Isolated Hepatic Perfusion With Melphalan Followed by Combination Chemotherapy in Treating Patients With Unresectable Liver Metastases From Colorectal Cancer
Isolated Hepatic Perfusion With Melphalan Followed by Combination Chemotherapy in Treating Patients With Unresectable Liver Metastases From Colorectal Cancer
RATIONALE: Drugs used in chemotherapy, such as melphalan, leucovorin, oxaliplatin, and
 fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the
 cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy)
 and giving the drugs in different ways may kill more tumor cells.

 PURPOSE: This phase II trial is studying how well isolated hepatic perfusion with melphalan
 followed by combination chemotherapy works in treating patients with unresectable liver
 metastases from colorectal cancer.
OBJECTIVES:

 Primary

 -  Determine the response and duration of response in patients with previously untreated
 unresectable liver metastases secondary to colorectal cancer treated with isolated
 hepatic perfusion with melphalan followed by leucovorin calcium, oxaliplatin, and
 fluorouracil.

 Secondary

 -  Determine the patterns of recurrence (liver vs systemic) in patients treated with this
 regimen.

 -  Determine progression-free and overall survival of patients treated with this regimen.

 -  Correlate health-related quality of life with length of survival of patients treated
 with this regimen.

 OUTLINE: Patients undergo exploratory laparotomy. Patients with evidence of carcinomatosis
 not previously visualized on scans but found on surgical exploration are removed from the
 study. All other patients then undergo isolated hepatic perfusion (IHP). Once IHP is
 established, melphalan is administered intra-arterially over 3-5 minutes and then circulated
 throughout the liver for 1 hour. Approximately 6-12 weeks later, patients receive systemic
 chemotherapy comprising oxaliplatin IV over 2 hours on day 1 and leucovorin calcium IV over 2
 hours and fluorouracil IV continuously over 22 hours on days 1-2. Courses with systemic
 chemotherapy repeat every 14 days for up to 1 year in the absence of disease progression or
 unacceptable toxicity.

 Quality of life is assessed at baseline, after laparotomy, after completion of systemic
 chemotherapy, and then every 6 months thereafter.

 After completion of study treatment, patients are followed every 3 months for 1 year, every
 3-4 months for 2 years, and then every 6 months until disease progression.

 PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study within 2-3 years.
DISEASE CHARACTERISTICS:

 -  Histologically or cytologically confirmed colorectal cancer

 -  Metastatic disease limited to the parenchyma of the liver

 -  No evidence of unresectable extrahepatic disease by preoperative radiology

 -  Limited extra-hepatic disease and dominant life-limiting liver disease
 allowed provided extra-hepatic sites are treatable by local ablative
 measures (e.g., surgical resection or external beam radiotherapy)

 -  At least 40% hepatic replacement by tumor by axial CT scan or MRI

 -  Unresectable liver metastases, defined by 1 of the following:

 -  More than 3 sites of disease in the liver

 -  Bilobar disease

 -  Tumor abutting major vascular or ductal structures

 -  Measurable disease

 -  Previously untreated disease

 PATIENT CHARACTERISTICS:

 Age

 -  18 and over

 Performance status

 -  ECOG 0-2

 Life expectancy

 -  Not specified

 Hematopoietic

 -  Hematocrit > 27.0%

 -  WBC > 3,000/mm^3

 -  Platelet count > 100,000/mm^3

 Hepatic

 -  Bilirubin < 2.0 mg/dL

 -  PT < 2 seconds above upper limit of normal

 -  Elevated transaminase levels allowed if due to liver metastases

 -  No cirrhosis by biopsy

 -  No significant portal hypertension as manifested by any of the following:

 -  Ascites

 -  Esophageal varices by endoscopy

 -  Significant collateral vessels around the organs drained by the portal venous
 system by radiography

 -  No chronic active hepatitis

 -  Hepatitis B and C surface antigen negative

 -  No history of veno-occlusive disease

 Renal

 -  Creatinine ≤ 1.5 mg/dL OR

 -  Creatinine clearance > 60 mL/min

 Cardiovascular

 -  No ischemic cardiac disease

 -  No history of congestive heart failure

 -  LVEF > 40% by echocardiogram or stress thallium scan (for patients with cardiac
 disease)

 Pulmonary

 -  No chronic obstructive pulmonary disease or other chronic pulmonary disease

 -  Pulmonary function tests ≥ 50% of predicted (for patients with pulmonary disease)

 Other

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  Weight > 30 kg

 -  No active infection

 -  No peripheral neuropathy ≥ grade 2

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  Not specified

 Chemotherapy

 -  Prior adjuvant chemotherapy (including leucovorin calcium, oxaliplatin, and
 fluorouracil) allowed provided it was administered > 6 months before liver metastases
 were diagnosed

 Endocrine therapy

 -  Not specified

 Radiotherapy

 -  More than 4 weeks since prior radiotherapy for this malignancy and recovered

 Surgery

 -  Not specified

 Other

 -  No concurrent chronic anticoagulation therapy

 -  No concurrent immunosuppressive drugs