Combination anastrozole and fulvestrant in metastatic breast cancer.
Combination anastrozole and fulvestrant in metastatic breast cancer.
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DOI：
10.1056/nejmoa1201622
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发表时间：
2012-08-02
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影响因子：
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通讯作者：
Hortobagyi GN
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作者：
Mehta RS;Barlow WE;Albain KS;Vandenberg TA;Dakhil SR;Tirumali NR;Lew DL;Hayes DF;Gralow JR;Livingston RB;Hortobagyi GN
芳香酶抑制剂阿那曲唑抑制雌激素合成。氟维司群结合并加速雌激素受体的降解。我们假设，这两种药物联合使用可能比阿那曲唑单用对受体（HR）阳性转移性乳腺癌患者更有效。既往未接受过治疗的转移性疾病的绝经后女性以1：1的比例随机分配接受每天口服1 mg阿那曲唑（第1组），如果疾病进展，强烈鼓励交叉至氟维司群单药，或阿那曲唑和氟维司群联合治疗（第2组）。根据既往接受或未接受他莫昔芬辅助治疗对患者进行分层。氟维司群肌内给药，第1天剂量为500 mg，第14天和第28天为250 mg，此后每月一次。主要终点是无进展生存期，总生存期被指定为预先指定的次要结局。第1组的中位无进展生存期为13.5个月，第2组为15.0个月（联合治疗进展或死亡的风险比为0.80; 95%置信区间[CI]为0.68 - 0.94;对数秩检验P = 0.007）。在所有亚组中，联合治疗通常比阿那曲唑单独治疗更有效，无显著相互作用。联合治疗的总生存期也更长（第1组的中位数为41.3个月，第2组为47.7个月;死亡风险比为0.81; 95% CI为0.65 - 1.00;对数秩检验P = 0.05），尽管第1组中41%的患者在进展后交叉至氟维司群。第2组发生了3例可能与给药相关的死亡。两组之间3至5级毒性反应的发生率无显著差异。阿那曲唑和氟维司群联合治疗HR阳性转移性乳腺癌上级阿那曲唑单药或阿那曲唑和氟维司群序贯治疗，尽管使用的氟维司群剂量低于当前标准。
The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)–positive metastatic breast cancer. Postmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progressionfree survival, with overall survival designated as a prespecified secondary outcome. The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P = 0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P = 0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups. The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard.