Electrochemotherapy with Irreversible Electroporation and FOLFIRINOX Improves Survival in Murine Models of Pancreatic Adenocarcinoma

• Published in: Annals of surgical oncology Vol. 27; no. 11; pp. 4348 - 4359
• Main Authors: Bhutiani, Neal, Li, Yan, Zheng, Qianqian, Pandit, Harshul, Shi, Xiaoju, Chen, Yujia, Yu, Youxi, Pulliam, Zachary R., Tan, Min, Martin, Robert C. G.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2020; Springer Nature B.V
• Subjects: 5-Fluorouracil; Adenocarcinoma; Adenocarcinoma - drug therapy; Animal models; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; Apoptosis; Caspase-3; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Chemotherapy; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Disease Models, Animal; Drug delivery; Electrochemotherapy; Electroconvulsive therapy; Electroporation; Fluorouracil - administration & dosage; Folinic acid; Gemcitabine; Humans; Irinotecan; Irinotecan - administration & dosage; Leucovorin - administration & dosage; Medicine; Medicine & Public Health; Mice; NCT; NCT03484299; Oncology; Oxaliplatin; Oxaliplatin - administration & dosage; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Patients; Polymerase chain reaction; RNA-directed DNA polymerase; Surgery; Surgical Oncology; Translational Research; Treatment Outcome; Tumor cells
• ISSN: 1068-9265; 1534-4681; 1534-4681
• DOI: 10.1245/s10434-020-08782-2

Background Previously published work has demonstrated that combining gemcitabine with irreversible electroporation (IRE) results in increased drug delivery to pancreatic adenocarcinoma cells in vivo. This study assessed the efficacy of IRE + gemcitabine and IRE + FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), the impact of the superior regimen on survival, and the safety of electrochemotherapy in human subjects. Methods Histologic analysis was performed after in vitro and in vivo treatment of S2013 and Panc-1 pancreatic cancer cells and S2013 orthotopic tumors, respectively, and levels of apoptotic machinery and cell cycle proteins were evaluated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot. Results Electrochemotherapy (ECT) with IRE and FOLFIRINOX resulted in increased tumor cells apoptosis compared with gemcitabine, gemcitabine + IRE, and FOLFIRINOX alone, and significantly improved overall survival when compared with mice treated with IRE or FOLFIRINOX. Increased tumor cell apoptosis, caspase-3 mRNA, active caspase-3 protein, and decreased cell proliferation were noted at the time of death or euthanasia in the ECT group compared with folinic acid alone. In five patients, ECT with either FOLFIRINOX or gemcitabine was well-tolerated and resulted in no dose-limiting toxicities. Conclusions ECT thus results in synergistic antitumor activity compared with either treatment modality used alone, resulting in increased tumor cell apoptosis as well as decreased tumor cell proliferation and improved overall survival. Pilot data suggest that ECT represents a promising modality for the treatment of patients with locally advanced pancreatic cancer. Trial Registration The human subject portion of this work was conducted as part of an investigator-initiated clinical trial at the University of Louisville (NCT03484299).