP, Peoria, IL; Ann Arbor Regional CCOP, Ann Arbor, MI; Toledo Community Hospital Oncology Program CCOP, Toledo, OH; and Meritcare Hospital CCOP, Fargo, ND. Address reprint requests to Charles L. Loprinzi, MD, Mayo Clinic 200 First St, SW Rochester, MN 55905; email cloprinzi{at}mayo.edu
PURPOSE: Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis. PATIENTS AND METHODS: This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects. RESULTS: Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed. CONCLUSION: The soy product did not alleviate hot flashes in breast cancer survivors.
HOT FLASHES CAN be a significant symptomatic complaint for women experiencing diminished ovarian function as a result of menopause. Hot flashes can also be a side-effect of breast cancer treatment with cytotoxic chemotherapy drugs or the antiestrogen, tamoxifen citrate. In a recent study, 78% of female chemotherapy recipients experienced disruptive hot flashes compared with 72% of tamoxifen users.1 A hot flash, as described by Kronenberg,2 is "a transient episode of flushing, sweating, and a sensation of heat, often accompanied by palpitations and a feeling of anxiety, and sometimes followed by chills." Hot flashes resulting from a chemically induced menopause can be of a more profound nature than hot flashes as a consequence of natural menopause.3,4 Patients who experience frequent and intense hot flashes maintain that they severely compromise their quality of life, and many desire intervention to alleviate these symptoms. Patients describe hot flashes that produce anxiety and result in sweats requiring changes of clothing and bedding, disruption of sleep, and a general diminishment of mental and physical quality of life.5 Estrogens have been the treatment of choice for women with menopausal symptoms. However, estrogens have been postulated by some as promoting breast cancer and, thus, have often been contraindicated.6 Many women reject hormone replacement therapy because of concern for this possible long-term effect. The North Central Cancer Treatment Group has developed several randomized clinical trials to prospectively evaluate various preparations for the treatment of hot flashes. In one such trial, low-dose megestrol acetate decreased hot flashes by approximately 80%.6 Long-term use (up to 3 years) of megestrol acetate seems efficacious and tolerable.7 There is no convincing evidence that low-dose progestational hormones would pose a risk to breast cancer survivors. However, there remains concern by many about placing breast cancer survivors on any hormonal agent. Nonhormonal preparations, such as clonidine, methyldopa, belladonna alkaloids, and vitamin E, have been evaluated with, at best, marginal results.8-12 Moreover, some of these preparations also have problematic side effects. An interest in studying soy products for cancer prevention occurred with the observation that Asians historically suffer lower rates of stomach, colon, prostate, and breast cancer.4,13-15 On further studying the health indices of Asian women, it was discovered they also have fewer climacteric complaints. More than 90% of Japanese women deny experiencing hot flashes.16 Recent interest in identifying the reason for the absence of menopausal symptoms in most Asian women has led to focusing on the differences between the Western and Eastern diets. The most obvious difference is the high consumption of plant foods, principally soybeans and soy-based dishes, that play a major role in the Asian diet. In Japan, the average dietary intake of soy isoflavonoids is 50 to 100 mg per day compared with less than 1 mg per day in Westernized diets.4 This prominent difference between Eastern and Western diets has caused scientists to focus on the physiologic benefits of what they have termed "the benevolent bean." The purported physiologic benefits may well be from phytoestrogens, which are contained in soy products. Phytoestrogens are nonsteroidal compounds derived from plants or from the in vivo metabolism of precursors in our diet.4 More than 300 plants are known to contain phytoestrogens, with soy and flax considered the richest sources. What makes the soybean unique is that it contains proteins called isoflavones, bioactive compounds very similar in chemical structure to estradiol. Isoflavones share many of the same properties of endogenous estrogens and, thus, compete with endogenous estrogens by binding to estrogen receptors and mimicking estrogen messages to the cells.17,18 Isoflavones seem to exert both estrogenic and antiestrogenic effects on metabolism, depending on many factors, including their concentration, the concentrations of endogenous estrogens, and individual characteristics such as sex and menopausal status.18 The three most abundant isoflavones in soybeans are genistein, diadzein, and glycitein. These isoflavones seem to be concentrated in the hypocotyl (the portion of the seedlings just below the seed leaves), with low to moderate amounts in the cotyledon (the first layer of leaves found on the seedling). The effects of these compounds in vitro have led to the hypothesis that soy isoflavones may be associated with a decrease in some cancers, especially hormone-dependent cancers such as breast and prostate, by inhibiting several key enzymes involved in carcinogenesis.19,20 In the past 5 years, genistein, an antioxidant and a tyrosine protein kinase inhibitor, has been receiving the most attention. It has demonstrated potent activity for inhibition of endothelial cell proliferation and in vitro angiogenesis at concentrations of 5 and 150 µmol/L. The results of several studies suggest that genistein may contribute to the preventive effect of plant-based diets on chronic diseases, including cancers, by this inhibition of neovascularization and cell proliferation.14 Pursuant to the hypothesis that soy phytoestrogens could alleviate hot flashes in breast cancer survivors, the current clinical trial was developed.
Patient Population Participants in this trial were women over 18 years of age with a history of breast cancer and currently without evidence of residual malignant disease. The study candidates were suffering from bothersome hot flashes, as defined by their occurrence of at least 14 times per week and of such severity to warrant intervention. Tamoxifen or raloxifene therapy was allowed if the patient had started such drug at least 4 weeks before registration and was planning to continue throughout the term of the trial. Patients must have had hot flashes for at least 1 month and had to have a life expectancy of 6 months or greater and an Eastern Cooperative Oncology Group performance score of 0 or 1. Current or planned therapies with antineoplastic chemotherapies, androgens, estrogens, progestational agents, or corticosteroids were contraindicated, as were any other agents for treating hot flashes, such as megestrol acetate, clonidine, vitamin E, and belladonna, phenobarbital, and ergotamine tartrate, or other soy products.
Study Design The soy product was formulated in 600-mg tablets containing 50 mg of soy isoflavones in each tablet. The formulated percentages of isoflavones were 40% to 45% genistein, 40% to 45% diadzein, and 10% to 20% glycitein. Patients were instructed to take one tablet three times a day, which would result in 150 mg of isoflavones per day, an amount similar to what would be consumed with three glasses of soy milk. The soy phytoestrogen and placebos were provided by Pharmavite, Mission Hills, CA. At randomization, patients were given a questionnaire booklet to record baseline hot flash frequency and intensity and any presence of diarrhea, nausea, vomiting, or excess bloating/gas. Patients were to document hot flash frequency and intensity daily and address toxicity questions weekly for 9 weeks using these questionnaires, which have been used in several previous trials.6,8,11,12 Patients were asked to grade the intensity of each hot flash as either mild, moderate, severe, or very severe. Although patients were allowed to make the final determination of how severe they considered each hot flash to be (eg, if a patient felt she was having a severe hot flash, who were we to tell her it was only a mild hot flash?), we did provide a definition of hot flash severities, as determined from patient-provided data from a previous study of ours.22 The weekly toxicity questions on these questionnaires asked patients to note (yes/no) whether they thought the study medications were causing any of the following side effects: diarrhea, nausea, vomiting, excess gas/bloating, or other (description requested). Compliance was monitored by the following two questions, which were to be addressed weekly: Are you continuing to take your study medication every day (yes/no) and how many tablets do you think you missed this week? Patients were to be contacted every 2 weeks by the oncology nurse, who was to document compliance, encourage completion of the questionnaires, and address any problems. At the completion of the 8-week double-blind phase, patients were asked to indicate their preference for one 4-week trial substance over the other on the last page of their questionnaire, then return their questionnaire to the medical center in a prepaid envelope.
Statistical Considerations
The following primary end point for this study is a bivariate construct representing hot flash activity: the number of hot flashes reported per day and a score combining the number and severity of hot flashes (ie, one point for a mild hot flash, two points for a moderate hot flash, three points for a severe hot flash, and four points for a very severe hot flash). The average value for each of these variables was calculated for each treatment period for input into a classic cross-over sums and differences analysis.25 This two-step procedure first tests for carryover effect. If carryover is observed, only data from the first time period is used. If carryover is not present, data from the second period is included in the analysis. Both procedures involve two-sample t tests and/or Wilcoxon rank-sum tests depending on the measurement level and normality of the data. The classic approach was supplemented by an approach using the intrapatient difference between hot flash activity (frequency and score) as a dependent variable in a linear model.25 The analyses were run using data from all 4 weeks in each treatment period and using only the last week in each treatment period to assess the sensitivity of results relative to the achievement of a steady-state level of hot flash activity by the fourth week of each treatment period. All treatment comparisons were made using two-sided testing and a 5% type I error rate. Because the bivariate primary end point involves two correlated constructs, we would consider as significant any test that achieved a P
Secondary end points included the amount of toxicity reported by patients when taking soy and placebo. This was examined by using the incidence of each toxicity reported in each treatment period. The analysis of this variable was the same as that for the primary end point. Other end points included the proportion of patients who reported a preference for soy or placebo and the proportion of patients who terminated protocol therapy prematurely on each treatment. These data were analyzed using simple Missing data were handled in a number of ways. First, only complete cases were used in the analysis (patients completing all 8 weeks of treatment). Subsequently, analyses using all available data were run in an intent-to-treat fashion. Finally, a series of analyses using various imputation methods (average value carried forward, last value carried forward, and minimum or maximum value carried forward) was carried out to assess the impact of missing data on the results. The amount of missing data in this study was small, and the results were consistent across the various approaches. The analytic procedures were supplemented by graphical representations of the daily and weekly hot flash activity data, both on individual patient data and aggregated into average scores for each treatment group. At study initiation, the calculated sample size was 150 women to provide 80% power for detecting a difference of one hot flash per day and two hot flash score points per day between the two groups using a two-sample t test and a two-sided alternative. The protocol accrued so rapidly that 182 patients were entered onto this protocol. Hence, the statistical procedures had sufficient power to declare any clinically important effect as statistically significant.
This protocol opened for accrual on March 6, 1998. A total of 182 patients were entered in the 2-month period between March 6, 1998, and May 11, 1998. All the patients were eligible for the study; however, five patients canceled their participation before starting any study treatment. Of the 177 eligible patients who initiated study medication, 155 patients (88%) provided useable data with regard to efficacy over the initial 5 weeks. One hundred forty-nine patients (84%) provided useable efficacy data for the entire 9 weeks of the study. The patients who did not provide useable hot flash data either stopped the study medications early or did not complete the diary forms appropriately or both. The patient characteristics at study entry are listed in Table 1 , illustrating that the two study arms seemed to be well-balanced for the all of the identified baseline factors.
The average hot flash scores over the baseline week are provided in Table 2 for the two treatment arms, demonstrating that the two study arms were well-balanced at baseline. Patients averaged roughly seven hot flashes per day (SD = 4.5), with an average score of 13 points (SD = 9.0). Thirty percent of the patients averaged more than 10 hot flashes per day at baseline, 53% had four to nine hot flashes per day, and the remaining 17% of patients had two to three hot flashes per day.
Efficacy evaluation is aptly illustrated in Fig 1, verifying the lack of any suggestion that the soy phytoestrogen preparation was any more effective in reducing hot flashes than was the placebo preparation. In fact, there was a mild trend for the placebo arm to do better than the soy phytoestrogen arm. If Fig 1 is prepared using hot flash number, as opposed to hot flash scores, an almost superimposable picture results. To better illustrate individual data, Fig 2 displays stream plots for patients receiving the soy product first and the placebo second. The reverse treatment order illustrates a similar picture. The percentages of patients reporting a less than 25%, 25% to 50%, and greater than 50% reduction in hot flash score were 40%, 22%, and 38%, respectively, for those receiving placebo and 44%, 21%, and 35%, respectively, for those receiving soy (P = .78). Among patients receiving placebo, 36% reported that hot flash frequency had been cut in half compared with only 24% of patients receiving soy (P = .01).
The analysis of variance methods23 for hot flash score and frequency produced nonsignificant P values for all treatment effect comparisons, regardless of period, sequence, or week of observation. The Bayesian analysis24 confirmed these findings, with P values ranging between .22 and.72 for the various test procedures for both hot flash frequency and score. Table 3 lists patient preferences at the end of the study period. These data failed to suggest any preference for the soy compound over the placebo preparation. Compliance analyses revealed that 91% of patients said they took their study medication every day, and 86% said that they missed less than 10% of all of their study tablets. There were no differences in these parameters between the two study products (soy v placebo). Toxicity analyses failed to demonstrate any suggestion of difference between the two study arms with regard to diarrhea, nausea, vomiting, or bloating/gas.
Recent lay literature and health magazines have been recommending soy-based products as a healthy and viable treatment for menopausal symptoms.4,13,17,27 An indication of the lay interest in soy products for hot flashes was illustrated by the enthusiastic patient response to this trial, leading to the accrual of 182 women in 2 months. Despite such claims and enthusiasm, we were unable to demonstrate any suggestion of benefit for the soy phytoestrogen we used in this current trial.
There have been three reported abstracts28-30 regarding phytoestrogens and hot flashes, but none of them present convincing evidence to suggest any substantial benefit for phytoestrogens, at least not more than might be expected from a placebo.6,8,11 To further elaborate on the most positive sounding of these three abstracts, an Israeli study randomized 78 assessable women to a phytoestrogen-rich diet versus 36 assessable women to a routine diet.30 Using a menopause symptoms questionnaire, this study did not note any substantial difference in menopause-associated symptoms (50% reduction of symptoms in the phytoestrogen group v 48% reduction in the control group). However, in what seems to be a subset analysis, these authors noted a 54% reduction in hot flashes in the phytoestrogen-rich diet group versus a 36% reduction in the control group (P Another manuscript32 reported that women taking a soy protein supplement had significantly fewer hot flashes than did those taking a casein placebo supplement. This was a randomized, double-blind, well-balanced study, with approximately 40 assessable patients per study arm. The reported magnitude of benefit over the placebo arm, however, was marginal. After 12 weeks in the soy group, there was a mean reduction of 1.59 hot flashes per day more than was seen in the placebo group (95% confidence interval, 1.2 to 1.95 hot flashes a day). This represents a 15% absolute reduction in hot flashes over the placebo (ie, approximately 30% reduction with placebo compared with approximately 45% reduction with the soy). These results are relatively similar to what has been previously reported with the use of vitamin E.11 Some critics might question the optimal daily dose required to recognize a clinical response. Cassidy et al33 cited a per capita estimated intake of 150 to 200 mg daily in the Asian diet, whereas Adlercreutz et al,34 after a small study of Japanese men and women, reported a daily intake of only 50 mg. These data endorse our choice of 150 mg per day as adequate. Others may consider the length of time on the soy isoflavones as too short to elicit a clinical response. However, it has been determined that genistein and diadzein plasma concentrations peak 6 to 8 hours after ingestion.35 Consequently, adherence to a daily ingestion of 150 mg should result in steady-state plasma concentrations early. We doubt that we might see a more positive response on a longer term trial. In summary, the available data strongly suggest that soy phytoestrogens do not substantially reduce hot flashes when compared with placebo. Admittedly, it is possible that another soy-based preparation might alleviate hot flashes, but a more definitive claim of such requires demonstration by a definitive clinical trial.
Additional participating members and institutions include: Roscoe Morton, MD, Iowa Oncology Research Association Community Clinical Oncology Program (CCOP), Des Moines, IA; John Michalak, MD, Siouxland Hematology-Oncology Associates, Sioux City, IA; Suresh Nair, MD, Geisinger Clinic and Medical Center CCOP, Danville, PA; Carl Kardinal, MD, Ochsner CCOP, New Orleans, LA; Maria Tria Tirona, MD, Saskatchewan Cancer Foundation, Saskatchewan, Canada; Loren Tschetter, MD, Sioux Community Cancer Consortium, Sioux Falls, SD; Daniel Walsh, MD, Altru Health Systems, Grand Forks, ND; Harold Windschitl, MD, CentraCare Clinic, St Cloud, MN; Ferdinand Addo, MD, Quain and Ramstad Clinic, Bismarck, ND; Larry Ebbert, MD, Rapid City Regional Oncology Group, Rapid City, SD.
Supported in part by Public Health Service grants no. CA-25224, CA-37404, CA-35195, CA-35113, CA-63848, CA-35269, CA-35415, CA-37417, CA-35101, CA-35103, CA-35448, and CA-35272 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.
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Loprinzi CL, Michalak JC, Quella SK, et al: Megestrol acetate for the prevention of hot flashes. N Engl J Med 331:347-352, 1994 7. Quella SK, Loprinzi CL, Sloan JA, et al: Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 82:1784-1788, 1998[Medline] 8. Goldberg RM, Loprinzi CL, O’Fallon JR, et al: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12:155-158, 1993[Abstract] 9. Nestheim B, Saetre T: Reduction of menopausal hot flashes by methyldopa: A double-blind crossover trial. Eur J Clin Pharmacol 20:413-416, 1981[Medline] 10. Bergmans M, Merkus J, Corbey R, et al: Effect of Bellergal retard on climacteric complaints: a double-blind, placebo-controlled study. Maturitas 9:227-34, 1987[Medline] 11. Barton DL, Loprinzi CL, Quella SK, et al: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. Oncol 16:495-500, 1998 12. Loprinzi CL, Pisansky TM, Fonseca R, et al: Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol 16:2377-2381, 1998[Abstract] 13. Franklin D: The healthiest women in the world. Health 9:57-63, 1996 14. Fotsis T, Pepper M, Adlercreutz H, et al: Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis. J Nutr 125:790S-797S, 1995 15. Barnes S, Peterson TG: Biochemical targets of the isoflavone genistein in tumor cell lines. Proc Soc Exp Biol Med 208:103-108, 1995[Medline] 16. Oddens BJ: The climacteric cross-culturally: The International Health Foundation South-East Asia study. Maturitas 19:155-6, 1994[Medline] 17. Barnes S, Kim H: Soy isoflavones, estrogens, and growth factor signaling. Connection 6:1-5, 1988
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Adlercreutz H, Honjo H, Higshi A, et al: Urinary excretion of ligands and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional Japanese diet. Am J Clin Nutr 54:1093-1100, 1991 35. Setchell KDR: Absorption and metabolism of isoflavones. Soy Connection 6:1-3, 1998 Submitted June 28, 1999; accepted November 1, 1999.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 years), the duration of their hot flashes (< 9 months v 
.025, using the Bonferroni approach.
2 tests. 
