University Hospital J Minjoz, Besançon, France.
Lancet Oncol. 2013 Jul;14(8):741-8. doi: 10.1016/S1470-2045(13)70225-0. Epub 2013 Jun 11.
Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer.
We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30-90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901.
1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1-51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6-94·9) in the 12-month group and 91·1% (89·7-92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05-1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001).
After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care.
French National Cancer Institute.
自 2005 年以来，曲妥珠单抗辅助治疗 12 个月一直是 HER2 阳性早期乳腺癌患者的标准治疗方法。然而，治疗的最佳持续时间一直存在争议。我们进行了一项非劣效性试验，比较了早期乳腺癌患者接受较短时间（6 个月）与标准 12 个月曲妥珠单抗治疗的效果。
我们在法国的 156 个中心进行了一项开放性、随机、3 期试验。符合条件的患者为 HER2 阳性早期乳腺癌患者，至少接受了 4 个周期的化疗，已行乳房-腋窝手术，并且在随机分组前已接受了长达 6 个月的曲妥珠单抗治疗（通过静脉输注每 3 周进行 30-90 分钟；初始负荷剂量 8mg/kg；此后 6mg/kg）。通过中央随机程序和基于网络的软件对患者进行随机分组，继续接受曲妥珠单抗治疗 6 个月（总治疗时间为 12 个月；对照组）或在 6 个月时停止曲妥珠单抗治疗（总治疗时间为 6 个月；实验组）。随机分组按曲妥珠单抗与化疗同时或序贯给药、雌激素受体状态和中心进行分层，采用最小化算法。主要终点是无病生存，预设非劣效性边界为 1.15。分析在意向治疗人群中进行。这项研究在 ClinicalTrials.gov 注册，编号为 NCT00381901。
1691 例患者被随机分配接受 12 个月的曲妥珠单抗治疗，1693 例患者接受 6 个月的曲妥珠单抗治疗；每组各有 1690 例患者纳入意向治疗分析。中位随访 42.5 个月（IQR 30.1-51.6）后，12 个月组有 175 例无病生存事件，6 个月组有 219 例。12 个月组的 2 年无病生存率为 93.8%（95%CI 92.6-94.9），6 个月组为 91.1%（89.7-92.4）（风险比 1.28，95%CI 1.05-1.56；p=0.29）。128 例心脏事件（临床或基于左心室射血分数评估）中有 119 例（93%）发生在患者接受曲妥珠单抗治疗期间。12 个月组发生心脏事件的患者明显多于 6 个月组（1690 例患者中有 96 例[5.7%]，1690 例患者中有 32 例[1.9%]，p<0.0001）。
在 3.5 年随访后，我们未能证明曲妥珠单抗治疗 6 个月非劣效于曲妥珠单抗治疗 12 个月。尽管心脏事件发生率较高，但 12 个月的辅助曲妥珠单抗治疗仍应作为标准治疗。
法国国家癌症研究所。
