Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial.
Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial.
复制标题
DOI：
10.1016/s1470-2045(13)70502-3
复制
发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
American College of Surgeons Oncology Group investigators
中科院分区：
文献类型：
--
作者：
Buzdar AU;Suman VJ;Meric-Bernstam F;Leitch AM;Ellis MJ;Boughey JC;Unzeitig G;Royce M;McCall LM;Ewer MS;Hunt KK;American College of Surgeons Oncology Group investigators
HER 2阳性乳腺癌患者使用曲妥珠单抗进行新辅助化疗可在30-65%的患者中产生病理性完全缓解。我们研究了曲妥珠单抗给药时机与蒽环类和紫杉烷类新辅助化疗的效果。这项随机试验在美国和波多黎各的36个中心进行。可手术的HER 2阳性浸润性乳腺癌患者采用偏倚硬币最小化算法随机分配（1：1），按年龄、肿瘤大小和激素受体状态分层。患者和研究者（心脏安全性审查小组除外）均未对治疗分配设盲。随机分配至序贯治疗组的患者在21天周期的第1天接受氟尿嘧啶500 mg/m2、表阿霉素75 mg/m2和环磷酰胺500 mg/m2（FEC-75），持续4个周期，随后接受紫杉醇80 mg/m2和曲妥珠单抗2 mg/kg（在4 mg/kg负荷剂量后）每周一次持续12周，而那些随机分配到并行治疗组的患者接受紫杉醇和曲妥珠单抗每周一次，持续12周，随后接受4个周期的FEC治疗。75（每个21天周期的第1天）和每周一次曲妥珠单抗，剂量与序贯组相同。在新辅助治疗完成后6周内进行手术，包括腋窝评估。主要结局是意向治疗人群中病理学完全缓解的患者百分比。该研究在ClinicalTrials.gov注册，编号NCT 00513292。从2007年9月15日至2011年12月15日，282名女性入组（序贯组140名，同期组142名）。序贯组中有2例患者在开始治疗前撤回了知情同意书。接受序贯治疗的138例患者中有78例（56.5%，95% CI 47.8-64.9）出现乳腺病理学完全缓解，而接受同时治疗的142例患者中有77例（54.2%，95% CI 45.7-62.6）出现乳腺病理学完全缓解（差异2.3%，95% CI-9.3 - 13.9）。未发生给药相关死亡。最常见的重度毒性反应为中性粒细胞减少（序贯组138例患者中35例[25.3%] vs同步组142例患者中45例[31.7%]）和疲乏（6例[4.3%] vs 12例[8.5%]）。左心室射血分数在第12周下降到低于正常的机构下限，（0.8%）的130例接受序贯治疗的患者和4例（2.9%）的137例患者同时接受治疗;到第24周，126例患者中有9例（7.1%）和130例患者中有6例（4.6%）的血糖水平下降到该限值以下。曲妥珠单抗与蒽环类药物同时给药不会带来额外获益，因此不需要。
Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30–65% of patients. We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy. This randomised trial was done at 36 centres in the USA and Puerto Rico. Women with operable HER2-positive invasive breast cancer were randomly assigned (1:1) with a biased coin minimisation algorithm, stratified for age, tumour size, and hormone receptor status. Neither patients nor investigators (except for a cardiac safety review panel) were masked to treatment assignment. Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m2 and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group. Surgery, including evaluation of the axilla, was done within 6 weeks of completion of neoadjuvant treatment. The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00513292. From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in the sequential group, 142 in the concurrent group). Two patients in the sequential group withdrew consent before starting treatment. 78 of 138 (56.5%, 95% CI 47.8–64.9) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 (54.2%, 95% CI 45.7–62.6) who received concurrent treatment (difference 2.3%, 95% CI–9.3 to 13.9). No treatment-related deaths occurred. The most common severe toxic effects were neutropenia (35 [25.3%] of 138 patients in the sequential group vs 45 [31.7%] of 142 patients in the concurrent group) and fatigue (six [4.3%] vs 12 [8.5%]). Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one (0.8%) of 130 patients who received sequential treatment and four (2.9%) of 137 patients who received concurrent treatment; by week 24, it had dropped below this limit in nine (7.1%) of 126 patients and in six (4.6%) of 130 patients, respectively. Concurrent administration of trastuzumab with anthracyclines off ers no additional benefi t and is not warranted.