PRIMARY OBJECTIVES:
I. To assess 2-year overall survival in each treatment arm (fluorouracil, irinotecan hydrochloride, and oxaliplatin \[modified (m)FOLFIRINOX\] and gemcitabine \[gemcitabine hydrochloride\]/nab-paclitaxel \[paclitaxel albumin-stabilized nanoparticle formulation\]) in patients with resectable pancreatic cancer.
II. If the stated threshold is met in one or both arms: to choose the better regimen with respect to 2-year overall survival.
SECONDARY OBJECTIVES:
I. To estimate, for all patients and within treatment arms: frequency and severity of adverse events associated with chemotherapy in the perioperative setting.
II. To estimate, for all patients and within treatment arms: proportion of patients going to surgery for resection after preoperative chemotherapy.
III. To estimate, for all patients and within treatment arms: proportion of patients achieving macroscopically complete tumor removal with negative microscopic surgical margins (R0) resection after preoperative chemotherapy.
IV. To estimate, for all patients and within treatment arms: overall response rate following preoperative chemotherapy, including confirmed and unconfirmed, complete and partial response, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
V. To estimate, for all patients and within treatment arms: pathologic response rates after R0 or macroscopically complete tumor removal with any positive microscopic surgical margin (R1) resection.
VI. To estimate, for all patients and within treatment arms: patterns of recurrence (loco-regional, distant) after R0 or R1 resection.
VII. To estimate, for all patients and within treatment arms: disease-free survival from the time of R0 or R1 resection.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours and irinotecan hydrochloride IV over 90 minutes on days 1 and 15. Patients also receive fluorouracil IV over 46 hours on days 1-3 and 15-17. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of oxaliplatin, irinotecan hydrochloride, and fluorouracil treatment in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or better undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients receive an additional 3 courses of paclitaxel albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride treatment in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 2 years.
Inclusion Criteria:
* Patients must have histologically or cytologically proven pancreatic adenocarcinoma; histologies other than adenocarcinoma, or any mixed histologies, will NOT be eligible
* Patients must have measurable disease in the pancreas; computed tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess measurable disease must have been completed within 28 days prior to registration; all disease must be assessed and documented on the baseline tumor assessment form
* Patients must have resectable primary tumor based on contrast-enhanced CT or MRI (CT or MRI without contrast as part of positron emission tomography \[PET\]/CT or PET/MRI is NOT acceptable; CT or MRI with contrast as part of PET/CT or PET/MRI is acceptable) of the chest, abdomen, and pelvis, where resectable is defined as:
* No involvement of the celiac artery, common hepatic artery, and superior mesenteric artery (and, if present, replaced right hepatic artery)
* No involvement, or \< 180° interface between tumor and vessel wall, of the portal vein and/or superior mesenteric vein; and patent portal vein/splenic vein confluence
* No evidence of metastatic disease
* Note: for tumors of the body and tail of the pancreas, involvement of the splenic artery and vein of any degree is considered resectable disease
* CT scans or MRIs used to assess disease at baseline must be submitted for central review
* Patients must have surgical consult to verify patient is a surgical candidate within 21 days prior to registration
* Patients must not have received prior surgery, radiation therapy, chemotherapy, targeted therapy, or any investigational therapy for pancreatic cancer
* Patients must have a Zubrod performance status of 0-1
* Absolute neutrophil count (ANC) \>= 1,500/mcL
* Platelets \>= 100,000/mcL
* Hemoglobin \>= 9 g/dL
* Total bilirubin =\< 1.5 x institutional upper limit of normal (IULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x IULN
* Serum albumin \>= 3 g/dL
* Serum creatinine =\< IULN within 14 days prior to registration
* Patients with 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 will NOT be eligible
* No prior malignancy is allowed except for adequately treated basal (or squamous cell) skin cancer, in situ cervical cancer, in situ breast (ductal or lobular) cancer, or other cancer for which the patient has been disease and treatment-free for two years
* Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method for up to 3 months after the final administered dose of chemotherapy; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures, he/she is responsible for beginning contraceptive measures
* Sites must seek additional patient consent for the future use of specimens
* Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
* As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
