Chemotherapy and Bevacizumab With or Without Radiofrequency Ablation in Treating Unresectable Liver Metastases in Patients With Colorectal Cancer

NCT ID: NCT00043004

Last Updated: 2012-09-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 119 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-05-31

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread by blocking blood flow. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiofrequency ablation uses high-frequency electric current to kill tumor cells. It is not yet known if chemotherapy is more effective with or without radiofrequency ablation in treating liver metastases.

PURPOSE: This randomized phase II trial is studying combination chemotherapy, bevacizumab, and radiofrequency ablation to see how well they work compared to combination chemotherapy and bevacizumab alone in treating unresectable liver metastases in patients with colorectal cancer.

Detailed Description

OBJECTIVES:

Primary

• Compare the 30-month overall survival rate of patients with unresectable liver metastases secondary to colorectal adenocarcinoma treated with chemotherapy and bevacizumab with or without radiofrequency interstitial ablation.

Secondary

• Compare overall survival of patients treated with these regimens.
• Compare quality of life of patients treated with these regimens.
• Determine the health economics associated with this study.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to treatment center, prior adjuvant chemotherapy for primary cancer (yes vs no), prior chemotherapy for liver metastases (yes vs no), and route of randomization (before surgery vs during surgery). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Within 4 weeks of randomization, patients undergo radiofrequency interstitial ablation (RFA) with or without additional resection of resectable lesions. Within 8 weeks after RFA, patients receive chemotherapy and bevacizumab.
• Arm II: Within 4 weeks of randomization, patients receive chemotherapy and bevacizumab.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Patients in both arms receive one of the following chemotherapy and bevacizumab regimens to be determined by participating center:

• Regimen A: Patients receive oxaliplatin IV over 2 hours on day 1 of weeks 1, 3, and 5 and leucovorin calcium IV over 2 hours followed by fluorouracil IV continuously over 24 hours on day 1 of weeks 1-6 and bevacizumab IV over 30-90 minutes on days 1 or 2, 15 or 16, and 29 or 30. Treatment repeats every 7 weeks for 4 courses.
• Regimen B: Patients receive oxaliplatin IV and leucovorin calcium IV over 2 hours on day 1 followed by fluorouracil IV continuously over 46 hours and bevacizumab IV over 30-90 minutes on day 1 or 3. Treatment repeats every 15 days for 12 courses.
• Regimen C: Patients receive oxaliplatin IV over 2 hours on day 1 and leucovorin calcium IV over 2 hours followed by fluorouracil IV continuously over 22 hours on days 1 and 2 and bevacizumab IV over 30-90 minutes on day 1 or 3. Treatment repeats every 15 days for 12 courses.

Quality of life is assessed at baseline, within 1 week after completion of RFA (arm I only), within 1 week before start of chemotherapy (arm I only), at weeks 6, 12, 18, and 24 during chemotherapy, every 3 months for 2 years after treatment, and then every 6 months thereafter.

After completion of study treatment, patients are followed every 3 months for 2½ years and then every 6 months thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 152 patients (71 per treatment arm) will be accrued for this study within 3 years.

Conditions

Colorectal Cancer; Metastatic Cancer

Keywords

liver metastases; stage IV colon cancer; stage IV rectal cancer

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

bevacizumab

Intervention Type: BIOLOGICAL

FOLFOX regimen

Intervention Type: DRUG

fluorouracil

Intervention Type: DRUG

leucovorin calcium

Intervention Type: DRUG

oxaliplatin

Intervention Type: DRUG

conventional surgery

Intervention Type: PROCEDURE

radiofrequency ablation

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Unresectable liver metastases secondary to colorectal adenocarcinoma, including:

• Metastases that cannot be radically resected due to size, location, or number of deposits
• Metastases invading right and left branches of hepatic artery or portal vein
• Metastases extended to the 3 main hepatic veins
• No detectable extra-hepatic disease
• Fewer than 10 metastatic deposits on liver
• Total metastatic involvement of liver no more than 50%
• Adequate treatment of all metastatic lesions deemed possible either by radiofrequency interstitial ablation (RFA) alone or by a combination of resection of resectable lesions and RFA of the remaining unresectable lesions

• Maximum diameter of 4 cm for lesions to be treated with RFA
• No maximum diameter of lesions to be resected as long as negative resection margins are obtainable
• If synchronous liver metastases, must have undergone prior resection of primary tumor

PATIENT CHARACTERISTICS:

Age

• 18 to 80

Performance status

• WHO 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count greater than 1,500/mm^3
• Platelet count greater than 100,000/mm^3
• No bleeding disorder or coagulopathy or need for full-dose anticoagulation

Hepatic

• Bilirubin less than 3 times upper limit of normal (ULN)
• Alkaline phosphatase less than 3 times ULN

Renal

• Creatinine less than 2 times ULN
• Protein < 0.5 g/24 hr urine collection if proteinuria positive by dipstick

Cardiovascular

• No uncontrolled congestive heart failure
• No uncontrolled angina pectoris
• No uncontrolled hypertension
• No uncontrolled arrhythmia
• No myocardial infarction within the past 12 months
• No cerebrovascular accident or transient ischemic attack within the past 6 months

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No greater than grade 1 peripheral neuropathy
• No significant neurologic or psychiatric disorder
• No active infection
• No contraindication to the use of fluorouracil, leucovorin calcium, oxaliplatin, or bevacizumab
• No other malignancy within the past 10 years except nonmelanoma skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy except for metastatic disease confined to the liver

• Prior fluorouracil, leucovorin calcium, and oxaliplatin allowed if administered for at least 3 courses (2 weeks each) but no longer than 3 months with at least stabilization of disease achieved
• Prior adjuvant chemotherapy for primary cancer allowed except for patients who received oxaliplatin and have been diagnosed with metastatic disease within 12 months after completion of adjuvant treatment

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• More than 28 days since major surgery or open biopsy past 28 days
• More than 28 days since significant traumatic injury

Other

• No other concurrent investigational treatment
• No other concurrent anticancer therapy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Arbeitsgruppe Lebermetastasen und Tumoren

OTHER

Sponsor Role: collaborator

Institute of Cancer Research, United Kingdom

OTHER

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Theo Ruers, MD

Role: STUDY_CHAIR

Universitair Medisch Centrum St. Radboud - Nijmegen

Wolf O. Bechstein, MD

Role: STUDY_CHAIR

Arbeitsgruppe Lebermetastasen und Tumoren

Jonathan A. Ledermann, MD

Role: STUDY_CHAIR

Cancer Research UK

Locations

Allgemeines Krankenhaus - Universitatskliniken

Vienna, , Austria

Ziekenhuis Netwerk Antwerpen Middelheim

Antwerp, , Belgium

Institut Jules Bordet

Brussels, , Belgium

Universitair Ziekenhuis Antwerpen

Edegem, , Belgium

Universitair Ziekenhuis Gent

Ghent, , Belgium

Clinique Universitaire De Mont-Godinne

Mont-Godinne Yvoir, , Belgium

National Cancer Institute - Cairo

Cairo, , Egypt

Centre Hospitalier Regional et Universitaire d'Angers

Angers, , France

Centre Hospitalier Universitaire Ambroise Pare - Boulogne

Boulogne-Billancourt, , France

Hopital Universitaire Hautepierre

Strasbourg, , France

Centre Alexis Vautrin

Vandœuvre-lès-Nancy, , France

Robert Roessle Comprehensive Cancer Center at University of Berlin - Charite Campus Buch

Berlin, , Germany

Kliniken Essen - Mitte

Essen, , Germany

Klinikum der J.W. Goethe Universitaet

Frankfurt, , Germany

Staedtische Kliniken Frankfurt am Main - Hoechst

Frankfurt, , Germany

Klinikum der Universitaet Regensburg

Regensburg, , Germany

National Institute of Oncology

Budapest, , Hungary

Azienda Ospedaliera S. Camillo-Forlanini

Rome, , Italy

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, , Netherlands

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Amsterdam, , Netherlands

Amphia Ziekenhuis - locatie Langendijk

Breda, , Netherlands

Medisch Spectrum Twente

Enschede, , Netherlands

Atrium Medical Centre - Heerlen

Heerlen, , Netherlands

Medisch Centrum Leeuwarden - Zuid

Leeuwarden, , Netherlands

Academisch Ziekenhuis Maastricht

Maastricht, , Netherlands

Universitair Medisch Centrum St. Radboud - Nijmegen

Nijmegen, , Netherlands

University Medical Center Utrecht

Utrecht, , Netherlands

Maxima Medisch Centrum - Veldhoven

Veldhoven, , Netherlands

Sahlgrenska University Hospital at Gothenburg University

Gothenburg (Goteborg), , Sweden

Karolinska University Hospital - Huddinge

Stockholm, , Sweden

Uppsala University Hospital

Uppsala, , Sweden

Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust

Birmingham, England, United Kingdom

Bristol Haematology and Oncology Centre

Bristol, England, United Kingdom

Leicester General Hospital

Leicester, England, United Kingdom

Royal Liverpool University Hospital

Liverpool, England, United Kingdom

Cancer Research UK and University College London Cancer Trials Centre

London, England, United Kingdom

University College of London Hospitals

London, England, United Kingdom

Manchester Royal Infirmary

Manchester, England, United Kingdom

Clatterbridge Centre for Oncology NHS Trust

Merseyside, England, United Kingdom

Churchill Hospital

Oxford, England, United Kingdom

Royal South Hants Hospital

Southampton, England, United Kingdom

Velindre Cancer Center at Velindre Hospital

Cardiff, Wales, United Kingdom

Glan Clywd District General Hospital

Rhyl, Denbighshire, Wales, United Kingdom

Countries

Austria; Belgium; Egypt; France; Germany; Hungary; Italy; Netherlands; Sweden; United Kingdom

References

Ruers T, van Coevorden F, Pierie J, et al.: Radiofrequency ablation (RFA) combined with chemotherapy for unresectable colorectal liver metastases (CRC LM): interim results of a randomised phase II study of the EORTC-NCRI CCSG-ALM Intergroup 40004 (CLOCC). [Abstract] J Clin Oncol 26 (Suppl 15): A-9535, 2008.

Reference Type: RESULT

Ruers T, Punt C, Van Coevorden F, Pierie JPEN, Borel-Rinkes I, Ledermann JA, Poston G, Bechstein W, Lentz MA, Mauer M, Van Cutsem E, Lutz MP, Nordlinger B; EORTC Gastro-Intestinal Tract Cancer Group; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO) and the National Cancer Research Institute Colorectal Clinical Study Group (NCRI CCSG). Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann Oncol. 2012 Oct;23(10):2619-2626. doi: 10.1093/annonc/mds053. Epub 2012 Mar 19.

Reference Type: DERIVED

PMID: 22431703 (View on PubMed)

Other Identifiers

EORTC-40004

Identifier Type: -

Identifier Source: secondary_id

ALM-CAO-EORTC-40004

Identifier Type: -

Identifier Source: secondary_id

NCRI-EORTC-40004

Identifier Type: -

Identifier Source: secondary_id

EORTC-40004

Identifier Type: -

Identifier Source: org_study_id