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© 1999 American Society for Clinical Oncology Randomized Phase III Trial Comparing the New Potent and Selective Third-Generation Aromatase Inhibitor Vorozole With Megestrol Acetate in Postmenopausal Advanced Breast Cancer PatientsFrom the Division of Hematology-Oncology, Toronto Hospital-General Division, Toronto, Ontario, Canada; Dana-Farber Cancer Institute, Boston, MA; Department of Medical Oncology/Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada; and Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Paul E. Goss, MD, Division of Hematology/Oncology, Toronto Hospital-General Division, 200 Elizabeth St, MLW 2-022, Toronto, Ontario M5G 2C4, Canada.
PURPOSE: To compare the efficacy and safety of vorozole (VOR) 2.5 mg once daily with that of megestrol acetate (MA) 40 mg four times per day as second-line therapy in postmenopausal women with advanced breast cancer whose disease progressed after tamoxifen treatment. PATIENTS AND METHODS: A total of 452 patients were enrolled onto an open, multicenter, randomized phase III trial comparing VOR to MA for tumor response, safety, and quality of life (as indicated by the Functional Living Index-Cancer score). RESULTS: Vorozole produced a response rate of 9.7%, compared with 6.8% for MA (P = .24). Clinical benefit (complete response + partial response + no change in > 6 months) was demonstrated in 23.5% and 27.2% of patients treated with VOR and MA, respectively (P = .42). Median duration of response was 18.2 months for VOR versus 12.5 months for MA (P = .074). There was no significant difference in time to progression or survival between the treatment groups. Discontinuation of treatment because of adverse events occurred less frequently in the VOR-treated group (3.1% v 6.2%; P = .18). Patients on the VOR arm reported significantly more nausea, hot flushes, arthralgia, upper respiratory tract infection, anorexia, and paresthesia, whereas those treated with MA had significantly more dyspnea, increased appetite, and weight increase. There was no difference between the two treatment groups in Functional Living Index-Cancer scores (total or subscales). However, when analyzed by objective response, patients with complete or partial responses (P = .032) or no change (P = .033) who were receiving VOR had significant improvement in the psychologic well-being subscale, compared with patients given MA. CONCLUSION: Vorozole is well tolerated and as effective as MA in the treatment of postmenopausal advanced breast cancer patients with disease progression after tamoxifen treatment.
APPROXIMATELY ONE THIRD OF human breast cancers are estrogen dependent and regress after estrogen deprivation.1 In postmenopausal women, estrogens are derived almost exclusively from the peripheral aromatization of androgens to estrogens catalyzed by the aromatase enzyme system.2 Inhibition of aromatase leads to a marked decrease in tissue estrogen levels, producing a therapeutic effect.3 In addition, breast tumors frequently show intratumoral aromatase activity, providing a local supply of estrogens in the tumor.4 The aromatase enzyme is therefore an important target for the treatment of postmenopausal women with breast cancer. The antiestrogen tamoxifen is currently the drug of choice for adjuvant and first-line hormonal treatment of postmenopausal breast cancer patients5,6 and may achieve response rates of up to 30% in unselected patients.7 However, as disease progression occurs eventually in all patients who receive treatment with tamoxifen for advanced breast cancer (ABC) and in many who receive adjuvant tamoxifen, there is a need for new, effective, and well-tolerated therapies for the second-line management of this disease. Progestins and aromatase inhibitors have been the most commonly used endocrine agents, after tamoxifen, for the treatment of ABC in postmenopausal women. Progestins, such as megestrol acetate (MA), have been recognized since the 1960s as an effective second-line treatment for metastatic breast cancer. They reduce serum androgen levels by approximately 40%, leading to a reduction of about 30% in estrogen levels. Response rates of 4% to 32% have been reported with MA in advanced breast cancer and are similar to those reported for other endocrine therapies.8-13 Although MA is tolerated quite well by most patients, it may cause a gain in weight and has been associated with nausea and vomiting, hot flushes, vaginal bleeding, edema, and rash.14 Occasionally, cardiovascular and thromboembolic adverse effects are seen.11,12,15,16 The most widely used aromatase inhibitor has been aminoglutethimide, which is commercially available in Europe and Canada. Aminoglutethimide is a weak, nonselective inhibitor of aromatase and inhibits adrenal mineralocorticoid and glucocorticoid synthesis, necessitating concurrent corticosteroid supplementation. In addition, other adverse effects, such as lethargy, vertigo, ataxia, mental depression, insomnia, nystagmus, and rash, have been observed, and these adverse effects have limited the clinical use of this agent.16 Response rates of 28% to 37% have been reported when aminoglutethimide is used as hormonal therapy for advanced breast cancer.17 Attempts to improve the specificity and therapeutic index of aminoglutethimide have led to the development of second- and third-generation aromatase inhibitors. Formestane is a second-generation, selective aromatase inhibitor. It is commercially available but requires intramuscular injections and is associated with reactions at the injection site.18 Objective response rates of 24% to 35% have been reported with this agent when given as first-line treatment of advanced breast cancer.19 Third-generation oral aromatase inhibitors have been synthesized with enhanced potency and specificity, and recently published data from large, comparative clinical trials with several of these agents (eg, anastrozole [Arimidex] and letrozole [Femara]) have demonstrated the efficacy of these compounds.20,21 Vorozole (VOR) is a highly potent and selective third-generation aromatase inhibitor that can be administered as a once-daily oral dose.22 In pharmacodynamic studies in postmenopausal ABC patients, multiple-dose administration of VOR (2.5 mg/d) suppressed circulating estradiol and estrone levels by at least 90% to below the detection limits of highly sensitive estrogen assays.23,24 In a comparative multiple-dose pharmacodynamic trial in postmenopausal breast cancer patients, VOR 2.5 mg/d orally was found to be the optimal dose for obtaining maximal estrogen suppression, and this dose was selected for clinical use.23 In postmenopausal women, VOR racemate inhibited in vivo peripheral aromatase activity by 94% after single-dose administration.25 In patients pretreated with VOR before breast cancer surgery, intratumoral aromatase activity in tumor tissue specimens was reduced significantly by 88%, compared with that in untreated controls. Furthermore, significantly lower intratumoral estradiol and estrone levels were observed in tissue samples from pretreated patients.26 In four phase II studies, including 115 postmenopausal ABC patients, an overall response rate of 24% (range, 17% to 33%) and disease stabilization in an additional 36% (range, 4% to 37%) of patients was observed with VOR.27 In all of these trials, VOR was well tolerated. In this report, we present the results of a phase III trial comparing VOR with MA with regard to clinical efficacy, tolerability, and safety in postmenopausal ABC patients with disease progression after tamoxifen treatment.
Trial Design The trial was an open-label, multicenter, parallel group design conducted at 29 Canadian and 38 U.S. centers. Patients were randomized to receive either vorozole (Rivizor; Janssen Research Foundation, Beerse, Belgium) 2.5 mg, taken once daily in the morning, or megestrol acetate (Megace; Bristol-Myers Squibb, Evansville, IN) 40 mg, taken four times per day. To expedite enrollment, patients with nonmeasurable/nonassessable disease were entered, and eligible patients were stratified into three groups according to whether they had measurable, assessable, or nonmeasurable/nonassessable disease. All randomized patients were observed until disease progression or death. The primary objective was to compare the treatment groups with respect to response rates. Secondary objectives were to compare the treatment groups with respect to duration of response, time to progression, survival, safety, and subjective symptoms such as pain, performance status, and quality of life.
Patient Population Patients were excluded if they were receiving concurrent chemotherapy, endocrine therapy (eg, systemic glucocorticoids), or radiation therapy; had received radiotherapy within 2 weeks of trial participation; had received previous MA therapy; or had received additional systemic therapy subsequent to recurrence after adjuvant tamoxifen (stage I or II disease) or after tamoxifen as initial therapy for stage IV disease. In addition, the following patients were excluded: patients whose disease progressed before they had received 6 months of therapy with tamoxifen for stage IV disease, as they were considered primary hormone therapy failures; patients with an estimated survival of less than 3 months; patients with life-threatening visceral disease (CNS metastases, meningeal metastases, bone marrow metastases, lymphangitic pulmonary disease, multinodular [> 6] pulmonary metastases, or extensive hepatic involvement); patients with concurrent illnesses or important laboratory abnormalities that could prevent interpretation of results; patients with a history of serious thromboembolic disease; patients with concurrent or previous malignancy within the past 5 years except for superficial squamous or basal cell carcinoma of the skin; and patients with known hypersensitivity to ketoconazole and other imidazole drugs. Written informed consent was obtained from all patients before trial participation, and the protocol was approved by the institutional review boards at participating sites.
Clinical and Radiologic Assessments Chest x-rays, abdominal CT scans, and bone x-rays were repeated during follow-up only in patients in whom the presence of bone and/or visceral metastatic disease was detected at baseline. If, at any visit, disease progression was suspected, abdominal CT scans and bone scans were performed. Body weight and vital signs were recorded at entry and at each consecutive visit until disease progression. A standard 12-lead ECG was also taken at baseline, at 1 month, and at the end of treatment.
Primary Clinical Efficacy Objective Patients whose disease progression had been verified were withdrawn from the study and treated at the physician's discretion. All patients were observed until death, including those with disease progression or withdrawal for any reason (serious adverse event, noncompliance, or protocol violation).
Secondary Clinical Efficacy Objectives
Assessment of Symptomatology
Safety Analysis
Statistical Analysis The original sample size estimation called for 176 progression end points per treatment group to detect a hazard ratio of 1.35 in time to progression at the .05 significance level with 80% power using a two-sided log-rank test. Therefore, accrual of 180 patients per treatment group was required according to Schoenfeld's method.30 Adjusting for 20% loss to follow-up, 216 patients per treatment group (432 in total) was needed. An interim analysis was preplanned and performed after disease progression had been noted in the first 100 patients (50 per treatment group) to test whether the efficacy of VOR was considerably worse than that of MA (null hypothesis: hazard ratio of VOR v MA > 1.5) and to update the sample size estimate if necessary. A one-sided test was conducted at the .1 significance level, and this test had 94% power to detect the alternative that the hazard ratio of VOR to MA was 1. Thus, if the hazard ratio were more than 1.5, the chance to continue the trial was .10; and if the hazard ratio was 1, the chance to stop the trial for lack of efficacy was .06. The results of these analyses were made available only to the trial management committee, and no adjustment to the P values was required in the final analysis. The comparability between the two treatment groups at baseline was evaluated with respect to the demographic and baseline prognostic variables. For continuous variables (age, weight, duration of breast cancer) a two-way analysis of variance (ANOVA) was used. For ordinal categorical variables (performance status, MPAC pain descriptor score) and other categorical variables (ER status, use of tamoxifen), treatment groups were compared using the Cochran-Mantel-Haenszel (CMH) mean score test stratified by disease status. The overall response rate was analyzed using the CMH test for general association stratified by disease status for those patients with disease assessable for response. The 95% confidence interval (CI) of the treatment difference was calculated using the normal approximation to the binomial distribution. The best confirmed outcome was analyzed using the CMH mean scores test. The comparison between treatment groups for survival time, time to progression, and the duration of response was assessed by a stratified log-rank test.31 Survival curves were determined by the Kaplan-Meier product-limit estimator.32 Estimates of hazards ratios of VOR versus MA were derived by the Cox proportional hazards model stratified by baseline disease status.33 The comparison between treatment groups for ECOG performance status scores used the CMH mean scores test stratified by baseline disease status. The MPAC pain score, MPAC relief score, MPAC mood score, and total and subscale FLIC scores were analyzed using a two-way ANOVA model with effects for treatment, disease status, and treatment-by-disease-status interaction. The MPAC relief score was not available at baseline and was analyzed only at each visit and end point. All other parameters were analyzed at baseline using the original values and at other visits and end points using the changes in the values from baseline. End point analyses of change from baseline in CR/PR and NC patients were performed for MPAC scores, WHO analgesic use, and FLIC (total and subscales) scores; in these analyses, the end point was taken as the last visit in which patient was assessed as CR/PR or NC. Adverse events and laboratory data were analyzed descriptively. Changes in body weight and vital signs were analyzed using a two-way ANOVA model with effects for treatment-by-disease-status interaction. ECG interpretation at baseline, month 2, and treatment end point were also analyzed using the CMH general association test.
Study Population Between November 1991 and December 1995, 67 study centers enrolled 453 postmenopausal patients with advanced breast cancer whose disease progressed after tamoxifen treatment. The cutoff for data analysis was February 20, 1996, and as of this date, the median follow-up time was 11.6 months (range, 2.1 to 36.8 months) for patients given VOR and 9.9 months (range, 2.0 to 44.0 months) for patients given MA. Patients were randomized to receive VOR (225 patients) or MA (227 patients). One patient was withdrawn from the study owing to pleural effusion before commencing treatment. There were no significant differences in the baseline characteristics between the two treatment groups (Table 1). Duration of previous tamoxifen treatment as well as previous surgery and radiation therapy were also comparable between the two treatment groups.
Of the 452 patients enrolled onto this study, at the time of data analysis, 296 had reached a treatment end point (death or disease progression), 41 had discontinued study medication owing to adverse events or other reasons, and 115 were continuing in the study. The reasons for withdrawal are listed in Table 2.
Primary Clinical Efficacy Objective
Secondary Clinical Efficacy Objectives
In the VOR group, 78 patients had died by the cutoff date, compared with 73 patients in the MA group. The median survival time was 26.3 months with VOR and 28.8 months with MA (P = .94, stratified log-rank test) (Fig 3), and the estimated hazards ratio also was not significant (estimated hazards ratio, 1.01; 95% CI, 0.73 to 1.40; P = .94). Study end points are listed in Table 3.
Assessment of Patient Symptomatology There were no significant differences between the two treatment groups with regard to the WHO analgesic use scale at baseline (P = .80). Results for both groups were similar throughout the trial; however, at month 2, the MA treatment arm had an increased number of patients with a lower score (P = .03) (data not shown). An analysis of change from baseline in the WHO analgesic score by responders (PR + CR) and stable responders showed no difference between the VOR and MA groups (data not shown). Performance status, assessed by the ECOG criteria, was similar in both groups throughout the study period. Analysis of quality of life data did not reveal any significant overall differences between the treatment groups in the total FLIC score. Vorozole-treated patients showed significant improvement from baseline at months 6, 8, and 10, whereas no significant differences from baseline were noted for the MA treatment group. When an end point analysis of change in the total FLIC and subscale scores was performed for responders (CR + PR) and stable responders, VOR-treated patients scored significantly better than MA-treated patients in psychologic well-being in both groups of responders (CR + PR, P = .040; SD, P = .033) and in social functioning in stable responders only (P = .011) (Table 4, A and B). In stable responders, there was a trend for the VOR arm to score lower on the nausea subscale (P = .082) (Table 4B). Both VOR- and MA-treated patients reported significantly lower total FLIC scores at disease progression than at baseline, consistent with a general worsening of the disease with time.
Clinical Toxicity
Significantly more nausea (20.4% VOR; 11.0% MA), hot flushes (19.6% VOR; 7.0% MA), arthralgia (13.3% VOR; 7.5% MA), upper respiratory tract infection (8.9% VOR; 4.0% MA), anorexia (7.6% VOR; 2.6% MA), and paresthesia (4.4% VOR; 0.4% MA) were observed in the VOR arm, whereas significantly more dyspnea (14.2% VOR; 25.1% MA), increased appetite (1.3% VOR; 4.4% MA), and weight increase (1.3% VOR; 13.7% MA) were found in the MA treatment group. As seen in Fig 4, the percentage of patients with a 10% or greater weight increase at each visit increased over the treatment period in patients receiving MA, whereas this was not observed in the VOR treatment group. At the treatment end point, patients in the VOR group had a mean decrease in weight of 0.82 kg (P
In the assessment of hematologic, biochemical, and urinary safety parameters, no clinically relevant abnormalities were noted in either treatment group. In addition, no clinically relevant changes in mean body temperature, heart rate, blood pressure, respiration rate, or ECG findings were observed during the trial.
Second-line endocrine therapy for breast cancer should produce durable responses and be well tolerated. Optimal tolerance is essential to promote patient compliance and deliver maximal clinical benefit to the patient. Results from this multicenter trial indicate that VOR treatment produces durable objective responses in postmenopausal women with relapsed advanced breast cancer. The overall response rates (CR + PR) for patients treated with VOR and MA in the study were 9.7% and 6.8%, respectively. Strict response assessment criteria were used during the study, because interpretation of response criteria can vary considerably among clinicians.34 For this reason, an independent, blinded radiologic review was essential for a response to be counted in the objective response rate. Response rates obtained in our study were similar to those seen in other trials that incorporated strict criteria to assess response.9,20,35-39 No significant difference was observed between the trial arms with regard to the number of patients who derived clinical benefit (CR + PR + NC in > 6 months) from treatment. The duration of response for VOR-treated patients (18.2 months) showed a trend (P = .074) to be longer when compared with that for MA-treated patients (12.5 months). No significant differences were observed for time to progression and survival. Results from phase III trials with other third-generation aromatase inhibitors have been reported recently. Buzdar et al20 compared the third-generation aromatase inhibitor anastrozole (1 mg and 10 mg once daily) with MA (40 mg four times daily) in two randomized, multicenter, parallel group trials in postmenopausal women whose disease progressed after tamoxifen treatment; they reported response rates of 10.3%, 8.9%, and 7.9% with anastrozole 1 and 10 mg and MA, respectively. The observed differences were not statistically significant. For the three treatment groups, the duration of response ranged from 3 to 18 months. Stable disease (> 24 weeks) was demonstrated in 25.1% (1 mg anastrozole) 22.6% (10 mg anastrozole), and 26.1% (MA) of patients in the respective trial arms. No significant difference was observed among the three treatment groups for time to progression and survival. However, in an updated analysis, significant improvement in overall survival of patients given anastrozole 1 mg versus those given MA has been reported (26.7 v 22.5 months; hazards ratio, 0.68; P = .02). This improvement in survival was not seen in patients receiving 10 mg daily in the same trial.40 Another phase III trial compared two doses of letrozole (0.5 mg and 2.5 mg) with MA (160 mg once daily) in 551 postmenopausal advanced breast cancer patients. The observed overall response rate was 24% with letrozole 2.5 mg versus 16% for MA (P = .04). Letrozole 2.5 mg was also shown to prolong significantly the duration of objective response and time to treatment failure; however, no survival advantage was shown.21,41 Table 6 summarizes and contrasts the data from these trials with those of our study. These data support the effectiveness of aromatase inhibitors as second-line therapeutic agents in metastatic breast cancer. It is difficult, however, to assess which, if any, of these agents is superior in this patient population.
Weight gain in MA-treated breast cancer patients is a well-known adverse effect and has been reported to occur in up to 64% of patients.15 In our study, weight gain became more pronounced with time; this represents a disadvantage for patients who continue treatment for longer periods. In our trial, weight gain was reported as an adverse event in 13.7% of MA-treated patients versus 1.3% of VOR-treated patients. Similar results are seen in the anastrozole (12% v 2%) and letrozole (8.5% v 2.3%) studies.20,21 Treatment with VOR was well tolerated and generally comparable to treatment with MA. Patient withdrawal owing to adverse events was generally low; however, there were differences in the incidence of certain individual adverse events. No specific differences between the treatment groups in terms of the severity of adverse events or their relationship to drug treatment were noted. When adverse events are compared with those reported in the literature for anastrozole and letrozole in comparative trials versus MA, the incidence of dyspnea was higher in the MA arm in all three trials (anastrozole 9% v MA 21%; letrozole 9.2% v MA 16.4%; VOR 14.2% v MA 25.1%), whereas the incidence of hot flushes (anastrozole 12% v MA 8%; letrozole 5.7% v MA 3.7%; VOR 19.6% v MA 7.0%) and nausea (anastrozole 16% v MA 11%; letrozole 10.9% v MA 9.0%; VOR 20.4% v 11.0%) seemed to be higher in the VOR-treated patients.20,21 Analysis of pain, performance status, and analgesic use did not reveal any overall advantage to either treatment regimen. Sporadic differences were observed between the groups, but these were few and inconsistent. Pain and mood scales (MPAC) worsened in both treatment groups during the study, as did performance status, presumably because of the progression of disease. Of interest is the observation that in VOR-treated patients who were responders or had disease stabilization, significant improvement of psychologic well-being and social functioning (stable disease patients only) was reported. If the subscale and total FLIC scores are compared (Table 4, A and B), the VOR-treated group seems to have a slight improvement in comparison with the MA-treated group. As different quality-of-life scales were used in the anastrozole (Rotterdam Symptom Checklist) and letrozole (QLQ-C30) trials, no general comparisons can be made.42,43 In a recent abstract, Weinfurt et al44 demonstrated that patients given letrozole experienced a significant positive change in cognitive function compared with patients given MA. Thus, there may be a tendency for patients receiving aromatase inhibitors to have a slightly better quality of life compared with those given MA, although these data are preliminary. In summary, the results of this large, randomized clinical trial demonstrate that VOR is as effective as MA in the treatment of postmenopausal advanced breast cancer patients with disease progression after tamoxifen treatment. Vorozole was well tolerated, and its toxicity profile is similar to that of MA overall, although there were differences between the VOR and MA groups in the incidence of certain individual adverse events. Another large, multicenter, randomized trial has shown that VOR has clinical advantages compared with the first-generation aromatase inhibitor aminoglutethimide.45 Vorozole is an appropriate agent for use as second-line hormonal therapy when there has been progression after tamoxifen treatment. The low overall response rate for both VOR and MA emphasizes the need for further improvement in the treatment of ABC. The paucity of significant side effects, in particular weight gain, make the third-generation aromatase inhibitors appropriate for testing in the adjuvant setting. Such trials are now under way for anastrozole and letrozole.
Additional members of the Vorozole Study Group in North America Dr J. Giesbrecht, Hôtel Dieu Hospital, St. Catherines, ON, Canada; Dr M. Blackstein, Mt. Sinai Hospital, Toronto, ON, Canada; Dr A. Arnold, Hamilton Regional Cancer Centre, Hamilton, ON, Canada; Dr G. Burton, University Medical Center, Shreveport, LA; Dr R. Goel, Ottawa Regional Cancer Centre Civic Division, Ottawa, ON, Canada; Dr H. Muss, Dr G. Kimmick, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC; Dr A. Lyss, Missouri Baptist Cancer Center, St. Louis, MO; Dr J.N. Atkins, Southeastern Medical Oncology Center, Goldsboro, NC; Dr A. Keller, Warren Cancer Research Foundation, Tulsa, OK; Dr G. Cohen, Greater Baltimore Medical Center, Baltimore, MD; Dr L. Kaizer, Credit Valley Hospital, Mississauga, ON, Canada; Dr P. Klimo, Lions Gate Hospital, North Vancouver, BC, Canada; Dr J. Kogler, Sharp Health Care Center for Medical Research, San Diego, CA; Dr S. Verma, Ottawa Regional Cancer Centre General Division, Ottawa, ON, Canada; Dr J. Ragaz, BC Cancer Agency, Vancouver, BC, Canada; Dr P. Whitsitt, Dr E. Brankston, Oshawa Civic Hospital, Oshawa, ON, Canada; Dr T. Alberico, Sentara Cancer Institute, Norfolk, VA; Dr D. Hayes, Maine Center for Cancer Medicine, Portland, ME; Dr M. Levitt, Manitoba Cancer Foundation, Winnipeg, MA, Canada; Dr C. Williams, Allan Blair Cancer Centre, Regina, SK, Canada; Dr M. Yoffe, Rex Cancer Center, Raleigh, NC; Dr J. Hainsworth, Nashville Oncology/Hematology, Nashville, TN; Dr R. Hart, Oncology of Wisconsin, Milwaukee, WI; Dr G. Sledge, Indiana University Medical Center, Indianapolis, IN; Dr M. Citron, Long Island Jewish Medical Center, New Hyde Park, NY; Dr J.L. Wade, Cancer Care Associates, Decatur, IL; Dr P. Eisenberg, Marin Oncology Associates, Greenbrae, CA; Dr G. Harper, Albany Medical College, Albany, NY; Dr B. Pressnail, Royal Victoria Hospital, Barrie, ON, Canada; Dr M. Trudeau, Women's College Hospital, Toronto, ON, Canada; Dr D. Vergidis, Thunder Bay Regional Cancer Centre, Thunder Bay, ON, Canada; Dr D. Walde, Group Health Centre, Sault Ste. Marie, ON, Canada; Dr J. Dancey, The Toronto Hospital, Toronto, ON, Canada; Dr R. Dreicer, University of Iowa Hospital, Iowa City, IA; Dr J. May, Richmond Oncology Associates, Richmond, VA; Dr B. Norris, Saskatoon Cancer Centre, Saskatoon, SK, Canada; Dr E. Sterns, Kingston General Hospital, Kingston, ON, Canada; Dr B. Aron, University of Cincinnati Medical Center, Cincinnati, OH; Dr W. Chow, York County Hospital, Newmarket, ON, Canada; Dr F. Couture, L'Hôtel Dieu de Levis, Levis, PQ, Canada; Dr B. Issell, Dr L. Kolonel, Cancer Research Center of Hawaii, Honolulu, HI; Dr M. King, Mississauga General Hospital, Mississauga, ON, Canada; Dr D. Petrylak, Dr A. Yagoda, Columbia Presbyterian Medical Center, New York, NY; Dr S. Reingold, Peel Memorial Hospital, Brampton, ON, Canada; Dr R. Rosenbluth, Northern New Jersey Cancer Center, Hackensack, NJ; Dr R.M. Schuman, Middlesex Oncology, Edison, NJ; Dr H.D. Teitelbaum, Crystal Run Health Care LLP, Middletown, NY; Dr M. Thirlwell, Montreal General Hospital, Montreal, PQ, Canada; Dr M. Blumenreich, J.G. Brown Cancer Center, Louisville, KY; Dr V. Caggiano, Sutter Cancer Center, Sacramento, CA; Dr R. Dillman, Hoag Cancer Center, Newport Beach, CA; Dr D. Drosick, The Christ Hospital, Cincinnati, OH; Dr R. Ostenson, Good Samaritan Hospital, Puyallup, WA; Dr J. Robert, Hôpital du St. Sacrement, Quebec, PQ, Canada; Dr J. Dufresne, Centre Hospitalier, Sherbrooke, PQ, Canada.
Supported by a grant from Janssen Research Foundation, Beerse, Belgium.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40 IU/L). ER+ status was defined by a tumor ER content of 3 fmol/mg of protein initially (10 fmol/mg of protein after protocol amendment) or a positive ER-ICA (Abbott Laboratories, Abbott Park, IL) result. When ER status was unknown, only patients with a disease-free interval (time from primary diagnosis to the development of recurrent disease) of more than 2 years were included. All patients were fully ambulatory and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3. 
.05) end point was noted in both treatment groups; this increase was likely explained by disease progression. There were no significant differences between the treatment groups in the MPAC pain descriptor scale across visits. No significant differences were seen in the MPAC mood "change from baseline" score, although there was one instance in which the within-treatment-group pain score significantly improved (VOR at month 6). A statistically significant decrease in the MPAC mood scale (P 
