Isolated Hepatic Perfusion With Melphalan Followed by Combination Chemotherapy in Treating Patients With Unresectable Liver Metastases From Colorectal Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Trial of Isolated Hepatic Perfusion (IHP) and Systemic FOLFOX4 for Subjects With Metastatic Unresectable Colorectal Cancers of the Liver With ≥ 40% Hepatic Tumor Burden

Conditions
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Colorectal Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: FOLFOX regimen
* Drug: fluorouracil
* Drug: isolated perfusion
* Drug: leucovorin calcium
* Drug: melphalan
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: FOLFOX regimen|nan|
|Drug: fluorouracil|nan|
|Drug: isolated perfusion|nan|
|Drug: leucovorin calcium|nan|
|Drug: melphalan|nan|
|Drug: oxaliplatin|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response and duration of response |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patterns of recurrence |  |  | 
| Progression-free and overall survival |  |  | 
| Correlation of health-related quality of life with length of survival |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent colon cancer, stage IV colon cancer, recurrent rectal cancer, stage IV rectal cancer, liver metastases