Lancet Oncol：在卡培他滨-顺铂基础上联用西妥昔单抗不能改善晚期胃癌患者临床预后

晚期胃癌患者的预后极差，目前鲜少有有效的治疗方案。来自德国Leipzig大学的Florian Lordick等为了评估在卡培他滨-顺铂化疗方案的基础上额外加用西妥昔单抗对晚期胃癌或胃食管交界处肿瘤患者的疗效而设计了相关研究，他们的研究结果发表在Lancet Oncol 4月最新的在线期刊上。
本研究为开放式标签、随机3期对照研究（EXPAND），研究所纳入的受试者为年龄在18岁或以上，组织学确诊为胃或胃食管交界处局部晚期不可经手术切除（M0）或转移性（M1）腺癌患者。研究者从25个国家的164个中心（教学医院和临床医院）纳入患者，并按照1:1的比例随机分为2组，一组接受一线化疗，另一组接受一线化疗联合西妥昔单抗。研究者根据所纳入的受试者的疾病分期（M0/M1）、既往是否接受过食管切除术或胃部切除术（是/否），以及既往是否接受过（新）辅助（放）化疗（是/否）而对其进行分层。在本研究中，患者所接受的治疗方案为每3周一个疗程，卡培他滨-顺铂方案为在第1-14天，每日两次按照1000mg/m2应用卡培他滨；第1天按照80mg/m2静脉内应用顺铂；卡培他滨-顺铂-西妥昔单抗方案则在上述方案的基础上加用西妥昔单抗——第1天按照400mg/m2，继之以250mg/m2每周应用一次。本研究的主要终点事件为无进展生存期（PFS），由一个独立的小组采用意向治疗分析法对研究结果进行评估，并且进行分析的人员不知道患者所接受的具体治疗方案。安全性分析所纳入的患者为至少接受过一个治疗药物剂量的患者。本研究在EudraCT注册，注册号为2007-004219-75。
在2008年6月30日至2010年12月15日期间，研究者共纳入了904名患者。其中卡培他滨-顺铂联合西妥昔单抗组中有455名患者，他们的中位PFS为4.4月，95%可信区间为4.2月至5.5月，而在卡培他滨-顺铂组中纳入了449名患者，他们的中位PFS为5.6月，95%可信区间为5.1月至5.7月，HR为1.09，两组差异不具有显著统计学意义。在化疗联合西妥昔单抗组中的446名患者中有369人（83%）出现3-4级不良反应事件，而在化疗组的436名患者中有337人（77%）出现3-4级不良反应事件，包括腹泻、低钾血症、低镁血症、皮疹和手足综合征。与联合西妥昔单抗治疗的受试者相比，仅接受化疗的受试者更容易出现3-4级的中性粒细胞减少。而3-4级的皮肤反应和痤疮样皮疹在化疗联合西妥昔单抗组更为多见。出现严重不良反应（任何级别）的受试者在西妥昔单抗组为239人（54%），而在化疗组为194人（44%）。
本研究结果指出，在晚期胃癌患者中，在卡培他滨-顺铂的方案的基础上额外加用西妥昔单抗并不会给上述患者带来额外的治疗获益。
与胃癌相关的拓展阅读：

• 关于印发胃癌等五种恶性肿瘤规范化诊疗指南的通知
• 频繁使用口红可引发胃癌
• Ann Oncol：HER-2靶向治疗方案对胃癌有效
• Lancet Oncol：一线胃癌，西妥昔单抗带来的失望结果
• IAI：高盐饮食与胃癌风险增加相关
• 胃癌D2淋巴结清扫技术要点与实施
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Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial
Background
Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer.
Methods
In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m2 (on days 1—14) and intravenous cisplatin 80 mg/m2 (on day 1), with or without weekly cetuximab (400 mg/m2 initial infusion on day 1 followed by 250 mg/m2 per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75.
Findings
Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4·4 months (95% CI 4·2—5·5) compared with 5·6 months (5·1—5·7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1·09, 95% CI 0·92—1·29; p=0·32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3—4 adverse events, including grade 3—4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3—4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3—4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event.
Interpretation
Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial.
Funding
Merck KGaA.