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© 2001 American Society for Clinical Oncology Phase III, Multicenter, Double-Blind, Randomized Study of Letrozole, an Aromatase Inhibitor, for Advanced Breast Cancer Versus Megestrol AcetateByFrom the University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine, Houston, TX; St Thomas Medical Group, Nashville, TN; Baptist Medical Center, Columbia, SC; Ziekenhuis Rijnstate, Arnhem, the Netherlands; North Middlesex Hospital, London, and St Margaret’s Hospital, Essex, United Kingdom; and Cross Cancer Institute, Edmonton, Alberta, Canada. Address reprint requests to Aman Buzdar, MD, Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, Box 424, 1515 Holcombe Blvd, Houston, TX 77030; email: abuzdar{at}mdanderson.org
PURPOSE: To compare two doses of letrozole (0.5 mg and 2.5 mg every day) and megestrol acetate (40 mg qid) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: This double-blind, randomized, multicenter, multinational study enrolled 602 patients, all of whom were included in the primary analysis in the protocol. Patients had advanced or metastatic breast cancer with evidence of disease progression while receiving continuous adjuvant antiestrogen therapy, had experienced relapse within 12 months of stopping adjuvant antiestrogen therapy given for at least 6 months, or had experienced disease progression while receiving antiestrogen therapy for advanced disease. Tumors were required to be estrogen receptor– and/or progesterone receptor–positive or of unknown status. Confirmed objective response rate was the primary efficacy variable. Karnofsky Performance Status and European Organization for Research and Treatment of Cancer quality-of-life assessments were collected for 1 year. RESULTS: There were no statistically significant differences among the three treatment groups for overall objective tumor response. Patients treated with letrozole 0.5 mg had improvements in disease progression (P = .044) and a decreased risk of treatment failure (P = .018), compared with patients treated with megestrol acetate. Letrozole 0.5 mg showed a trend (P = .053) for survival benefit when compared with megestrol acetate. Megestrol acetate was more likely to produce weight gain, dyspnea, and vaginal bleeding, and the letrozole groups were more likely to experience headache, hair thinning, and diarrhea. CONCLUSION: Given a favorable tolerability profile, once-daily dosing, and evidence of clinically relevant benefit, letrozole is equivalent to megestrol acetate and should be considered for use as an alternative treatment of advanced breast cancer in postmenopausal women after treatment failure with antiestrogens.
UNTIL A CURE can be found, the treatment of advanced breast cancer focuses on slowing or stopping tumor growth for as long as possible and maintaining the patient’s quality of life. Endocrine therapy, an effective, minimally toxic, palliative treatment, represents the best therapeutic option for many patients. Tamoxifen is currently the most widely used endocrine therapy. Approximately 40% to 50% of patients who relapse after tamoxifen may achieve clinical benefit from second-line endocrine agents.1-3 Progestins and nonspecific aromatase inhibitors have been the most commonly used second-line agents, with megestrol acetate and aminoglutethimide historically selected as the mainstay of second-line therapy. However, new molecules have been discovered that more specifically target aromatase.4 These include anastrozole, formestane, and letrozole, and all of them seem to provide better tolerability and more convenient administration than megestrol acetate or aminoglutethimide.5-7 Response rates for the new options seem to be similar in metastatic breast cancer. About 20% to 30% of patients achieve an objective response with an additional 10% to 20% of patients achieving stable disease.4,6-9 Thus, the more specific aromatase inhibitors are a reasonable choice for second-line therapy. Letrozole is a highly potent, orally active, nonsteroidal competitive inhibitor of the aromatase enzyme system that effectively inhibits the conversion of androgens to estrogens, both in vitro and in vivo.10,11 In postmenopausal patients with advanced breast cancer, daily doses of letrozole from 0.1 to 5 mg suppress plasma levels of estradiol, estrone, and estrone sulfate to more than 75% to 95% from baseline in all patients, with no clinically relevant effects on other hormones of the endocrine system, including glucocorticoids, mineralocorticoids, and thyroid hormones.12-15 Two large randomized, controlled, multinational studies were conducted to assess the efficacy and safety of letrozole in postmenopausal women with advanced breast cancer who progressed despite antiestrogen therapy. Results from the first study indicated that once-daily treatment with letrozole 2.5 mg demonstrated a significantly higher objective tumor response rate than both letrozole 0.5 mg every day (qd) (P = .004) and 160 mg of megestrol acetate qd (P = .04), with overall objective tumor response rates of 24%, 13%, and 16%, respectively.8 Letrozole 2.5 mg was also notably more effective than megestrol acetate, considering the duration of objective response (median, 33 months v median, 18 months; P = .02) and time to treatment failure (TTF) (P = .04).8,16 Results from the second study indicated that once-daily treatment with letrozole 2.5 mg was superior to aminoglutethimide 250 mg given twice daily along with corticosteroid supplementation for time to progression (TTP) (P = .008), TTF (P = .003), overall survival (P = .002), and duration of clinical benefit.17 The majority of adverse experiences were mild or moderate in severity. The five most frequently reported adverse events in letrozole-treated patients were musculoskeletal pain, fatigue, headache, nausea, and arthralgia. The present multicenter, international, double-blind, randomized study was conducted to compare two doses of once-daily letrozole, 0.5 mg and 2.5 mg, to megestrol acetate qid in postmenopausal women with advanced breast cancer previously treated with an antiestrogen. Previously published studies involving the new generation of aromatase inhibitors had a limited follow-up period. Data reported here, beginning with the first visit of the first enrolled patient, cover a 4-year period that included a 30-month enrollment period and 18 months of follow-up from the first visit of the last patient enrolled. In addition, a survival update was performed 37 months after the first visit of the last patient enrolled. Fifty-six patients were still on treatment at the time of the primary analysis, which included objective response rate (ORR), duration of response, TTP, and TTF.
Patients Postmenopausal women with histologically or cytologically confirmed breast cancer who presented with either locally advanced or locoregionally recurrent disease or had metastatic disease were enrolled onto the study. Tumors were required to be either estrogen receptor (ER) and/or progesterone receptor (PgR) positive. Unknown status of ER and PgR was acceptable for study entry if no assay had been conducted. Patients were eligible if they had either relapsed while receiving continuous adjuvant antiestrogen therapy (eg, tamoxifen) or had relapsed within 12 months of stopping adjuvant antiestrogen therapy that had been administered for at least 6 months. Patients were also eligible if they progressed while receiving first-line antiestrogen therapy for advanced disease. Patients were permitted to have received up to two regimens of chemotherapy for advanced disease before trial entry provided that at least one had been administered before antiestrogen therapy. At the start of the study, patients were required to have the bulk (> 50%) of their tumor burden measurable and/or assessable. This criterion was found to unduly restrict patient enrollment, so inclusion criteria were amended to require patients to have at least one measurable and/or assessable tumor lesion. Patients were entered onto the study within 3 months of objective evidence of disease progression.
Patients included women previously treated with chemotherapy, corticosteroids, immunotherapy/biologic response modifiers (eg, interferon), antiestrogen treatment, either as adjuvant therapy or as therapy for advanced disease, or neoadjuvant treatment with endocrine therapy or chemotherapy. Patients were required to have discontinued any systemic anticancer treatment at the time of study entry. Any radiation therapy was completed at least 14 days before study entry. Patients had to have recovered from all reversible toxicities of any therapy administered before study entry. All patients were required to be postmenopausal as defined by one of the following criteria: women
All patients were estimated to have, in the opinion of the investigator, a life expectancy of at least 6 months and a Karnofsky performance status score of
Exclusion criteria included the existence of malignancies at other sites All patients gave written informed consent to participate in the study, which was approved by the local institutional review board or ethics committee for each study site. The study was conducted according to Good Clinical Practice guidelines.
Study Design Patients were allowed to receive radiotherapy to areas not being evaluated for tumor response or corticosteroids (topical or aerosol) for obstructive airway disease or nonmalignant skin lesions. Patients who received anticancer treatments, concomitant corticosteroid treatments other than those noted, bisphosphonates, or investigational drugs were not eligible participants for this study. A single treatment course of bisphosphonate, however, was permitted during the study for the treatment of hypercalcemia resulting from tumor flare, if saline hydration, diuretics, or calcitonin had been ineffective. Patient visits were scheduled at the beginning of study participation, at 2 weeks, 4 weeks, monthly through 6 months, and then every 3 months. Patients who responded with either a complete response (CR) or partial response (PR) or had stable disease continued treatment until disease progression or withdrawal for another reason. On discontinuation from the study, patients were to be followed until death or until lost to follow-up for a period of 60 months from their first study visit. Patient survival information was collected every 6 months. Patients were evaluated for tumor response at 3 months after the start of therapy and then every 3 months thereafter. An evaluation was also done if the patient discontinued treatment. Tumor response was evaluated by the investigator at the site according to International Union Against Cancer criteria specified by the protocol and by a designated central radiologist at each site who remained blinded. Measurable disease, whether bi- or unidimensional, was assessed either by palpation or on radiologic assessment (x-ray, abdominal ultrasound, or computed tomography scan). For multiple lesions, the tumor size equaled the sum of the products of the diameters of all lesions. Nonmeasurable, assessable tumors were not measurable by ruler or caliper but were assessed and evaluated by physical or radiologic evaluation. Response or increasing disease could only be estimated. Methodology for tumor assessment was to remain consistent throughout the course of the study. Full tumor evaluation, including the above procedures, was performed at baseline and at months 6 and 9. At month 3 and at visits subsequent to month 9, only areas positive for disease were evaluated unless warranted by the development of signs and symptoms indicating disease progression. All evaluations of objective tumor response (CR or PR) required confirmation after at least 4 weeks. Patients who did not show persistence of the initially observed response at the confirmatory evaluation were not considered to be responders.
Response was defined as CR, PR, no change, or progressive disease. A CR was defined by the disappearance of all known disease, confirmed by two observations not less than 4 weeks apart. PR was defined as a decrease in tumor size of 50% or more (either measured or estimated in the case of measurable or assessable disease), confirmed by two observations not less than 4 weeks apart. In addition, there could be no appearance of any new lesions or progression of any known lesion(s). Objective tumor response included both confirmed CR and PR. Secondary efficacy measures included duration of response, duration of clinical benefit, TTF, TTP, and time to death (TTD). Duration of response was defined as the time from the date of randomization to the earliest date of documented disease progression or death from cancer or unknown cause. The time was censored at the cutoff date for analysis for patients still in response. Duration of clinical benefit was calculated only for those patients who had a confirmed objective tumor response or stable disease for Tumor symptoms were evaluated at every visit. Assessments of Karnofsky performance status and measures of quality of life, including physical, role-related, emotional, cognitive, and social functioning; fatigue; nausea or vomiting; pain; dyspnea; insomnia; appetite loss; constipation; diarrhea; and financial difficulties, using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (EORTC QLQ-C30 version 2.0)18,19 were obtained each month for the first 6 months and at 9 and 12 months. These assessments, though not part of the planned efficacy or safety analyses, were planned to support the safety and tolerability data collected during this trial. Patients received a complete physical examination at study initiation and at 3, 6, 9, and 12 months. Safety was assessed using the National Imstitutes of Health/National Cancer Institute common toxicity criteria and selected laboratory parameters to score severity of adverse experiences.20 Additionally, routine measurements of weight, blood pressure, pulse rate, ECG, chest x-ray, hematology/chemistries, and urinalysis were completed.
Statistical Methodology All analyses were based on the intent-to-treat approach. All statistical tests performed were two-sided, with a .05 level of significance. Two-sided 95% confidence intervals for the odds ratio for each treatment comparison were also presented. No adjustments for multiple comparisons or multiple end points were made. The primary efficacy variable was the confirmed best overall objective tumor response rate and was analyzed using a logistic regression procedure both adjusted and unadjusted for prognostic baseline covariates (disease-free interval, dominant site of disease, prior antiestrogen therapy, stage of disease, and locally advanced, locoregionally recurrent, or metastatic breast cancer at study entry). Although there were two letrozole arms, the statistical significance was based only on pair comparison. Cochran Mantel-Haenszel tests were performed to compare ORRs according to the covariates that were thought to have an effect on overall objective response (disease-free interval, dominant site of disease, stage of disease at study entry, and history of antiestrogen therapy). A Cox proportional hazards regression analysis was performed on the intent-to-treat population for the median time to event and 95% confidence intervals for variables, including duration of response, duration of clinical benefit, time to response, TTP, TTF, and TTD. No adjustments for multiple comparisons or multiple end points were made. A longitudinal analysis on quality of life was performed using a pattern-mixture model. The criterion for the pattern classification was based on whether the patient was receiving the study drug 6 months or longer. Adverse experiences were summarized in terms of the number of patients who experienced an event in each treatment arm, and by relationship to treatment, severity of the event, and duration of exposure to study medication.
Patients A total of 602 patients from 120 centers in seven countries were randomized in the study over a 30-month period, with approximately two thirds of the enrolled patients treated in the United States. All analyses were based on the intent-to-treat approach, where the intent-to-treat population was defined as the set of randomized patients who took at least one dose of trial medication. All patients, regardless of their length of trial treatment, were included in the intent-to-treat analysis. Of the 602 patients included in the intent-to-treat analyses, a total of 23 patients (3.8%) were considered noneligible and therefore were excluded from the acceptable patient analyses of tumor. A separate analysis of the primary end points conducted on the acceptable patient population showed no difference in results to the same analysis on the intent-to-treat population.
The primary analysis was based on an unadjusted statistical model. An analysis adjusted for key baseline variables was also conducted, and results were consistent with the presented unadjusted analysis. Randomization was similar in the three treatment arms (letrozole 0.5 mg, n = 202; letrozole 2.5 mg, n = 199; megestrol acetate, n = 201). Table 1 shows that the three treatment arms were similar with respect to demographics, disease characteristics, and extent of prior treatment at the beginning of the study. The median duration of treatment was approximately 5 to 7 weeks longer for the letrozole 0.5 mg arm when compared to the letrozole 2.5 mg and megestrol acetate treatment arms (171.5 days, 120.0 days, and 136.0 days, respectively). The prognostic factors identified as having a significant impact on the various outcome variables for efficacy (age, disease-free interval, number of anatomic sites involved, best response to prior antiestrogen therapy, and stage of disease at study entry) were evenly distributed in all three arms and were present in frequencies expected in this population of patients. Results of
Efficacy Best objective overall tumor response. Although the letrozole treatment groups had somewhat higher response rates than the megestrol acetate–treated group (Table 2), no statistically significant differences were noted when the groups were analyzed by logistic regression to compare the number of patients with a confirmed objective response (CR + PR) (Table 3). Table 4 presents the response rates (CR + PR) by treatment within each baseline covariate. However, no statistically significant differences between treatments were detected within subgroups.
Duration of response and clinical benefit. Median duration of objective tumor response was 23 months for letrozole 0.5 mg, 25 months for letrozole 2.5 mg, and 30 months for megestrol acetate (Table 5). Median duration of clinical benefit (objective response and stable disease lasting at least 6 months) was 21 months for letrozole 0.5 mg, 18 months for letrozole 2.5 mg, and 15 months for megestrol acetate. There were no statistically significant differences noted in any of the pair comparisons for duration of response nor duration of clinical benefit (Table 6).
TTP. At the time of the analysis, 158 patients (78%) in the letrozole 0.5 mg treatment arm, 163 (82%) in the letrozole 2.5 mg arm, and 162 (80%) in the megestrol acetate arm had progressed or died. Figure 1 shows the Kaplan-Meier estimates for TTP. Median TTP was longer for letrozole 0.5 mg–treated patients (6 months), compared with both the letrozole 2.5 mg and megestrol acetate treatment arms (3 months). Patients treated with letrozole 0.5 mg had a significantly lower risk of disease progression (hazard ratio, 0.80; P = .044) than patients treated with megestrol acetate. The differences in TTP between the letrozole treatment groups and the letrozole 2.5 mg–treated patients and megestrol acetate–treated patients were not statistically significant (Table 6).
TTF. Median TTF of 5 months was longer for the letrozole 0.5 mg treatment group, compared with 3 months for both the letrozole 2.5 mg and megestrol acetate treatment arms. A statistically significant lower risk of treatment failure was detected in patients treated with letrozole 0.5 mg when compared with patients treated with megestrol acetate (hazard ratio, 0.78; P = .018). No significant difference was found when comparisons were made between the letrozole treatment groups or between letrozole 2.5 mg and megestrol acetate (Table 6). TTD. Two thirds of the patients were deceased at the time of the survival update. There were fewer deaths in the letrozole 0.5 mg arm (61%) than in the letrozole 2.5 mg arm (69%) or in the megestrol acetate arm (70%). Figure 2 shows the Kaplan-Meier estimates for TTD. Median TTD was 33 months for letrozole 0.5 mg, 29 months for letrozole 2.5 mg, and 26 months for megestrol acetate. There were no statistically significant differences in TTD among the three treatment groups, although a trend is noted for letrozole 0.5 mg in comparison to megestrol acetate (P = .053) (Table 6).
Subject assessments. Treatment groups were similar in the time trend for the Karnofsky performance scale or global health status/quality-of-life scale based on an exploratory longitudinal analysis of the two scores. In general, decreases from baseline in performance status were less in the letrozole treatment groups, and quality-of-life scores were comparable between the two letrozole groups and the megestrol acetate group, with roughly half of the scales favoring letrozole treatment and half favoring megestrol acetate treatment. Dyspnea was reported more frequently in the megestrol acetate group, and insomnia was reported more frequently in the letrozole group.
Tolerability and Safety
Discontinuation At the time of analysis, a total of 546 patients had discontinued study participation. This included 88% of the letrozole 0.5 mg–treated patients, 89% of the letrozole 2.5 mg–treated patients, and 95% of the megestrol acetate patients. The majority of patients discontinued the study as a result of disease progression. Discontinuation because of adverse events, irrespective of study drug relationship, occurred more often for megestrol acetate–treated patients (11.4%) than for patients treated with letrozole (letrozole 0.5 mg, 6.9%; letrozole 2.5 mg, 6.6%). Fifteen patients discontinued the study due to death: 3.5% (seven of 202 patients) in the letrozole 0.5 mg arm, 2.0% ( four of 199) in the letrozole 2.5 mg arm, and 2.0% (four of 201) in the megestrol acetate arm. For nine of the patients, death was attributed to disease progression. Three patients died as a result of cardiac abnormalities, one died from bronchopneumonia, one from mesenteric thrombosis, and one from sudden death of unknown etiology.
This is a report of the second major phase III, randomized study conducted to compare the effects of the aromatase inhibitor, letrozole, with megestrol acetate, an established treatment for postmenopausal women with advanced breast cancer who experience disease progression after treatment with an antiestrogen. The first reported study of letrozole 2.5 mg and megestrol acetate 160 mg showed letrozole superior for multiple efficacy end points, including ORR, duration of response, duration of clinical benefit, TTF, performance status, and tolerability.8 A dose response between letrozole 2.5 mg and letrozole 0.5 mg was noted in that study and in a separate study comparing letrozole to aminoglutethimide.8,17,21 The primary results reported for these two studies were the adjusted analyses. The primary results for the present study are the unadjusted analyses and have not confirmed the dose response for letrozole. The unadjusted and the adjusted analyses for this study were consistent. Treatment with letrozole 0.5 mg, compared with megestrol acetate, was statistically superior in TTP and TTF and showed a favorable trend in survival (P = .053). Although data from this study did not replicate the statistical superiority of letrozole 2.5 mg versus megestrol acetate, letrozole 0.5 mg did show clinical benefit, providing further evidence of the activity of letrozole in patients with advanced breast cancer who have experienced progression despite antiestrogen therapy. This is an important factor because, in breast cancer, disease stabilization is often considered comparable to objective response.17 Objective response rates of 21%, 16%, and 15% were observed for letrozole 0.5 mg, letrozole 2.5 mg, and megestrol acetate, respectively. These response rates are consistent with those reported in other studies. Daily doses of 1 mg and 10 mg of anastrozole tested in two large randomized studies produced ORRs of 5% to 13% in postmenopausal patients with advanced breast cancer, compared with responses with megestrol acetate of 6% to 10%.22,23 Although the letrozole 0.5 mg–treated patients in this study experienced a slightly higher ORR than patients treated with letrozole 2.5 mg, the differences were not statistically significant. Further, the degree of estrogen suppression and inhibition of in vivo aromatization of androstenedione to estrone for letrozole 2.5 mg and 0.5 mg were reported to be similar.17 When reviewing the data from the three studies discussed, the weight of the evidence supports the use of letrozole 2.5 mg as the effective dose likely to produce good ORRs and longer disease control when used as second-line hormonal therapy (data on file, Novartis Pharmaceuticals Corporation, East Hanover, NJ). Tolerability of letrozole was at least equal to that of megestrol acetate, and there was no dose-dependent effect noted between letrozole 0.5 mg and letrozole 2.5 mg. Given the tolerability profile and evidence of clinically relevant benefits, letrozole can be offered as an effective alternative to megestrol acetate as hormonal therapy for the treatment of advanced breast cancer in postmenopausal women.
APPENDIX *CDN, Canada; DK, Denmark; D, Germany; I, Italy; NL, the Netherlands; UK, United Kingdom; no country noted, United States.
Supported by Novartis Pharmaceuticals Corp, East Hanover, NJ. We acknowledge the collaboration and commitment of all the local investigators and their staff, without whom the present study would not have been possible.
1. Rose C, Mouridsen HT: Endocrine therapy of advanced breast cancer. Acta Oncol 27: 721-728, 1988[Medline] 2. Santen RJ, Manni A, Harvey H, et al: Endocrine treatment of breast cancer in women. Endocr Rev 11: 221-265, 1990[Medline] 3. Cheung KL, Willsher PC, Pinder SE, et al: Predictors of response to second-line endocrine therapy for breast cancer. Breast Cancer Res Treat 45: 219-224, 1997[Medline]
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Hamilton A, Piccart M: The third-generation non-steroidal aromatase inhibitors: A review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer. Ann Oncol 10: 377-384, 1999 5. Hannaford M: Role of new selective aromatase inhibitor in therapy for metastatic breast cancer in postmenopausal women. Nurse Pract 22: 195-196, 1997[Medline] 6. Rose C: Proper sequence of endocrine therapies in advanced breast cancer. Acta Oncol 35: 44-49, 1996 (suppl 5) 7. Wiseman LR, Goa KL: Formestane: A review of its pharmacological properties and clinical efficacy in the treatment of postmenopausal breast cancer. Drugs 9: 292-306, 1996 8. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: 453-461, 1998[Abstract] 9. Harvey HA: Emerging role of aromatase inhibitors in the treatment of breast cancer. Oncology 12: 32-35, 1998 (suppl 5) 10. Bhatnagar AS, Hausler A, Schieweck K, et al: Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new nonsteroidal aromatase inhibitor. J Steroid Biochem Mol Biol 37: 1021-1027, 1990[Medline] 11. Demers LM, Lipton A, Harvey HA, et al: The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with advanced breast cancer. J Steroid Biochem Mol Biol 44: 687-691, 1993[Medline] 12. Trunet PF, Mueller PH, Bhatnagar AS, et al: Open dose-finding study of a new potent and selective nonsteroidal aromatase inhibitor, CGS 20 267, in healthy male subjects. J Clin Endocrinol Metab 77: 319-323, 1993[Abstract] 13. Iveson TJ, Smith IE, Ahern J, et al: Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women. J Clin Endocrinol Metab 77: 324-331, 1993[Abstract]
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Iveson TJ, Smith IE, Ahern J, et al: Phase I study of the oral non-steroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res 53: 266-270, 1993 15. Lipton A, Demers LM, Harvey HA, et al: Letrozole (CGS 20267): A phase I study of a new potent oral aromatase inhibitor of breast cancer. Cancer 75: 2132-2138, 1995[Medline] 16. Chaudri HA, Trunet PF: Letrozole: Updated duration of response. J Clin Oncol 17: 3859-3860, 1999 (letter)
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Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a new oral aromatase inhibitor: Randomised trial comparing 2.5 mg daily, 0.5 mg daily, and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol 9: 639-645, 1998 18. Aaronson NK, Ahmedzai S, Bullinger M, et al: The EORTC core quality-of-life questionnaire: Interim results of an international field study, in Osoba D (ed): Effect of Cancer on Quality of Life. London, United Kingdom, CRC Press Inc, 1991, pp 185-203
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Sprangers MAG, Groenvold M, Arraras JI, et al: The European Organization for Research: A Treatment of Breast Cancer–Specific Quality-of-Life Questionnaire Module: First Result from a Three-Country Field Study. J Clin Oncol 14: 2756-2768, 1996 20. Common Toxicity Criteria: National Institutes of Health. Bethesda, MD, Cancer Therapy Evaluation Program, Division of Cancer Treatment, 1993 21. Possinger K, Gershanovich M, Campos D, et al: Letrozole (Femara), a new potent, selective aromatase inhibitor (AI): Superior to another AI, aminoglutethimide (AG) in postmenopausal women with advanced breast cancer (ABC), after relapse or progression on previous anti-estrogen therapy. Eur J Cancer 33: S145, 1997 (suppl 8, abstr 643) 22. Jonat W, Howell A, Blomqvist C, et al: A randomized trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer 32A: 404-412, 1996 23. Buzdar A, Jones S, Vogel C, et al: A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Cancer 79: 730-739, 1997[Medline] Submitted August 4, 2000; accepted April 19, 2001. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
50 years of age who had not menstruated during the preceding 12 months or had castrate follicle-stimulating hormone levels (> 40 IU/L), women less than 50 years of age who had castrate follicle-stimulating hormone levels, or women who had undergone a bilateral oophorectomy. 
5 years before study entry or concurrent with study participation, with the exception of cone-biopsied in situ carcinoma of the cervix or uterus and adequately treated basal and squamous cell carcinoma of the skin. Patients were also excluded if they had inflammatory breast cancer; extensive hepatic metastases, defined as more than 33% of the liver replaced by metastases noted on sonogram and/or computed tomography scan; metastases to the CNS; pulmonary lymphangitic metastases involving more than 50% of the lung; history of deep venous thrombosis or pulmonary embolism within 3 years unless the thrombosis was known to be directly related to tumor obstruction of circulation; severe uncontrolled cardiac disease (eg, congestive heart failure of the New York Heart Association 
2 and Kruskal-Wallis tests showed no statistically significant difference among treatment groups at the .05 level of significance for any of the demographic, cancer history, or baseline prognostic variables. No patients had prior exposure to letrozole or megestrol acetate. 
