Preoperative chemo-CIRT in Re/BRe pancreatic cancer: Insights from a multicenter prospective phase II clinical study (NCT03822936)

Purpose: There is debate about the optimal management of borderline resectable (bRe) and resectable (Re) pancreatic ductal adenocarcinoma (PDAC). Both preclinical and clinical evidence showed that carbon ion radiotherapy (CIRT) produces superior control on radioresistant histologies compared to conventional photon beam radiotherapy (RT). However, so far there is a lack of data concerning the integration of CIRT in a multimodal approach with chemotherapy and surgery for bRe/Re. Methods: We recently presented the first analysis of a multicenter prospective phase II clinical study aimed at assessing the feasibility and effectiveness of a neoadjuvant chemotherapy + short course of CIRT followed by surgery and adjuvant chemotherapy in the management of bRe/Re PDAC. The study was terminated early due to low patient enrollment.Herein, we reported a post-hoc analysis focusing on toxicity, dosimetry and translational assessment. Results: In our experience, CIRT can be integrated into a multimodal treatment strategy for bRe/Re PDAC, alongside chemotherapy and surgery. A case of fatal liver failure occurring three months post-surgery has been documented, likely related to the combination approach. Although the treatment plans were satisfactory according to the Local Effect Model (LEM) model, recalculations using the modified Microdosimetric Kinetic Model (mMKM) revealed suboptimal target coverage. Additionally, we observed an increased expression of PD-L1 following CIRT. Conclusions: This multimodal approach was well tolerated; however, clinicians should carefully monitor for vascular disorders during follow-up and further investigate surgical techniques after CIRT. The increased PD-L1 expression supports the immunogenic effects of particle therapy and lays the groundwork for future studies. To enhance the therapeutic ratio of CIRT treatments, integrating dose-averaged LETd (LETd-based objectives into the plan optimization process should be considered. Trial Registration Number: ClinicalTrials.gov