Final survival data from a randomized phase II trial comparing high-dose with standard-dose twice-daily (BID) thoracic radiotherapy (TRT) in limited stage small-cell lung cancer (LS SCLC).

8512 Background: Concurrent chemotherapy and TRT is standard treatment of LS SCLC. BID TRT of 45 Gy/30 fractions is the most recommended schedule. Trials report 5-year survival rates of up to 36%, illustrating that some are cured but also need for better treatment. Many treatment failures are due to relapses within TRT fields, and it has been proposed that higher TRT doses might improve local control and consequently survival. However, high-dose once-daily (QD) TRT of 66-70 Gy do not prolong survival. We investigated whether high-dose BID TRT of 60 Gy/40 fractions was tolerable and improved survival compared with the established 45 Gy schedule (NCT02041845). Primary analyses presented at ASCO 2020 showed that the trial was highly positive for the primary endpoint, 2-year survival (60 Gy: 74.2%, 45 Gy: 48.1%, OR 3.09 [95% CI 1.62-5.89]; p=0.0005). We now present updated and final survival data. Methods: Patients ≥18 years with PS 0-2, confirmed SCLC, LS according to the IASLC definition after PET CT staging received 4 courses of platinum/etoposide and were randomized to receive 60 Gy or 45 Gy to PET CT positive lesions. TRT started concurrently with the 2 nd chemotherapy course. Responders were offered QD prophylactic cranial irradiation of 25-30 Gy. All patients were followed for 5 years or until death. Results: 170 eligible patients were randomized at 22 Scandinavian hospitals from 2014-2018 (60 Gy: n=89, 45 Gy: n=81). Median age was 65, 31.2% were ≥70 years, 57.1% women, 89.4% had PS 0-1, 83.5% stage III disease, 7.6% pleural effusion and 20.0% ≥5% weight loss last three months before enrollment. Baseline patient and disease characteristics and TRT planning target volumes were well balanced between treatment arms. Completion rates of chemotherapy (60 Gy: 92.1%, 45 Gy: 87.7%) and TRT (60 Gy: 96.6%, 45 Gy: 91.4%) were similar. Patients on the high-dose arm did not experience more grade 3-4 esophagitis (60 Gy: 21.2%, 45 Gy: 18.2%; p=0.83) or pneumonitis (60 Gy: 3.4%, 45 Gy: 0.0%; p=0.39), other grade 3-4 toxicity or treatment related deaths. The 60 Gy group had numerically longer PFS (median PFS 60 Gy: 18.6 months [95% CI 11.6-25.6], 45 Gy: 10.9 months [95% CI 8.7-13.2], HR 0.76 [95% CI 0.53-1.08]; p=0.13). Results for the primary endpoint remain unchanged. The higher TRT dose significantly prolonged survival (median OS 60 Gy: 43.5 months [95% CI 30.4-56.6], 45 Gy: 22.6 months [95% CI 17.2-28.0], HR 0.69 [0.48-0.99]; p=0.043) and provided higher 4.5 year survival rate (60 Gy: 41.6% [95% CI 30.4-56.6], 45 Gy: 28.4% [95% CI 18.9-39.5], OR: 1.79 [95% CI 0.95-3.41]). 5-year survival rates will be presented at the meeting. Conclusions: Compared with LS SCLC patients who received standard TRT, patients receiving high-dose BID TRT of 60 Gy did not experience more toxicity, had a substantial prolongation of survival and a much higher long term survival rate. Clinical trial information: NCT02041845 .