Chemoembolization in Treating Patients With Primary Liver Cancer or Metastases to the Liver

Study Overview
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Brief Summary
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RATIONALE: Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping chemotherapy drugs near the tumor. PURPOSE: Phase II trial to study the effectiveness of chemoembolization in treating patients who have primary liver cancer or metastases to the liver that cannot be surgically removed.

Detailed Description
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OBJECTIVES: Evaluate time to progression of disease in patients with unresectable hepatocellular carcinoma or neuroendocrine hepatic metastases undergoing chemoembolization. Evaluate tumor response achievable with chemoembolization in this patient population. Evaluate the toxicities of this treatment in these patients. Evaluate survival of these patients following this treatment. Evaluate extrahepatic patterns of failure following chemoembolization, to determine whether intrahepatic progression may be forestalled and survival affected in these patients. Validate a consistent method of performing chemoembolization in a multicenter setting. OUTLINE: Patients are stratified according to disease (hepatocellular carcinoma vs neuroendocrine hepatic metastases). Patients undergo placement of a visceral arterial catheter. Patients receive doxorubicin, mitomycin, and cisplatin as a chemoemulsion via the arterial catheter into 1 hepatic lobe only. Immediately following delivery of the chemoemulsion, particulate embolization is performed. The opposite lobe, if involved, is treated within 3-5 weeks of treatment of the initial lobe. In the absence of unacceptable toxicity, each involved lobe is treated separately a second time, in the same sequence, beginning 8 weeks after the last lobular chemoembolization. After completion of all protocol therapy, retreatment on study of either lobe is allowed for regrowth, recurrence, or new disease, provided at least 3 months have elapsed since the initial treatment of that lobe. Patients are followed for 5 years. PROJECTED ACCRUAL: A total of 19-42 patients will be accrued for this study within 1 year.

Official Title
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Chemoembolization in Hepatocellular Carcinoma or Neuroendocrine Hepatic Metastases: A Phase II Multi-Center Trial

Conditions
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Liver Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: doxorubicin
* Drug: mitomycin
* Procedure: embolization


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-proven intrahepatic hepatocellular carcinoma or neuroendocrine tumor. Unresectable. Bidimensionally measurable disease by Computed Tomography (CT), Magnetic resonance imaging (MRI), or UltraSound Scanning (US) within 6 weeks of registration. Evidence of patent portal vasculature by Doppler US, MRI, or angiography. Serum total bilirubin < 2.0 mg/dl and serum creatinine < 2.0 mg/dl within 4 weeks of registration. Absolute neutrophil count (ANC) > 2000/µl and platelets > 50,000/µl within 4 weeks of registration. Expected survival of at least 3 months. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Age >= 18 years. Exclusion Criteria: Evidence of extrahepatic disease that is likely to be life-threatening within 3 months, such as brain or symptomatic lung metastases. Previous intra-arterial or intra-hepatic chemotherapy or prior systemic chemotherapy within 4 weeks. Concurrent malignancy. Pregnant or breast-feeding women. History of life-threatening contrast allergy.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hepatocellular carcinoma<br>Chemoemulsion (doxorubicin, mitomycin and cisplatin) followed by embolization. The entire procedure will be repeated separately to each involved lobe beginning within 8 weeks of the last lobar chemoembolization. | Drug: cisplatin<br>* Doxorubicin 30 mg, mitomycin 30 mg, and cisplatin 100 mg (all in powdered form) should be dissolved in 10-15 cc of contrast agent (such as isovue or optiray).<br>* Other names: NSC 119875;Drug: doxorubicin<br>* Doxorubicin 30 mg, mitomycin 30 mg, and cisplatin 100 mg (all in powdered form) should be dissolved in 10-15 cc of contrast agent (such as isovue or optiray).<br>* Other names: ADR;Drug: mitomycin<br>* Doxorubicin 30 mg, mitomycin 30 mg, and cisplatin 100 mg (all in powdered form) should be dissolved in 10-15 cc of contrast agent (such as isovue or optiray).<br>* Other names: Mutamycin,;Procedure: embolization<br>* Immediately following delivery of the chemoemulsion, particulate embolization is performed. The particulate embolic material is prepared on a separate table or tray, using absorbable gelatin sponge (Gelfoam, Upjohn, Kalamazoo, MI), in either powder or pledget form. Approximately 1 g of this temporary occlusive agent is dissolved in 20-30 cc of full-strength contrast with 2.4 cc of absolute alcohol.<br>* Other names: TACE;|
| Experimental: Neuroendocrine hepatic metastases<br>Chemoemulsion (doxorubicin, mitomycin and cisplatin) followed by embolization. The entire procedure will be repeated separately to each involved lobe beginning within 8 weeks of the last lobar chemoembolization. | Drug: cisplatin<br>* Doxorubicin 30 mg, mitomycin 30 mg, and cisplatin 100 mg (all in powdered form) should be dissolved in 10-15 cc of contrast agent (such as isovue or optiray).<br>* Other names: NSC 119875;Drug: doxorubicin<br>* Doxorubicin 30 mg, mitomycin 30 mg, and cisplatin 100 mg (all in powdered form) should be dissolved in 10-15 cc of contrast agent (such as isovue or optiray).<br>* Other names: ADR;Drug: mitomycin<br>* Doxorubicin 30 mg, mitomycin 30 mg, and cisplatin 100 mg (all in powdered form) should be dissolved in 10-15 cc of contrast agent (such as isovue or optiray).<br>* Other names: Mutamycin,;Procedure: embolization<br>* Immediately following delivery of the chemoemulsion, particulate embolization is performed. The particulate embolic material is prepared on a separate table or tray, using absorbable gelatin sponge (Gelfoam, Upjohn, Kalamazoo, MI), in either powder or pledget form. Approximately 1 g of this temporary occlusive agent is dissolved in 20-30 cc of full-strength contrast with 2.4 cc of absolute alcohol.<br>* Other names: TACE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to progression was defined as time from embolization to documented disease progression. Patients without documented progression were censored at the time of the last documented disease evaluation or of the last treatment ended, whichever was more recent.Disease progression was defined as significant increase in size of lesions or appearance of new metastatic lesions. Specifically, 1) >=25% increase in the area of any malignant lesions greater than 2 cm² or in the sum of the products of the individual lesions in a given organ site; 2)>=50% increase in the size of the product of diameters if only one lesion is available for measurement and was less than or equal to 2 cm² in size at the initiation of therapy; 3)>=25% increase in the sum of the liver measurements below the costal margins and xyphoid; 4)Appearance of new malignant lesions | Assessed every 3 months for 2 years, then every 6 months for 3 year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response | Clinical complete response was defined as complete disappearance of all clinically detectable malignant disease for at least 4 weeks. Partial response was defined as >= 50% decrease in tumor size for at least 4 weeks without increase in size of any area of known malignant disease of greater than 25%, or appearance of new areas of malignant disease. Tumor response was defined as complete response + partial response. | Assessed every 6 weeks | 
| Overall Survival | Overall survival was defined as time from registration to death from any causes. | Assessed every 3 months for 2 years, then every 6 months for 3 year. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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localized unresectable adult primary liver cancer, advanced adult primary liver cancer, recurrent adult primary liver cancer, adult primary hepatocellular carcinoma, liver metastases