Combination Chemotherapy and Interferon Alfa-2b in Treating Patients With Nonmetastatic Liver Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, doxorubicin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Interferon alfa may interfere with the growth of tumor cells. Giving combination chemotherapy together with interferon alfa may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with interferon alfa-2b works in treating patients with nonmetastatic liver cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary Determine the response rate in patients with unresectable, nonmetastatic hepatocellular carcinoma treated with neoadjuvant oxaliplatin, doxorubicin hydrochloride, fluorouracil, and recombinant interferon alfa-2b. Secondary Determine the overall survival of patients treated with this regimen. Determine the progression-free survival of patients treated with this regimen. Determine the rate of conversion to resectability of tumor in patients treated with this regimen. Determine the toxicity profile of this regimen in these patients. Assess the quality of life of patients treated with this regimen. Correlate changes in serological markers of angiogenesis before and after treatment with clinical outcome in these patients. Correlate and validate the use of functional imaging before and after treatment with clinical outcome in these patients. OUTLINE: Patients receive neoadjuvant OXAFI therapy comprising oxaliplatin IV and doxorubicin hydrochloride IV on days 1, 8 and 15; fluorouracil IV continuously on days 1-28; and recombinant interferon alfa-2b subcutaneously three times weekly in weeks 1-4. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients receive at least 2 courses of neoadjuvant therapy before undergoing evaluation for response. Patients whose disease becomes resectable after achieving a complete or partial response proceed to surgery. Patients whose disease remains unresectable are reevaluated until their disease either becomes resectable, they complete neoadjuvant therapy, or they meet discontinuation criteria. At least 2 weeks after receiving neoadjuvant therapy, patients whose disease is resectable undergo surgery for potentially complete resection of their tumors with curative intent. Patients who achieve complete resection proceed to adjuvant therapy. At least 4 weeks after surgery, patients may restart OXAFI as adjuvant therapy, provided they have fully recovered from surgery and have received fewer than 6 courses of neoadjuvant therapy. Adjuvant therapy repeats every 28 days for a total of 6 courses (including neoadjuvant OXAFI) in the absence of disease progression or unacceptable toxicity. Patients undergo blood and tissue collection at baseline and periodically during study for evaluation of circulating and tissue biomarkers of angiogenesis. Serum from venous blood samples is analyzed for concentration of VEGF by ELISA. Tumor tissue obtained before and after treatment is examined for tumor VEGF expression, microvessel density, and cellular proliferation by IHC. Patients complete quality of life questionnaires at baseline, monthly during study treatment, after course 6 of neoadjuvant chemotherapy, or upon discontinuation of study treatment. Patients are followed periodically for up to 5 years after curative resection of their tumors. PROJECTED ACCRUAL: A total of 54 patients will be accrued for this study.

Official Title
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A Phase II Trial of Oxaliplatin/Adriamycin/5 Fluorouracil in Continuous Infusion / Interferon α-2b (OXAFI) Combination as Neoadjuvant Therapy in Unresectable Non-Metastatic Hepatocellular Carcinoma

Conditions
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Liver Cancer

Intervention / Treatment
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* Biological: recombinant interferon alfa-2b
* Drug: doxorubicin hydrochloride
* Drug: fluorouracil
* Drug: oxaliplatin
* Other: diagnostic laboratory biomarker analysis
* Other: immunoenzyme technique
* Other: immunohistochemistry staining method
* Procedure: adjuvant therapy
* Procedure: biopsy
* Procedure: neoadjuvant therapy
* Procedure: therapeutic conventional surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed hepatocellular carcinoma Advanced, unresectable, nonmetastatic disease Multifocal disease within the same lobe of the liver allowed Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan No intractable ascites that cannot be controlled by medical therapy No extrahepatic metastases PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy > 3 months WBC ≥ 3,000/mm³ ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 g/dL Bilirubin ≤ 2.9 mg/dL AST and ALT ≤ 5 times upper reference range (URR) Albumin > 30 g/L Creatinine ≤ 1.5 times URR Creatinine clearance > 50 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after completion of study therapy No other prior malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix No concurrent substantial medical illness, such as cardiac or renal disease MUGA heart study normal No history of allergic reactions attributed to compounds of similar chemical or biological composition used in the study No history of autoimmune disease No thyroid dysfunction No active hepatitis B or C flare or chronic active hepatitis Hepatitis B surface antigen (HBsAg) status known If HBsAg is negative, anti-HBc antibodies should be tested; if anti-HBc is positive, then hepatitis B virus (HBV) DNA detection should be performed to discern presence of mutant HBV carriage No alcohol or drug abuse No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia No psychiatric illness or social situation that would preclude study compliance Patients with a history of depression or psychiatric disorders are ineligible PRIOR CONCURRENT THERAPY: No prior chemotherapy and/or radiotherapy No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 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 |
| --- |
|Biological: recombinant interferon alfa-2b|nan|
|Drug: doxorubicin hydrochloride|nan|
|Drug: fluorouracil|nan|
|Drug: oxaliplatin|nan|
|Other: diagnostic laboratory biomarker analysis|nan|
|Other: immunoenzyme technique|nan|
|Other: immunohistochemistry staining method|nan|
|Procedure: adjuvant therapy|nan|
|Procedure: biopsy|nan|
|Procedure: neoadjuvant therapy|nan|
|Procedure: therapeutic conventional surgery|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective tumor response rate as measured by RECIST criteria |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum VEGF levels |  |  | 
| Tissue VEGF expression |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult primary hepatocellular carcinoma, localized unresectable adult primary liver cancer, advanced adult primary liver cancer, childhood hepatocellular carcinoma, stage III childhood liver cancer, stage IV childhood liver cancer