Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer

Abstract

IMPORTANCEPatients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. OBJECTIVE To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTSA single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. INTERVENTIONS Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. MAIN OUTCOMES AND MEASURES R0 resection rate. RESULTSOf the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached).CONCLUSIONS AND RELEVANCE Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%.

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

“…CRT was also associated with higher expression of MHC class II (MHC-II) (CD74, HLA-DPA1, HLA-DPB1) and TGF-β pathway genes in macrophages ( Figures 2D, S5B). Concomitantly, the lower expression of the TGF-β pathway in CAFs from treated tumors ( Figure S11A) suggests a potential myeloid-specific immunosuppressive mechanism and may partly explain the efficacy of the TGF-β modulator, losartan, in combination with neoadjuvant CRT (6,70).…”

“…Neoadjuvant therapy has been increasingly adopted to aggressively address the risk of micrometastatic spread and to circumvent concerns of treatment tolerance in the postoperative setting. Recent clinical trials support the use of preoperative treatment over upfront surgery (5,6). Nonetheless, tumor resistance to CRT remains a profound challenge for PDAC.…”

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

“…Natural and synthetic molecules, as well as Food and Drug Administration (FDA)-approved drugs candidate for repurposing in oncology are currently being considered as single compounds, or in combination for PC therapy [3][4][5][6][7][8]. Repurposing of approved non-anticancer drugs in cancer therapy may have several advantages, including good safety profiles and recognized pharmacokinetic properties in term of absorption, metabolism and toxicity, which may accelerate the clinical translation in cancer therapy of preclinical results obtained with these drugs [9][10][11].…”

Neoadjuvant treatment for resectable pancreatic adenocarcinoma: What is the best protocol?

“…56 The group also reported the effect of TNT for UR PDAC, with excellent survival. 57 These strategies might also improve the survival outcome of R PDAC. The use of radiation should be examined, rather than assuming an either/or scenario in a prospective trial.…”