ES11.02 Advances in Thoracic Radiation in SCLC

Abstract

Concurrent chemotherapy and thoracic radiotherapy (TRT) have been standard treatment for limited stage (LS) small-cell lung cancer (SCLC) since the 1990's, but the optimal dose and schedule of TRT is debated. The Intergroup 0096 trial published in 1999 established twice-daily (BID) TRT of 45 Gy in 30 fractions as the best documented schedule.1 However, BID TRT caused more esophageal toxicity than once daily (QD) TRT, and it has been argued that the biologically effective dose (BED) in the control arm (45 Gy in 25 fractions) was inferior, and population based studies show that BID TRT is poorly implemented.2,3 Results from single arm studies suggest that high dose QD TRT might be an alternative to 45 Gy BID, and such schedules are widely used. However, the first randomized trial comparing high dose QD with BID TRT failed to show that 66 Gy in 33 fractions was superior to 45 Gy BID, and numerically, survival was better in the 45 Gy BID arm.4 At this year's ASCO Annual meeting (2021), the first survival data from the long awaited CALGB 20610/RTOG 0538 trial were presented. Patients were randomized to 45 Gy BID, 70 Gy in 35 fractions (QD) or 61.2 Gy in 34 fractions (QD in 16 days followed by BID in 9 days). After a preplanned interim toxicity analysis, the 61.2 Gy arm was dropped in March 2012. The trial was designed to show superiority of the higher TRT-dose. Survival data in the 45 Gy BID and 70 Gy QD arms were similar, and the trial was per definition negative, but 70 Gy QD appears to be an alternative to 45 Gy BID. Notably, there was no difference in radiotoxicity between treatment arms.5 A systematic review concluded that a shorter time from start of chemotherapy until end of TRT is associated with improved survival.6 Consequently, it seems reasonable that high dose TRT might improve survival if it is accelerated, i.e. the treatment period is reduced, and two trials published this year have investigated such TRT schedules. A Chinese study randomized patients to receive moderately hypofractionated TRT of 65 Gy in 26 fractions or 45 Gy BID and showed that the hypofractionated schedule prolonged PFS (median PFS 17.2 vs. 13.4 months; p=0.031). There was, however, no statistically significant survival benefit (median OS 39.3 vs. 33.6 months; p=0.14), though the survival data are not yet mature.7 A Nordic trial employed a different strategy. In this trial, patients were randomized to receive standard BID TRT of 45 Gy in 30 fractions or high-dose TRT of 60 Gy in 40 fractions. There was a large improvement for the primary endpoint, 2-year survival (74% vs. 48%; p=0.0005), and in median overall survival (37.2 vs. 22.6 months; p=0.012), though the difference in median PFS was not statistically significant (18.6 vs. 10.9 months; p=0.13). Final survival data will be presented in 2023.8 There are differences in patient selection, definitions of limited stage disease, target volume definitions and radiotherapy techniques between these trials (and the Intergroup 0096), and they are not necessarily directly comparable. However, it appears that with improvement in assessing extent of disease, using modern radiotherapy techniques and omitting elective nodal irradiation, there is now far less radiotoxicity from 45 Gy BID than observed in the Intergroup 0096. Furthermore, the high dose TRT schedules mentioned here are not more toxic than 45 Gy BID. It has been commented that a non-inferiority trial is needed to establish high-dose QD TRT as an alternative to 45 Gy BID, but one might question whether this is a priority. Not many randomized LS SCLC trials have been completed the last 20 years (e.g. the CALGB/RTOG trial took 11 years to complete), and it seems more appropriate to further investigate the accelerated schedules which seem to hold a larger potential for improved survival. However, it might be a good idea to await final survival data from the Chinese and Nordic trials. Another factor to consider before designing the next TRT trial is the potential role of immune checkpoint inhibitors (ICIs) in the treatment of LS SCLC. Two trials have shown a survival improvement of adding atezolizumab or durvalumab to chemotherapy in extensive stage SCLC,9,10 and several ongoing trials are investigating whether concurrent or consolidation ICI therapy improves survival also in LS SCLC. 1. Turrisi et al: Twice-daily compared with once-daily thoracic radiotherapy in LS SCLC treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-71, 1999 2. Schreiber et al: Utilization of Hyperfractionated Radiation in SCLC and Its Impact on Survival. J Thorac Oncol 10:1770-5, 2015 3. Damhuis R et al: Population-based Results of Chemoradiotherapy for LS SCLC in The Netherlands. Clin Oncol (R Coll Radiol) 30:17-22, 2018 4. Faivre-Finn et al: Concurrent once-daily versus twice-daily chemoradiotherapy in patients with LS SCLC (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol 18:1116-1125, 2017 5. Bogart et al: Phase 3 comparison of high-dose once-daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID) TRT in LS SCLC: CALGB 30610 (Alliance)/RTOG 0538. Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 8505-8505, 2021 6. De Ruysscher et al: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in LS SCLC. J Clin Oncol 24:1057-63, 2006 7. Qiu et al: Moderately Hypofractionated Once-Daily Compared With Twice-Daily Thoracic Radiation Therapy Concurrently With Etoposide and Cisplatin in LS SCLC: A Multicenter, Phase II, Randomized Trial. Int J Radiat Oncol Biol Phys, 2021 8. Gronberg et al: High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with LS SCLC: an open-label, randomised, phase 2 trial. Lancet Oncol 22:321-331, 2021 9. Paz-Ares et al: Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of ES SCLC (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394:1929-1939, 2019 10. Horn et al: First-Line Atezolizumab plus Chemotherapy in ES SCLC. N Engl J Med 379:2220-2229, 2018