Definitive SBRT in unresectable pancreatic cancer: Long-term outcomes with moderate vs high dose approaches.

677 Background: Locally advanced pancreatic cancer (LAPC) represents a substantial clinical challenge. Chemotherapy (CT) remains the backbone of therapy; consolidation radiotherapy (RT) is often used to enhance local control. Stereotactic body RT (SBRT) has attracted increasing interest due to its ability to deliver high RT doses to the tumor while minimizing dose to organs at risk and associated lymphopenia. Prior studies of dose escalation have reported mixed results. Methods: This analysis of a prospectively maintained single-institution database included 206 LAPC patients treated with definitive intent, using a range of SBRT doses between 2008-24. Biologic effective dose (BED) was calculated as follows: BED = nd * (1 + d/α:β), where n = # of doses, d = dose per fraction; α:β was set at 10. Results: Median age at diagnosis was 70 years; 50.5% of patients were women, and median KPS was 80. 171 patients received CT before SBRT, most commonly FOLFIRINOX or gemcitabine/nab-paclitaxel. Median overall survival (OS) in patients receiving CT was 17.5 (95% CI 16 -19) vs 7.8 months (mos) without CT (95% CI6.5-9.1), p<0.01. SBRT regimen was significantly correlated with OS, with better outcomes associated with lower-dose SBRT; OS was 10.6 (95% CI 5.3-15.9), 14.8 (95% CI 12.7-16.9), and 20 (95% CI15.8-24.3) mos in very high (BED10≥75 Gy), high (BED10 56-75 Gy), and moderate (BED 37.5-55 Gy) dose regimens, respectively, p<0.01. Markers of improved SBRT response included a post-SBRT drop in CA19-9, with OS 19.4 mos (95%CI 15.7-23) in patients with a CA19-9 drop after SBRT vs 13.6 mos (95% 12.7-14.4) when CA-19.9 increased, p<0.01. SBRT-induced lymphopenia (LP) was associated with worse OS; median OS was 18 (95%CI 15.8-20) with gr 0-1 LP vs 13 mos (95% CI 11.1-14.8) with gr 2-4 LP, p=0.04. Outcomes improved over time, with OS from 2005-2009 10.6 mos (95% CI 3.6-17.7) vs 2020-2024 OS 21.5 mos (95%CI 17.3-25.8) p<0.001. Local progression free survival (LPFS) with induction CT was 14.7 mos (95%CI 13.4-15.8) vs 7.7 (95% CI 7.2-8.1) mos without, p<0.001. No benefit to dose escalation was observed in patients treated with very high, high, and moderate doses, with median LPFS of 10.6 (95% CI 5.1-16.1), 13.2 (95% CI 11.4-15.1) and 14.9 (95% CI13.5-16.2) mos, respectively (p<0.05 for very-high vs moderate). CA19-9 decrease and the development of ≥grade 2 LP were also significantly correlated with LPFS. Conclusions: Dose escalation was not associated with an OS or LPFS benefit following definitive SBRT for LAPC. Induction CT was associated with better outcomes. CT and SBRT regimens co-evolved over the course of this study, with the implementation of lower-BED RT regimens coinciding with the increasing adoption of highly active multiagent CT regimens. More studies are needed to understand how RT dosing affects outcomes. CA-19.9 and LP are potential biomarkers of better response to SBRT in this setting.