新辅助化疗联合改良 FOLFOXIRI 方案治疗局部进展期直肠癌：有效转化 EMVI 和 MRF 由阳性转为阴性的结果——一项长期单中心 2 期临床试验。

PURPOSE: Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC. PATIENTS AND METHODS: The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.

目的：放化疗（CRT）仍是局部晚期直肠癌（LARC）的标准治疗方法。本Ⅱ期临床试验旨在评估新辅助三联化疗（mFOLFOXIRI[亚叶酸钙、5-氟尿嘧啶、奥沙利铂和伊立替康]）在 LARC 中的疗效和安全性。

患者和方法：LARC 患者（肛缘下缘>5cm）接受多达 5 个周期的 mFOLFOXIRI。MRI 用于评估基线和化疗后 TN 分期。如果肿瘤缩小或保持稳定，在最后一次化疗后 4-6 周内进行根治性切除术。建议术后行 mFOLFOX6 或 XELOX 辅助化疗。对于 R1 切除、ypT4b、ypN2 和 CRM 阳性的患者，计划进行术后放疗。主要终点为病理完全缓解（pCR）率。

结果：从 2016 年 2 月至 2019 年 3 月，共纳入 50 例患者。48 例（96%）为临床淋巴结阳性，28 例（56.5%）有 MRF 侵犯，39 例（78.4%）为 EMVI 阳性。新辅助 mFOLFOXIRI 化疗的中位数周期数为 5（范围，1-5）。共有 50 例中的 46 例（92%）患者接受了全直肠系膜切除术（TME），均为 RO 切除。pCR 率为 4.3%（2/46）。23 例 cN+患者获得病理淋巴结阴性状态。CRM 和 EMVI 阳性的比例分别为 2.2%和 34.7%。14/46（30.4%）例患者接受了辅助放疗。新辅助化疗期间最常见的 3 级或以上毒性包括中性粒细胞减少症（50%）、白细胞减少症（14%）和腹泻（12%）。术后有临床意义的并发症包括肺炎（n=1）、骨盆感染（n=1）和吻合口瘘（n=1）。中位随访时间为 51.2 个月，3 例（6.5%）患者局部复发，9 例（19.6%）患者远处转移。3 年无病生存率（DFS）和总生存率（OS）分别为 75.8%和 86.8%。

结论：mFOLFOXIRI 新辅助化疗可显著降期，并可有效消除 EMVI，并将阳性 MRF 转化为 LARC 阴性。生存结果令人鼓舞。长期随访显示，DFS 和 OS 率均有较好的结果，安全性良好。

临床试验注册：ClinicalTrials.gov 标识符：NCT03443661，2018 年 2 月 23 日。