The purpose of this study is to test a new treatment of pancreatic cancer that cannot be removed by surgery. This treatment is a Phase I dose escalation research study which will combine one drug at increasing doses with a fixed dose of a second drug and radiation therapy. The drug that will be used at increasing doses is gemcitabine whereas 5-fluorouracil will remain the same for all patients.

• Ultimately we plan to find the maximum tolerated dose of the combination of gemcitabine, 5-fluorouracil and radiation therapy. We also hope to assess the number of people who respond to this therapy and to assess the feasibility of giving intraoperative radiation therapy following gemcitabine, 5-fluorouracil, and external beam radiation therapy.
• A surgical procedure, either laparotomy or laparoscopy, will be required to check the amount of disease before treatment is started.
• All patients will receive the same two chemotherapy drugs and radiation therapy. Both gemcitabine and 5-fluorouracil will begin on the first week of radiation therapy. 5-fluorouracil will be given continuously by intravenous infusion and will continue until the external beam radiation therapy is completed. The gemcitabine will be given (at different doses for each cohort of patients) once per week for seven weeks. Radiation therapy will be given daily for five days for seven weeks. On those days when gemcitabine is given, radiation therapy will be given approximately four hours after the gemcitabine dose.
• Four weeks after completing the radiation therapy and chemotherapy, patients will undergo a scan to check the extent of disease. Following the scan, patients will be considered for a repeat surgical procedure to remove the tumor, if possible. If removal of the tumor is not possible, patients will receive intraoperative radiation therapy.
• After completing the therapy, patients will be seen at least every 3 months for one year. A complete physical exam and CT scan will be done regularly.

Inclusion Criteria:

• Histologic confirmation of locally unresectable pancreatic adenocarcinoma. Patients with either measurable of evaluable disease are eligible.
• Unresectable, non-metastatic tumors. Unresectable patients include those with local extension of the tumor into adjacent structures and/or nodal metastasis.
• Total bilirubin < 2.0 mg/dl
• AST < 3x ULN
• Serum creatinine < 2.0 mg/dl
• WBC > 3,000/mm3
• Platelets > 100,000/mm3
• ECOG performance status < or = to 2
• Life expectancy of greater than 12 weeks

Exclusion Criteria:

• Evidence of peritoneal seeding by malignancy
• Prior radiation therapy or chemotherapy for pancreatic cancer
• Myocardial infarction in the past 6 months
• Major surgery in past two weeks
• Uncontrolled serious medical or psychiatric illness
• Pregnant or lactating women
• Concurrent malignancy of any site, except limited basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.