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

CLOCC Trial (Chemotherapy + Local Ablation Versus Chemotherapy) Randomized Phase II Study Of Local Treatment Of Liver Metastases By Radiofrequency Combined With Chemotherapy Versus Chemotherapy Alone In Patients With Unresectable Colorectal Liver Metastases

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.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer; Metastatic Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin; Procedure: conventional surgery; Biological: bevacizumab; Drug: FOLFOX regimen; Procedure: radiofrequency ablation

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.

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Allgemeines Krankenhaus - Universitatskliniken
• Belgium
  • Antwerp, Belgium, 2020
    • Ziekenhuis Netwerk Antwerpen Middelheim
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Edegem, Belgium, B-2650
    • Universitair Ziekenhuis Antwerpen
  • Ghent, Belgium, B-9000
    • Universitair Ziekenhuis Gent
  • Mont-Godinne Yvoir, Belgium, 5530
    • Clinique Universitaire De Mont-Godinne
• Egypt
  • Cairo, Egypt
    • National Cancer Institute - Cairo
• France
  • Angers, France, 49033
    • Centre Hospitalier Regional et Universitaire d'Angers
  • Boulogne Billancourt, France, F-92104
    • Centre Hospitalier Universitaire Ambroise Pare - Boulogne
  • Strasbourg, France, 67098
    • Hopital Universitaire Hautepierre
  • Vandoeuvre-les-Nancy, France, 54511
    • Centre Alexis Vautrin
• Germany
  • Berlin, Germany, D-13122
    • Robert Roessle Comprehensive Cancer Center at University of Berlin - Charite Campus Buch
  • Essen, Germany, D-45136
    • Kliniken Essen - Mitte
  • Frankfurt, Germany, D-60590
    • Klinikum der J.W. Goethe Universitaet
  • Frankfurt, Germany, D-65929
    • Staedtische Kliniken Frankfurt am Main - Hoechst
  • Regensburg, Germany, D-93053
    • Klinikum der Universitaet Regensburg
• Hungary
  • Budapest, Hungary, 1122
    • National Institute of Oncology
• Italy
  • Rome, Italy, 00152
    • Azienda Ospedaliera S. Camillo-Forlanini
• Netherlands
  • 's-Hertogenbosch, Netherlands, 5211 NL
    • Jeroen Bosch Ziekenhuis
  • Amsterdam, Netherlands, 1066 CX
    • Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
  • Breda, Netherlands, 4800 RL
    • Amphia Ziekenhuis - locatie Langendijk
  • Enschede, Netherlands, 7500 KA
    • Medisch Spectrum Twente
  • Heerlen, Netherlands, 6401 CX
    • Atrium Medical Centre - Heerlen
  • Leeuwarden, Netherlands, 8934 AD
    • Medisch Centrum Leeuwarden - Zuid
  • Maastricht, Netherlands, 6202 AZ
    • Academisch Ziekenhuis Maastricht
  • Nijmegen, Netherlands, NL-6500 HB
    • Universitair Medisch Centrum St. Radboud - Nijmegen
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
  • Veldhoven, Netherlands, 5500 MB
    • Maxima Medisch Centrum - Veldhoven
• Sweden
  • Gothenburg (Goteborg), Sweden, S-413 45
    • Sahlgrenska University Hospital at Gothenburg University
  • Stockholm, Sweden, S - 141 86
    • Karolinska University Hospital - Huddinge
  • Uppsala, Sweden, SE 75185
    • Uppsala University Hospital
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B15 2TH
      • Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
    • Bristol, England, United Kingdom, BS2 8ED
      • Bristol Haematology and Oncology Centre
    • Leicester, England, United Kingdom, LE5 4PW
      • Leicester General Hospital
    • Liverpool, England, United Kingdom, L69 3GA
      • Royal Liverpool University Hospital
    • London, England, United Kingdom, NW1 2ND
      • Cancer Research UK and University College London Cancer Trials Centre
    • London, England, United Kingdom, WIT 3AA
      • University College of London Hospitals
    • Manchester, England, United Kingdom, M13 9WL
      • Manchester Royal Infirmary
    • Merseyside, England, United Kingdom, CH63 4JY
      • Clatterbridge Centre for Oncology NHS Trust
    • Oxford, England, United Kingdom, OX3 7LJ
      • Churchill Hospital
    • Southampton, England, United Kingdom, SO14 0YG
      • Royal South Hants Hospital
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 2TL
      • Velindre Cancer Center at Velindre Hospital
    • Rhyl, Denbighshire, Wales, United Kingdom, LL 18 5UJ
      • Glan Clywd District General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Survival rate as measured by Kaplan Meier method at 30 months

Secondary Outcome Measures

Outcome Measure
Overall survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter
Progression-free survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter
Toxicity as measured by CTC version 2.0 every 3 months for 30 months then every 6 months thereafter
Quality of life as measured by Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 at baseline, weeks 6, 12, 18, and 24, every 3 months for years 1-2 after start of treatment, then every 6 months thereafter
Response to treatment (arm II) as measured by RECIST criteria from start of treatment until disease progression

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Institute of Cancer Research, United Kingdom; Arbeitsgruppe Lebermetastasen und Tumoren
• Investigators: Study Chair: Wolf O. Bechstein, MD, Arbeitsgruppe Lebermetastasen und Tumoren; Study Chair: Theo Ruers, MD, Universitair Medisch Centrum St. Radboud - Nijmegen; Study Chair: Jonathan A. Ledermann, MD, Cancer Research UK

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2002
• Primary Completion (Actual): June 1, 2007

Study Registration Dates

• First Submitted: August 5, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): September 24, 2012
• Last Update Submitted That Met QC Criteria: September 20, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: stage IV rectal cancer; stage IV colon cancer; liver metastases
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: EORTC-40004; ALM-CAO-EORTC-40004; NCRI-EORTC-40004