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This phase III trial compares perioperative chemotherapy (given before and after surgery) versus adjuvant chemotherapy (given after surgery) for the treatment of pancreatic cancer that can be removed by surgery (removable/resectable). Chemotherapy drugs, such as fluorouracil, irinotecan, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before and after surgery (perioperatively) may work better in treating patients with pancreatic cancer compared to giving chemotherapy after surgery (adjuvantly).

Primary Objectives:

1. To evaluate and compare overall survival (OS) in patients with resectable pancreatic adenocarcinoma treated with perioperative fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (modified [m]FOLFIRINOX) and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

Secondary Objectives:

1. To evaluate and compare disease-free survival (DFS) in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

2. To evaluate and compare time to locoregional recurrence (TLR) in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

3. To evaluate and compare time to distant metastases (TDM) in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

4. To evaluate and compare the R0 resection rate in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

5. To evaluate and compare rate of unresectability in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

6. To evaluate rate of pathologic complete response in patients randomized to the perioperative therapy arm.

7. To evaluate and compare mFOLFIRINOX dose intensity delivered and number of cycles received in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

8. To evaluate and compare adverse event profile in patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

9. To compare physical functioning, nausea/vomiting, and diarrhea, as measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) between patients with resectable pancreatic adenocarcinoma treated with perioperative mFOLFIRINOX and surgery versus up-front surgery followed by adjuvant mFOLFIRINOX.

10. To prospectively assess the influence of diet, body mass index, weight loss, physical activity, and other lifestyle habits on the disease-free survival and overall survival among patients with localized pancreatic cancers.

11. To assess the influence of diet, obesity, physical activity, and other lifestyle habits on the risk of toxicity associated with chemotherapy.

12. To evaluate the ability of computed tomography (CT)-based radiomics in distinguishing post-neoadjuvant chemotherapy (NAC) fibrosis from viable tumor in patients randomized to the perioperative therapy arm.

13. To determine whether CT-based radiomics retrieved from baseline examination may act as non-invasive predictors of survival outcome in patients randomized to the adjuvant therapy arm.

Outline: Patients are randomized to 1 of 2 arms.

Arm I: Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Within 2-8 weeks of completing neoadjuvant chemotherapy, patients undergo surgical resection. Patients then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

Arm II: Patients undergo surgical resection. Beginning 3-12 weeks after surgery, patients then receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-3. Treatment repeats every 14 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 6 years.

Inclusion Criteria:

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

• 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

• 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)

• 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