Phase II Gemcitabine + Fractionated Stereotactic Radiotherapy for Unresectable Pancreatic Adenocarcinoma

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.