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促性腺素释放素类似物（GnRHa）又称促黄体素释放素（LHRH）可抑制卵泡刺激素和黄体生成素的分泌，使绝经前女性体内雌激素达到绝经后水平，被日益广泛用于绝经前乳腺癌患者。GnRHa可抑制雌激素相关肿瘤生长，作用与手术去势或化疗相当；同时可保护卵巢功能，防止卵巢功能过早减退；还可降低乳腺密度、子宫内膜厚度，对预防乳腺癌高风险人群及提高乳腺癌患者生存质量具有潜在价值。不过，关于GnRHa保护肿瘤放化疗患者卵巢功能的研究结果相互矛盾，卵巢功能评价标准也不一致，机制尚不明确。而且，迄今为止尚无中国或亚洲人群乳腺癌相关卵巢功能的前瞻随机对照研究。 2021年12月30日，《美国医学会杂志》肿瘤学分册在线发表上海交通大学附属第六人民医院（上海市第六人民医院）宗祥云、刘思旋、李晓林、陈璇、黄润、中国科学院大学附属肿瘤医院（浙江省肿瘤医院）俞洋、杨红健、陈文虎、丁小文、李晓林、蒋春儿、夏想厚、竺美珍、扈杰杰、梁晨露等学者的研究报告，探讨了GnRHa能否减少中国绝经前女性乳腺癌化疗所致卵巢功能损害。 JTU-6H-20150731001 (NCT02518191): Effects of GnRHa on Ovarian Function Against Chemotherapy-induced-gonadotoxicity in Women With Breast Cancer in China 该双中心非盲随机对照研究于2015年9月～2017年8月从上海市第六人民医院和浙江省肿瘤医院入组18～49岁绝经前女性可手术早期（I～III期）乳腺癌患者330例（其中29例患者基线抗米勒管激素水平低于0.5ng/mL）按1∶1的比例随机分为两组各165例，分别给予术后辅助或术前新辅助含环磷酰胺化疗±GnRHa（从第一轮化疗前1～2周至最后一轮化疗后4周，每28天皮下注射戈舍瑞林3.6mg或亮丙瑞林3.75mg），随访至2020年12月，并于2021年3月进行数据分析。主要终点为化疗后12个月卵巢功能过早减退（抗米勒管激素水平低于0.5ng/mL）发生率，次要终点为总体生存和无瘤生存。 结果，其中301例（91.2%，GnRHA组146例平均年龄40.6±6.7岁，对照组155例平均年龄40.2±5.9岁）符合主要终点分析条件。 化疗结束后12个月，GnRHa组146例与对照组155例患者相比：
中位随访49个月（范围25～60个月）后，GnRHa组与对照组相比：
事后分析表明，对于其中54例年龄小于35岁患者，GnRHa组30例与对照组24例患者相比：
因此，该小样本随机对照研究结果表明，绝经前乳腺癌患者环磷酰胺化疗同时给予GnRHa可降低卵巢功能过早减退风险，从而促进卵巢功能恢复，并且可能提高年龄小于35岁患者的生存率，故有必要进一步开展多中心大样本随机对照研究进行验证。 相关链接 JAMA Oncol. 2021 Dec 30. Online ahead of print. Effects of Gonadotropin-Releasing Hormone Analogs on Ovarian Function Against Chemotherapy-Induced Gonadotoxic Effects in Premenopausal Women With Breast Cancer in China: A Randomized Clinical Trial. Xiangyun Zong; Yang Yu; Hongjian Yang; Wenhu Chen; Xiaowen Ding; Sixuan Liu; Xiaolin Li; Xuan Chen; Chuner Jiang; Xianghou Xia; Run Huang; Meizhen Zhu; Jiejie Hu; Chenlu Liang. Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital, Shanghai, China; Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China. This randomized clinical trial examines the effect of administering gonadotropin-releasing hormone analogs during treatment with chemotherapy in premenopausal Chinese women with breast cancer on reducing ovarian impairment. QUESTION: What is the effect of gonadotropin-releasing hormone analogs (GnRHa) on ovarian function in women undergoing chemotherapy for breast cancer? FINDINGS: In this randomized clinical trial that included 330 premenopausal women, the premature ovarian insufficiency rate was 10.3% in the GnRHa group vs 44.5% in the control group, a significant difference. Additionally, findings of a post hoc analysis indicated that GnRHa was associated with improved tumor-free survival in patients younger than 35 years. MEANING: Gonadotropin-releasing hormone analogs should be used to protect ovarian function in premenopausal women who are receiving chemotherapy for breast cancer. IMPORTANCE: Studies of the use of gonadotropin-releasing hormone analogs (GnRHa) to protect ovarian function have shown mixed results. OBJECTIVE: To determine whether administering GnRHa during chemotherapy in premenopausal women with breast cancer can reduce ovarian impairment. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial, conducted at the Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital and Zhejiang Cancer Hospital in China, was an open-label trial involving premenopausal women aged 18 to 49 years with operable stage I to III breast cancer for which treatment with adjuvant or neoadjuvant cyclophosphamide-containing chemotherapy was planned in 2 parallel groups: treatment with chemotherapy with or without GnRHa. Enrollment occurred from September 2015 to August 2017, and follow-up ended December 2020. The data were analyzed in March 2021. A total of 405 patients were enrolled in the study, among whom 27 patients (6.7%) quit participation voluntarily, 33 (8.1%) did not meet the inclusion criteria and were excluded, and 15 (3.7%) were lost to follow-up. Ultimately 330 patients were included in the primary analysis, including 29 patients with baseline anti-Müllerian hormone levels less than 0.5 ng/mL. INTERVENTIONS: Eligible patients were randomly assigned (1:1) to receive chemotherapy with (n=165) or without (n=165) GnRHa. In patients randomized to receive GnRHa, 3.6 mg of goserelin or 3.75 mg of leuprorelin was injected subcutaneously once every 28 days from 1 to 2 weeks before the first cycle of chemotherapy to 4 weeks after the last cycle of chemotherapy. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of premature ovarian insufficiency (POI) at 12 months after chemotherapy. Premature ovarian insufficiency was defined as anti-Müllerian hormone levels of less than 0.5 ng/mL in this study. The secondary end point was overall survival (OS) and tumor-free survival (TFS). RESULTS: A total of 330 eligible patients could be evaluated with complete data, among whom 301 patients (91.2%; GnRHA group: mean [SD] age, 40.6 [6.7] years; control group: mean [SD] age, 40.2 [5.9] years) were eligible for primary end point analysis. At 12 months after the completion of chemotherapy, the POI rate was 10.3% (15 of 146) in the GnRHa group and 44.5% (69 of 155) in the control group (odds ratio, 0.23; 95% CI, 0.14-0.39; P<.001). Anti-Müllerian hormone resumption in the GnRHa group was significantly better than that in the control group (15 of 25 vs 6 of 44; odds ratio, 4.40; 95% CI, 1.96-9.89; P<.001). After a median follow-up of 49 months (range, 25-60 months), the differences in 4-year OS and TFS between the 2 groups were not significant. A post hoc analysis showed that in patients younger than 35 years, the TFS was higher in the GnRHa group than in the control group (93% vs 62%; P=.004; hazard ratio, 0.15; 95% CI, 0.03-0.82; P=.03). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that administering GnRHa in treatment with chemotherapy for premenopausal patients with breast cancer reduces the risk of POI, which promotes the recovery of ovarian function. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02518191 DOI: 10.1001/jamaoncol.2021.6214
2021版CBCS指南与规范完整版 2021版CBCS指南与规范精编版 2021版CBCS指南与规范小程序
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