Preoperative Carbon Ion Radiotherapy (CIRT) with Chemotherapy in Resectable and Borderline Resectable Pancreatic Adenocarcinoma (PCa): A Multicenter Prospective Phase II Clinical Study (Pioppo Study NCT 03822936).

PURPOSE/OBJECTIVE(S): Preoperative chemoradiation and surgery may improve survival for resectable (Re) or borderline resectable (BRe) PCa. However, there is a lack of evidence regarding the feasibility of combined chemotherapy (CT) and CIRT in the neoadjuvant setting for Re/BRe PCa, especially in the Caucasian population. To assess the safety and efficacy of this challenging combination, we designed a prospective multicentric single-arm phase II trial MATERIALS/METHODS: PIOPPO trial was opened in September 2014. We prospectively treated patients with Re/BRe Pca with a neoadjuvant CT (3 cycles of FOLFIRINOX) and a short-course of CIRT (38.4 GyRBE, 8 fractions, 4 fractions per week) planned with 4D-imaging and delivered with breath-gating and rescanning. Four-6 weeks after CIRT patients (pts) received surgery followed by adjuvant-CT (FOLFIRINOX for 9 or gemcitabine for 6 cycles). After each step patients underwent a re-staging. The primary endpoint was Local Progression Free Survival (LPFS).

RESULTS: Fourteen (47%) of the foreseen 30 pts were evaluated for enrollment. There were 4 screening failures for duodenum infiltration. Ten Caucasian pts (M = 7; 70%; F = 3;30%) with a median age of 65.5 (range:46-76) started the treatment. There were four (40%) Re and 6 (60%) BRe Pca. 100% of the Re and 50% of BRe PCa completed the planned combined treatment for a total of 7 (70%) pts. Three (30%) pts developed systemic progression after CT and underwent palliative care (2 cases) or a second line of CT (1 case). With regards to toxicities, we recorded 2 (28.6%) cases of neutropenia during CT, none acute CIRT toxicity and one (14%) case of intra-operative ulceration of the gastro-enteric anastomosis. Moreover, we reported one (14%) case of fatal liver failure due to portal vein stenosis due to the combo approach (CT+CIRT+surgery). Six (86%) pts experienced Tumor Regression Grade (TRG) = 2 according to the College of American Pathologists (CAP) and 1 (14%) a TRG = 3. At the last follow-up, among pts who completed the scheme, 2 (28%) are currently alive and disease-free at 57 and 49 months, respectively. With a median follow-up of 13 months, the median LPFS was 9.4 months (range:4.9-57), with 1 case (14%) of systemic progression and 3 cases (43%) of local recurrence + systemic progression. The study was early closed due to low accrual in August 2022.

CONCLUSION: Although the small sample size limits the interpretation of the endpoints, a neoadjuvant approach combining CT and a short course of CIRT for resectable/borderline Pca seems feasible. Liver toxicity was similar to the Japanese series and needs to deepen investigation on the vascular dose constraints and surgical techniques. Considering the worse outcomes, a better selection of patients to treat also with a centralized imaging interpretation is mandatory.