背景： 盡管缺乏 1 級證據，但在臨床實踐中，大多數 LSCLC 患者采用高劑量 QD TRT方案治療。CALGB 30610/RTOG 0538 用於檢測在采用放化療方式治療局限期小細胞肺癌病人時，與標準 45 gy BID TRT 相比，高劑量 TRT 能否提高患者的總生存率(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：符合條件的患者為患有局限期小細胞肺癌, ECOG 表現狀態(PS) 0-2，區域淋巴結累及但不包括對側門或鎖骨上淋巴結。3 期試驗分 2 個階段進行。第一階段，患者按 1:1:1 隨機分組，3 周 45 Gy BID, 7 周 70 Gy QD，或 5 周 61.2 Gy 增強放療(CB)。在第二階段，該研究計劃在對患者中期毒性分析的基礎上終止一個高劑量組，然後在剩下的兩個組中隨機 1:1。TRT 從第 1 或第 2 個化療周期(共 4 個化療周期)開始。主要終點為隨機分組後的 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.

結果： 該試驗於 2008 年 3 月 15 日開始，並於 2019 年 12 月 1 日結束，經中期分析後 CB 組於 2013 年 11 月 3 日停止。該分析包括 638 例，後隨機分給 45gy BID TRT 組(n = 313)或 70gy QD TRT 組(n = 325)。中位年齡為 63 歲(範圍 37-81)，大多數患者為白種人(86%)，女性(52%)，ECOG PS 0-1(95%)。存活患者的中位隨訪時間為 2.84 年(IQR:1.35 -5.61), QD 與 BID相比，OS 沒有顯著差異(HR 0.94, 95% CI: 0.76-1.2, p = 0.9)。中位，2 年和 4 年生存率分別為 30.5 個月(95% CI: 24.4-39.6)，56% (95%置信區間: 0.51-0.62)，39%(95%置信區間:0.33-0.45)， BID 為 28.7 個月(95%置信區間:26.2-35.5)，為 59% (95%置信區間:0.53—-0.65)和 35%(95%置信區間:0.29—-0.42)。QD 也沒有導致 PFS 有顯著性差異(HR 0.96, 95% CI: 0.78-1.18, p = 0.94)。兩組間大多數 3+級血液和非血液不良事件(AEs)相似。QD 患者 3 級以上發熱性中性粒細胞減少、呼吸困難、食管疼痛和吞咽困難的發生率為 12.6%，7%， 11.6%和 11.3%，BID 為 13.6%，4%，11.2%和 9.5%。QD 和 BID 隊列中分別報告了 3.7%和 1.7%的五級不良反應事件。結果將在演示時更新。

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.

結論： 高劑量 QD TRT 至 70 Gy 與標準 45gy BID TRT 相比，OS 沒有明顯改善。然而， QD 組有利的結局提供了最有力的證據，支持在局限期小細胞肺癌中每日一次的高劑量 TRT作為可接受的選擇。這項研究是迄今為止在 lclc 中進行的規模最大的研究，其結果將有助於指導這一患者群體的 TRT 決定。

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.