Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas
Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas
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DOI：
10.1200/jco.2015.62.4304
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发表时间：
2015-12-20
影响因子：
45.3
通讯作者：
Blay, Jean-Yves
中科院分区：
文献类型：
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作者：
Casali, Paolo G.;Le Cesne, Axel;Blay, Jean-Yves
目的 2004 年，我们开始了一项针对局部、高危或中危胃肠道间质瘤 (GIST) 患者进行 R0-R1 手术后辅助伊马替尼与不进一步治疗的组间随机试验。患者和方法患者被随机分配接受 2 年伊马替尼每日 400 mg 治疗或术后不进一步治疗。主要终点是总生存期；无复发生存期（RFS）、无复发间隔和毒性是次要终点。 2009年，鉴于晚期GIST患者预后的同时改善，我们在独立数据监测委员会的同意下将主要终点改为伊马替尼无失败生存期（IFFS）。我们报告了计划中的中期分析。结果 2004 年 12 月至 2008 年 10 月期间，共有 908 名患者被随机分配：454 名接受伊马替尼治疗，454 名接受观察。其中，835 名患者符合条件。中位随访时间为 4.7 年，伊马替尼组的 5 年 IFFS 为 87%，而对照组为 84%（风险比，0.79；98.5% CI，0.50 至 1.25；P = 0.21）； 3 年时 RFS 分别为 84% 和 66%，5 年时 RFS 分别为 69% 和 63%（对数秩 P < .001）；和 5 年总生存率分别为 100% 和 99%。在当地病理学家诊断的 528 例高危 GIST 患者中，5 年 IFFS 分别为 79% 和 73%；在 336 名集中审查的高危患者中，这一比例分别为 77% 和 73%。 结论 这项研究证实伊马替尼辅助治疗对 RFS 有明显影响。尽管在高风险亚组中存在有利于辅助组的趋势，但未观察到 IFFS 存在显着差异。 IFFS 被认为是辅助治疗中的一个潜在终点，因为它对继发耐药敏感，而继发耐药是晚期 GIST 患者的主要不良预后因素。
Purpose In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery patients with localized, high- or intermediate-risk GI stromal tumor (GIST).Patients and Methods Patients were randomly assigned to 2 years of imatinib 400 mg daily or no further therapy after surgery. The primary end point was overall survival; relapse-free survival (RFS), relapse-free interval, and toxicity were secondary end points. In 2009, given the concurrent improvement in prognosis of patients with advanced GIST, we changed the primary end point to imatinib failure-free survival (IFFS), with agreement of the independent data monitoring committee. We report on a planned interim analysis.Results A total of 908 patients were randomly assigned between December 2004 and October 2008: 454 to imatinib and 454 to observation. Of these, 835 patients were eligible. With a median follow-up of 4.7 years, 5-year IFFS was 87% in the imatinib arm versus 84% in the control arm (hazard ratio, 0.79; 98.5% CI, 0.50 to 1.25; P = .21); RFS was 84% versus 66% at 3 years and 69% versus 63% at 5 years (log-rank P < .001); and 5-year overall survival was 100% versus 99%, respectively. Among 528 patients with high-risk GIST by local pathologist, 5-year IFFS was 79% versus 73%; among 336 centrally reviewed high-risk patients, it was 77% versus 73%, respectively.Conclusion This study confirms that adjuvant imatinib has an overt impact on RFS. No significant difference in IFFS was observed, although in the high-risk subgroup there was a trend in favor of the adjuvant arm. IFFS was conceived as a potential end point in the adjuvant setting because it is sensitive to secondary resistance, which is the main adverse prognostic factor in patients with advanced GIST.