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

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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Cancer; Liver Cancer
• Intervention / Treatment: Drug: cisplatin; Drug: doxorubicin; Drug: mitomycin; Procedure: embolization

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Fort Collins, Colorado, United States, 80524
      • Front Range Cancer Specialists
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute - Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
    • Decatur, Georgia, United States, 30033
      • Veterans Affairs Medical Center - Atlanta (Decatur)
  • Illinois
    • Aurora, Illinois, United States, 60507
      • Rush-Copley Cancer Care Center
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60625
      • Swedish Covenant Hospital
    • Chicago, Illinois, United States, 60611
      • Hematology and Oncology Associates
    • Chicago, Illinois, United States, 60611
      • Veterans Affairs Medical Center - Lakeside Chicago
    • Chicago, Illinois, United States, 60616
      • Mercy Hospital and Medical Center
    • Hinsdale, Illinois, United States, 60521
      • Hinsdale Hematology Oncology Associates
    • Joliet, Illinois, United States, 60435
      • Joliet Oncology-Hematology Associates, Limited - West
    • Joliet, Illinois, United States, 60432
      • Midwest Center for Hematology/Oncology
    • Libertyville, Illinois, United States, 60048
      • North Shore Oncology and Hematology Associates, Limited - Libertyville
    • Skokie, Illinois, United States, 60076
      • Hematology Oncology Associates - Skokie
    • Skokie, Illinois, United States, 60076
      • Hematology/Oncology of the North Shore at Gross Point Medical Center
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center at Carle Foundation Hospital
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Indiana
    • Michigan City, Indiana, United States, 46360
      • Saint Anthony Memorial Health Centers
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • CCOP - Iowa Oncology Research Association
    • Des Moines, Iowa, United States, 50309
      • John Stoddard Cancer Center at Iowa Methodist Medical Center
    • Des Moines, Iowa, United States, 50309
      • Medical Oncology and Hematology Associates at John Stoddard Cancer Center
    • Des Moines, Iowa, United States, 50314
      • Medical Oncology and Hematology Associates at Mercy Cancer Center
    • Des Moines, Iowa, United States, 50314
      • Mercy Cancer Center at Mercy Medical Center - Des Moines
    • Des Moines, Iowa, United States, 50307
      • Mercy Capitol Hospital
    • Des Moines, Iowa, United States, 50316-2301
      • John Stoddard Cancer Center at Iowa Lutheran Hospital
    • West Des Moines, Iowa, United States, 50266
      • Medical Oncology and Hematology Associates - West Des Moines
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Carol G. Simon Cancer Center at Morristown Memorial Hospital
    • Somerville, New Jersey, United States, 08876
      • Somerset Medical Center
    • Summit, New Jersey, United States, 07902
      • Overlook Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Comprehensive Cancer Center
    • Lima, Ohio, United States, 45801
      • St. Rita's Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hepatocellular carcinoma; 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; 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).; Other Names: NSC 119875; Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II),; diaminedichloroplatinum,; cis-platinum,; platinum,; Platinol,; Platinol-AQ,; DDP,; CDDP,; DACP,; Drug: doxorubicin; 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).; Other Names: ADR; Adriamycin,; Rubex,; Adriamycin RDF,; Adriamycin PFS,; hydroxydaunorubicin,; hydroxydaunomycin,; Drug: mitomycin; 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).; Other Names: Mutamycin,; Procedure: embolization; 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.; Other Names: TACE; trans-arterial chemoembolization,
Experimental: Neuroendocrine hepatic metastases; 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; 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).; Other Names: NSC 119875; Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II),; diaminedichloroplatinum,; cis-platinum,; platinum,; Platinol,; Platinol-AQ,; DDP,; CDDP,; DACP,; Drug: doxorubicin; 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).; Other Names: ADR; Adriamycin,; Rubex,; Adriamycin RDF,; Adriamycin PFS,; hydroxydaunorubicin,; hydroxydaunomycin,; Drug: mitomycin; 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).; Other Names: Mutamycin,; Procedure: embolization; 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.; Other Names: TACE; trans-arterial chemoembolization,

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Keith E. Stuart, MD, Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 1999
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: October 8, 2003
• First Posted (Estimated): October 9, 2003

Study Record Updates

• Last Update Posted (Actual): July 5, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: liver metastases; advanced adult primary liver cancer; recurrent adult primary liver cancer; localized unresectable adult primary liver cancer; adult primary hepatocellular carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Neoplastic Processes; Neoplasm Metastasis; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cisplatin; Doxorubicin; Liposomal doxorubicin; Mitomycins; Mitomycin
• Other Study ID Numbers: CDR0000067083; U10CA021115 (U.S. NIH Grant/Contract); E4298 (Other Identifier: Eastern Cooperative Oncology Group (ECOG))