Goss Paul E
Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.
Am J Clin Oncol. 2003 Aug;26(4):S27-33. doi: 10.1097/00000421-200308001-00005.
Aromatase inhibitors (AIs) have been approved as second-line treatment for estrogen receptor-positive (ER+) metastatic breast cancer after first-line treatment with the selective estrogen receptor modulator (SERM) tamoxifen. Anastrozole and letrozole have also recently been widely approved as first-line endocrine therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer. The three third-generation selective oral AIs approved for use in the United States include two nonsteroidal agents, anastrozole (Arimidex) and letrozole (Femara), and the irreversible steroidal inhibitor exemestane (Aromasin). Several major ongoing clinical trials with a variety of treatment regimens are comparing the relative efficacy of tamoxifen with the steroidal and nonsteroidal AIs in the adjuvant setting. The first strategy compares an AI against tamoxifen directly. Among these are the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (anastrozole), the BIG FEMTA (Femara-Tamoxifen Breast International Group) trial (letrozole), and the EXEM and TEAM (exemestane) trials. A second strategy is examining the use of an AI as an extension after the initial 5 years of tamoxifen. Examples of this trial design are the MA-17 (letrozole) and the National Surgical Adjuvant Breast and Bowel Project (NSABP B-33, exemestane) trials. A third approach is the use of these agents in sequence with tamoxifen as therapy within the initial 5 postoperative years. Examples of this approach are the International Collaboration Cancer Group trial (tamoxifen for 2-3 years followed by either tamoxifen or exemestane for the remainder of the 5-year period), the BIG FEMTA trial (patients are crossed over from tamoxifen to Ietrozole or letrozole to tamoxifen), and the Arimidex-Nolvadex (ARNO) trial (patients receiving tamoxifen are randomized either to continue with tamoxifen or to switch to anastrozole). A single trial is comparing tamoxifen and anastrozole as initial 5-year therapy, or a combination of the two. The study addressing this design is the ATAC trial. Finally, a small trial in Norway is comparing 2 years of an AI versus a placebo in very low-risk patients with receptor-positive breast tumors. Most adjuvant trials have companion studies associated with the main protocol. These are to determine the end-organ effects of the inhibitors and include measurements of quality of life, bone and lipid metabolism, and endometrial effects. This review addresses the clinical implications of these studies of AIs.
芳香化酶抑制剂（AIs）已被批准作为选择性雌激素受体调节剂（SERM）他莫昔芬一线治疗后的雌激素受体阳性（ER+）转移性乳腺癌的二线治疗药物。阿那曲唑和来曲唑最近也被广泛批准作为激素受体阳性转移性乳腺癌绝经后妇女的一线内分泌治疗药物。在美国被批准使用的三种第三代选择性口服AIs包括两种非甾体类药物，阿那曲唑（瑞宁得）和来曲唑（弗隆），以及不可逆甾体抑制剂依西美坦（阿诺新）。几项正在进行的涉及多种治疗方案的大型临床试验正在比较他莫昔芬与甾体类和非甾体类AIs在辅助治疗中的相对疗效。第一种策略是直接将一种AI与他莫昔芬进行比较。其中包括ATAC（阿那曲唑、单独使用或联合使用他莫昔芬）试验（阿那曲唑）、BIG FEMTA（弗隆-他莫昔芬国际乳腺癌研究组）试验（来曲唑）以及EXEM和TEAM（依西美坦）试验。第二种策略是研究在他莫昔芬初始治疗5年后使用AI进行延长治疗。这种试验设计的例子有MA-17（来曲唑）试验和国家外科辅助乳腺和肠道项目（NSABP B-33，依西美坦）试验。第三种方法是在术后最初5年内将这些药物与他莫昔芬序贯使用作为治疗方案。这种方法的例子有国际癌症协作组试验（他莫昔芬治疗2 - 3年，然后在5年剩余时间内继续使用他莫昔芬或改用依西美坦）、BIG FEMTA试验（患者从他莫昔芬交叉换用至来曲唑或从来曲唑换用至他莫昔芬）以及阿那曲唑-诺瓦得士（ARNO）试验（接受他莫昔芬治疗的患者被随机分为继续使用他莫昔芬或改用阿那曲唑）。一项单一试验正在比较他莫昔芬和阿那曲唑作为初始5年治疗方案，或两者联合使用的情况。涉及这种设计的研究是ATAC试验。最后，挪威的一项小型试验正在比较在极低风险的受体阳性乳腺肿瘤患者中使用2年AI与使用安慰剂的效果。大多数辅助试验都有与主要方案相关的配套研究。这些研究旨在确定抑制剂对终末器官的影响，包括生活质量、骨和脂质代谢以及子宫内膜影响的测量。本综述阐述了这些AI研究的临床意义。
