Takahashi Shin, Ouchi Kota, Sakamoto Yasuhiro, Mori Takahiro, Shimodaira Hideki, Takahashi Masahiro, Ohori Hisatsugu, Kudo Chieko, Takahashi Yoshikazu, Imai Hiroo, Akiyama Shoko, Takahashi Masanobu, Suto Takeshi, Murakawa Yasuko, Oishi Takayuki, Isobe Hideki, Okada Yoshinari, Kawai Sadayuki, Yoshioka Takashi, Sato Toshihiko, Shindo Yoshiaki, Sugiyama Shunsuke, Komine Keigo, Chiba Natsuko, Okita Akira, Yamaguchi Takuhiro, Ishioka Chikashi
Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan.
Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan.
J Gastrointest Oncol. 2023 Apr 29;14(2):676-691. doi: 10.21037/jgo-22-862. Epub 2023 Mar 27.
Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment.
Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay.
Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months].
Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.
关于西妥昔单抗与化疗联合用于转移性结直肠癌（mCRC）二线治疗的每两周一次方案，目前所知甚少。最近，有报道称DNA甲基化状态可能是抗表皮生长因子受体（EGFR）抗体治疗疗效的一种新的预测指标。本研究旨在探讨每两周一次的西妥昔单抗联合mFOLFOX6或mFOLFIRI作为外显子2野生型mCRC二线治疗的疗效和安全性。我们还研究了DNA甲基化状态对含EGFR抗体治疗疗效的预测性。
纳入对一线化疗难治或不耐受的患者，并给予每两周一次的西妥昔单抗联合mFOLFOX6或mFOLFIRI治疗。主要终点为无进展生存期（PFS）。每2个月使用实体瘤疗效评价标准（RECIST）1.1版进行肿瘤评估。根据不良事件通用术语标准4.0版评估不良事件（AE）。采用改良的MethyLight分析法定义结肠癌细胞的DNA甲基化状态。
共纳入66例患者。中位PFS（mPFS）为5.1[95%置信区间（CI），3.8 - 7.6]个月。中位总生存期（mOS）为12.7（95%CI，7.5 - 15.3）个月。53.0%的患者发生3级或更高等级的中性粒细胞减少，而3级或更高等级的皮肤疾病发生在不到15%的患者中。多因素分析显示，DNA甲基化状态不能作为PFS[风险比（HR），1.43；P = 0.39]和OS（HR，2.13；P = 0.086）的独立预测指标。然而，在野生型患者中，低甲基化结直肠癌（LMCC）组的mPFS和mOS在数值上优于高甲基化结直肠癌（HMCC）组，尽管差异无统计学意义[mPFS：8.5（95%CI，6.1 - 10.9）对3.3（95%CI，1.2 - 未达到）个月，P = 0.79；ΔmPFS，5.2个月；mOS：15.3（95%CI，11.9 - 23.5）对6.5（95%CI，3.1 - 未达到）个月，P = 0.53；ΔmOS，8.8个月]。
每两周一次的西妥昔单抗联合mFOLFOX6或mFOLFIRI是mCRC有用的二线治疗方案。DNA甲基化状态作为mCRC中抗EGFR疗效的预测生物标志物值得进一步探索。
