Patient must have newly diagnosed untreated biopsy proven metastatic adenocarcinoma of the pancreas. If a patient had a biopsy of the pancreatic mass and the clinical picture is consistent with metastatic pancreatic cancer, another biopsy of a metastatic site is not required for this trial. Patients with acinar cell or adenosquamous carcinoma histology are ineligible. Patients with neuroendocrine histology are ineligible

Patients who have had previous surgery, adjuvant/neoadjuvant chemotherapy and/or radiation therapy will be allowed to enroll, provided therapy was completed at least 6 months prior to randomization. Palliative radiation to a metastatic site prior to study enrollment is allowed

Patient must be >= 70 years of age

Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Patient is an English speaker with the ability to understand and complete the informed consent and questionnaires

Leukocytes >= 3,000/mcL (obtained within 4 weeks of randomization)

Absolute neutrophil count >= 1,500/mcL (obtained within 4 weeks of randomization)

Platelets >= 100,000/mcL (obtained within 4 weeks of randomization)

Total bilirubin =< institutional upper limit of normal (ULN) (obtained within 4 weeks of randomization)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained within 4 weeks of randomization)

Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 (obtained within 4 weeks of randomization)

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this protocol. HIV positive (+) patients who are on ritonavir or/and cobicistat-based regimen must be switched to alternative anti-retroviral therapy (ART)

For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

Patients must agree not to father children while on study and for 3 months after the last dose of protocol treatment.

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this protocol, patients should be class 2 or better

Patients must have measurable disease and scans must be done within 4 weeks of randomization

Patients classified to have mild-moderate abnormalities in any of the domains evaluated in the screening geriatric assessment and are classified as “vulnerable” are eligible. Patients classified without any abnormalities (“fit”) or with severe cognitive/functional impairment or high co-morbidity score (“frail”) on the screening geriatric assessment are ineligible

Patients should avoid taking any medications or substances that are strong inhibitors or inducers of CYP3A4. Those who are randomized to liposomal irinotecan treatment arm should avoid drugs that are UGT1A1 inhibitors

PRIMARY OBJECTIVE:
I. Overall survival.

SECONDARY OBJECTIVES:
I. Progression-free survival.
II. Objective tumor response.
III. Comprehensive Geriatric Assessment (CGA)/quality of life (QOL) related objectives:
IIIa. Hypothesize that lower scores in functional status assessment tool – instrumental activities of daily living (IADL) will correlate with higher rates of grade 3 or higher chemotherapy toxicity.
IV. CGA/QOL related exploratory objectives:
IVa. Evaluation of other pre-treatment CGA domains including co-morbidities, depression, nutrition and cognition as predictors of chemotherapy tolerance.
IVb. Evaluation of the association between change in functional status during treatment course (comparison between activities of daily living [ADL] and IADL score pre-treatment and at time of disease evaluation) as predictors of chemotherapy tolerance.
IVc. Evaluation of the correlation between CGA domains and overall survival by treatment arm.
IVd. Evaluation of the difference in QOL scores (Functional Assessment of Cancer Therapy - Hepatitis [FACT-Hep] version 4) between baseline measures and assessment during treatment course between by treatment arms.
V. Focused evaluation of toxicities that are of interest for older patients including: peripheral neuropathy, fatigue, falls, emergency room visits, hospitalization, treatment modification and discontinuation.
VI. Imaging correlative study objectives:
VIa. Evaluate the association between baseline and change during treatment of skeletal muscle index (SMI) and intermuscular adipose tissue (IMAT) and rates of grade 3 or higher chemotherapy toxicity experienced on treatment.
VIb. Evaluate the association between baseline and change during treatment of skeletal muscle index (SMI) and intermuscular adipose tissue (IMAT) and overall survival among older patients with metastatic pancreatic cancer.
VIc. Evaluate the association between baseline and change during treatment of skeletal muscle index (SMI) and intermuscular adipose tissue (IMAT) and geriatric assessment scores evaluating functional status.
VII. Laboratory correlative study objectives:
VIIa. Evaluation of the correlation between baseline levels of biomarkers of aging (CRP and IL-6) and rates of grade 3 or higher chemotherapy toxicity during therapy.
VIIb. Evaluation of the correlation between changes in levels of CRP and IL-6 during therapy and rates of grade 3 chemotherapy toxicity.
VIIc. Evaluation of the correlation between baseline levels of biomarkers of aging (CRP and IL-6) and overall survival among older patients with metastatic pancreatic cancer.
VIId. Evaluation of the correlation between levels of baseline biomarkers of aging (CRP and IL-6) and geriatric assessments scores evaluation functional status.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive gemcitabine intravenously (IV) over 30 minutes and nab-paclitaxel IV over 30 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive fluorouracil IV over 46 hours starting on day 1. Patients also receive leucovorin IV over 90-120 minutes and liposomal irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection and computed tomography (CT) scan while on study.