Hypofractionated Stereotactic Body Radiation Therapy and Fluorouracil or Capecitabine With or Without Zoledronic Acid in Treating Patients With Locally Advanced Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of hypofractionated radiation therapy concurrently with
zoledronic acid (Zometa) and fluorouracil (5Fu) or capecitabine.

SECONDARY OBJECTIVES:

I. To examine the toxicity of Zometa while it is used concurrently with hypofractionated
radiation therapy.

II. To evaluate local failure-free survival and overall survival, surgical resection rate and
tumor response rate.

TERTIARY OBJECTIVES:

I. To quantify the amplitude of the expression of genes that are involved in cholesterol
biosynthesis (ACAT2, DHCR7, ELFN2, FASN, SC4MOL, and SQLE) in pancreatic tumor tissue prior
to and following the Zometa and radiation therapy if the pancreatic cancer tissue is
available.

II. To measure Zometa pharmacokinetics at steady-state. III. To evaluate tumor and organ
motion with 4 dimension(D) computed tomography (CT) and respiratory gating system and to
evaluate the effect of tumor/organ motion on the dosimetry, local control and survival.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo hypofractionated stereotactic body radiation therapy in 5 fractions
on days 1-5. Patients receive fluorouracil intravenously (IV) over 24 hours on day 1 weekly
for 4 weeks or capecitabine orally (PO) every 12 hours starting the evening before day 1 of
radiation therapy for 4 weeks as per standard of care. Patients then undergo surgery 6-8
weeks after completion of radiation therapy.

ARM B: Patients receive zoledronic acid IV over no less than 15 minutes 1 week prior to
radiation therapy. Patients undergo hypofractionated stereotactic body radiation therapy and
receive treatment with fluorouracil IV or capecitabine PO as in Arm A. Patients then undergo
surgery 6-8 weeks after completion of radiation therapy.

After completion of study treatment, patients are followed up for 30 days, every 3 months for
the first year, every 4 months for the second year, and then every 6 months thereafter.

Inclusion Criteria:

- Pathologically confirmed adenocarcinoma of the pancreas; patients with either
initially diagnosed or recurrent locally advanced disease; the maximum dimension of
the treatment target must be =<10 cm; locally advanced disease defined as: T 1-2N+MO
or T3-4 NxMo, or borderline resectable and unresectable adenocarcinoma without distant
metastatic disease or resectable T3-4 NxMo disease or M1 with controlled distant
disease

- Patients with inoperable conditions with resectable disease (T1-2NoMo)

- Karnofsky performance status of 60% or better

- Patients who received recent chemotherapy for pancreatic cancer are eligible; patients
who received chemotherapy > 5 years ago for malignancies other than pancreatic cancer
are also eligible, provided that chemotherapy was completed > 5 years ago and that
there is no evidence of the second malignancy at the time of study entry

- Patients who received radiation therapy > 5 years ago for malignancies other than
pancreatic cancer and whose radiation therapy field is not overlapping with the 20%
isodose line of current radiation field are eligible, provided that radiation therapy
was completed > 5 years ago and that there is no evidence of the second malignancy at
the time of study entry

- All malignant disease must be able to be encompassed within a single irradiation field

- Patients must have an absolute neutrophil count (ANC) greater than or equal to 1500/uL

- All patients must have radiographically assessable disease

- Platelet count greater than or equal to 100,000/uL

- Patients must have a serum creatinine less than or equal to 2.0 mg/dL and total
bilirubin less than or equal to 2.0 mg/dL in the absence of biliary obstruction; if
the patient has biliary obstruction, biliary decompression will be required; either
endoscopic placement of a biliary stent or percutaneous transhepatic drainage is
acceptable; once biliary drainage has been established, institution of protocol
therapy may proceed when the total bilirubin falls to 4.0 mg/dL or lower)

- Patients must have a calculated creatinine clearance of >= 35

- The patient must be aware of the neoplastic nature of his/her disease and willingly
provide written, informed consent after being informed of the procedure to be
followed, the experimental nature of the therapy, alternatives, potential benefits,
side-effects, risks, and discomforts

Exclusion Criteria:

- Patients with a known allergy to Zometa or to antiemetics appropriate for
administration in conjunction with protocol-directed therapy

- Uncontrolled inter-current illness including, but not limited to ongoing or active
infection requiring intravenous antibiotics, symptomatic congestive heart failure,
unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might
jeopardize the ability of the patient to receive the therapy program outlined in this
protocol with reasonable safety

- Pregnant and nursing women are excluded from this study

- Patients with prior malignancy will be excluded except for adequately treated basal
cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other
cancers from which the patient has been disease-free for at least 5 years

- Patients with active duodenal ulcer or bleeding or history of a gastrointestinal
fistula or perforation or other significant bowel problems (severe nausea, vomiting,
inflammatory bowel disease and significant bowel resection)

- Patients with known human immunodeficiency virus (HIV) infection, or hepatic
insufficiency

- Patients may not be receiving or have received Zometa during/or within 3 weeks prior
to treatment with Zometa