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

Tytuł:: Electrochemotherapy with Irreversible Electroporation and FOLFIRINOX Improves Survival in Murine Models of Pancreatic Adenocarcinoma.
Autorzy:: Bhutiani N; Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA.
Li Y; Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA.
Zheng Q; Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang, China.
Pandit H; Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA.
Shi X; Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China.
Chen Y; Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, China.
Yu Y; Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China.
Pulliam ZR; Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA.
Tan M; Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA.
Martin RCG 2nd; Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, Louisville, KY, USA. .
Źródło:: Annals of surgical oncology [Ann Surg Oncol] 2020 Oct; Vol. 27 (11), pp. 4348-4359. Date of Electronic Publication: 2020 Jul 17.
Typ publikacji:: Clinical Trial; Journal Article
Język:: English
Imprint Name(s):: Publication: 2005- : New York, NY : Springer
Original Publication: New York, NY : Raven Press, c1994-
MeSH Terms:: Adenocarcinoma*/drug therapy
Antineoplastic Combined Chemotherapy Protocols*/administration & dosage
Antineoplastic Combined Chemotherapy Protocols*/therapeutic use
Electrochemotherapy*
Pancreatic Neoplasms*/drug therapy
Animals ; Cell Line, Tumor ; Deoxycytidine/administration & dosage ; Deoxycytidine/analogs & derivatives ; Disease Models, Animal ; Fluorouracil/administration & dosage ; Humans ; Irinotecan/administration & dosage ; Leucovorin/administration & dosage ; Mice ; Oxaliplatin/administration & dosage ; Treatment Outcome ; Gemcitabine
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Molecular Sequence:: ClinicalTrials.gov NCT03484299
Substance Nomenclature:: 0 (folfirinox)
04ZR38536J (Oxaliplatin)
0W860991D6 (Deoxycytidine)
7673326042 (Irinotecan)
Q573I9DVLP (Leucovorin)
U3P01618RT (Fluorouracil)
0 (Gemcitabine)
Entry Date(s):: Date Created: 20200719 Date Completed: 20210401 Latest Revision: 20221207
Update Code:: 20240105
DOI:: 10.1245/s10434-020-08782-2
PMID:: 32681477
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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).

Comment in: Ann Surg Oncol. 2020 Dec;27(Suppl 3):954-955. (PMID: 33011913)

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