德国辅助性国际协作组淋巴结阳性研究（GAIN）：一项比较两种剂量密集方案（iddEPC 与 ddEC-PwX）在高危早期乳腺癌患者中的 III 期试验。
German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients.
机构信息
Department of Gynecology and Obstetrics, Klinikum Frankfurt Höchst, Academic Hospital of the Goethe University Frankfurt, Frankfurt.
German Breast Group, Neu-Isenburg.
出版信息
Ann Oncol. 2017 Aug 1;28(8):1803-1810. doi: 10.1093/annonc/mdx203.
BACKGROUND
Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine.
PATIENTS AND METHODS
Women (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4.
RESULTS
From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10).
CONCLUSION
Adding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.
背景
对于中高危的乳腺癌患者，密集剂量（dd）方案是辅助治疗的首选方案之一。德国辅助肿瘤学组淋巴结阳性试验旨在通过评估药物联合方案和卡培他滨的加入来优化强化 dd（idd）策略。
患者和方法
组织学上腋窝淋巴结受累的女性（年龄 18 岁且生物学年龄<65 岁）随机分配接受每 2 周一次的三个疗程的表柔比星（E）150mg/m2、紫杉醇（P）225mg/m2 和环磷酰胺（C）2500mg/m2（在招募了 1200 名患者后减少至 2000mg/m2）静脉内（iv）（iddEPC 方案）或 ddEC（E 112.5mg/m2+ C 600mg/m2，iv，每 2 周一次，共 4 个周期），随后每周一次紫杉醇（Pw 67.5mg/m2 iv q8d 共 10 周）加卡培他滨（X 2000mg/m2 po，第 1-14 天，每 22 天一次，共 4 个周期）（ddEC-PwX 方案）。进一步的随机分组将患者分配至伊班膦酸盐治疗 2 年与观察，以及培非格司亭第 2 天与第 4 天。
结果
从 2004 年 6 月至 2008 年 8 月，2994 名患者被随机分配至 iddEPC（N=1498）或 ddEC-PwX（N=1496）并开始治疗。中位年龄为 50 岁；pN1（37.8%）、pN2（35.3%）、pN3（26.9%）；46.4%为 G3 肿瘤；76.9%激素受体阳性，22% HER2 阳性。中位随访 74 个月后，记录了 645 例事件和 383 例死亡。iddEPC 组出现 3-4 级血液学不良事件更为常见（P<0.001），ddEC-PwX 组出现非血液学不良事件更为常见（P=0.04），即使两种方案的毒性谱不同。5 年无病生存率为 ddEC-PwX 组 81.7%（95%CI 79.5-83.6）和 iddEPC 组 80.2%（95%CI 78.0-82.2）。危险比（HR）=0.95（95%CI 0.81-1.11，对数秩检验 P=0.49）。ddEC-PwX 组 5 年总生存率为 89.4%（95%CI 87.7-91.0），iddEPC 组为 89.0%（95%CI 87.2-90.6），HR=0.85（95%CI 0.69-1.04，对数秩检验 P=0.10）。
结论
与 iddEPC 相比，在 ddEC-Pw 中添加卡培他滨并未改善预后，但增加了毒性，不应推荐进一步使用。
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