Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.
Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.
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DOI：
10.1016/s1470-2045(15)00004-2
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发表时间：
2015-08
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Timing of Rectal Cancer Response to Chemoradiation Consortium
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Garcia-Aguilar J;Chow OS;Smith DD;Marcet JE;Cataldo PA;Varma MG;Kumar AS;Oommen S;Coutsoftides T;Hunt SR;Stamos MJ;Ternent CA;Herzig DO;Fichera A;Polite BN;Dietz DW;Patil S;Avila K;Timing of Rectal Cancer Response to Chemoradiation Consortium
局部进展期直肠癌患者在新辅助放化疗后病理学完全缓解，预后改善。这些患者是否需要手术一直受到质疑，但达到病理完全缓解的患者比例很小。我们的目的是评估在放化疗和手术之间增加mFOLFOX 6周期是否会增加达到病理学完全缓解的患者比例。我们在美国和加拿大的17家机构进行了一项2期非随机试验，包括4个连续的II-III期局部晚期直肠癌患者研究组。所有患者均接受化放疗（氟尿嘧啶225 mg/m2/d，在整个放疗期间持续输注，45.0戈伊，分25次，每周5天，持续5周，随后最小剂量为5.4戈伊）。第1组患者在放化疗后6-8周行全直肠系膜切除术。第2-4组的患者在放化疗和全直肠系膜切除之间分别接受了2个、4个或6个周期的mFOLFOX 6。mFOLFOX 6的每个周期包括外消旋亚叶酸200 mg/m2或400 mg/m2（根据治疗研究者的判断）、奥沙利铂85 mg/m2 2小时输注、第1天推注氟尿嘧啶400 mg/m2和氟尿嘧啶2400 mg/m2 46小时输注。主要终点是达到病理学完全缓解的患者比例，通过意向治疗进行分析。该试验在ClinicalTrials.gov注册，编号NCT 00335816。2004年3月24日至2012年11月16日期间，登记了292例患者，其中259例（第1组60例，第2组67例，第3组67例，第4组65例）符合分析标准。第1组60例患者中有11例（18%，95% CI 10-30）、第2组67例患者中有17例（25%，16-37）、第3组67例患者中有20例（30%，19-42）和第4组65例患者中有25例（38%，27-51）达到病理学完全缓解（p=0.0036）。研究组与病理学完全缓解独立相关（第4组与第1组相比的比值比为3.49，95% CI 1.39-8.75; p=0.011）。在第2组中，67例患者中有2例（3%）发生与mFOLFOX 6新辅助给药相关的3级不良事件，1例（1%）发生4级不良事件;在第3组中，67例患者中有12例（18%）发生3级不良事件;在第4组中，65名患者中有18名（28%）发生了3级不良事件，5名（8%）发生了4级不良事件。第2-4组中与mFOLFOX 6新辅助给药相关的最常见3级或以上不良事件为中性粒细胞减少症（第3组5例，第4组6例）和淋巴细胞减少症（第3组3例，第4组4例）。在所有研究组中，发生了25例3级或更严重的手术相关并发症（第1组10例，第2组5例，第3组3例，第4组7例）;最常见的是盆腔积液（7例患者）和吻合口漏（7例患者）。在放化疗后和全直肠系膜切除术前给予mFOLFOX 6有可能增加符合微创治疗策略的患者比例;该策略正在III期临床试验中进行测试。国立卫生研究院/国立癌症研究所R 01 CA 090559;和核心资助P30 CA 008748
Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response. We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II–III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m2 per day by continuous infusion throughout radiotherapy, and 45.0 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 5.4 Gy). Patients in group 1 had total mesorectal excision 6–8 weeks after chemoradiation. Patients in groups 2–4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m2 or 400 mg/m2, according to the discretion of the treating investigator, oxaliplatin 85 mg/m2 in a 2-h infusion, bolus fluorouracil 400 mg/m2 on day 1, and a 46-h infusion of fluorouracil 2400 mg/m2. The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816. Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10–30) of 60 patients in group 1, 17 (25%, 16–37) of 67 in group 2, 20 (30%, 19–42) of 67 in group 3, and 25 (38%, 27–51) of 65 in group 4 achieved a pathological complete response (p=0.0036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 3.49, 95% CI 1.39–8.75; p=0.011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients). Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to increase the proportion of patients eligible for less invasive treatment strategies; this strategy is being tested in phase 3 clinical trials. National Institutes of Health/National Cancer Institute R01 CA090559; and Core Grant P30 CA008748