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