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