A Trial of Gemcitabine, Infusional 5-Fluorouracil and Cisplatin for Advanced Pancreatic and Biliary Cancers

Overview

Multi-agent chemotherapy has value for patients with advanced pancreatic-biliary cancers leading to responses in a substantial minority and increasing survival. The use of the FOLFIRINOX regimen is limited by its' intensity and toxicity. Previous protocol and clinical experience within the University of Michigan Pancreatic Program leads to an expectation of tolerance and efficacy of the proposed regimen. Advantages of the proposed regimen relative to FOLFIRINOX include: 1. Substitution of gemcitabine for irinotecan. Single agent activity of gemcitabine is at least as good as irinotecan (probably better, especially when delivered by FDR \[fixed-dose rate\] infusion) and gemcitabine is much better tolerated with less diarrhea, nausea/emesis, myelosuppression and alopecia. 2. Deletion of leucovorin infusion and 5FU bolus injection will lessen myelosuppression, mucositis and diarrhea. 3. Substitution of cisplatin for oxaliplatin will reduce cost of therapy and avoid cold aggravated dysesthesia. Presuming evidence of efficacy and confirmation of tolerance with the proposed regimen, the investigators believe this treatment may be more widely applicable to pancreatic-biliary cancer patients, including those with advanced disease as well as being considered for use in locally advanced and neo- and adjuvant settings.

Gemcitabine combined with 5FU may enhance the activity of 5-FU in vivo. Gemcitabine is an inhibitor of ribonucleotide reductase, an enzyme needed for synthesis of deoxynucleotides, and 5-FU interferes with dTTP synthesis by inhibition of thymidylate synthase (TS). It is likely that concomitant administration of gemcitabine and 5FU results in increased cytotoxicity by reducing intracellular dTTP thru two different mechanisms, thereby inhibiting DNA replication and repair. Platinum compounds lead to cell death by forming DNA adducts and causing double strand breaks. By inhibiting DNA synthesis and repair, both gemcitabine and 5-FU potentiate the activity of cisplatin. These interactions underlie the clinical synergism that has been observed with platinum/5FU and platinum/gemcitabine combinations.