Lancet:CLASSIC试验表明辅助化疗可延缓胃癌发展

2012-02-11 MedSci MedSci原创

近日,发表于Lancet的一项亚洲研究表明,对于可手术的胃癌病人,使用卡倍他滨和奥沙利铂的辅助化疗应该被视为新的治疗方案。 在一个III期临床试验中,他们发现D2胃癌手术切除术后进行6个月的联合化疗,与单独手术相比,可提高3年无疾病生存期(74% vs 59%;HR, 0.56;P < 0.0001) 。 然而,化疗带来的疗效伴随着3或4级不良事件的高发生率 (56%)。研究纳入了10

近日,发表于Lancet的一项亚洲研究表明,对于可手术的胃癌病人,使用卡倍他滨和奥沙利铂的辅助化疗应该被视为新的治疗方案。 在一个III期临床试验中,他们发现D2胃癌手术切除术后进行6个月的联合化疗,与单独手术相比,可提高3年无疾病生存期(74% vs 59%;HR, 0.56;P < 0.0001) 。

然而,化疗带来的疗效伴随着3或4级不良事件的高发生率 (56%)。研究纳入了1035名II到IIIB期胃癌患者,涉及37个临床中心,多数在韩国,这项试验被称为胃癌患者卡倍他滨和奥沙利铂辅助化疗研究(CLASSIC)。

这项临床试验因为其显示的效益已被终止。中期疗效分析的结果发表在1月28日的柳叶刀杂志上。研究者Yung-Jue Bang 写到,这项发现可能也适用于D2手术后的其他部位。

然而,在同期述评中,一位来自日本的专家Toshirou Nishida对这项结果的普遍性提出了质疑。他写到,在亚洲,我们有2种辅助治疗的选择,这两项选择是卡倍他滨联合奥沙利铂,和口服氟尿嘧啶类药物S- 1,该辅助治疗已经在胃癌患者TS-1辅助化疗试验(ACTS-GS)中进行了研究。Nishida没有说非亚洲国家也有两种选择,说明一个病人所在的国家对癌症治疗有重要的影响。

Nishida博士写到,辅助治疗是用来消除根治术后潜在的微转移,治疗策略的选择依赖于术后预期的局部疾病控制、治疗机构和国家。在亚洲,D2胃切除术是标准治疗,全身辅助化疗已经是常规,主要是因为ACTS-GS的早期结果。在非亚洲国家,D1手术指最常见的手术。

该研究的作者也探讨了普遍性的问题。他们承认他们的研究人群比起欧洲和美国的胃癌研究人群,具有较少的晚期疾病(T3和T4病变),西方研究中的人群历来比亚洲的生存结局要坏。但作者认为,研究得出的比较好的结局并不是因为人群具有较少的晚期疾病。这项好的结果是因为一贯使用D2手术而且手术质量高的原因。他们建议到,非亚洲国家也可以做高质量的D2手术。毕竟,D2胃切除术在欧洲和美国都是标准治疗。但是作者没有讨论过标准治疗和实际治疗可能存在的潜在差异。

胃癌治疗的安全性和依从性问题

在CLASSIC试验中,经历D2胃切除术的病人被随机分配到化疗组或单独手术组,化疗组中,有8个三周的循环,口服卡倍他滨(1000 mg/m^2,每个循环的第1~14天,每天2次),加上静脉注射奥沙利铂(130 mg/m^2,每个循环的第1天),持续6个月。

研究结果产生了一个简单的问题,Nishida博士提出:所有可手术的胃癌病人都应该在术后进行化疗吗?这个不是简单能够回答的。病人和医生应该权衡复发风险,治疗负担包括不良事件、花费,以及治疗的疗效,然后做出决定。有相当比例的病人通过手术就可达到治愈。

在对CLASSIC的评论中,Nishida博士强调了化疗组的不良事件,最常见的是恶心(n=326),中性粒细胞减少(n=300),食欲下降(n=294)。化疗组有超过一半的人群经历3或4级的不良事件,近10%因为不良事件而退出治疗,从治疗中退出的总人数更多,达到33%。

卡倍他滨+奥沙利铂的总体生存效益还未确定,确定下来至少需要5年的随访。(生物谷Bioon.com)

Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial

Yung-Jue Bang, Young-Woo Kim, Han-Kwang Yang, Hyun Cheol Chung, Young-Kyu Park, Kyung Hee Lee, Keun-Wook Lee, Yong Ho Kim, Sang-Ik Noh, Jae Yong Cho, Young Jae Mok, Yeul Hong Kim, Jiafu Ji, Ta-Sen Yeh, Peter Button, Florin Sirzén, Sung Hoon Noh

Background

D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II—IIIB gastric cancer.

Methods

The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II—IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m2 twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229).

Findings

1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4—41·7) in the chemotherapy and surgery group and 34·3 months (25·6—41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69—79) in the chemotherapy and surgery group and 59% (53—64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44—0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294).

Interpretation

Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer.

Funding

F Hoffmann-La Roche and Sanofi-Aventis

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