Aflibercept and FOLFOX6 Treatment for Previously Untreated Stage IV Colorectal Cancer

Inclusion Criteria: * Histologically confirmed adenocarcinoma of colorectal origin that is metastatic or locally advanced and unresectable * Measurable disease, as defined by RECIST 1.1 criteria: one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 10 mm with spiral computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) malignant lymph nodes will be considered measurable if they are \>= 15 mm in short axis * Must not have received any prior systemic therapy for metastatic or locally advanced CRC; prior VEGF inhibitors are not allowed * Prior adjuvant therapy for CRC including fluoropyrimidines either alone or in combination with oxaliplatin is allowed, provided that all therapy was completed \>= 12 months from cancer recurrence, therapy duration was =\< 6 months, and all prior toxicities have completely resolved (residual grade 1 neuropathy is allowed) * Life expectancy \>= 12 weeks * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Hemoglobin \>= 9 g/dL (blood transfusion permitted to attain this value) * Absolute neutrophil count \>= 1,500/uL * Platelets \>= 100,000/uL * Total bilirubin =\< 2 x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN (may be =\< 5x ULN if increase is due to metastatic disease) * Creatinine =\< 1.5 x institutional ULN or creatinine clearance \>= 60 mL/min/1.73 m2 for patients with creatinine levels above institutional U * Urine protein:creatinine ratio (UPCR) \< 1 or \< 500 mg protein/24 hr * Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: * May not be receiving any other investigational agents * Patients who have received any prior locoregional therapy for metastatic disease (e.g. radiofrequency/microwave ablation, Yttrium-90 radioembolization, transarterial chemoembolization, or surgical resection) are excluded * Patients with known or suspected brain metastases, carcinomatous meningitis, uncontrolled seizure disorder, active intracranial bleeding or active neurologic disorder are excluded * Patients with an active second primary malignancy or history of malignancy within the 5 years of enrollment are excluded, with the exception of non-melanoma skin cancers and cervical cancer which has been treated with curative therapy * Grade \>= 2 sensory neuropathy at the time of enrollment * Major surgery within 4 weeks of study start date; the surgical incision should be fully healed prior to initiation of aflibercept * Female or male patients of reproductive capacity unwilling to use methods appropriate to prevent pregnancy are excluded; effective contraception is required for at least 3 months following the last administration of aflibercept * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled hypertension (blood pressure \[BP\] must be well controlled \< 160/90), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, or any condition that the principal investigator (PI) feels would make the patient ineligible * Positive pregnancy screening test with a minimum sensitivity of 25 IU/L of human chorionic gonadotropin (hCG) within 72 hours of registration; breastfeeding women are also excluded * History of pulmonary embolus within 3 months or deep venous thrombosis (DVT) within 4 weeks of enrollment; patients on anticoagulation must be on a stable dose of warfarin with a therapeutic-range international normalized ratio (INR) or on a stable dose of low molecular weight heparin * Active congestive heart failure (New York Heart Association \[NYHA\] class II-IV) * History of an arterial thrombotic vascular event including cerebrovascular accident (CVA), myocardial infarction (MI), unstable angina, coronary or peripheral arterial bypass graft, or transient ischemic attack (TIA) within 6 months * Serious or non-healing wound, ulcer or bone fracture at the time of medication administration * History of treatment-resistant peptic ulcer disease, erosive esophagitis, gastritis, or diverticulitis within 3 months * History of gastrointestinal (GI) perforation within 5 years; current or prior intestinal fistulas are also excluded * Known chronic infectious disease including human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) * History of major hemorrhage including gastrointestinal bleeding (grade 2-4), pulmonary hemorrhage, or clinically significant hemoptysis (\> 1 tsp in 24 hours) within the last 5 years; patients with underling conditions that predispose to bleeding, such as bleeding diathesis, known esophageal varices, or tumor involving major vessels, are also excluded * Inability to understand or comply with study protocol * Known hypersensitivity to Chinese hamster ovary cell products or to recombinant human or murine antibodies, or any of the treatments in this protocol