PD-1 Blockade Combined with Heated Intraperitoneal Chemotherapy Improves Outcome in Experimental Peritoneal Metastases from Colonic Origin in a Murine Model.

BACKGROUND: Heated intraperitoneal chemotherapy (HIPEC) was shown to induce immunogenicity of peritoneal metastases from colorectal cancer (PM-CRC) by induction of immunogenic cell death. We aimed to explore whether the addition of a checkpoint inhibitor would augment the effect of HIPEC in an experimental murine model of PM-CRC. METHODS: PM-CRC was established in C57BL mice by intraperitoneal inoculation of MC38 colon cancer cells. HIPEC was administered using the closed technique with mitomycin C (MMC). Clinical and immunological parameters were compared between animals treated with HIPEC alone and those treated with HIPEC + anti-programmed death receptor-1 (aPD-1). RESULTS: MMC-based HIPEC increased the overall survival of animals compared with sham-treated animals (22.8; 95% confidence interval [CI] 21.14-24.53 vs. 18.9 days; 95% CI 17.6-20.3, p < 0.001). The extent of peritoneal disease as measured by the modified peritoneal carcinomatosis index was also reduced by HIPEC. This clinical benefit was accompanied by increased infiltration of CD8+, CD68+, and CD20+ cells into tumor metastases in HIPEC-treated animals compared with sham-treated animals. We identified heat shock protein (HSP) 90 as a potential immunogenic cell death protein whose expression is increased under HIPEC conditions (fold change: 2.37 ± 1.5 vs. 1 without HIPEC, p < 0.05). Combined HIPEC + PD-1 treatment ameliorated survival compared with HIPEC alone and sham treatment (24.66; 95% CI 20.13-29.2 vs. 19; 95% CI 15.85-22.14 and 14.33 days; 95% CI 9.6-19.04, respectively; p = 0.008). This clinical effect was accompanied by increased CD8+ tumor infiltration. CONCLUSIONS: HIPEC induced the expression of immunogenic cell death signals that can support an anti-tumor immune response. This response can be further exploited by a checkpoint inhibitor.

Prognostic significance of pancreatic fistula and postoperative complications after pancreaticoduodenectomy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The influence of postoperative complications, specifically, pancreatic fistula (PF), on long-term oncologic outcome in patients with pancreatic ductal adenocarcinoma (PDAC) is unclear. METHODS: Prospectively collected data of patients who underwent pancreaticoduodenectomy (PD) for PDAC between 2008 and 2016 were retrospectively reviewed and analyzed. Deaths within 90 days were excluded. Median follow-up time was 22 months for the entire cohort (range 2-102 months). PF was graded as biochemical leak, grade B, or grade C according to the criteria of the International Study Group on Pancreatic Fistula. Postoperative complications were graded according to the Clavien-Dindo classification (CDC). Data on clinical and pathological characteristics as well as on recurrence and survival were collected. RESULTS: Twenty-nine of the 148 identified patients (19%) developed PF, of whom 17 (11.4%) had a PF grade B or C. 29 patients developed a postoperative complication CDC grade 3 or 4. The respective 3-year disease-free survival was 15.5% and 19.2% (P = 0.725), and the 5-year overall survival was 20% and 16% (P = 0.914) in patients with and without PF. On multivariate analysis, the use of adjuvant chemotherapy, lymph node involvement, surgical margin involvement, and tumor grade were associated with patient survival. PF and postoperative complications CDC grade 3 or 4 were not associated with decreased long-term survival, disease-free survival or local recurrence rate. CONCLUSIONS: While acknowledging the limited sample size, no association was seen between PF or postoperative complications and overall or disease-free survival in patients undergoing PD for PDAC.

Adjuvant FOLFIRINOX in Patients with Resectable Pancreatic Cancer Is Effective but Rarely Feasible in Real Life: Is Neoadjuvant FOLFIRINOX a Better Option?

BACKGROUND: The recommended treatment for resectable pancreatic cancer (PC) is resection followed by adjuvant FOLFIRINOX. We assessed the proportion of patients that managed to complete the 12 courses of adjuvant FOLFIRINOX and compared their outcome with that of patients with borderline resectable pancreatic cancer (BRPC) who underwent resection after neoadjuvant FOLFIRINOX. METHODS: A retrospective analysis was performed on a prospectively maintained database of all PC patients who underwent resection with (2/2015-12/2021) or without (1/2018-12/2021) neoadjuvant therapy. RESULTS: A total of 100 patients underwent upfront resection, and 51 patients with BRPC received neoadjuvant treatment. Only 46 resection patients started adjuvant FOLFIRINOX, and only 23 completed 12 courses. The main reasons for not starting/completing adjuvant therapy were poor tolerance and rapid recurrence. Significantly more patients in the neoadjuvant group received at least six FOLFIRINOX courses (80.4% vs. 31%, p < 0.001). Patients who completed at least 6 courses, either pre- or postoperatively, had better overall survival (p = 0.025) than those who did not. In spite of having more advanced disease, the neoadjuvant group had comparable overall survival (p = 0.062) regardless of the number of treatment courses. CONCLUSION: Only a minority of patients (23%) undergoing upfront pancreatic resection completed the planned 12 courses of FOLFIRINOX. Patients who received neoadjuvant treatment were significantly more likely to receive at least six treatment courses. Patients receiving at least six courses had better overall survival than those who received fewer than six courses, regardless of the timing of treatment relative to surgery. Potential ways to increase chemotherapy adherence, such as administering treatment before surgery, should be considered.