Critical role of bevacizumab scheduling in combination with pre-surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: results of the branch trial
Critical role of bevacizumab scheduling in combination with pre-surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: results of the branch trial
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DOI：
10.18632/oncotarget.4724
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发表时间：
2015-10-06
期刊：
影响因子：
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通讯作者：
Delrio, Paolo
中科院分区：
文献类型：
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作者：
Avallone, Antonio;Pecori, Biagio;Delrio, Paolo
背景资料：我们之前已经证明，在术前盆腔放疗期间，包括奥沙利铂+雷替曲塞和5-氟尿嘧啶/亚叶酸（OXATOM/FUFA）在内的强化术前方案对局部晚期直肠癌（LARC）产生了有希望的结果。临床前的证据表明，贝伐单抗的调度可能是至关重要的，以优化其组合与chemo-radiotherapy.Patients和methods：这个非随机，非比较，II期研究进行了MRI定义的高风险LARC。患者在RT期间接受3个双周周期的OXATOM/FUFA治疗。在放化疗开始前2周，以及在化疗3个周期的同一天（伴随方案A）或在化疗第一和第二周期前4天（序贯方案B）给予贝伐珠单抗。主要终点是病理学完全肿瘤消退（TRG 1）率。结果：伴随时间表的累积提前终止，因为TRG 1的数量（16例患者中有2例）在统计学上与待检验的活性假设（30%）不一致。相反，序贯方案达到终点，46例入组患者的最终TRG 1率为50%（95% CI 35%-65%）。中性粒细胞增多症是两种给药方案中最常见的≥ 3级毒性，但序贯给药方案中的发生率低于伴随给药方案（30% vs. 44%）。A和B方案中分别有8/15（53%）和13/46（28%）例患者发生术后并发症。在5年随访的PFS和OS的概率分别为80%（95%CI，66%-89%）和85%（95%CI，69%-93%），分别为序贯schedule.Conclusions：这些结果突出了贝伐单抗调度的相关性，以优化其与术前化疗，放疗在LARC的管理相结合。
Background: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy.Patients and methods: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemoradiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate.Results: The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade >= 3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95% CI, 66%-89%) and 85% (95% CI, 69%-93%), respectively, for the sequential-schedule.Conclusions: These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.