PURPOSE Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer. METHODS This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up). RESULTS This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial's stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar. CONCLUSION For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.

中文翻译：

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质子束治疗与调强放射治疗治疗局部晚期食管癌的随机 IIB 期试验

目的 与调强放射治疗 (IMRT) 相比，质子束治疗 (PBT) 的剂量学优势是否会转化为改善的临床结果仍不清楚。这项随机试验比较了这些食管癌治疗方式之间的总毒性负担 (TTB) 和无进展生存期 (PFS)。方法 这项 IIB 期试验将患者随机分配到 PBT 或 IMRT (50.4 Gy)，根据组织学、可切除性、诱导化疗和分期进行分层。预设的共同主要终点是 TTB 和 PFS。TTB 是 11 种不同不良事件 (AE) 的综合评分，包括手术患者的常见毒性和术后并发症 (POC)，量化了治疗后 1 年期间经历的 AE 严重程度。该试验是使用贝叶斯组序贯设计进行的，其中有 33%、50% 和 67% 的预期收益（针对随访进行调整）的三个计划中期分析。结果 该试验（2012 年 4 月开始）在 2019 年 3 月激活 NRG-GI006 后被批准关闭和分析，这发生在计划的 67% 中期分析之前。总共有 145 名患者被随机分配（72 名 IMRT，73 名 PBT），107 名患者（61 名 IMRT，46 名 PBT）是可评估的。中位随访时间为 44.1 个月。51 名患者（30 名 IMRT，21 名 PBT）接受了食管切除术；80% 的 PBT 是被动散射。IMRT 的后平均 TTB（39.9；95% 最高后密度间隔，26.2-54.9）是 PBT（17.4；10.5-25.0）的 2.3 倍。IMRT (19.1; 7.3-32.3) 的平均 POC 得分是 PBT (2.5; 0.3-5.2) 的 7.6 倍。与 IMRT 相比，PBT 的平均 TTB 较低的后验概率为 0.9989，在 67% 的中期分析中超过了试验的停止边界 0.9942。3 年 PFS 率（50.8% 对 51.2%）和 3 年总生存率（44.5% 对 44.5%）相似。结论 对于局部晚期食管癌，与 IMRT 相比，PBT 降低了 AE 的风险和严重程度，同时保持了相似的 PFS。