Intraperitoneal Oxaliplatin and Fluorouracil for the Treatment of Patients With Peritoneal Metastases From Colorectal Cancer

Inclusion Criteria:

* Age \>= 18 years
* Biopsy proven colorectal cancer with peritoneal metastasis. Patients with extraperitoneal metastases will not be eligible. Patients with involvement of intra-abdominal lymph nodes may be eligible at the discretion of the treating physician
* Primary colorectal cancer may either be left in place or have been resected prior to study enrollment
* Patients are allowed to have received prior colorectal cancer-directed systemic therapy.
* Not previously undergone cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at the time of enrollment
* Absolute neutrophil count (ANC) ≥ 1,500 /mcL
* Platelets ≥ 100,000 / mcL
* Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance ≥ 60 mL/min for patient with creatinine levels \> 1.5 x institutional ULN (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\])

  * Creatinine clearance should be calculated per institutional standard
* Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patient with total bilirubin levels \> 1.5 ULN
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

  * Both values must be in the specified range
* Albumin \>= 2.5 g/dL
* International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
* Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Patients on anticoagulation or antiplatelet agents may be enrolled at the discretion of the treating physician, provided these can be safely held as needed for surgical procedures
* Anticipated life expectancy of ≥ 6 months
* Willing to comply with study procedures
* Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study and at least 9 months after the last dose of study medication
* For female patients of childbearing potential, a negative pregnancy test is required at or within 7 days prior to enrollment
* Be willing and able to understand and sign the written informed consent document
* Be willing to undergo two diagnostic laparoscopies with tumor biopsy tissue. Patients must consent to on-treatment biopsies prior to initiation of clinical trial
* Be willing to provide peripheral blood and peritoneal samples for correlative studies

Exclusion Criteria:

* Patients who are receiving any other investigational drugs
* Evidence of metastatic disease other than peritoneum based on standard of care (SOC) imaging
* Patients with primary mucinous appendiceal tumors will not be eligible. These tumors often produce mucin, which may affect the penetration of IP chemotherapy. Patients with non-mucinous appendiceal adenocarcinomas will be eligible.
* Patients with \>= grade 2 peripheral neuropathy
* Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, active bleeding diatheses, and psychiatric illness/social situations that would limit compliance with study requirements
* Major surgical procedure or significant traumatic injury less than 3 weeks or those who receive minor surgical procedures within 1 week from first dose of study drug administration
* Known active chronic infections - uncontrolled human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), known active (i.e., with detectable polymerase chain reaction \[PCR\]) hepatitis B or C
* Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
* Pregnancy or breastfeeding
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating physician