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8505 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. 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. 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. 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. Support: U10CA180821, U10CA180882; Clinical trial information: NCT00632853.

RTOG 0617, a randomized phase III cooperative group trial using 2 x 2 factorial design, with radiation dose as one factor and cetuximab as the other factor. Materials/Methods: Patients enrolled in RTOG 0617 with retrievable RT dosimetry were eligible for this study. Circulating immune cells, including rapidly circulating ones in the heart, lung and blood vessels, and slowly circulating ones in the lymphatic system and blood reservoirs (a portion of veins/capillaries), were considered as a surrogate for OARIS. The effective dose to the immune cells (EDIC) was modeled with assumptions that in each fraction, radiation dose was uniformly delivered to all cells for rapidly circulating ones, and only to those in the irradiated volume for slowly circulating ones. EDIC was thus calculated as a function of the number of RT fractions and doses to the lung, heart, and the whole body (integral dose). Associations between EDIC and local tumor control, denoted as local progression-free survival (LPFS), and OS were assessed using Cox regression model. Results: The analysis included 464 patients (261 from 60-Gy arm and 203 patients from 74-Gy arm). EDIC was significantly higher in the 74-Gy group (6.9 AE 2.1 Gy) than in the 60-Gy group (5.7 AE 1.7 Gy) (P < 0.0001). EDIC was associated with LPFS (P < 0.0001) and OS (P < 0.0001) in the whole group of all 464 patients, and within the 60-Gy (P Z 0.007 for LPFS and P < 0.0001 for OS) and 74-Gy groups (P Z 0.04 for LPSF and P Z 0.003 for OS). The 2-year OS rates were 72, 52, 49, and 15% for EDIC in the range of <4.0, 4.0-6.5, 6.5-9.5, and >9.5 Gy, respectively (P < 0.0001). Conclusion: Radiation dose to OARIS was significantly associated with local tumor control and overall survival for patients with stage-III NSCLC, suggesting that radiation-induced immune toxicity could be an important contributing factor to tumor progression and death. In-depth study of OARIS is warranted and will be reported at the meeting.Purpose/Objective(s): Recent data demonstrate an association between radiation (RT) dose to the heart and Grade 3+ cardiac events (CEs) in patients with locally advanced non-small cell lung cancer. Those with baseline coronary artery disease (CAD) were at particularly increased risk. A majority of patients, however, do not have overt pretreatment CAD and we sought to determine which combinations of pretreatment cardiac risk and RT dose are associated with an elevated CE rate.