1 Breast Cancer Center, Toyosu Hospital, Showa University School of Medicine, Tokyo; 2 Department of Medical Oncology, National Cancer Center Hospital, Tokyo; 3 Division of OncologyHematology, National Cancer Center Hospital East, Chiba; 4 First Department of Internal Medicine, Saitama Cancer Center, Saitama; 5 Department of Surgery, School of Medicine, Keio University, Tokyo; 6 Department of Surgery, Kansai Rosai Hospital, Hyogo; 7 Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo; 8 Department of Surgery, Omiya Red Cross Hospital, Saitama; 9 Department of Biostatistics, School of Health Sciences and Nursing, University of Tokyo, Tokyo, Japan
Received 7 February 2002; revised 27 June 2002; accepted 17 July 2002
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Abstract |
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To compare the efficacy, safety and tolerability of letrozole, an advanced non-steroidal aromatase inhibitor, and fadrozole hydrochloride, an older-generation drug in this class, we conducted a randomised double-blind trial in postmenopausal women with advanced breast cancer.
Patients and methods:
One hundred and fifty-seven postmenopausal women with advanced breast cancer were enrolled and randomly assigned to receive letrozole or fadrozole in a multicentre, randomised double-blind trial in Japan. One hundred and fifty-four eligible patients were treated with either letrozole 1.0 mg once daily (n = 77) or fadrozole 1.0 mg twice daily (n = 77), for a minimum of 8 weeks.
Results:
Letrozole showed a significantly higher overall objective response rate [complete response (CR) + partial response (PR)] than fadrozole (31.2% and 13.0%, respectively; P = 0.011, Fishers exact test). Clinical benefits defined as CR, PR and stable disease (no change in status for more than 24 weeks) were also higher in patients treated with letrozole (50.6%) than fadrozole (35.1%). Letrozole was significantly superior to fadrozole in terms of the dominant lesion in soft tissue, bone and viscera (P = 0.011, stratified MantelHaenszel test). Median time to progression was 211 days in the letrozole group and 113 days in the fadrozole group with no significant difference (P = 0.175, log-rank test). Letrozole markedly reduced the estradiol, estrone and estrone sulfate levels in peripheral blood within 4 weeks. The suppressive effect of fadrozole on these hormone levels was insufficient. Adverse drug reactions were observed in 35.9% of the patients treated with letrozole and in 39.5% of those treated with fadrozole with no significant difference between the two groups (P = 0.74, Fishers exact test). Most of the adverse drug reactions were rated as grade 1 or 2.
Conclusions:
The results show letrozole at a dose of 1.0 mg once daily to be more effective in treating postmenopausal women with advanced breast cancer than fadrozole at 1.0 mg twice daily, with similar safety and tolerability profiles.
Key words: aromatase inhibitor, breast cancer, letrozole, randomised trial
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Introduction |
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Aminoglutethimide (AG) and 4-hydroxy-androstenedione (4-OHA) were the first two aromatase inhibitors to be developed for clinical use and have been used in postmenopausal breast cancer treatment as one of the standard therapies [57]. However, the older generation of aromatase inhibitors have certain limitations. They have low specificity for aromatase enzyme, and therefore suppress the secretion of other hormones, such as cortisol. For this reason, corticosteroid supplementation was required in combination with AG or 4-OHA [8]. Fadrozole hydrochloride (FAD), a second-generation aromatase inhibitor with a higher specificity for aromatase than AG and 4-OHA, was subsequently developed, and is approved for the treatment of advanced breast cancer in Japan [911].
Letrozole (LET) is a newer, highly specific and potent non-steroidal inhibitor of aromatase [12]. LET is approximately 150- to 10 000-fold more potent than AG in inhibiting aromatase activity, and exhibits specificity for aromatase that is approximately 400- to 10 000-fold higher than that of AG [1315]. LET reduced the serum concentrations of estrone (E1) and estradiol (E2) to undetectable levels in a study in healthy postmenopausal women, without affecting cortisol, aldosterone or progesterone [16].
The efficacy of LET in second-line therapy for postmenopausal women with advanced breast cancer has been studied at oral doses of 0.5 mg and 2.5 mg in comparative clinical trials against megestrol acetate (MA) [17, 18]. The results from these studies revealed that LET was superior to MA in terms of the response rate (at 2.5 mg/day) and the time to progression (TTP) (at 0.5 mg/day). LET (2.5 mg/day) was also found be superior to AG in the TTP [19]. LET has recently been approved in many countries for first-line therapy in the treatment of postmenopausal women with advanced breast cancer. The approval was based on the results obtained from a large multinational, double-blind, randomised phase III trial comparing once-daily oral LET at 2.5 mg with oral tamoxifen at 20 mg. LET reduced the risk of progression by 30% compared with tamoxifen [20].
In dose-ranging studies in Japan, overall objective response rates [ORR, i.e. complete response (CR) + partial response (PR)] of patients treated with LET for advanced and relapsed breast cancer were 31.4 and 42.2% at doses of 0.5 mg/day and 1 mg/day, respectively [2123]. Although the difference between ORR was not statistically significant (P = 0.080, stratified Mantel test), there was a trend torwards a greater difference at 1.0 mg with no difference in safety between the two doses. Based on the above finding, a multicentre, randomised double-blind trial was undertaken to compare the clinical efficacy and safety of once-daily LET 1.0 mg with twice-daily FAD 1.0 mg in patients with advanced or recurrent breast cancer.
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Patients and methods |
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Inclusion criteria
Postmenopausal women with breast cancer proven histologically or cytologically were eligible for the study, regardless of ER status. Objectively measurable or assessable pathological lesions were required. If patients had received radiation therapy before the study, measurable tumour or assessable pathological lesions other than the sites where X-ray irradiation was applied were required. Postmenopausal women between 20 and 74 years old were eligible for inclusion, where menopause was defined by termination of menstruation >12 months before study entry or bilateral oophorectomy. If menopause was induced by chemotherapy, patients were required to be older than 51 years of age. Patients who had received a hysterectomy (performed conservatively while leaving lateral or bilateral ovaries in situ) after 51 years of age were also eligible for inclusion. Patients with objective evidence of disease progression, who had been treated with chemotherapy and/or hormonal therapy, or postsurgical adjuvant therapy before participating in this study, were included. Normal laboratory values were established as follows: haemoglobin 9.5 g/dl, white blood cell count
3000/mm3, platelet count
7 x 104/mm3, aspartate aminotransferase (AST)
2 x upper limit of normal (ULN) set at the institution, alanine aminotransferase (ALT)
2 x (ULN) set at the institution, and blood urea nitrogen
25 mg/dl. Enrolment criteria also included the PS score (Clinical Oncology, Japan Society of Cancer Therapy) of grade 02.
Exclusion criteria
Patients were excluded if they demonstrated evidence of any malignancies other than breast tumour. Patients were also precluded from enrolment if they had received antimetabolites or biological response modifier therapy within 2 weeks before enrolment. Furthermore, if they had received any hormonal therapy or chemotherapy within 4 weeks before initiation, the patients were excluded. The concomitant use of other anticancer agents, including hormone therapy, was prohibited during the protocol treatment.
Clinical assessments
The primary end points in this trial were to evaluate the ORR and safety of LET compared with FAD. Antitumour effects, PS, incidences of adverse events, clinical laboratory findings, tumour markers (i.e. blood carcinoembryonic antigen and CA1503), and plasma levels of hormones [E1, E2, estrone sulfate (E1S), cortisol, aldosterone, androstenedione, testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH)] were examined at the times of drug administration as a baseline, every 4 weeks following the baseline visit, and on completion or discontinuation of treatment. Measurement of antitumour effects was carried out in accordance with the General Rules for Clinical and Pathological Recording of Breast Cancer (edited by the Japanese Breast Cancer Society) [24]. X-ray or computed tomography (CT) was employed for pulmonary lesion assessment, while ultrasonography or CT was employed for assessing the hepatic lesion. Bone lesions were assessed by X-ray, CT or magnetic resonance imaging. The same lesion was assessed by the same method during this trial. The occurrence of any new lesions in these organs was properly examined. Plasma levels of E1, E2 and E1S were measured after disclosure of a key-code table. An Evaluation Committee consisting of six members (see Acknowledgements), none of whom was affiliated with the study, confirmed the evaluation of antitumour effects and made revaluations if necessary before disclosure of the key-code table.
The safety of either agent was assessed based on adverse events, clinical laboratory findings (haematology/blood biochemistry) and PS. The safety rating was determined according to the General Rules for Reporting on Clinical Oncology of the Japan Society for Cancer Therapy [25].
Statistical methodology
It was suggested that a sample size of 84 and 68 subjects per group would be required with a 90% power and a two-sided significance level of 5% and 10% each, based on an estimated ORR (for the primary end point) of 43% for LET, and 20% for FAD from prior clinical study. The planned sample size was therefore 150 subjects (75 per group). In addition, with this number of subjects there would be 85.4% power at = 0.05 and 90.5% power at
= 10% from a simulation-based normal distribution.
The characteristics of patients were summarised by treatment group and compared between groups using the chi-square test or the Wilcoxon rank sum test. Antitumour effects were compared between two treatment groups, and the primary end points were analysed principally by the stratified (extended) Mantel test following stratification by site of assessment. In addition, the simple Mantel test was used. Response rates were analysed by Fishers exact test, and 95% confidence intervals (CIs) were determined exactly on the F-distribution. The primary analysis of the primary end points was defined prospectively. We planned to analyse the primary end points with the stratified (extended) Mantel test following stratification by site of assessment. TTP and survival rates were calculated by the KaplanMeier method. The log-rank test was employed to compare TTP and survival rates between two treatment groups. The Cox regression was conducted as a supplementary analysis using site of assessment, PS and age as covariants.
As regards adverse drug reactions, symptoms were summarised by the time of occurrence and severity, and abnormal changes in clinical laboratory findings were also summarised by group. Intergroup comparisons of adverse drug reactions were made with Fishers exact test.
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Results |
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Median treatment periods were 7.5 and 6.3 months in the LET and FAD groups, respectively. The median follow-up period was 13.3 months in both groups.
Antitumour effects
The resulting antitumour effects are presented in Table 2. The ORR was 31.2% (24 of 77) and 13.0% (10 of 77) in the LET and FAD groups, respectively, showing that LET had induced a significantly higher response rate (P = 0.013, Mantel test; P = 0.011, Fishers exact test). In addition, when stable disease (SD), which was defined as no change for 24 weeks or longer, was included in the rate, the response rates (clinical benefits) were 50.6% (39 of 77) and 35.1% (27 of 77) in the LET and FAD groups, respectively (P = 0.073, Fishers exact test).
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Time to progression
TTP of 73 patients treated with LET and 75 patients treated with FAD, excluding unevaluable cases are presented in Figure 1. TTP was apparently longer in the LET group than FAD group for up to 500 days, but there was no significant difference between two groups by the log-rank test (P = 0.175). Median TTP was 211 days (95% CI 132337 days) in the LET group and 113 days (95% CI 80185 days) in the FAD group
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Safety
The incidence of adverse drug reactions in the LET and FAD groups was 35.9% and 39.5%, respectively, with no significant difference between these groups (P = 0.740, Fishers exact test). Table 5 presents the incidence of adverse drug reactions that occurred in the LET or FAD group. The highest incidence was for rash, which was observed at 3.8% and 5.3% in the LET and FAD groups, respectively.
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Kinetics of hormones
Hormonal levels in plasma were measured in 110 patients.
Time-course changes of E1, E2 and E1S in 87 evaluable patients (LET group: 47 cases, FAD group: 40 cases) are represented in Figure 2. In the LET group, plasma levels of E1, E2 and E1S had decreased markedly by the 4th week after the beginning of administration compared with baseline levels. These parameters were below the sensitivity limit in all patients, and in most cases the reduced levels persisted throughout the study. In the FAD group, plasma levels of E1, E2 and E1S also had decreased dramatically by week 4, but there were large variations in individual responses. There were no clinically serious changes in the plasma levels of cortisol, aldosterone, androstenedione, testosterone, LH and FSH in either groups (data not shown). These results suggest that LET is a highly potent and specific inhibitor of the biosynthesis of estrogen.
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Discussion |
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Currently, there is no study comparing a third-generation aromatase inhibitor with a second-generation aromatase inhibitor. We conducted a randomised double-blind trial to confirm the clinical superiority of LET over a second-generation aromatase inhibitor. Our data showed that LET was significantly superior to FAD in ORR and was effective in both first-line and second-line patients. In addition, LET revealed a high ORR in patients who had received prior treatment with an antiestrogen. These response rates demonstrated the consistently superior efficacy of LET in advanced/relapsed breast cancer. When ORR were stratified by sites of assessment, it was 51.9% in the LET-treated patients with metastatic lesions in soft tissue, which could be an advantage, as metastasis of breast cancer frequently occurs in soft tissues such as lymph nodes and skin. The median time required for achieving efficacy was shorter in the LET-treated group than FAD group, indicating that LET is thus more appropriate for treating breast cancer in the clinical setting. Although TTP was longer in the LET group, there was no significant difference between these two groups. The period of patient follow-up was insufficient for definitive conclusions and 17 patients from both groups who achieved CR, PR or SD were entered in the extension study and out of these, 14 patients were administered with LET. Therefore, it is possible that TTP is prolonged in the LET group.
Recently, a large phase III study comparing LET with MA has been conducted and at LET 0.5 mg showed superiority over MA in TTP [18]. The efficacy of LET at 1 mg has not been reported previously. We have conducted randomised comparative phase II studies with dose levels of 0.5 mg and 1 mg in the past. From the results, 1 mg was selected as the dosage of LET for this type of study for the first time [2123]. This dose was proven to be sufficient for obtaining antitumour efficacy of LET in this study. On the other hand, there were many reports that 2.5 mg LET had high antitumour activity. These results showed that the efficacy of LET does not depend on the dose.
The ORR of patients treated with LET (2.5 mg/day) has been reported to be 23.6%, 19.5% and 16.1% in three large-scale comparative studies; lower than that of this study [1719]. Participation in these large-scale studies was limited to patients who were resistant to antiestrogens, but patients with relapse after adjuvant therapy were enrolled in the present study in addition to the resistant patients. This factor partially appears to explain the difference in the response.
The incidence of adverse drug reactions to LET and FAD was 35.9% and 39.5%, respectively, with no significant difference between the groups. Gastrointestinal and skin symptoms were the main adverse drug reactions observed in the LET group, and there were no obvious differences in adverse events compared with the results from the study in which LET was compared with AG and MA [1719]. Increases in parameters of hepatic factors were observed in the LET group, but these were not serious. The results suggest a high tolerability for LET.
In the analysis of circulating hormone levels in blood in the first 4 weeks of therapy, both LET and FAD reduced plasma levels of E1, E2 and E1S. LET reduced estrogens to undetectable levels in all cases. Plasma levels of other circulating hormones were only slightly affected, which indicates that LET is highly specific for aromatase, and has a low affinity for other hormones. There have been reports that LET and anastrozole, another third-generation aromatase inhibitor, significantly reduced estrogen levels in the tumours of breast cancer patients. A suppressive effect of LET and anastrozole on the estrogen level in peripheral blood and total body aromatisation has also been reported [2628]. The potency of LET was higher in suppressing estrogen in peripheral blood and total body aromatisation [28]. However, the therapeutic correlation between the reduction in estrogen levels below the detection limits and antitumour efficacy of these agents has not yet been determined. Large comparative clinical trials to assess the efficacy and safety of LET and anastrozole are currently on-going and the results will no doubt provide important information regarding the relationship between the suppression of estrogen and anti tumour effects.
LET was demonstrated to be superior to AG, a first-generation aromatase inhibitor [19]. The results obtained in this clinical study show that LET was more effective in the treatment of postmenopausal breast cancer than FAD, a second-generation aromatase inhibitor. The results also suggest that LET could have higher therapeutic efficacy than other conventional aromatase inhibitors.
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Acknowledgements |
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The Evaluation Committee were: K. Asaishi, Sapporo-Kotoni Breast Clinic, T. Wada, Osaka Cancer Prevention and Detection Center, K. Yayoi, Kaizuka City Hospital, K. Morimoto, Osaka City University Medical School, K. Hisamatsu, Department of Surgery, Hiroshima City Asa Hospital, T. Morimoto, School of Medical Sciences, University of Tokushima.
We would like to thank the members of the advisory board, R. Abe, S. Yamaguchi, M. Yoshida, H. Koyama, S. Takashima and Y. Nomura, for their beneficial advice on conducting this study. We would also like to thank the members of the monitoring committee, O. Abe, S. Tsukagoshi and H. Niitani, for helpful suggestions regarding evaluation of the safety and effectiveness of the study. Lastly, we would like to thank C. Hamada for statistical consultation.
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Footnotes |
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References |
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