肿瘤

胃切除术伴或不伴S-1联合顺铂新辅助治疗4型和巨大3型胃癌短期安全性和手术结果的III期随机临床试验

作者:小闪 编译 来源:医学论坛网 日期:2015-10-19
导读

         背景:即使在接受扩大切除手术和辅助化疗之后,皮革胃(4型)和巨大(8 cm)浸润溃疡型(3型)胃癌患者的预后仍极差。基于我们既往评估S-1联合顺铂(CDDP)新辅助化疗(NAC)的II期临床研究的鼓舞性结果,我们继续进行了III期临床研究以在这些亚组患者中证实NAC的有效性。 方法:入选标准包括组织学证实胃腺癌;4型或巨大3型临床可切除胃癌。分期腹腔镜检查是必需的。患者被随机给予NAC(

关键字:  胃癌 

        背景:即使在接受扩大切除手术和辅助化疗之后,皮革胃(4型)和巨大(>>8 cm)浸润溃疡型(3型)胃癌患者的预后仍极差。基于我们既往评估S-1联合顺铂(CDDP)新辅助化疗(NAC)的II期临床研究的鼓舞性结果,我们继续进行了III期临床研究以在这些亚组患者中证实NAC的有效性。

        方法:入选标准包括组织学证实胃腺癌;4型或巨大3型临床可切除胃癌。分期腹腔镜检查是必需的。患者被随机给予NAC(S-1,80~120 mg/body,第1~21天;顺铂60 mg/m2,第8天,28天为一周期,2周期)继之以胃切除术+辅助化疗(S-1,第1~28天,42天为一周期,治疗1年)(PERI),或胃切除术联合S-1辅助化疗(POST)。主要终点为总生存期(OS),次要终点为无进展生存期、应答率、R0切除率和不良事件(AE)。以单侧5%显著性水平和80%功效,检出3年OS的10%差异共需300例患者。由于入组缓慢,方案被加以修订在入组期间纳入伴有局部腹膜转移或腹膜细胞学阳性的患者。

        结果:在2007年2月至2013年7月之间,300例患者被纳入研究(PERI 151,POST 149)。患者背景方面无显著差异。133例患者完成NAC(88%)。NAC终止的原因:肿瘤进展2例,AE相关12例,患者拒绝1例,其他3例。在NAC期间,观察到1例4级胃穿孔和2例4级低钠血症。在30/147(19.7%)患者中观察到实验室数据之外的3级非血液学AE。在NAC期间3/4级严重AE为中性粒细胞减少(29.3%)、恶心(5.4%)、腹泻(4.8%)和疲乏(2.7%)。1例患者出现伴中性粒细胞减少感染。POST组中147例患者(99%)行胃切除术,PERI组139例(92%)。POST组中98例(66%)患者可行R0切除,PERI组112例(74%)。PERI组患者的失血量相对较少(中位;POST组420 ml,PERI组330 ml)。PERI组手术时间稍短。两组患者在死亡率方面无显著差异。POST组2例患者因急性细菌性肠炎和绞窄性肠梗阻死亡,PERI组1例患者因绞窄性肠梗阻死亡。整体而言,3年和5年总生存率分别为61%和47%。

        结论:NAC治疗4型和巨大3型胃癌继之行D2胃切除术可安全实施,未增加发病率和死亡率。经过适当辅助治疗后皮革胃仍为可手术疾病。最终生存结果将在2017年公布。UMIN-C000000279

Background: The prognosis of patients with linitis plastica (type 4) and large (≥8cm) ulcero-invasive-type (type 3) are extremely poor even after extended surgery and adjuvant chemotherapy. Based on the promising results in our previous phase II study evaluating neoadjuvant chemotherapy (NAC) with S-1 plus cisplatin (CDDP), we proceeded to phase III study to confirm the efficacy of NAC in these subtypes of patients.

Material and Methods: Eligibility criteria included histologically proven adenocarcinoma of the stomach; clinically resectable gastric cancer of type 4 or large type 3. Staging laparoscopy was mandatory. Patients were randomized to NAC (S-1, 80–120mg/body, days 1–21 and cisplatin, 60mg/m2, day 8, q28, 2courses) followed by gastrectomy + adjuvant chemotherapy (S-1, days 1–28, q42 days for 1 year) (PERI) or gastrectomy plus adjuvant chemotherapy with S-1 (POST). Primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival, response rate, R0 resection rate and adverse event (AE). A total of 300 patients were required to detect 10% difference in 3-year OS with a one-sided 5% significance level and 80% power. Protocol was revised to include patients with localized peritoneal metastasis or positive peritoneal cytology in the midst of the accrual period due to slow accrual.

Results: Between Feb 2007 and Jul 2013, 300 patients were accrued (PERI 151, POST 149). There was no significant difference of patients' background. NAC was completed in 133 patients (88%). The reasons for termination of NAC were tumor progression in 2, AEs related in 12, patient refusal in 1 and others in 3. During NAC, grade 4 gastric perforation was observed in 1 and grade 4 hyponatremia in 2. Grade 3 non-hematological AE except for laboratory data was observed in 30/147(19.7%). Major grade 3/4 AEs during NAC were neutropenia (29.3%), nausea (5.4%), diarrhea (4.8%), and fatigue (2.7%). One patient revealed infection with neutropenia. Gastrectomy was performed in 147 patients (99%) in POST and 139 patients (92%) in PERI. R0 resection was possible in 98 patients (66%) in POST and 112 patients (74%) in PERI. The blood loss was relatively smaller in PERI (median; 420 ml in POST vs 330 ml in PERI). The operation time was slightly shorter in PERI. There were no remarkable differences in morbidity between the groups. Two patients in POST died due to acute bacterial enteritis and strangulated ileus, and 1 patient in PERI due to strangulated ileus. The 3-year and 5-year overall survival as a whole were 61% and 47%, respectively.

Conclusions: NAC for type 4 and large type 3 gastric cancer followed by D2 gastrectomy can be safely performed without increasing morbidity and mortality. Linitis plastica remains surgical disease with appropriate adjuvant treatment. Final survival result will be demonstrated in 2017.

UMIN-C000000279

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