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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4765-4771 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.8274 Comparison of Menopausal Symptoms During the First Year of Adjuvant Therapy With Either Exemestane or Tamoxifen in Early Breast Cancer: Report of a Tamoxifen Exemestane Adjuvant Multicenter Trial Substudy
From US Oncology Research Inc, Houston, TX Address reprint requests to Stephen E. Jones, MD, Baylor-Charles A. Sammons Cancer Center, Texas Oncology PA, 3535 Worth St, Suite 600 Collins, Dallas, TX 75246; e-mail: Steve.Jones{at}usoncology.com
Purpose Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane. Patients and Methods Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor–positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom. Results Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane. Conclusion At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.
In the last 10 years, aromatase inhibitors (AIs) have been investigated as alternatives to tamoxifen for the treatment of postmenopausal women with hormone receptor–positive breast cancer (BC). Three major phase III randomized adjuvant trials (Arimidex, Tamoxifen, Alone or in Combination, Intergroup Exemestane Study [IES], and MA.17) have assessed anastrozole, letrozole, and exemestane, respectively, versus either tamoxifen or placebo de novo, or after treatment with tamoxifen.1-7 All three trials support the importance of AI therapy in the adjuvant treatment of postmenopausal women as an option for initial use or after treatment with tamoxifen.8 The absolute benefit of the anastrozole over tamoxifen is approximately 3%.3,4 A modest survival advantage has been observed when patients switch to exemestane from tamoxifen,3,4 and when letrozole is administered after tamoxifen in women with node-positive BC,3-7,9,10 but no survival benefit has been seen when anastrozole or letrozole was compared with tamoxifen. However, many quality-of-life (QOL) issues remain regarding long-term endocrine therapy for BC, especially the toxicities and risks associated with estrogen deprivation, including the onset of menopausal status or worsening of menopausal symptoms. Other long-term potential effects of AI therapy, such as those on cardiac or bone health, have recently been reported elsewhere3,4,11-13 but are not the subject of this study. This report presents the final analysis of a US Oncology substudy of the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial—a phase III, randomized, parallel-group, multicenter trial designed to compare the disease-free survival after 5 years of adjuvant exemestane versus 2.5 years of tamoxifen followed by 2.5 years of exemestane among postmenopausal women with early BC. Nine participating countries have contributed to the overall accrual of the TEAM trial. Results from this trial will be reported in the future for all patients entered onto the trial. Each country had the option of performing one or more substudies and reporting these separately. Researchers from Greece have published their substudy on lipids.14 US Oncology has conducted two substudies: one on bone mineral density15,16 and this substudy on the prevalence and changes over time of menopausal symptoms in 1,614 women registered onto the trial in the United States.17-19 Menopausal symptoms are common problems affecting the QOL for many women, including those receiving treatment for BC. Chemotherapy may produce temporary or permanent menopausal status in premenopausal women, and endocrine therapy can also exacerbate existing symptoms (eg, hot flashes, mood swings, vaginal symptoms, changes in libido, loss of memory) in hormone receptor–positive women who are already postmenopausal. In this substudy, we assessed the prevalence of 10 common menopausal symptoms in postmenopausal women as they entered onto the trial comparing exemestane to tamoxifen. Registration for the cohort of patients on the US Oncology portion (substudy of menopausal symptoms) of the TEAM trial began October 2, 2001, and the accrual of 1,628 patients was completed by July 8, 2003. Treatment during the first year of the substudy was double-blinded, allowing assessment of the differences in the prevalence and severity of symptoms between exemestane and tamoxifen.
Study Design Patients were randomly assigned 1:1 to receive oral therapy with 25 mg of exemestane daily for 5 years, or tamoxifen 20 mg daily for 2.5 or 3 years followed by 2 or 2.5 years of exemestane, for a total of 5 years, either as their only adjuvant therapy or after completion of adjuvant chemotherapy and/or radiation therapy. The trial was double-blinded for year 1 only, followed by open-label administration of the study drugs. The randomization procedure used a fixed block size within each of the stratification cells defined by two stratification factors: lymph node status (node negative, one to three nodes positive, or four or more nodes positive) and prior adjuvant chemotherapy (none; cyclophosphamide, methotrexate, and fluorouracil; anthracycline based; or taxane based). Patients previously treated with both a taxane and an anthracycline were assigned to a taxane substrata. Baseline prevalence, the incidence and severity of hot flashes, and other menopausal symptoms were assessed during the first year. The protocol for this substudy was approved by a central institutional review board with jurisdiction over specific sites that registered patients onto the study, and all patients signed an informed consent form before enrolling onto the study. The study was conducted in compliance with Good Clinical Practice guidelines (sixth International Conference on Harmonisation and the Declaration of Helsinki).20
Patients Patients were ineligible if their cancer could not be completely surgically resected with negative margins or if they had any one or more of the following: inflammatory BC, histologically positive supraclavicular nodes, ulceration/infiltration of local skin metastasis, neoadjuvant chemotherapy, ER- and/or PR-negative primary tumor or ER-negative and/or PR-unknown status, or evidence of distant metastasis. Patients currently receiving hormonal therapy as adjuvant therapy for prior BC, or with uncontrolled cardiac disease, other significant malignancies within the past 3 years, or other serious illnesses were also excluded.
Treatment Patients who stopped study medication for more than 4 weeks due to toxicities were considered to be off study treatment. Patients who missed doses for fewer than 4 weeks due to toxicities did not need to make up the doses. No dose escalations, reductions, or modifications of either study drug were permitted. In the case of any relapse, patients were to stop study medication and be placed off study treatment. Treatment after relapse was at the discretion of the investigator. Patients were to discontinue treatment if a serious adverse event occurred, consent was withdrawn, or unacceptable toxicity was experienced. Follow-up was continued for all patients, whether or not they discontinued treatment prematurely.
Assessments The following 10 common symptoms and their severity were assessed: vaginal discharge, vaginal dryness, vaginal bleeding, mood alteration (anxiety, irritability, and/or depression), impaired word finding and/or short-term memory, bone and/or muscle aches, low energy level, decreased libido, difficulty sleeping, and hot flashes. The first nine symptoms were assessed using a modified Kupperman index.22 Hot flashes were assessed using the validated tool of Loprinzi et al,24 which resulted in a hot flash score calculated for each patient. The questionnaire was self-administered. Patients estimated the average number of hot flashes they experienced in a 24-hour period (range, 0 to > 15) and the average intensity of the hot flashes (mild, 1; moderate, 2; severe, 3; and very severe, 4) over each preceding week to determine their score.24
Statistical Analysis A hot flash score was calculated for each patient as a bivariate construct represented by average hot flash count per 24 hours during the last 7 days x average intensity (0 to > 15 score, 1 to 4 severity).24
Data were analyzed and P values were assigned using repeated-measures analysis of variance; A total of 1,628 patients were registered between October 2, 2001, and July 8, 2003, of whom 1,618 were eligible. Four patients withdrew consent and the remaining 1,614 patients completed questionnaires; 7,286 completed questionnaires were analyzed. A total of 1,606 patients (99%) completed the questionnaires at baseline, 1,533 patients (95%) completed the questionnaires at 3 months, 1,453 patients (90%) completed the questionnaires at 6 months, 1,382 patients (85%) completed the questionnaires at 9 months, and 1.312 patients completed questionnaires for all five time periods, for an overall completion rate of 81% at 12 months. The sample size at each point was robust. Missing data, although infrequent, were not included in the analysis.
Demographics Of the 1,628 patients registered onto this substudy, 10 were found to be ineligible (six patients received neoadjuvant chemotherapy, one patient was found not to be menopausal, one patient did not show clear margins at surgery, one patient was ER negative/PR negative, and one patient received nonprotocol therapy during treatment). A total of 806 patients were randomly assigned to receive tamoxifen and 808 patients were randomly assigned to receive exemestane (Fig 1). The cohorts were demographically well matched. Patient characteristics are summarized in Table 1.
Comparison of Menopausal Symptoms During the first year of treatment, there were few instances of vaginal bleeding among women in either arm at baseline or throughout the study; no significant difference was observed between the arms. At baseline, 13.6% of women receiving tamoxifen and 12.2% of women receiving exemestane reported vaginal discharge; at 12 months, significantly more women treated with tamoxifen reported vaginal discharge than did those receiving exemestane (32% v 12%; P < .0001; Fig 2A). However, exemestane was associated with a significantly greater incidence of vaginal dryness at 12 months (50% v 42%; P = .0004; Fig 2B).
Mood alterations were common, as were incidences of impaired word finding. These symptoms were reported at baseline by 52% and 51% of women receiving tamoxifen, respectively, and 53% and 52% of women receiving exemestane, respectively. There were no significant differences between the two groups for either symptom at 12 months. More than 50% of the women reported bone and/or muscle aches at the time of study entry, with significantly fewer women treated with tamoxifen experiencing this symptom at 12 months than those treated with exemestane (70% v 77%; P < .0001; Fig 2C). There was no significant difference between the treatment arms in the incidence of low energy, even though the symptom was reported by approximately 74% of women at baseline and throughout the study. From baseline to 12 months, the incidence of decreased libido increased from 46% to 54% among women treated with tamoxifen and increased significantly from 47% to 58% among women receiving exemestane (P = .03; Fig 2D). Likewise, significantly more women treated with exemestane experienced difficulty sleeping during the study (P = .03, Fig 2E). For both treatment arms, the mean hot flash score (±SEM) peaked at 3 months at 3.9 ± 4.3 for tamoxifen versus 3.4 ± 3.9 for exemestane and decreased thereafter. At 12 months, women receiving tamoxifen had a significantly higher mean hot flash score (3.6 ± 3.9 v 2.9 ± 3.5; P = .03; Fig 3).
After 12 months of therapy, tamoxifen was associated with more frequent hot flashes and more vaginal discharge than exemestane. Exemestane was associated with increased incidences of vaginal dryness, bone and/or muscle aches, and difficulty sleeping. There was no significant difference between the agents for vaginal bleeding, mood alteration, impaired word finding, or low energy. Table 2 summarizes the results of the significance of each menopausal symptom during the first year of treatment.
The use of AIs has produced clear benefits over tamoxifen for disease-free survival (Arimidex, Tamoxifen, Alone or in Combination trial, IES, MA.17, and Breast International Group 1-98)1-7,9,10 as well as for overall survival in some trials (IES, MA.17).3-7 The potential toxicity/long-term consequences of AIs have been evaluated as well.2 The main concerns have been bone health and possible cardiovascular effects.1,2 Vascular events, in particular, have been presented in detail.1-4,9,10 In the current study, we evaluated short-term symptoms during 1 year, not toxicities or consequences of exemestane or tamoxifen during the first year of adjuvant hormonal therapy. Menopausal symptoms are common and troubling for many women, not only those with BC. The prevalence of hot flashes, mood changes, perceived memory loss, low energy level, decreased libido, and difficulty sleeping prompts many women to seek treatment to prevent or ameliorate these symptoms. Moreover, some younger women receiving adjuvant chemotherapy experience premature menopause, resulting in increased and sometimes abrupt onset of symptoms. In this report, we assessed the prevalence of 10 common menopausal symptoms among 1,614 postmenopausal women using a modified Kupperman index22 and Loprizi's hot flash score methodology.24 The focus of our study was the first year of double-blinded therapy, when we could assess differences in symptoms over time and between the use of exemestane and tamoxifen without patients' or physicians' awareness of which drug was administered. The tool we used was a self-administered questionnaire, which was completed at baseline (before any endocrine treatment) and every 3 months during the first year of double-blinded therapy. Modified versions of this questionnaire have been widely used.25-28 In addition, we included the hot flash score methodology utilized by Loprinzi et al.24 Patients self-reported the absence or presence of each symptom and the corresponding degree of severity. This was not a classic QOL study using other types of validated instruments as reported in some trials,29-32 but an assessment of a large cohort of patients over time using established techniques. The strengths of this study were the large number of women evaluated (n = 1,614), excellent compliance (7,286 completed questionnaires; 81% completion at 12 months), and the double-blinded design. We learned that menopausal symptoms are quite common in postmenopausal women not receiving endocrine therapy (baseline data; Table 3), with vaginal bleeding occurring rarely at baseline or within the first 12 months. Vaginal discharge also was uncommon at baseline (12% to 14%). Other symptoms were quite common among patients at baseline: vaginal dryness, mood alteration, or impaired word finding (approximately 40%); decreased libido (approximately 50%); bone/muscle aches and difficulty sleeping (approximately 60%); and low energy (approximately 75%; Table 3). At baseline, there were no differences between groups of women based on assigned treatment. This was the background against which we observed differences in endocrine symptoms between hormonal agents and over time during the first year of treatment.
It is well known that tamoxifen increases vaginal discharge. This finding was also observed in our study by 3 months, and the discharge increased over time. Exemestane was not associated with increased vaginal discharge. Conversely, there was slightly more vaginal dryness associated with exemestane compared with tamoxifen; both increased with time. Bone/muscle aches were common in both groups, but increased with exemestane over time. This observation was likely confirmation of the arthralgias observed with all AIs in other QOL studies,29-32 although a specific question regarding arthralgias or joint pains was not asked. Some of the bone/muscle aches observed were most likely related to age (60% of patients at baseline had bone or muscle pain), making it difficult for the clinician to determine the cause. This is an important distinction because drug-related symptoms can be ameliorated by stopping the AI or, anecdotally, switching to another AI in some patients. Unfortunately, when our study was developed in 2000, we did not specifically investigate arthralgias. Decreased libido was a frequent complaint that also worsened slightly (P = .03) with exemestane by the 1-year time point. Difficulty sleeping was similarly common but became more bothersome with exemestane throughout the 1-year study. Hot flashes increased in both frequency and intensity by 3 months and decreased thereafter, and were perceived as being significantly worse with tamoxifen versus exemestane. This finding has been supported by other AI trials and QOL substudies. Fallowfield et al30 found that hot flashes were the most commonly reported symptom (exemestane, 46%; tamoxifen, 45%), and that hot flashes decreased over time in both groups. Whelan et al32 reported significant differences in hot flashes between patients receiving placebo (17%) versus patients receiving letrozole after 5 years of tamoxifen (22%; P = .0002). For some patients, the difference in hot flash score between tamoxifen and exemestane might not be noticeable, but for others, switching from tamoxifen to exemestane might be perceived as an improvement. Our study, performed with a very large sample size, has confirmed the prevalence and severity of menopausal complaints in postmenopausal women with BC even at baseline. Some symptoms are exacerbated by the use of any endocrine agent over time, and others are product specific and may be related to the mechanism of estrogen blockade. Exemestane induces a pure estrogen deprivation state, whereas tamoxifen may exert an antagonist/agonist effect. Some of the differences between exemestane and tamoxifen may be clinically significant and quite noticeable to patients, whereas others may not. We hope this study raises awareness among oncology care providers about these symptoms, which may well be QOL issues faced by women receiving endocrine therapy for early BC. Although some menopausal symptoms may require only reassurance and practical management, such as for the vaginal discharge produced by tamoxifen, others may require multiple interventions or be refractory to treatment. Oncology care providers should be prepared to help patients choose among possible interventions for these symptoms, perhaps even including using the various AIs or tamoxifen followed by an AI to best suit their needs and to ensure long-term compliance with endocrine therapy.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: Stephen E. Jones, Pfizer Inc; Joyce O'Shaughnessy, Pfizer Inc Stock: N/A Honoraria: Stephen E. Jones, Pfizer Inc; Joyce O'Shaughnessy, Pfizer Inc; Frankie Ann Holmes, Pfizer Inc Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Stephen E. Jones, Joyce O'Shaughnessy Administrative support: Jean Kochis, Lina Asmar Provision of study materials or patients: Stephen E. Jones, James Cantrell, Svetislava J. Vukelja, John Pippen, Joyce O'Shaughnessy, Joanne L. Blum, Robert Brooks, Nicole L. Hartung, Donald A. Richards, Ragene Rivera, Frankie Ann Holmes, Sreeni Chittoor, Thomas L. Whittaker, James H. Bordelon, Steven J. Ketchel Collection and assembly of data: Stephen E. Jones, Angel G. Negron, Jennifer C. Davis, Lina Asmar Data analysis and interpretation: Stephen E. Jones, Joyce O'Shaughnessy, Frankie Ann Holmes, Des Ilegbodu, Lina Asmar Manuscript writing: Stephen E. Jones, Jean Kochis, Lina Asmar Final approval of manuscript: Stephen E. Jones, James Cantrell, Joyce O'Shaughnessy, Ragene Rivera, Thomas L. Whittaker, Lina Asmar Other: Jennifer C. Davis [Project management]
The following medical oncologists From the USON network institutions also participated in this study: Steven M. Abrams, Lauderhill, FL; Yousif Abubakr, Jacksonville, FL; Jose M. Acostamadiedo, Norfolk, VA; Sohail Akbani, Arlington, TX; Sohail Akbani, Arlington, TX; Burton F. Alexander, III, Norfolk, VA; Elsayed Aly, Indianapolis, IN; Mammo Amare, Dallas, TX; Thomas C. Anderson, Bedford, TX; W. Abe Andes, Pulaski, VA; Ruth C. Atkinson, Birmingham, AL; Larry J. Barker, Sherman, TX; David Barrera, Fort Worth, TX; Rebecca E. Barrington, Kerrville, TX; Stephen Beck, Birmingham, AL; Robert J. Belt, Kansas City, MO; Maury B. Berger, Ocala, FL; William R. Berry, Cary, NC; Roy A. Beveridge, Annandale/Fairfax, VA; Samer Bibawi, Cary, NC; George R. Birchfield, Seattle, WA; Stephen Boswank, Mesquite, TX; Michael A. Boxer, Tucson, AZ; Marcus P. Braun, Vancouver, WA; Barry D. Brooks, Dallas, TX; Donald Brooks, Tucson, AZ; Matthew Brouns, Vancouver, WA; Steven C. Buck, Tulsa, OK; Leslie Busby, Boulder, CO; Vikki A. Canfield, Oklahoma City, OK; Birmingham, AL; Thomas H. Cartwright, Ocala, FL; Michela Caruso, Mesquite, TX; John R. Caton, Jr, Spokane, WA; Aparna R. Chacko, Tyler, TX; Edward Chang, Tualatin, OR; Byron Chesbro, El Paso, TX; Ernest W. Cochran, Paris, TX; Charles Connor, Plano, TX; Dennis Costa, Lewisville, TX; John V. Cox, Dallas, TX; Jeffrey M. Crane, Raleigh, NC; Thomas J. Cunningham, Troy, NY; Galen M. Custer, Overland Park, KS; Kathy Dagg, Norman, OK; John Davis, Kansas City, MO; Randall T. Davis, Bedford, TX; Robert Delaune, Maplewood, MN; Pasquale R. Delizio, Wichita Falls, TX; David Dennis, Plantation, FL; Nicholas J. DiBella, Aurora, CO; Philip Y. Dien, Burnsville, MN; Kawaljit Dinsa-Chester, Spokane, WA; David Dong, Seattle, WA; Thomas P. Ducker, St. Paul, MN; Joseph J. Dudek, Albany, NY; Lewis A. Duncan, Longview, TX; Gerald Edelman, Irving, TX; Manana Elia, Lee's Summit, MO; Maha A. Elkordy, Cary, NC; Sukumar Ethirajan, Overland Park, KS; Anne M. Favret, Annandale/Fairfax, VA; William Fintel, Salem, VA; John T. Fleagle, Boulder, CO; Peter S. Francis, Alexandria, VA; Stephen J. Frank, Lakewood, CO; Larry Frase, Longview, TX; Susan E. Myers Freeman, Aurora, CO; David J. Friedman, San Antonio, TX; Ralph Ganick, Oklahoma City, OK; Lawrence E. Garbo, Albany, NY; Bonni Lee Gearhart, Colorado Springs, CO; Larry J. Geier, Kansas City, MO; Brian V. Geister, Oklahoma City, OK; Edward R. George, Norfolk, VA; Robert H. Gersh, Spokane, WA; Dean H. Gesme, Cedar Rapids, IA; Habib Ghaddar, Weslaco, TX; Chirantan Ghosh, Cedar Rapids, IA; Jeffrey K. Giguere, Easley, SC; William Larry Gluck, Greenville, SC; Jane B. Golden, Seattle, WA; Rudolf H. Good, Sherman, TX; David H. Gordon, San Antonio, TX; Ira Gore, Jr., Birmingham, AL; Allen Greenberg, Plantation, FL; Bruce Greenfield, Santa Fe, NM; Andrew R. Greenspan, Indianapolis, IN; Daniel Gruenberg, Portland, OR; Manish Gupta, Garland, TX; David Hakimian, Niles, IL; Keith Hansen, Portland, OR; Elizabeth A. Harden, Newport News, VA; Jimmie H. Harvey, Birmingham, AL; Lanny I. Hecker, Phoenix, AZ; Ioana Hinshaw, Denver, CO; Stuart Hinton, Kansas City, MO; Pamela J. Honeycutt, Columbia, MO; Judith O. Hopkins, Winston-Salem, NC; Victor W. Horadam, Mesquite, TX; John Russell Hoverman, Austin, TX; Kevin K. Hunger, Jacksonville, FL; Jack R. Hutcheson, Jr., Roanoke, VA; James K. Hwang, Fishers, IN; William J. Hyman, Tyler, TX; Jeffrey D. Isaacs, Phoenix, AZ; Don V. Jackson, Asheville, NC; Jaswant S. Jadeja, Jacksonville, FL; Sharad K. Jain, Denton, TX; Michael J. Johnson, Boulder, CO; Nadine Johnson, Kansas City, KS; Rodger L. Johnson, St. Paul, MN; Monte F. Jones, Plano, TX; Keith M. Justice, St. Augustine, FL; Bruce Kaden, Niles, IL; Michael Kahn, Wheaton, IL; Daniel Katcher, Manassas, VA; Vivek S. Kavadi, Dallas, TX; Stephen S. Kennedy, Roanoke, VA; J. Michael Kerley, Paris, TX; John F. Kessler, Newport News, VA; Pankaj Khandelwal, Odessa, TX; Bibi Khoyratty, Edina, MN; Robert L. Kirby, Plano, TX; Leonard Kosova, Niles, IL; Rama K. Koya, Longview, TX; Lea K. Krekow, Bedford, TX; Scott Kruger, Newport News, VA; Paul R. Kuefler, Flagstaff, AZ; Leila Kutteh, Cedar Rapids, IA; Alan D. Langerak, Tulsa, OK; Lisa C. Larson, Birmingham, AL; Gary L. Lee, Eugene, OR; Henry K. Lee, Scottsdale, AZ; Michael E. Lee, Norfolk, VA; Irving J. Lerner, St. Paul, MN; Deborah L. Lindquist, Sedona, AZ; David M. Loesch, Indianapolis, IN; Keith W. Logie, Fishers, IN; John (Jay) H. Lohrey, Bartlesville, OK; Regan M. Look, Portland, OR; Arsenio G. Lopez III, El Paso, TX; Jose A. Lopez, Fredericksburg, TX; Bruce T. Lyman, Albany, NY; Suneel Laxman Mahajan, Jacksonville, FL; Romeo Mandanas, Oklahoma City, OK; Billie J. Marek, McAllen, TX; Robert Marsh, Manassas, VA; Thomas A. Marsland, Orange Park, FL; Carmen Matei, Colorado Springs, CO; John Q.A. Mattern II, Newport News, VA; Harry E. McCoy, Christiansburg, VA; Joseph D. McCracken, San Antonio, TX; Robert McCreary, Clearwater, FL; Richard A. McGee, Edmonds, WA; Kristi J. McIntyre, Dallas, TX; Scott A. McKenney, Beaumont, TX; Barry McKenzie, Springfield, OR; Richard J. McKittrick, Kansas City, MO; Diana C. Medgyesy, Ft. Collins, CO; Anton Melnyk, Jr., Abilene, TX Jose Melo, Plantation, FL; Robert G. Mennel, Dallas, TX; Clinton F. Merrill, Ft. Collins, CO; Manuel R. Modiano, Tucson, AZ; Michael A. Monticelli, Springfield, OR; Linda Moors, Tucson, AZ; Richard J. Mundis, Overland Park, KS; Magaral S. Murali, Fishers, IN; Bronagh Murphy, St. Paul, MN; J. William Myers, Austin, TX; Mark C. Myron, Overland Park, KS; Sowjanya Nagabhirava, Denton, TX; Mohammed Nashawaty, Minneapolis, MN; Marcus Neubauer, Overland Park, KS; Joni C. Nichols, Spokane, WA; John E. Nugent, Fort Worth, TX; Jairo Olivares, Garland, TX; Kevin Olson, Tualatin, OR; Gregory J. Orloff, Annandale/Fairfax, VA; Mark A. O'Rourke, Greenville, SC; Rebecca L. Orwoll, Portland, OR; Brian M. Osgood, Lee's Summit, MO; Alvin L. Otsuka, Lakewood, CO; Yvonne L. Ottaviano, Owings Mills, MD; William J. Paladine, New Port Richey, FL; Michael Park, Lewisville, TX; Gregory A. Parker, Oklahoma City, OK; Mrugesh P. Patel, Arlington, TX; Devchand Paul, Denver, CO; Kelly Pendergrass, Kansas City, MO; George M. Perrine, Birmingham, AL; Robert E. Pluenneke, Kansas City, MO; Sucharu Prakash, Paris, TX; Christina W. Prillaman, Williamsburg, VA; Robert Quackenbush, Spokane, WA; Robert N. Raju, Dayton/Kettering, OH; Ashutosh Rastogi, Midland, TX; Syed N. Raza, Abilene, TX; Mark W. Redrow, Fort Worth, TX; James Reeves, Oklahoma City, OK; Alvaro Restrepo, McAllen, TX; Craig H. Reynolds, Ocala, FL; Randy Rich, Arlington Heights, IL; Paul D. Richards, Salem, VA; Veronica Roa, Eugene, OR; Gerald Robbins, New Port Richey, FL; Nicholas J. Robert, Annandale/Fairfax, VA; Michael Roberts, Phoenix, AZ; Tammy Roque, Sherman, TX; Larry A. Rosen, Lee's Summit, MO; Richard K. Rosenberg, Tucson, AZ; Paul E. Rosenthal, North Adams, MA; Robert Rotche, Christiansburg - Radford, VA; Steven R. Rousey, Edina, MN; Robert L. Ruxer Jr, Fort Worth, TX; John Sandbach, Austin, TX; Michael A. Savin, Dallas, TX; Robert L. Sayre, Colorado Springs, CO; Mark D. Sborov, Edina, MN; Gerald L. Schertz, Roanoke, VA; Andrew M. Schneider, Lauderhill, FL; Joseph J. Schulz, Newport News, VA; Jonathan E. Schwartz, Tucson, AZ; Scot M. Sedlacek, Denver, CO; Ketan S. Shah, Dayton/Kettering, OH; Spencer Shao, Portland, OR; Neeraj R. Sharma, Longview, TX; Maureen H. Sheehan, Kansas City, MO; Richard S. Siegel, Arlington Heights, IL; Sandeep Singh, Bedford, TX; Christopher Sirridge, Kansas City, MO; Mark A. Sitarik, Boulder, CO; David A. Smith, Vancouver, WA; Gary Spitzer, Greenville, SC; Jack J. Sternberg, Little Rock, AR; Christopher T. Stokoe, Plano, TX; Scott Stone, Plano, TX; J. Wynn Sullivan, Palatka, FL; Linda S. Sylvester, Orange Park, FL; Raymond Taetle, Tucson, AZ; Valiant Dee Tan, Norfolk, VA; Matthew A. Taub, Plantation, FL; Sudha Teerdhala, Mesquite, TX; Daniel S. Temeles, Roanoke, VA; John Thachil, Wichita Falls, TX; Unni Thomas, Jacksonville, FL; Laurence K. Tokaz, Austin, TX; Russell C. Tolley, Thornton, CO; Stephen J. Tremont, Raleigh, NC; Kent A. Tucker, Birmingham, AL; Elizabeth A. Valentine, Rexford, NY; Mark J. Vellek, Columbia, MO; Hemachandra Venkatesh, Indianapolis, IN; Frank Ward, Tyler, TX; Jeffery C. Ward, Edmonds, WA; David L. Watkins, Midland, TX; Robert S. Wehbie, Raleigh, NC; Kevin S. Weibel, Tulsa, OK Eric L. Weinshel, Burnsville, MN; Ralph Weinstein, Portland, OR; Charles S. White, Dallas, TX; Martin Wiesenfeld, Cedar Rapids, IA; Sharon Wilks, San Antonio, TX; Kevin S. Windsor, Birmingham, AL; Nini Wu, Albany, NY; Kim Hont A. Yee, Spartanburg, SC; Mark Yoffe, Raleigh, NC; James A. Young, Tulsa, OK; Kenneth D. Zeitler, Raleigh, NC; Harvey Zimbler, Pittsfield, MA; Charles J. Zinn, Colorado Springs, CO; Alexander Zweibach, New Braunfels, TX
We thank the patients who shared their experiences with US Oncology physicians (see Appendix); the site coordinators in the field; data reviewer Tamara Young, who ensured the accuracy and integrity of the data; and Kristi A. Boehm, who provided writing and editing assistance.
Supported by Pfizer Inc, New York, NY. Presented at the San Antonio Breast Cancer Symposium, December 3-6, 2003, and December 8-11, 2005, San Antonio, TX, and the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
was set at .05. The GenMod procedure (general models) was used to calculate the probabilities of levels for all 10 menopausal symptoms. At each visit (3, 6, 9, and 12 months), the proportion of patients with the combined intensity of mild, moderate, and severe was plotted by treatment arm. 
