Study of Chemotherapy With or Without Hepatic Arterial Infusion for Patients With Unresectable Metastatic Colorectal Cancer to the Liver

Inclusion Criteria: * History of histologically confirmed colorectal adenocarcinoma metastatic to the liver with no clinical or radiographic evidence of extrahepatic disease. Confirmation of diagnosis must be performed by the enrolling institution. * Patients must have a primary L sided colorectal cancer, (at or distal to the splenic flexure) * Confirmed RAS/RAF wild type tumor. Paraffin-embedded tumor tissue obtained from the primary tumor or metastasis * Have received prior treatment for metastatic disease with oxaliplatin-based regimen and either * Had disease progression OR * Had stable disease OR * Discontinued oxaliplatin due to neuropathy * Patients must meet the following criteria for unresectability as determined by two hepatobiliary surgeons and one radiologist: * When a margin negative resection would require resection of all three hepatic veins, both portal veins, or the retrohepatic vena cava. * Requiring a resection that leaves less than 2 hepatic segments (not including the caudate lobe) behind with adequate arterial/portal inflow, venous outflow and biliary drainage. \*\* \*\*A patient is considered resectable if the procedure includes a minor wedge or thermo-ablation encompassing 10% or less of the volume of the remaining 2 segments. * Patient"s liver metastases must comprise \<70% of the liver parenchyma. All patients must be clinically fit to undergo surgery as determined by the pre-operative evaluation * Lab values within 14 days prior to enrollment/randomization: * WBC ≥ 3.0 K/uL * ANC \> 1.5 K/uL * Platelets ≥ 100,000/uL * Renal function (≤ 10 days prior to enrollment/randomization) °Creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min calculated by the Cockcroft-Gault method as follows: Cockcroft-Gault method as follows: * Male creatinine clearance = (140 -age in years) x (weight in Kg) / (serum Cr in mg/dl x 72) * Female creatinine clearance = (140 - age in years) x (weight in Kg) x 0.85 / (serum Cr in mg/dl x 72) (use of creatinine clearance per protocol based on chemotherapy regimen) * Hepatic function, as follows: (≤ 10 days prior to enrollment/randomization) * Total Bilirubin ≤ 1.5 mg/dl * Calcium ≥ lower limit of normal (≤ 48 hours prior to enrollment/randomization) * KPS ≥ 60% (ECOG (or Karnofsky) performance status (preferably 0 or 1/≥ 60% for Karnofsky)) Exclusion Criteria: * Patients \< 18 years of age * Patients who have received more than one chemotherapy regimen for metastatic disease * Patients who are chemotherapy naïve * Prior radiation to the liver (Prior radiation therapy to the pelvis is acceptable if completed at least 4 weeks prior to registration) * Active infection °Active infection includes patients with positive blood cultures * Prior treatment with HAI FUDR * Prior TACE * Female patients who are pregnant or lactating - or planning to become pregnant within 6 months after the end of the treatment (female patients of child-bearing potential must have negative pregnancy test ≤ 72 hours before enrollment and randomization, and must have a negative pregnancy test ≤ 72 hours prior to treatment start) * If a patient has any serious medical problems which may preclude receiving this type of treatment * Patients with history or known presence of primary CNS tumors, seizures not well-controlled with standard medical therapy, or history of stroke will also be excluded. * Serious or non-healing active wound, ulcer, or bone fracture * History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan * Patients who have a diagnosis of Gilbert"s disease * History of other malignancy, except: 1. Malignancy treated with curative intent and with no known active disease present for ≥ 3 years prior to randomization and felt to be at low risk for recurrence by the treating physician 2. Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease 3. Adequately treated cervical carcinoma in situ without evidence of disease