Adding cetuximab to combination therapy with irinotecan, fluorouracil, and leucovorin as the first-line treatment for metastatic colorectal cancer reduces the risk of disease progression, according to the results of a large randomized study.

In the open-label, phase III trial of nearly 1,200 patients, addition of cetuximab cut the risk of progression by 15% and raised the overall tumor response rate by nearly 10%, study investigators reported in the April 2 issue of the New England Journal of Medicine.

However, the addition of cetuximab did not improve overall survival.

The investigators compared a regimen of folinic acid (leucovorin), fluorouracil, and irinotecan (known as FOLFIRI) alone against the same combination plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR).

The study, conducted at 184 medical centers, included 1,198 patients who already had metastases when they presented with adenocarcinoma of the colon or rectum that could not be resected for curative purposes. A total of 599 patients were randomized to cetuximab plus FOLFIRI, and 599 patients to FOLFIRI alone.

After a median follow-up of 29.9 months for cetuximab plus FOLFIRI and 29.4 months for FOLFIRI alone, disease progression was noted in 298 patients and 322 patients, respectively – a 15% difference.

Median progression-free survival was 8.9 months for the cetuximab-FOLFIRI combination, significantly longer than the 8.0-month progression-free survival without cetuximab. Complete or partial tumor responses were confirmed in 46.9% of patients who received cetuximab, compared with 38.7% of those who did not, wrote Dr. Eric Van Cutsem of the University Hospital Gasthuisberg, Leuven, Belgium, and his associates.

However, there was no significant difference between the two groups in overall survival, Dr. Van Cutsem and his colleagues said (N. Engl. J. Med. 2009;360:1408-17).

The incidence of adverse events, particularly skin reactions, diarrhea, and infusion-site reactions, was significantly higher with the cetuximab-FOLFIRI combination.

Previous studies indicated that certain mutations of the KRAS gene are associated with poor response to cetuximab and to other anti-EGFR monoclonal antibodies. Tumor tissue from approximately half the patients in this study was tested for such mutations. The results suggested that cetuximab’s benefit occurred primarily in patients who had wild-type KRAS tumors.

The study was designed, supervised, and supported by Merck (Darmstadt, Germany). Dr. Van Cutsem has received consulting or advisory fees from Amgen, Merck, Pfizer, Roche, and Sanofi-Aventis; lecture fees from Amgen, Merck, Roche, and Sanofi-Aventis; and grant support from Merck and Roche.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

据一项大型随机研究结果显示，西妥昔单抗联合依立替康、氟尿嘧啶和亚叶酸钙作为一线治疗方案可降低转移性结直肠癌疾病进展的风险。

研究人员在《新英格兰医学杂志》4月2日发表的文章中指出，一项入选患者达1,200例的开放性III期临床试验显示，加入西妥昔单抗可降低结直肠癌疾病进展风险达15个百分点，并提高总体肿瘤反应率近10个百分点。

但是，加入西妥昔单抗并未改善总生存时间。

研究人员比较了单纯FOLFIRI(亚叶酸钙、氟脲嘧啶、伊立替康)方案与FOLFIRI联合表皮生长因子受体单克隆抗体(EGFR)西妥昔单抗的疗效。

该项研究在184个医学中心展开，共入选1,198例已出现转移但无法进行治疗目的切除的结直肠腺癌患者。对入选患者随机分配，599例分在FOLFIRI 联合西妥昔单抗组，另外599例则分在单纯FOLFIRI组。

FOLFIRI联合西妥昔单抗组随访时间中位数为29.9个月，单纯FOLFIRI组为29.4个月，随访发现出现疾病进展的分别为298例和322例，两组相差15%。

比利时Leuven大学Gasthuisberg 医院的Eric Van Cutsem博士和他的合作者报道：FOLFIRI联合西妥昔单抗组中位数无进展生存期为8.9个月，超过单纯FOLFIRI组的8.0个月；使用西妥昔单抗组达到完全或部分缓解的患者比例为46.9%，而未使用西妥昔单抗组则只有38.7%。

然而，两组之间的总体存活率无显著差异，Van Cutsem博士及他的同事说。(N. Engl. J. Med. 2009;360:1408-17)

FOLFIRI联合西妥昔单抗组的不良事件，尤其是皮肤反应、腹泻、输液部位反应的发生率显著上升。

以往的研究表明，KRAS基因某些突变与西妥昔单抗及其他抗EGFR单克隆抗体存在弱相关性。本研究中大约半数患者的肿瘤组织经检测存在此类突变。结果表明， 野生型KRAS基因患者可从西妥昔单抗治疗中受益。

此项研究由默克公司（德国，达姆施塔特）设计、监督和资助。Van Cutsem博士接受了安进、默克、辉瑞、罗氏及赛诺菲-安万特提供的咨询或咨询费用，以及安进、默克、罗氏及赛诺菲-安万特提供的讲座报酬。研究由默克和罗氏提供基金资助。

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