改良剂量的FOLFOXIRI化疗方案（氟尿嘧啶、奥沙利铂、伊立替康）治疗结直肠癌的安全性和初步疗效分析

Analysis on safety and preliminary efficacy of dose-modified regimen of 5-fluorouracii plus oxaliplatin and irinotecan （FOLFOXIRI） in advanced colorectal cancer

目的评估改良剂量的mFOLFOXIRI化疗方案（氟尿嘧啶、奥沙利铂、伊立替康）治疗结直肠癌的安全性和初步疗效。方法对2012年10月至2016年12月期间，中山大学附属第六医院收治的单独三药治疗或三药联合靶向治疗的312例经病理证实结直肠癌的患者进行回顾性病例研究。剔除此前接受过完整6个月的辅助治疗（或新辅助治疗）或姑息性化疗的结直肠癌患者：同时剔除一般状态差（ECOG评分标准〉2）或2级神经病变的患者以及对奥沙利铂过敏的患者。mFOLFOXIRI方案为：奥沙利铂85mg／m。溶于5％葡萄糖液500ml静脉输注2h；伊立替康150～165mg／m2溶于0．9％氯化钠250ml静脉滴注90min；继之静脉滴注亚叶酸400mg／m2，持续2h，第1天；5-FU 2800mg／m2,48h连续静脉输注；每2周1次。可联合使用靶向药物，贝伐单抗，5mg／kg，每两周；两妥昔单抗500mg／m2，每两周。使用美国国家癌症研究所常见不良反应术语评定标准（NCI CTCAE 4．0．3）对不良反应进行分级。在至少4个化疗周期后，根据实体瘤的疗效评价标准（RECIST 1．1）评估客观反应率。结果纳入的312例患者中位年龄为52（16-73）岁，其中局部晚期结直肠癌113例（36．2％），转移性结直肠癌199例（63．8％）。有87．8％（274／312）的患者用三药之前没有接受任何治疗。全组共1651个化疗周期，中位数为6个周期（范围1～19）。其中有124个化疗周期（7．5％）进行了剂量调整；176个周期（10．7％）延迟，中位数5（3～13）d；124个周期（7．5％）需要减少剂量。整体相对剂量强度〉90％；具体药物的剂量强度分别为氟尿嘧啶93．6％（2620mg·m-2·d-1），奥沙利铂97．8％（83mg·m-2·d-1），伊立替康94．2％（155mg·m-2·d-1）。23例患者（7例肠穿孔，7例肠梗阻，1例4级血液学毒性，8例3级疲劳）由于无法耐受的毒性而拒绝了随后的化疗。主要3或4级不良事件为中性粒细胞减少69例（22．1％）、疲劳35例（11．2％）和贫血28例（8．9％）；共发生20例（6．4％）严重不良事件：其中中性粒细胞减少性发热13例（4．2％）；肠穿孔7例（2．2％，有4例为上段直肠癌，2例乙状结肠癌，1例横结肠癌其原发灶局部分期T4b并侵犯小肠）；9例（2．9％）随后出现败血症（肠穿孔者6例）。所有肠穿孔患者均接受急诊手术治疗。全组没有治疗相关的死亡患者。对199例转移性结直肠癌患者进行了初步疗效评估，由于22例患者未进行影像学评估，实际初步疗效评估者177例。共观察到113个客观缓解事件，总客观缓解率为63．8％（113／177）。其中部分缓解109例（61．6％），临床完全缓解4例（2．3％），疾病稳定53例（29．9％），疾病进展11例（6．2％）；疾病控制率为93．8％（166／177）。127例接受〉4个周期的三药方案的患者客观缓解率为81．1％（103／127），高于该组患者接受≤4个周时的客观缓解率（40．9％，52／127）。结论mFOLFOXIRI可以安全地用于结直肠癌患者．并可在短期疗效方面取得良好效果。

Objective To evaluate the safety and preliminary efficacy of dose-modified regimen of 5-fluorouracil plus oxaliplatin and irinotecan （mFOLFOXIRI） for patients with advanced colorectal cancer （CRC）. Methods Data of 312 CRC patients confirmed by pathology receiving triplet drug alone or combined with target therapy between October 2012 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. CRC patients who had previously completed adjuvant therapy （or neoadjuvant therapy） within 6 months or palliative chemotherapy were excluded, meanwhile those with poor general condition （ECOG score 〉 2） or grade 2 neuropathy and allergy to oxaliplatin were excluded as well. Regimen of mFOLFOXIRI： oxaliplatin 85 mg/m2 dissolved in 5% glucose solution 500 ml by intravenous infusion for 2 h; irinotecan 150 to 165 mg/m2 dissolved in 0.9% sodium chloride 250 ml by intravenous infusion for 90 rain; following intravenous infusion of leucovorin 400 mg/m2 for 2 h, day 1; 5-FU 2800 mg/m2, 48-h continuous intravenous infusion; once every 2 weeks. Therapy could be combined with a targeted drug, bevaeizumab 5 mg/kg every two weeks; cetuximab 500 mg/m2 every two weeks. Side effect was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events （NCI CTCAE 4.0.3）. The objective response rate was evaluated according to the Response Evaluation Criteria in Solid Tumors （RECIST 1.1 ） after administering at least four eyeles of ehemotherapy. Results The median age was 52 years （range 16- 73） in the whole group; 113 patients （36.2%） had locally advanced CRC, and 199 （63.8%） had metastatic CRC. Most patients （274/312, 87.8%） did not receive any treatment earlier. There were a total of 1651 chemotherapy cycles in the whole group, with a median of 6 （1-19） cycles. Of these 1651 cycles, 124 cycles of chemotherapy （7.5%） were dose-adjusted ; 176 cycles of chemotherapy （10.7%） were delayed for median 5 （3-13） days; 124 cycles （7.5%） required dose decrease. The overall relative dose intensity was 〉90%; the specific drug dose intensity was 93.6%（2620 mg·m-2·d-1） for fluorouracil, 97.8% （83 mg·m-2·d-1） for oxaliplatin, and 94.2% （155 mg·m-2·d-1） for irinotecan. Twenty-three patients （7 of intestinal perforation, 7 of intestina] obstruction, 1 of grade 4 hematologic toxicity, and 8 of grade 3 fatigue） refused subsequent chemotherapy due to intolerable toxicity. Main grade 3 or 4 adverse events in patients were neutropenia in 69 cases （22.1%）, fatigue in 35 cases （11.2%）, and anemia in 28 cases （8.9%）. Twenty serious adverse events （6.4%） occurred, including 13 patients of febrile neutropenia （4.2%）, 7 patients of intestinal perforation （2.2%, 4 patients in upper rectum, 2 in sigmoid colon, and 1 in transverse colon cancer）, and 9 of them had subsequent sepsis （2.9%）. All the patients with intestinal perforation underwent emergency operation. No treatment- related deaths occurred. In 199 patients with metastatic CRC, because 22 patients did not receive image evaluation, the preliminary efficacy of 177 patients was actually evaluated. A total of 113 objective response events were observed. The overall response rate was 63.8% （113/177）, partial response rate was 61.6% （109/177）, clinically complete response rate was 2.3% （4/177）, stable disease was 29.9% （ 53 / 177 ）, prngressive disease was 6.2% （ 11 / 177 ）, and the disease control rate was 93.8% （ 166/177 ）. In 127 patients receiving triplet drug, objective response rate was 40.9% for those with less than four cycles and 81.1% for those with more than four cycles （P〈0.001）. Conclusion The mFOLFOXIRI regimen with reduced dose can be safely used in advanced CRC and has achieved promising results in terms of short-term efficacy.