Lamb H M, Adkins J C
Adis International Limited, Auckland, New Zealand.
Drugs. 1998 Dec;56(6):1125-40. doi: 10.2165/00003495-199856060-00020.
Letrozole is an oral reversible nonsteroidal aromatase inhibitor. Clinical tracer studies show that it inhibits peripheral aromatase by over 98% and suppresses blood and urinary estrogen levels by over 95% after 2 weeks of treatment in postmenopausal women. Letrozole also significantly inhibits intratumoral aromatase in vivo. The action of letrozole appears to be selective for aromatase; long term administration did not affect basal levels of 17 alpha-hydroxyprogesterone or aldosterone, although slight decreases in cortisol levels were observed in 2 studies, these did not appear to be clinically significant. In 2 phase IIb/III trials, letrozole 2.5 mg/day achieved objective response rates of 19.5 and 23.6% which were sustained for a median duration of 24 and 33 months, respectively. The median duration of response compared favourably with both comparator agents, aminoglutethimide and megestrol (15 and 18 months, respectively), as did objective response rates (12.4 and 16.4%). Letrozole 2.5 mg/day was associated with an increase in median survival time of 8 and 3 months compared with aminoglutethimide and megestrol, respectively. According to analyses of overall function, letrozole 2.5 mg/day was significantly superior to both comparators with respect to duration of response and aminoglutethimide with respect to survival. Letrozole has a good short term tolerability profile. The adverse events reported most commonly in association with letrozole 2.5 mg/day in the 2 phase IIb/III trials were headache (1.1 and 7%), nausea (6 and 10.3%), fatigue (3.2 and 5%), hot flushes (4.9 and 5%) and peripheral oedema (6%). Events were usually mild to moderate in severity; adverse events necessitated discontinuation of treatment in 3% of letrozole 2.5 mg/day recipients.
Letrozole, in common with vorozole and anastrozole, offers greater selectivity and potency of aromatase inhibition than the prototype aromatase inhibitor, aminoglutethimide, and can be administered once daily. Available clinical data suggest that letrozole achieves a significantly longer duration of response than megestrol and aminoglutethimide and longer overall survival than aminoglutethimide. However, direct comparisons are required to distinguish between the newer aromatase inhibitors. For this reason, letrozole should be recommended as a second-line treatment in postmenopausal women with advanced breast cancer whose disease has progressed on or failed to respond to antiestrogen therapy.
来曲唑是一种口服可逆性非甾体类芳香化酶抑制剂。临床示踪研究表明，它能抑制外周芳香化酶活性超过98%，并在绝经后妇女治疗2周后使血液和尿液中的雌激素水平降低超过95%。来曲唑在体内也能显著抑制肿瘤内芳香化酶。来曲唑的作用似乎对芳香化酶具有选择性；长期给药不影响17α-羟孕酮或醛固酮的基础水平，尽管在两项研究中观察到皮质醇水平略有下降，但这些变化在临床上似乎并无显著意义。在两项IIb/III期试验中，来曲唑2.5mg/天的客观缓解率分别为19.5%和23.6%，缓解持续时间中位数分别为24个月和33个月。与对照药物氨鲁米特和甲地孕酮相比，来曲唑的缓解持续时间中位数（分别为15个月和18个月）及客观缓解率（分别为12.4%和16.4%）均更优。与氨鲁米特和甲地孕酮相比，来曲唑2.5mg/天分别使中位生存时间延长了8个月和3个月。根据总体功能分析，来曲唑2.5mg/天在缓解持续时间方面显著优于两种对照药物，在生存方面优于氨鲁米特。来曲唑具有良好的短期耐受性。在两项IIb/III期试验中，与来曲唑2.5mg/天相关的最常见不良事件为头痛（1.1%和7%）、恶心（6%和10.3%）、疲劳（3.2%和5%）、潮热（4.9%和5%）及外周水肿（6%）。这些事件的严重程度通常为轻至中度；在接受来曲唑2.5mg/天治疗的患者中，有3%因不良事件而停药。
与伏罗唑和阿那曲唑一样，来曲唑比原型芳香化酶抑制剂氨鲁米特具有更高的芳香化酶抑制选择性和效力，且可每日给药一次。现有临床数据表明，来曲唑的缓解持续时间显著长于甲地孕酮和氨鲁米特，总生存期长于氨鲁米特。然而，需要进行直接比较以区分新型芳香化酶抑制剂。因此，对于疾病进展或对抗雌激素治疗无反应的绝经后晚期乳腺癌妇女，应推荐来曲唑作为二线治疗药物。
