局部晚期直肠癌术前同步放化疗中卡培他滨联合奥沙利铂剂量递增的I期临床研究

Phase I study of dose escalation of oxaliplatin added to capecitabine during intensity-modulated radiation therapy patients with locally advanced rectal cancer

目的 探讨局部晚期直肠癌术前同步放化疗基于5-Fu类药物的联合方案中奥沙利铂的最大耐受剂量。方法 本试验设计为前瞻性研究，自2015年3月至2015年10月，入组经病理确诊的局部晚期（T3、T4/N＋）直肠癌患者15例，接受调强放疗以及卡培他滨联合奥沙利铂方案的同步化疗。放疗采用同步局部加量， 总剂量GTV为50.6 Gy，CTV 41.8 Gy，共22次，30 d内完成。同期化疗，卡培他滨为固定剂量825 mg/m^2，2次/d，每周1-5服用，伴随放疗全程；奥沙利铂剂量分别为100、110、120、130 mg/m^2，共4个递增剂量水平组，每21天为1个周期。15例患者，前12例按随机数字表法分为4组，每组3例，最后一组因出现剂量限制性毒性又入组了3例患者，因此，第4组为6例。治疗后充分评估不良反应和有效率。结果 近期治疗相关不良反应主要表现为放射性肠炎、皮肤反应、恶心、乏力、泌尿系不良反应和骨髓抑制，并随奥沙利铂剂量的提高而增多、加重。观察100、110 和120 mg/m^2组中未出现3级以上不良反应，130 mg/m^2组中则出现了剂量限制性毒性：1例3级血小板减少和1例3级恶心，该剂量为最大耐受剂量。手术后病理显示，所有患者均达到降期，4组患者分别有0、1、2、3例达到完全缓解。结论 局部晚期直肠癌调强放疗同步联合卡培他滨及奥沙利铂方案安全有效。奥沙利铂的最大耐受剂量为130 mg/m^2，1次/3周。

Objective To discuss the maximum tolerated dose of oxaliplatin based on 5-fluorouracil derivative in patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy. Methods From Mar 2015 to Oct 2015, 15 locally advanced rectal cancer patients （T3, T4/N＋） who received intensity modulated radiotherapy and concurrent chemotherapy with capecitabine and oxaliplatin were enrolled in this study. The prescription dose was 50.6 Gy for gross tumor volume（GTV） and 41.8 Gy for clinical tumor volume（CTV） in 22 fractions within 30 d with concomitant boost. There were four dose-level groups of oxaliplatin as 100, 110, 120 and 130 mg/m^2 tri-weekly and fixed capecitabine dose （825 mg/m^2 bid d1-5 per week）. The first 12 patients were randomly assigned into 4 groups. For the 130 mg/m3 group, another 3 patients were enrolled because of dose-limiting toxicity（DLT）. Treatment related toxicities and response rates were evaluated.Results The most common adverse events（AE） were radiation enteritis, skin reactions, nausea, fatigue, urinary system AE and bone marrow suppression. There was a trend of increase by the dose level of oxaliplatin for toxicities. Groups 100, 110 and 120 mg/m^2 had none DLT, while group 130 mg/m^2 had 1 patient for grade 3 thrombopenia and 1 patient for grade 3 nausea. Postoperative pathology showed that all patients achieved tumor downstaging, among which 0, 1, 2, 3 cases achieved complete remission of the four groups, respectively. Conclusions The combination regimen of capecitabine and oxaliplatin is safe and effective according to the preliminary results.The maximum tolerated dose of oxaliplatin was 130 mg/m^2 tri-weekly.