背景： 尽管缺乏 1 级证据，但在临床实践中，大多数 LSCLC 患者采用高剂量 QD TRT方案治疗。CALGB 30610/RTOG 0538 用于检测在采用放化疗方式治疗局限期小细胞肺癌病人时，与标准 45 gy BID TRT 相比，高剂量 TRT 能否提高患者的总生存率(OS)。

Background: Although level 1 evidence is lacking, the majority of patients (pts) with LSCLC are treated with a high dose QD TRT regimen in clinical practice. CALGB 30610/RTOG 0538 was designed to determine if administering high dose TRT would improve overall survival (OS), compared with standard 45 Gy BID TRT, in LSCLC pts treated with chemoradiotherapy.

方法：符合条件的患者为患有局限期小细胞肺癌, ECOG 表现状态(PS) 0-2，区域淋巴结累及但不包括对侧门或锁骨上淋巴结。3 期试验分 2 个阶段进行。第一阶段，患者按 1:1:1 随机分组，3 周 45 Gy BID, 7 周 70 Gy QD，或 5 周 61.2 Gy 增强放疗(CB)。在第二阶段，该研究计划在对患者中期毒性分析的基础上终止一个高剂量组，然后在剩下的两个组中随机 1:1。TRT 从第 1 或第 2 个化疗周期(共 4 个化疗周期)开始。主要终点为随机分组后的 OS。

Methods: Eligible pts had LSCLC, ECOG performance status (PS) 0-2 and regional lymph node involvement excluding contralateral hilar or supraclavicular nodes. This phase 3 trial was conducted in 2 stages. In the first stage, pts were randomized 1:1:1 to 45 Gy BID over 3 weeks, 70 Gy QD over 7 weeks, or 61.2 Gy concomitant boost (CB) over 5 weeks. For the second stage, the study planned discontinuation of one high dose arm based on interim toxicity analysis with patients then randomized 1:1 in the two remaining arms. TRT was given starting with either the 1st or 2nd (of 4 total) chemotherapy cycles. The primary endpoint was OS measured from date of randomization.

结果： 该试验于 2008 年 3 月 15 日开始，并于 2019 年 12 月 1 日结束，经中期分析后 CB 组于 2013 年 11 月 3 日停止。该分析包括 638 例，后随机分给 45gy BID TRT 组(n = 313)或 70gy QD TRT 组(n = 325)。中位年龄为 63 岁(范围 37-81)，大多数患者为白种人(86%)，女性(52%)，ECOG PS 0-1(95%)。存活患者的中位随访时间为 2.84 年(IQR:1.35 -5.61), QD 与 BID相比，OS 没有显著差异(HR 0.94, 95% CI: 0.76-1.2, p = 0.9)。中位，2 年和 4 年生存率分别为 30.5 个月(95% CI: 24.4-39.6)，56% (95%置信区间: 0.51-0.62)，39%(95%置信区间:0.33-0.45)， BID 为 28.7 个月(95%置信区间:26.2-35.5)，为 59% (95%置信区间:0.53—-0.65)和 35%(95%置信区间:0.29—-0.42)。QD 也没有导致 PFS 有显著性差异(HR 0.96, 95% CI: 0.78-1.18, p = 0.94)。两组间大多数 3+级血液和非血液不良事件(AEs)相似。QD 患者 3 级以上发热性中性粒细胞减少、呼吸困难、食管疼痛和吞咽困难的发生率为 12.6%，7%， 11.6%和 11.3%，BID 为 13.6%，4%，11.2%和 9.5%。QD 和 BID 队列中分别报告了 3.7%和 1.7%的五级不良反应事件。结果将在演示时更新。

Results: The trial opened 03/15/2008 and closed 12/01/2019 upon completing accrual, with the CB arm discontinued 3/11/2013 after interim analysis. This analysis includes 638 pts randomized to 45 Gy BID TRT (n = 313) or 70 Gy QD TRT (n = 325). Median age was 63 years (range 37-81), the majority of pts were Caucasian (86%), female (52%), and with ECOG PS 0-1 (95%). After median follow-up of 2.84 years (IQR:1.35 -5.61) for surviving pts, QD compared to BID did not result in a significant difference in OS (HR 0.94, 95% CI: 0.76-1.2, p = 0.9). Median, 2- and 4-year OS for QD were 30.5 months (95% CI: 24.4-39.6), 56% (95% CI: 0.51-0.62), and 39% (95% CI: 0.33-0.45), and for BID 28.7 months (95% CI: 26.2-35.5), 59% (95% CI: 0.53-0.65), and 35% (95% CI: 0.29-0.42). QD also did not result in a significant difference in PFS (HR 0.96, 95% CI: 0.78-1.18, p = 0.94). Most grade 3+ hematologic and non-hematologic adverse events (AEs) were similar between cohorts. Rates of grade 3+ febrile neutropenia, dyspnea, esophageal pain and dysphagia for QD were 12.6%,7%, 11.6% and 11.3%, and for BID 13.6%, 4%, 11.2 % and 9.5%. Grade 5 AEs were reported in 3.7% and 1.7% of the QD and BID cohorts, respectively. Results will be updated at presentation.

结论： 高剂量 QD TRT 至 70 Gy 与标准 45gy BID TRT 相比，OS 没有明显改善。然而， QD 组有利的结局提供了最有力的证据，支持在局限期小细胞肺癌中每日一次的高剂量 TRT作为可接受的选择。这项研究是迄今为止在 lclc 中进行的规模最大的研究，其结果将有助于指导这一患者群体的 TRT 决定。

Conclusions: High dose QD TRT to 70 Gy did not significantly improve OS compared with standard 45 Gy BID TRT. Nevertheless, favorable outcomes on the QD arm provide the most robust evidence available supporting high dose once-daily TRT as an acceptable option in LSCLC. Outcomes from this study, the largest conducted in LSCLC to date, will help guide TRT decisions for this patient population.