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

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.

Inclusion criteria

• Patients must have histologic or cytologic diagnosis of pancreatic adenocarcinoma or biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma or gallbladder carcinoma).
• Patients must have clinical/radiologic evidence of metastatic disease.
• Previous systemic therapy for metastatic disease limited to one cytotoxic chemotherapy regimen not containing cisplatin. Previous therapy for metastatic disease might have included gemcitabine or infusional 5-FU but not both agents.
• ECOG (Eastern Cooperative Oncology Group) performance status < 1 (A measure of quality of life where 0 represents asymptomatic and 5 represents death).
• Patients must have adequate bone marrow (absolute neutrophil count >1,500/mm3, platelet count >100,000/mm3) and renal function (serum creatinine < 1.25 x ULN).
• Patients must have at least one measurable lesion per RECIST criteria.
• Patients must be free of serious concomitant medical disorders incompatible with study participation including active infection requiring systemic therapy.
• Previous malignancies are permitted provided that they have been treated with curative intent and patient is without evidence of active systemic disease.
• Patients must be informed of the investigational nature of this study and provide written informed consent prior to receiving protocol treatment.

Exclusion criteria

• Patients with pre-existing peripheral neuropathy > grade 2 are ineligible.
• Previous systemic therapy for metastatic disease limited to one cytotoxic chemotherapy regimen not containing cisplatin.
• Previous therapy for metastatic disease might have included gemcitabine or infusional 5-FU but not both agents.
• Serious concomitant medical disorders incompatible with study participation including active infection requiring systemic therapy.