Aims

We assessed the efficacy and safety of total neoadjuvant therapy, including targeted agent plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by intensified chemoradiotherapy (CRT) and surgical resection, in patients with locally advanced rectal cancer.

Materials and methods

This was a single-arm, single-centre phase II trial. Eligible patients had non-metastatic locally advanced rectal adenocarcinoma. Based on Ras-BRAF status, patients were treated with bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) plus FOLFOXIRI regimen followed by oxaliplatin–5-fluorouracil-based CRT and surgery. The primary end point was pathological complete response rate. Secondary end points were toxicity, compliance, tumour downstaging, complete resection, surgical complications, local and distant failures and overall survival. The sample size was planned to expect an absolute 20% improvement in pathological complete response rate over historical literature data with an α error of 0.05 and a power of 80%.

Results

Between October 2015 and September 2019, 28 patients (median age 66 years) were enrolled. All patients had regional lymph node involvement at diagnosis. FOLFOXIRI plus bevacizumab was administered in 11 mutated Ras-BRAF patients, whereas the 17 wild-type Ras-BRAF patients received FOLFOXIRI plus panitumumab/cetuximab. Overall, total neoadjuvant therapy was well tolerated and 26 patients (92.9%) completed the programmed strategy. A complete response was achieved in nine cases (32.1%) and a nearly pathological complete response (ypT1 ypN0) in two patients (7.2%). There was no evidence of febrile neutropenia and no grade 4 adverse events were recorded. Radical resection was achieved in all cases.

Conclusion

FOLFOXIRI plus targeted agent-based induction chemotherapy and intensified CRT before surgery showed promising clinical activity and was well tolerated in locally advanced rectal cancer patients. This phase II trial provides a strong rationale for phase III studies.

中文翻译：

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局部晚期直肠癌患者的强化总新辅助治疗：一项 II 期试验

宗旨

我们评估了全新辅助治疗的有效性和安全性，包括靶向药物加 FOLFOXIRI（5-氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康）诱导化疗，然后是强化放化疗 (CRT) 和手术切除，用于局部晚期直肠癌患者。

材料和方法

这是一项单臂、单中心 II 期试验。符合条件的患者患有非转移性局部晚期直肠腺癌。根据 Ras-BRAF 状态，患者接受贝伐珠单抗（Ras-BRAF 突变）或帕尼单抗/西妥昔单抗（野生型 Ras-BRAF）加 FOLFOXIRI 方案，随后接受基于奥沙利铂-5-氟尿嘧啶的 CRT 和手术治疗。主要终点是病理完全缓解率。次要终点是毒性、依从性、肿瘤降期、完全切除、手术并发症、局部和远处失败以及总生存期。样本量计划预期病理完全反应率比历史文献数据有 20% 的绝对改善，α 误差为 0.05，功效为 80%。

结果

2015 年 10 月至 2019 年 9 月期间，招募了 28 名患者（中位年龄 66 岁）。所有患者在诊断时都有区域淋巴结受累。FOLFOXIRI 加贝伐珠单抗用于 11 名 Ras-BRAF 突变患者，而 17 名野生型 Ras-BRAF 患者接受 FOLFOXIRI 加帕尼单抗/西妥昔单抗。总体而言，总体新辅助治疗耐受性良好，26 名患者 (92.9%) 完成了程序化策略。9 例 (32.1%) 获得完全缓解，2 例患者 (7.2%) 获得接近病理学完全缓解 (ypT1 ypN0)。没有发热性中性粒细胞减少的证据，也没有记录到 4 级不良事件。所有病例均实现根治性切除。

结论

FOLFOXIRI 联合靶向药物诱导化疗和术前强化 CRT 显示出有希望的临床活性，并且在局部晚期直肠癌患者中具有良好的耐受性。该 II 期试验为 III 期研究提供了强有力的理由。