Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23) : a multicentre, randomised, open-label, phase 3 trial
Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23) : a multicentre, randomised, open-label, phase 3 trial
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DOI：
10.1016/s1470-2045(21)00079-6
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发表时间：
2021-04-28
期刊：
影响因子：
51.1
通讯作者：
Borg, Christophe
中科院分区：
文献类型：
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作者：
Conroy, Thierry;Bosset, Jean-Francois;Borg, Christophe
背景：局部晚期直肠癌的化疗、手术和辅助化疗可以控制局部疾病，但远处转移仍然很常见。我们的目的是评估在术前放化疗前进行新辅助化疗是否可以降低远处复发的风险。方法我们在法国的35家医院进行了一项第三阶段的开放标签、多中心、随机试验。符合条件的患者为18-75岁的成年人，有新诊断的、经活检证实的直肠腺癌，分期为ct3或ct4-m0，WHO表现状态为0-1。患者被随机分配(1：1)到新辅助化疗组或标准护理组，使用一个独立的基于网络的系统，通过最小化方法按中心分层，根据MRI、肿瘤位置和分期将肿瘤扩展到直肠周围脂肪中。调查人员和参与者没有被蒙蔽进行治疗分配。新辅助化疗组采用新辅助化疗方案(奥沙利铂85 mg/m(2)，伊立替康180 mg/m(2)，亚叶酸钙400 mg/m(2)，氟尿嘧啶2400 mg/m(2)，每14天静脉滴注，共6个周期)、放化疗(50Gy5周，800 mg/m(2)同时口服卡培他滨，每日2次，每周5天)，全直肠系膜切除，辅助化疗(3个月改良FOLFOX6[奥沙利铂85 mg/m(2)，亚叶酸钙400 mg/m(2)，3个月)。然后静脉滴注氟尿嘧啶400 mg/m(2)，剂量为2400 mg/m(2)，连续滴注46h，每14天一次，共6个周期[卡培他滨[1250 mg/m(2)，每日2次，第1~14天，每21天2次]。标准护理组接受放化疗、全直肠系膜切除和辅助化疗(为期6个月)。主要终点是在意向治疗人群中评估3年的无病存活率。对接受治疗的患者进行安全性分析。这项试验在EudraCT(2011-004406-25)和ClinicalTrials.gov(NCT01804790)上注册，现已完成。中位随访时间为46.5月(IQR35.4~61.6)，新辅助化疗组3年无瘤生存率为76%(95%可信区间69~81)，标准护理组3年无瘤生存率为69%(62~74)(分层危险比0.69，95%可信区间0.49~0.97；p=0.034)。在新辅助化疗期间，最常见的3-4级不良反应是中性粒细胞减少症(225例患者中38例(17%))和腹泻(226例患者中25例(11%))。在放化疗期间，最常见的3-4级不良反应是淋巴细胞减少(新辅助化疗组212人中59人(28%)，标准护理组226人中67人[30%])。在辅助化疗期间，最常见的3-4级不良事件是淋巴细胞减少(新辅助化疗组161例中有18例[11%])，标准护理组中有42例(27%)，中性粒细胞减少症(161例中9例[6%]对155例中28例[18%])，周围感觉神经病(162例中19例[12%]对155例中32例[21%])。在整个治疗期间，新辅助化疗组2331名参与者中有63人(27%)和护理标准组230名患者中有50人(22%)在整个治疗期间发生了严重不良事件(p=0.167)。在辅助治疗期间，新辅助化疗组的163名参与者中有18名(11%)发生了严重的不良事件，而护理标准组的患者中有36名(23%)发生了严重的不良反应(p=0.0049)。与治疗相关的死亡有一例(
Background Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences.Methods We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and fluorouracil 2400 mg/m(2) intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m(2) concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m(2) and leucovorin 400 mg/m(2), followed by intravenous 400 mg/m(2) fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m(2) over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m(2) orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete.Findings Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46.5 months (IQR 35.4-61.6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0.69, 95% CI 0.49-0.97; p=0.034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-ofcare group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0.167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0.0049). Treatment-related deaths occurred in one (