Cohen Martin H, Johnson John R, Li Ning, Chen Gang, Pazdur Richard
Division of Oncology Drug Products (HFD-150), Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA.
Clin Cancer Res. 2002 Mar;8(3):665-9.
Letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a nonsteroidal inhibitor of aromatase enzyme complex. It inhibits the peripheral conversion of circulating androgens to estrogens. In postmenopausal women, letrozole decreases plasma concentrations of estradiol, estrone, and estrone sulfate by 75-95% from baseline with maximal suppression achieved within 2-3 days of treatment initiation. Suppression is dose related, with doses of >or=0.5 mg giving estrone and estrone sulfate values that were often below assay detection limits. At clinically used dosage, letrozole does not impair adrenal synthesis of glucocorticoids or aldosterone. In 1998, letrozole was approved by the United States Food and Drug Administration (FDA) for the treatment of advanced breast cancer in postmenopausal women, with hormone receptor positive or unknown breast cancer, who had failed one prior antiestrogen treatment (i.e., for "second-line" treatment). Approval was based on two randomized trials comparing tumor RRs of patients receiving 0.5 mg of letrozole, 2.5 mg of letrozole, and either megestrol acetate (MA) or aminoglutethimide. In the megestrol trial, 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and MA (RRs 24, 13, and 16%, respectively), whereas in the aminoglutethimide trial, there was no significant difference in 2.5 mg of letrozole and 0.5 mg of letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of letrozole over aminoglutethimide (P = 0.06). Letrozole (2.5 mg) was the dose chosen for comparison with tamoxifen in the first-line setting. In July 2000, a marketing application for first-line letrozole treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer was submitted to the FDA. A single double-blind, double dummy, randomized, and multicenter trial compared 2.5 mg of letrozole to 20 mg of tamoxifen (456 patients/arm). Letrozole was superior to tamoxifen with regard to time to progression (TTP) and objective response rate (RR). The median TTP for letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1-12.2] versus 6.2 months (95% CI 5.8-8.5) for tamoxifen, P = 0.0001, hazard ratio 0.713, (95% CI 0.61-0.84). RR was 32% for letrozole versus 21% for tamoxifen (odds ratio 1.74, 95% CI 1.29-2.34, P = 0.0003). Preliminary survival data (survival data are still blinded) indicate that letrozole is unlikely to be worse than tamoxifen. Both treatments were similarly tolerated. On the basis of these results, the United States FDA approved letrozole tablets, 2.5 mg/day, for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer. The manufacturer made a commitment to provide updated information on survival.
来曲唑（芙瑞；诺华制药公司，新泽西州东哈嫩）是一种芳香化酶复合物的非甾体抑制剂。它可抑制循环雄激素向雌激素的外周转化。在绝经后女性中，来曲唑可使雌二醇、雌酮和硫酸雌酮的血浆浓度从基线水平降低75% - 95%，在开始治疗的2 - 3天内达到最大抑制效果。抑制作用与剂量相关，剂量≥0.5mg时，雌酮和硫酸雌酮的值常常低于检测限。在临床使用剂量下，来曲唑不会损害肾上腺合成糖皮质激素或醛固酮的功能。1998年，来曲唑被美国食品药品监督管理局（FDA）批准用于治疗绝经后患有激素受体阳性或未知的乳腺癌且先前接受过一种抗雌激素治疗失败（即“二线”治疗）的晚期乳腺癌患者。批准基于两项随机试验，比较了接受0.5mg来曲唑、2.5mg来曲唑以及醋酸甲地孕酮（MA）或氨鲁米特治疗的患者的肿瘤缓解率（RR）。在甲地孕酮试验中，来曲唑2.5mg/天优于0.5mg来曲唑和MA（RR分别为24%、13%和16%），而在氨鲁米特试验中，2.5mg来曲唑和0.5mg来曲唑的RR无显著差异（分别为20%和17%）。2.5mg来曲唑的RR有高于氨鲁米特的趋势（P = 0.06）。来曲唑（2.5mg）是在一线治疗中与他莫昔芬进行比较时所选用的剂量。2000年7月，一项关于来曲唑一线治疗绝经后激素受体阳性或激素受体未知的局部晚期或转移性乳腺癌的上市申请提交给了FDA。一项单中心双盲、双模拟、随机、多中心试验比较了2.5mg来曲唑与20mg他莫昔芬（每组456例患者）。来曲唑在疾病进展时间（TTP）和客观缓解率（RR）方面优于他莫昔芬。来曲唑治疗的中位TTP为9.9个月[95%置信区间（CI）9.1 - 12.2]，而他莫昔芬为6.2个月（95%CI 5.8 - 8.5），P = 0.0001，风险比0.713（95%CI 0.61 - 0.84）。来曲唑的RR为32%，他莫昔芬为21%（优势比1.74，95%CI 1.29 - 2.34，P = 0.0003）。初步生存数据（生存数据仍处于盲态）表明来曲唑不太可能比他莫昔芬差。两种治疗的耐受性相似。基于这些结果，美国FDA批准了2.5mg/天的来曲唑片用于一线治疗绝经后激素受体阳性或激素受体未知的局部晚期或转移性乳腺癌。制造商承诺提供关于生存的最新信息。
