乳腺癌辅助化疗能否短疗程或去蒽环

　　对于早期乳腺癌，术后辅助化疗可显著减少复发死亡风险。标准的辅助化疗方案包括12周蒽环类＋环磷酰胺，随后12周紫杉类，总疗程长达24周，而且蒽环类对老年患者的心脏毒性较大、长期生存者的白血病风险较高。那么，早期乳腺癌术后化疗方案能否去掉蒽环或缩短疗程？

　　2021年5月13日，英国《柳叶刀》区域健康西太平洋分册在线发表复旦大学附属肿瘤医院余科达、刘西禹、陈力、莫淼、吴炅、柳光宇、狄根红、范蕾、邵志敏等学者的MASTER研究报告，探讨了无蒽环或短疗程与标准有蒽环长疗程辅助化疗方案对可手术HER2阴性乳腺癌患者的效果是否相似。

MASTER (NCT01314833): Minus Anthracycline or Short-Term Versus Epirubicin and Cyclophosphamide Followed by Paclitaxel Regimen for Adjuvant Breast Cancer Therapy (Adjuvant 6 Cycles of Docetaxel and Cyclophosphamide or 3 Cycles of Cyclophosphamide/Epirubicin/Fluorouracil Followed by 3 Cycles of Docetaxel Versus 4 Cycles of Epirubicin and Cyclophosphamide Followed by Weekly Paclitaxel in HER2-negative Operable Breast Cancer)

　　该多中心前瞻非盲三组随机对照非劣效三期临床研究于2010年6月1日～2017年6月1日从复旦大学附属肿瘤医院等单位入组病理T1～T3期淋巴结阳性或病理T2～T3期淋巴结阴性但高风险（II～III级、淋巴血管浸润、年龄≤35岁或激素受体阴性）HER2阴性可手术乳腺癌患者1571例，按1∶1∶1的比例随机分为三组：

  • TC组524例：18周（每3周×6）多西他赛＋环磷酰胺

  • CEF-T组523例：9周（每3周×3）环磷酰胺＋表柔比星＋氟尿嘧啶 → 9周（每3周×3）多西他赛

  • EC-P组524例：12周（每3周×4）表柔比星＋环磷酰胺 → 12周（每周×12）紫杉醇

　　主要终点为无病生存，无病生存事件包括局部区域复发、远处转移、对侧原发乳腺癌、乳腺以外第二浸润癌（除了非黑色素瘤皮肤癌）或任何原因所致死亡。假设EC-P组5年无病生存率为89%，预设非劣效临界值为4.5%，对应风险比为1.44（单侧α=0.05）。根据年龄、激素受体分型、分级、增殖指数Ki-67、病理肿瘤分期、病理淋巴结分期进行亚组分析。

　　结果，意向治疗患者年龄中位50岁、四分位45～57岁，雌激素受体阳性占92%，病理淋巴结阳性占59%，94%的患者完成分配治疗。

　　随访至2019年7月，中位随访5.5年，5年无病生存率：

  • EC-P组：85.9%

  • TC组：85.0%（风险比：1.05，90%置信区间：0.79～1.39，非劣效P=0.048）

  • CEF-T组：85.1%（风险比：0.99，90%置信区间：0.75～1.30，非劣效P=0.045）

　　亚组分析结果相似。

　　3或4级不良事件：

  • TC组：皮疹（3.9%）、周围神经病变（2.8%）

  • CEF-T、EC-P组：腹泻、恶心呕吐

　　因此，该研究结果表明，对于雌激素受体阳性HER2阴性乳腺癌患者，18周TC和18周CEF-T都是24周EC-P的非劣效术后化疗方案。尤其TC可避免蒽环类相关副作用，是一种比较安全的方案。

Lancet Reg Health West Pac. 2021 Jun;11:100158.

Anthracycline-free or short-term regimen as adjuvant chemotherapy for operable breast cancer: A phase III randomized non-inferiority trial.

Ke-Da Yu, Xi-Yu Liu, Li Chen, Miao Mo, Wu Jiong, Liu Guang-Yu, Di Gen-Hong, Claire Verschraegen, Daniel G. Stover, Zhuang Zhi-Gang, Francois Bertucci, Armando Orlandi, Wang Jie, Giuseppe Lippi, Wu Ke-Jin, Mohammed A.Osman, Lei Fan, Zhi-Ming Shao.

Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Breast Cancer, Shanghai, China; Ohio State University Comprehensive Cancer Center, Columbus, OH, United States; Shanghai First Maternity and Infant Hospital, Shanghai, China; The International Peace Maternity & Child Health Hospital of China Welfare Institute, Shanghai, China; Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China; Institut Paoli-Calmettes, Marseille, France; Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; University Hospital of Verona, Piazzale LA Scuro, Verona, Italy; General Organization for Teaching Hospitals, Cairo, Egypt.

BACKGROUND: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

METHODS: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1-3N+ or pT2-3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P.

FINDINGS: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45-57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79-1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75-1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar.

INTERPRETATION: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects.

DOI: 10.1016/j.lanwpc.2021.100158

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