5-FU Based Maintenance Therapy in RAS Wild Type Metastatic Colorectal Cancer After Induction With FOLFOX Plus Panitumumab

Inclusion Criteria: * Metastatic or locally advanced (unresectable) colorectal cancer with histological confirmation of adenocarcinoma (patients with or without measurable disease by imaging are eligible) * No prior systemic chemotherapy for metastatic disease; subjects who received adjuvant therapy with FOLFOX and at the time of recurrence are at least 6 months away from last chemotherapy are eligible for this study * At the time of randomization to maintenance therapy only patients who didn't progress by Response Evaluation Criteria in Solid Tumors (RECIST) criteria are eligible; patients with complete response (CR) and those who are candidates for resection will not be eligible for randomization to maintenance therapy, subjects who undergo surgery potentially have curable disease with defined duration of treatment and use of EGFR in the adjuvant setting is deemed to be detrimental in these population; likelihood of achieving CR is low and standard of care in this unique patient population is not well defined * Provide written informed consent * RAS wild-type tumor * Negative serum or urine pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only * Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0 or 1 * Total serum bilirubin =\< institutional upper limit of normal (ULN) * Absolute neutrophil count (ANC) \>= 1500/mm\^3 * Platelet count \>= 100,000/mm\^3 * Hemoglobin \>= 9.0 g/dL (hemoglobin may be supported by transfusion) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN (=\< 5 x ULN for subjects with liver involvement of their cancer) * Creatinine within institutional limits of normal OR creatinine clearance \> 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal * Magnesium \>= lower limit of normal * Willing to provide tissue and blood samples for mandatory correlative and research purposes Exclusion Criteria: * Patients who are candidates for upfront metastasectomy (defined as those with limited liver metastatic disease) are not eligible for this study; the candidacy for resectability can be determined by the treating physician and or local surgeon; in ambiguous situations, please discuss the case with the principle investigator (PI) * Known or suspected brain or central nervous system (CNS) metastases * Active, uncontrolled infection, including hepatitis B, hepatitis C * Patients with history of interstitial lung disease/pulmonary fibrosis * Concurrent anti-cancer therapy, including chemotherapy agents, targeted agents, or biological agents not otherwise specified in this protocol * Radiation therapy =\< 2 weeks prior to randomization * Any of the following * Pregnant or nursing women * Men or women of childbearing potential who are unwilling to employ adequate contraception * Co-morbid systemic illnesses or other severe concurrent disease, history of any psychiatric or addictive disorder, or laboratory abnormality, which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens * Patients known to be human immunodeficiency virus (HIV) positive * Uncontrolled intercurrent illness whom in the opinion of the investigator, may increase the risks associated with study participation or study treatment, or may interfere with the conduct of the study or the interpretation of the study results * Receiving any other investigational agent, which would be considered as a treatment for the primary neoplasm * Other active malignancy =\< 3 years prior to registration; exceptions are: nonmelanoma skin cancer or carcinoma-in-situ of the cervix that has been treated * History of prior malignancy for which patient is receiving other specific treatment for their cancer * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs