Arterial Administration of DNA Crosslinking Agents with Restraint of Homologous Recombination Repair by Intravenous Low-Dose Gemcitabine Is Effective for Locally Advanced Pancreatic Cancer.

Abstract

Simple SummaryPancreatic cancer is considered incurable, and most cases are detected in the advanced stages. Establishing a new, effective interventional treatment for advanced pancreatic cancer is a pressing issue. Pretreatment with gemcitabine had a restraining effect on the homologous DNA recombination repair (HRR) of DNA crosslinking, inhibiting the function of Rad51, of which expression is found to be increased in pancreatic cancer. The aim of our prospective study was to assess the potential value of the arterial administration of DNA crosslinking agents after intravenous administration of low-dose gemcitabine for patients with advanced pancreatic cancer. We confirmed, among forty-five patients with unresectable advanced pancreatic cancer, that a patient subgroup of locally advanced pancreatic cancer (LAPC, 10 patients) who underwent these treatment courses successively more than twice in the first 6 months had 33 months of overall survival, 31 months of local progression free survival, and a complete response of 40%. This treatment can be a new treatment option for LAPC.(1) Background: Pretreatment by Rad51-inhibitory substances such as gemcitabine followed by arterial chemotherapy using antineoplastic agents causing DNA crosslink might be more beneficial for patients with locally advanced pancreatic cancers than conventional treatments. The efficacy of arterial administration of DNA crosslinking agents with pretreatment of intravenous low-dose gemcitabine for patients with unresectable locally advanced or metastatic pancreatic cancer (LAPC or MPC) is evaluated. (2) Methods: A single-arm, single-center, institutional review board-approved prospective study was conducted between 2005 and 2015. Forty-five patients (23 LAPC, 22 MPC) were included. Patients received a weekly low dose of gemcitabine intravenously for three weeks followed by arterial administration of mitomycin C and epirubicin hydrochloride at tumor-supplying arteries on the fifth or sixth week. This treatment course was repeated at 1.5-to-2-month intervals. Overall survival (OS), local progression-free survival (LPFS), and therapeutic response were evaluated. LAPC or MPC were divided according to treatment compliance, excellent or poor (1 or 2), to subgroups L1, L2, M1, and M2. (3) Results: OS of LAPC and MPC were 23 months and 13 months, respectively. The OS of LAPC with excellent treatment compliance (subgroup L1, 10 patients) was 33 months with 31 months of LPFS, and four patients (40%) had a complete response (CR). The OS of the L1 subgroup was significantly longer than those of other subgroups L2, M1, and M2, which were 17 months, 17 months, and 8 months, respectively. As Grade 3 adverse effects, severe bone marrow suppression, interstitial pneumonitis, and hemolytic uremic syndrome were observed in six (13.0%), three (6.5%), and three (6.5%) patients, respectively. (4) Conclusions: Arterial DNA crosslinking with the systemic restraint of homologous recombination repair can be a new treatment option for LAPC.