Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer
Authors: Cecchini Michael , Salem Ronald R. , Robert Marie , Czerniak Suzanne , Blaha Ondrej , Zelterman Daniel , Rajaei Moein , Townsend Jeffrey P. , Cai Guoping , Chowdhury Sumedha , Yugawa Deanne , Tseng Robert , Mejia Arbelaez Carlos , Jiao Jingjing , Shroyer Kenneth , Thumar Jaykumar , Kortmansky Jeremy , Zaheer Wajih , Fischbach Neal , Persico Justin , Stein Stacey , Khan Sajid A. , Cha Charles , Billingsley Kevin G. , Kunstman John W. , Johung Kimberly L. , Wiess Christina , Muzumdar Mandar D. , Spickard Erik , Aushev Vasily N. , Laliotis George , Jurdi Adham , Liu Minetta C. , Escobar-Hoyos Luisa , Lacy Jill 
Published: June 2024

Importance

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection.

Objective

To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival.

Design, Setting, and Participants

This open-label, single-arm, phase 2 nonrandomized clinical trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023.

Interventions

Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression.

Main Outcomes and Measures

The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator.

Results

Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07).

Conclusions and Relevance

This nonrandomized clinical trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies.

Trial Registration

ClinicalTrials.gov Identifier: NCT02047474