Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial
Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial
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DOI：
10.1016/s1470-2045(16)30531-9
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发表时间：
2016-12-01
期刊：
影响因子：
51.1
通讯作者：
Tannapfel, Andrea
中科院分区：
文献类型：
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作者：
Al-Batran, Salah-Eddin;Hofheinz, Ralf D.;Tannapfel, Andrea
多西他赛为基础的化疗对转移性胃和胃-食管交界腺癌有效，但尚未在可切除患者的背景下进行评估。在这里，我们报告了2/3期FLOT4试验的2期研究结果，该研究比较了手术切除前接受多西他赛三联化疗和蒽环类三联化疗的患者的组织病理学退化。在这项随机、开放标签、2/3期研究中，从28个德国肿瘤中心招募了符合条件的参与者。可切除的胃癌或胃食管结癌患者，临床分期为cT2或更高，淋巴结阳性（cN+）疾病，或两者兼有，随机分配(1)：1)术前3个周期，术后3个周期，第1天静脉滴注表柔比星50 mg/m(2)，第1天静脉滴注顺铂60 mg/m(2)，氟尿嘧啶200 mg/m(2)连续静脉滴注，或卡培他滨1250 mg/m(2)口服（每天两次剂量625 mg/m(2)），第1至21天（ECF/ECX组）或术前4个周期，术后4个周期，多西紫杉醇50 mg/m(2)，静脉注射奥沙利铂85 mg/m(2)，静脉注射亚叶酸素200 mg/m(2)，氟脲嘧啶2600 mg/m(2) 24 h输注，均在第1天（FLOT组）。随机化是通过交互式网络响应系统集中完成的，该系统基于由东部肿瘤合作组织的表现状态、原发肿瘤的位置、年龄和淋巴结状态分层的区块（区块大小为2）生成的序列。没有做掩蔽。病理回归的中心评估根据贝克标准进行。主要终点是病理完全消退（肿瘤消退等级TRG1a），并在修改意向治疗人群中进行分析，意向治疗人群定义为所有随机分配治疗的患者，不包括接受手术但未提供切除标本用于中心评估的患者。该研究（包括3期部分）已完成入组，但随访仍在进行中，这是一项中期分析。该试验已在ClinicalTrials.gov注册，编号NCT01216644。在2010年8月18日至2012年8月10日期间，300名患者（ECF/ECX组152名患者，FLOT组148名患者）被纳入研究的2期部分，其中265名患者（ECF/ECX组137名，FLOT组128名）可在修改后的意向治疗基础上进行评估。FLOT组128例患者中的119例（93%）和ECF/ECX组137例患者中的126例（92%）接受了所有计划的术前周期治疗。FLOT与实现病理完全消退的患者比例显著高于ECF/ECX（128例患者中有20例[16%；95% CI 10-23] vs 137例患者中有8例[6%；3-11];p= 0）。02)。ECF/ECX组111例患者中有44例（40%）和FLOT组119例患者中有30例（25%）至少发生一次涉及围手术期内科或外科并发症的严重不良事件。最常见的非手术3-4级不良事件是中性粒细胞减少（ECF/ECX组137例患者中有52例[38%]，FLOT组128例患者中有67例[52%]）、白细胞减少（28例[20%]对36例[28%]）、恶心（23例[17%]对12例[9%]）、感染（16例[12%]对15例[12%]）、疲劳（19例[14%]对11例[9%]）和呕吐（13例[10%]对4例[3%]）。围手术期FLOT是积极和可行的，可能是局部晚期，可切除的胃或胃-食管交界处腺癌患者的一种选择。
Background Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection.Methods In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1: 1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m(2) on day 1, intravenous cisplatin 60 mg/m(2) on day 1, and either fluorouracil 200 mg/m(2) as continuous intravenous infusion or capecitabine 1250 mg/m(2) orally (two doses of 625 mg/m(2) per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m(2), intravenous oxaliplatin 85 mg/m(2), intravenous leucovorin 200 mg/m(2), and fluorouracil 2600 mg/m(2) as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644.Findings Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p= 0 . 02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]).Interpretation Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma.