Clinical trial NCT00043004: Chemotherapy and Bevacizumab With or Without Radiofrequency Ablation in Treating Unresectable Liver Metastases in Patients With Colorectal Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Colorectal Cancer
Metastatic Cancer
Keywords: liver metastases
stage IV colon cancer
stage IV rectal cancer
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Arbeitsgruppe Lebermetastasen und Tumoren
name: Institute of Cancer Research, United Kingdom
First posted: 2003-01-27
Enrollment: 119
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Survival rate as measured by Kaplan Meier method at 30 months
Secondary outcomes:
measure: Overall survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter
measure: Progression-free survival as measured by Logrank every 3 months for 30 months then every 6 months thereafter
measure: Toxicity as measured by CTC version 2.0 every 3 months for 30 months then every 6 months thereafter
measure: 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
measure: Response to treatment (arm II) as measured by RECIST criteria from start of treatment until disease progression
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Allgemeines Krankenhaus - Universitatskliniken
city: Antwerp
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen Middelheim
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Ghent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Mont-Godinne Yvoir
country: Belgium
facility: Clinique Universitaire De Mont-Godinne
city: Cairo
country: Egypt
facility: National Cancer Institute - Cairo
city: Angers
country: France
facility: Centre Hospitalier Regional et Universitaire d'Angers
city: Boulogne Billancourt
country: France
facility: Centre Hospitalier Universitaire Ambroise Pare - Boulogne
city: Strasbourg
country: France
facility: Hopital Universitaire Hautepierre
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Berlin
country: Germany
facility: Robert Roessle Comprehensive Cancer Center at University of Berlin - Charite Campus Buch
city: Essen
country: Germany
facility: Kliniken Essen - Mitte
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Frankfurt
country: Germany
facility: Staedtische Kliniken Frankfurt am Main - Hoechst
city: Regensburg
country: Germany
facility: Klinikum der Universitaet Regensburg
city: Budapest
country: Hungary
facility: National Institute of Oncology
city: Rome
country: Italy
facility: Azienda Ospedaliera S. Camillo-Forlanini
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis - locatie Langendijk
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Heerlen
country: Netherlands
facility: Atrium Medical Centre - Heerlen
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden - Zuid
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Nijmegen
country: Netherlands
facility: Universitair Medisch Centrum St. Radboud - Nijmegen
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Veldhoven
country: Netherlands
facility: Maxima Medisch Centrum - Veldhoven
city: Gothenburg (Goteborg)
country: Sweden
facility: Sahlgrenska University Hospital at Gothenburg University
city: Stockholm
country: Sweden
facility: Karolinska University Hospital - Huddinge
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
state: England
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Leicester
country: United Kingdom
facility: Leicester General Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: England
city: London
country: United Kingdom
facility: Cancer Research UK and University College London Cancer Trials Centre
state: England
city: London
country: United Kingdom
facility: University College of London Hospitals
state: England
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: England
city: Merseyside
country: United Kingdom
facility: Clatterbridge Centre for Oncology NHS Trust
state: England
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: England
city: Southampton
country: United Kingdom
facility: Royal South Hants Hospital
state: England
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Center at Velindre Hospital
state: Wales
city: Rhyl, Denbighshire
country: United Kingdom
facility: Glan Clywd District General Hospital
state: Wales
Study officials:
affiliation: Universitair Medisch Centrum St. Radboud - Nijmegen
name: Theo Ruers, MD
role: STUDY_CHAIR
affiliation: Arbeitsgruppe Lebermetastasen und Tumoren
name: Wolf O. Bechstein, MD
role: STUDY_CHAIR
affiliation: Cancer Research UK
name: Jonathan A. Ledermann, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.