Primary Objective: To determine the rate of downstaging to resectability in patients with borderline resectable pancreatic cancer receiving FOLFIRINOX and SBRT as preoperative therapy.

Secondary Objective(s):

1. To assess the disease-free-survival, overall survival, time to recurrence and site of recurrence in patients with borderline resectable pancreatic cancer receiving preoperative FOLFIRINOX followed by SBRT
2. To investigate the safety and tolerability of FOLFIRINOX and SBRT in patients with resectable pancreatic cancer
3. To determine the radiologic and pathological response associated with preoperative SBRT and FOLFIRINOX therapy
4. To assess quality of life through and after treatment using the FACT-Hep questionnaire

The study investigators hypothesize that neoadjuvant FOLFIRINOX can be safely and efficaciously delivered using a sequential regimen with SBRT as an alternative to standard neoadjuvant chemoradiotherapy. Standard of care neoadjuvant treatment typically requires about six weeks of treatment with sub-systemic dosing of chemotherapy. The feasibility of the sequential delivery of the FOLFIRINOX followed by SBRT will be evaluated by capturing the prevalence of grade 3 toxicity and the treatment delay rate.

In our study, SBRT is planned sequentially to follow cycle 4 of chemotherapy treatment, provided toxicity has resolved to grade 2 or less. Thus, allowing for resolution of chemotherapy toxicity prior to initiation of radiation therapy. This interval and the fact that there is no concurrent delivery of chemo-RT, based on previously discussed experiences, including approaches where SBRT safely follows other intense chemotherapy regimens (see Polistina et al and Chuong [35,36]) makes this study feasible without establishing toxicity profile.

The proposed regimen of 4 cycles of FOLFIRINOX followed by 30 Gy/5 fractions using SBRT will be safely tolerated and will improve resectability rates in borderline resectable PDAC patients. In addition, this regimen will not compromise the ability to achieve a successful Whipple resection.

This regimen will improve the local control rate and overall disease free survival in this patient population. The investigators further hypothesize that early administration of FOLFIRNOX will provide optimal systemic therapy to control clinically occult micrometastases.

Inclusion Criteria:

• ≥ 18 years at diagnosis.
• Biopsy proven pancreatic adenocarcinoma.
• Borderline resectable per NCCN criteria (No distant metastases, venous involvement of the portal vein/SMV, demonstrating tumor abutment and narrowing of the lumen, encasement of the portal vein/SMV without encasement of the nearby arteries, or short-segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal or distal to this area of vessel involvement, allowing for safe resection and reconstruction; gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis; tumor abutment of the SMA not to exceed 180 degrees of the circumference of the vessel wall.).
• Radiologically measurable or clinically evaluable disease.
• Pancreas protocol CT and/or MRI if required for further clarification of disease tissue planes within 4 weeks of registration.
• ECOG PS of 0-2.
• Able to get a Whipple resection per surgeon assessment performed within 4 weeks of registration.
• The following laboratory values obtained ≤ 28 days prior to registration:
• Absolute neutrophil count (ANC) ≥ 1,500/mm3.
• Platelet count ≥ 100,000/mm3.
• Hemoglobin > 8.0 g/dL.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN).
• SGOT (AST) ≤ 2 x ULN.
• SGPT (ALT) ≤ 2 x ULN.
• Creatinine ≤ 1.5 x ULN.
• CA 19-9 level (to establish baseline).
• A negative pregnancy test within 7 days prior to registration for women of childbearing potential. In addition, male and female participants must commit to adequate contraception while on study.
• Able to provide written informed consent.
• Willing to return for all required study assessments.
• Neurological assessment for pre-existing peripheral neuropathy.
• Documentation of pre-existing hearing deficits.

Exclusion Criteria:

• Any pancreatic adenocarcinoma that does not meet criteria for borderline resectable disease.
• Prior history of abdominal radiation therapy.
• History of autoimmune disease such as scleroderma, lupus, and inflammatory bowel disease.
• Patients with tumor-caused symptomatic bowel obstruction.
• Chemotherapy (including hormonal therapy) within the past 5 years from date of registration.
• Other invasive malignancies within the past 5 years from date of registration.
• Pregnant or nursing women or women of childbearing age that are unwilling to employ adequate contraception.
• Other co-morbid conditions which, based on the judgment of the physicians obtaining informed consent, would make the patient inappropriate for this study.