结直肠癌肝转移灶切除术后患者辅助性FOLFOX/FOLFIRI联合或不联合肝动脉灌注氟尿苷的安全性和有效性（HARVEST试验）：一项随机对照试验

Safety and efficacy of adjuvant FOLFOX/FOLFIRI with versus without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastasectomy (HARVEST trial): A randomized controlled trial.

作者信息

Wang De-Shen, Pat Fong William, Wen Lei, Cai Yan-Yu, Ren Chao, Wu Xiao-Jun, Zhang Tian-Qi, Cao Fei, Zuo Meng-Xuan, Li Bin-Kui, Zheng Yun, Li Li-Ren, Chen Gong, Ding Pei-Rong, Lu Zhen-Hai, Zhang Rong-Xin, Yuan Yun-Fei, Pan Zhi-Zhong, Li Yu-Hong

机构信息

Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.

Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

出版信息

Eur J Cancer. 2025 Jan;214:115154. doi: 10.1016/j.ejca.2024.115154. Epub 2024 Nov 30.

DOI:10.1016/j.ejca.2024.115154

PMID:39644535

Abstract

BACKGROUND

Hepatic artery infusion (HAI) chemotherapy, particularly with floxuridine (FUDR), has previously shown effectiveness in improving recurrence-free survival (RFS) in colorectal cancer (CRC) patients with colorectal liver metastases (CRLM). Nonetheless, its adjuvant use alongside modern systemic chemotherapy remains unevaluated.

PATIENTS AND METHODS

The HARVEST trial is an open-label, randomized, controlled study conducted from May 2018 to August 2021. CRC patients with resectable primary tumors and CRLM were recruited and randomized to receive standard systemic chemotherapy only (non-HAI group) or in combination with HAI-FUDR (HAI group). However, due to a FUDR manufacturing shortage, the study was terminated early after enrolling 92 patients. The primary endpoint was the 3-year RFS rate, with secondary endpoints including overall survival (OS), liver-specific RFS, and adverse events.

RESULTS

Of the 92 randomized patients, 77 were included in the modified intention-to-treat analysis. Three-year RFS rates were comparable between the HAI (N = 38) and non-HAI (N = 39) groups (31.4 % vs. 34.4 %; P = 0.28). However, improved 1-year RFS and a longer expected five-year OS were observed in the HAI group. While exploratory subgroup analysis suggested potential RFS benefits for patients with multiple liver metastases, RAS/BRAF mutations, and positive postoperative ctDNA methylation, multivariable analysis did not identify these as independent factors. Safety analysis showed comparable chemotherapy-related adverse events, except for a higher occurrence of ALT elevation in the HAI group.

CONCLUSIONS

While our study showed no significant difference in three-year RFS, adjuvant chemotherapy intensification with HAI-FUDR is feasible and may offer early benefits in RFS and long-term OS. Nonetheless, a larger sample size is needed for validation and identifying which patient subgroup might benefit from this regimen.

TRIAL REGISTRATION

ClinicalTrials.gov: NCT03500874.

摘要

背景

肝动脉灌注（HAI）化疗，尤其是使用氟尿苷（FUDR），此前已显示出可提高结直肠癌肝转移（CRLM）患者的无复发生存期（RFS）。尽管如此，其与现代全身化疗联合的辅助应用仍未得到评估。

患者与方法

HARVEST试验是一项从2018年5月至2021年8月进行的开放标签、随机对照研究。招募了可切除原发性肿瘤和CRLM患者，并随机分为仅接受标准全身化疗（非HAI组）或联合HAI-FUDR（HAI组）。然而，由于FUDR生产短缺，在招募92例患者后研究提前终止。主要终点是3年RFS率，次要终点包括总生存期（OS）、肝脏特异性RFS和不良事件。

结果

在92例随机分组的患者中，77例纳入了改良意向性分析。HAI组（N = 38）和非HAI组（N = 39）的3年RFS率相当（31.4%对34.4%；P = 0.28）。然而，HAI组观察到1年RFS改善和预期5年OS延长。虽然探索性亚组分析表明多肝转移、RAS/BRAF突变和术后ctDNA甲基化阳性患者可能从RFS中获益，但多变量分析未将这些确定为独立因素。安全性分析显示化疗相关不良事件相当，但HAI组ALT升高发生率更高。