Van Cutsem Eric, Köhne Claus-Henning, Hitre Erika, Zaluski Jerzy, Chang Chien Chung-Rong, Makhson Anatoly, D'Haens Geert, Pintér Tamás, Lim Robert, Bodoky György, Roh Jae Kyung, Folprecht Gunnar, Ruff Paul, Stroh Christopher, Tejpar Sabine, Schlichting Michael, Nippgen Johannes, Rougier Philippe
University Hospital Gasthuisberg, Digestive Oncology Unit, Herestraat 49, 3000 Leuven, Belgium.
N Engl J Med. 2009 Apr 2;360(14):1408-17. doi: 10.1056/NEJMoa0805019.
We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab.
We randomly assigned patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival.
A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab-FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P=0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P=0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P=0.03) but not for progression-free survival (P=0.07) or overall survival (P=0.44). The hazard ratio for progression-free survival among patients with wild-type-KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab-FOLFIRI group. The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, P<0.001), infusion-related reactions (in 2.5% vs. 0%, P<0.001), and diarrhea (in 15.7% vs. 10.5%, P=0.008).
First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. (ClinicalTrials.gov number, NCT00154102.)
我们研究了西妥昔单抗联合伊立替康、氟尿嘧啶和亚叶酸钙（FOLFIRI）作为转移性结直肠癌一线治疗的疗效，并探寻肿瘤中KRAS基因的突变状态与西妥昔单抗临床反应之间的关联。
我们将表皮生长因子受体阳性且有不可切除转移灶的结直肠癌患者随机分组，分别接受单纯FOLFIRI或联合西妥昔单抗治疗。主要终点为无进展生存期。
共有599例患者接受西妥昔单抗联合FOLFIRI治疗，599例患者接受单纯FOLFIRI治疗。与FOLFIRI组相比，西妥昔单抗 - FOLFIRI组无进展生存期的风险比为0.85（95%置信区间[CI]，0.72至0.99；P = 0.048）。两组的总生存期无显著差异（风险比，0.93；95% CI，0.81至1.07；P = 0.31）。治疗组与KRAS突变状态在肿瘤反应方面存在显著交互作用（P = 0.03），但在无进展生存期（P = 0.07）或总生存期（P = 0.44）方面不存在。KRAS野生型肿瘤患者中，西妥昔单抗 - FOLFIRI组无进展生存期的风险比为0.68（95% CI，0.50至0.94）。与单纯FOLFIRI相比，西妥昔单抗联合FOLFIRI时以下3级或4级不良事件更常见：皮肤反应（仅为3级）（患者比例分别为19.7%和0.2%，P < 0.001）、输液相关反应（分别为2.5%和0%，P < 0.001）以及腹泻（分别为15.7%和10.5%，P = 0.008）。
与单纯FOLFIRI相比，西妥昔单抗联合FOLFIRI一线治疗可降低转移性结直肠癌的进展风险。西妥昔单抗的获益仅限于KRAS野生型肿瘤患者。（ClinicalTrials.gov编号，NCT00154102。）
