PRE-REGISTRATION:

Pathology: Histologic or cytologic proof of pancreatic adenocarcinoma or adenosquamous carcinoma
TNM Stage: Tx-4, N0-1, M0 (M0 disease does not include spread to distant lymph nodes and organs)
Resectable Primary Tumor: Local radiographic reading must be consistent with resectable disease defined as the following on 1) arterial and venous phase contrast-enhanced abdominal/pelvic CT scan or abdominal/pelvic magnetic resonance imaging (MRI) scan and 2) chest CT:

No involvement or abutment of the celiac artery, common hepatic artery, superior mesenteric artery, or replaced right hepatic artery (if applicable)
Less than 180 degree interface between tumor and vessel wall of the portal vein or superior mesenteric vein, and patent portal vein/splenic vein confluence
No evidence of metastatic disease
Measurable disease or non-measurable disease o Non-measurable disease is defined as cytologic or histologic confirmation of adenocarcinoma of adenosquamous carcinoma by fine needle aspiration or core-biopsy of the pancreas without measurable disease by radiographic imaging
REGISTRATION: Confirmation of resectable disease by real-time central imaging review by the Alliance Imaging Core Lab at Imaging and Radiation Oncology Core (IROC) Ohio
Determined to be appropriate candidate for curative-intent pancreatectomy by surgeon intending to perform the resection

women of childbearing potential only, a negative pregnancy test done =\< 14 days prior to registration is required
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Total Neuropathy Score \< 2
Absolute neutrophil count (ANC) \>= 1,500/uL
Platelet count \>= 100,000/uL
Total bilirubin =\< 1.5 x upper limit of normal (ULN) (If obstructive jaundice is present, then biliary drainage must be initiated and total bilirubin =\< 3.0)
Creatinine =\< 1.5 x ULN OR calculated (Calc.) creatinine clearance \>= 30 mL/min (Calculated using the Cockcroft-Gault equation)

Please contact study team for more eligibility criteria

No involvement or abutment of the celiac artery, common hepatic artery, superior mesenteric artery, or replaced right hepatic artery (if applicable)
Less than 180 degree interface between tumor and vessel wall of the portal vein or superior mesenteric vein, and patent portal vein/splenic vein confluence
No evidence of metastatic disease
No prior radiation therapy, chemotherapy, targeted therapy, investigational therapy, or surgery for pancreatic cancer
Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects.
Therefore, for women of childbearing potential only, a negative pregnancy test done =\< 14 days prior to registration is required
No known Gilbert's Syndrome or known homozygosity for UGAT1A1\*28 polymorphism
No comorbid conditions that would prohibit curative-intent pancreatectomy
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug prior to registration
Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inducers must discontinue the drug prior to registration
Please contact study team for more eligibility criteria

• Oncology (Adult)

• Antidotes

• Antimetabolites

• Antimetabolites, Antineoplastic

• Antineoplastic Agents

• Calcium

• Calcium-Regulating Hormones and Agents

• Carcinoma, Adenosquamous

• Digestive System Diseases

• Digestive System Neoplasms

• Endocrine Gland Neoplasms

• Endocrine System Diseases

• Enzyme Inhibitors

• Fluorouracil

• Immunologic Factors

• Immunosuppressive Agents

• Irinotecan

• Leucovorin

• Levoleucovorin

• Micronutrients

• Molecular Mechanisms of Pharmacological Action

• Neoplasms

• Neoplasms by Histologic Type

• Neoplasms by Site

• Neoplasms, Complex and Mixed

• Neoplasms, Glandular and Epithelial

• Oxaliplatin

• Pancreatic Diseases

• Pancreatic Neoplasms

• Physiological Effects of Drugs

• Protective Agents

• Topoisomerase I Inhibitors

• Topoisomerase Inhibitors

• Vitamin B Complex

• Vitamins

• Carcinoma

• Alliance for Clinical Trials in Oncology