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