This multi-institutional trial aims to evaluate the potential benefit and side effects of adding fractionated stereotactic body radiotherapy/surgery (SBRT) before and after chemotherapy with gemcitabine for locally advanced pancreatic cancer.

Treatment on this protocol requires placement of 3-5 gold (99.9% pure, 1-5 mm length, or visicoils) fiducials for targeting purposes. The fiducials will be used as surrogates for targeting the daily tumor position during treatment. The fiducials will be placed directly into the tumor and/or periphery under endoscopic ultrasound or CT guidance. Gemcitabine prior to SBRT is optional. If given, up to 3 weeks in a 6-week period is allowable, and may be given prior to study enrollment. Administration should be on a 3-week on, 1-week off schedule, weekly at 1,000 mg/m2. Simulation should be done 5 days or more following placement of fiducials. For simulation patients will be positioned supine in an Alpha Cradle or equivalent immobilization device will be custom made for each patient. Standard free-breathing CT and respiratory-correlated 4-D pancreatic protocol CT will be obtained on each patient The 4D-CT scan will be used for characterizing target motion during quiet respiration. Following simulation, patients may be treated either in a respiratory gated (Trilogy, Elekta, Novalis) or a respiratory tracking (Cyberknife) manner. The selection of which radiotherapy treatment machine to use is left to each investigator. All patients will receive 5 fractions of 6.6 Gy delivered over a five-day period. Ideally all 5 fractions should be delivered Monday through Friday, however it may be delivered over 2 weeks as long as the patient receives at least 2 fractions a week. Gemcitabine, cycles should resume up to 4 weeks following SBRT on a 3-week on, 1-week off schedule, administered weekly at 1,000 mg/m2.A detailed medical history with physical examination and quality of life assessment will be performed at 4 months, 6 months, 9 months and 1 year. A follow-up visit at 4 weeks is optional and may be done by patient's Medical Oncologist. Scans may be done at 4-6 week visit if patient is being re-evaluated for resection.

In years 2-5 the follow up interval will be every 3-6 months, as determined by the investigator at each participating institution. Follow up intervals may also be more frequent as indicated clinically. A complete blood count (CBC), comprehensive chemistry panel, tumor marker studies, and quality of life assessment will be performed at each follow-up interval until death. As permitted by each participating institution, separate samples of blood will be drawn and retained for research efforts to develop novel serum biomarkers.

Inclusion Criteria:

3.1.1 Histologically confirmed adenocarcinoma of the pancreas.

3.1.2 Unresectable disease as determined by a pancreatic cancer surgeon and assessment at a GI oncology tumor board (JHU - Johns Hopkins University, SU - Stanford University, or MSKCC - Memorial Sloan Kettering Cancer Center).

3.1.3 Up to 3 weeks of gemcitabine chemotherapy is allowed prior to SBRT.

3.1.4 Pancreatic tumors must be less than 7.5 cm in greatest axial dimension (or <1000 cc in volume) at the time of treatment planning.

3.1.5 No prior upper abdominal or liver radiation therapy.

3.1.6 No chemotherapy within 2 weeks of radiotherapy, or chemotherapy within parameters set by Investigator for each institution.

3.1.7 Age >=18 years.

3.1.8 No infections requiring systemic antibiotic treatment.

3.1.9 Karnofsky >= 70% (see Appendix III).

3.1.10 Patients must have acceptable organ and marrow function as defined below (within 1 month prior to radiotherapy):

• leukocytes: >=3,000/microliter (uL)
• absolute neutrophil count: >=1,500uL
• platelets: >=100,000/uL
• total bilirubin: within 1.5 times (1.5X) normal institutional limits
• AST (aspartate aminotransferase)(SGOT -Serum glutamic oxaloacetic transaminase)/ALT(alanine aminotransferase)(SGPT-serum glutamic-pyruvic transaminase): <=2.5 X institutional upper limit of normal
• creatinine: within normal institutional limits

OR

- creatinine clearance: >=60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

3.1.11 The effects of radiation on the developing human fetus at recommended therapeutic doses can result in death of the fetus. If a woman is of child-bearing potential, a negative urine or serum pregnancy test must be demonstrated prior to treatment. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for up to 4 weeks following the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

3.1.12 Ability to understand and the willingness to sign a written informed consent document.

3.1.13 Life expectancy > 6 months

Exclusion Criteria:

3.2.1 Patients who have had prior radiotherapy to the upper abdomen.

3.2.2 Patients receiving more than 1 cycle of gemcitabine chemotherapy or other therapy prior to SBRT.

3.2.3 Children are excluded because pancreatic tumors rarely occur in this age group. Furthermore, treatment requires a great deal of patient cooperation including the ability to lie still for several hours in an isolated room.

3.2.4 No laboratory personnel will be included.

3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

3.2.6 Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder cancer, or carcinoma in situ of the cervix. Patients with a previous malignancy without evidence of disease for > 5 years will be allowed to enter the trial.

3.2.7 Pregnant and breastfeeding women are excluded. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to 4 weeks after the study are excluded. This applies to any woman who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months, or women on hormone replacement therapy with serum FSH (follicle stimulating hormone) levels greater than 35 IU/mL (international units/milliliter). A negative urine or serum pregnancy test must be obtained within 72 hours prior to the start of study medication in all women of childbearing potential. Male subjects must also agree to use effective contraception for the same period as above.