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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Terminated

CT.gov ID

NCT00043004

Collaborator

Arbeitsgruppe Lebermetastasen und Tumoren (Other), Institute of Cancer Research, United Kingdom (Other)

119

Enrollment

Locations

2.8

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic Cancer	Biological: bevacizumab Drug: FOLFOX regimen Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Procedure: conventional surgery Procedure: radiofrequency ablation	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

119 participants

Allocation:

Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

May 1, 2002

Actual Primary Completion Date :

Jun 1, 2007

Outcome Measures

Primary Outcome Measures

Survival rate as measured by Kaplan Meier method at 30 months []

Secondary Outcome Measures

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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

European Organisation for Research and Treatment of Cancer - EORTC
Arbeitsgruppe Lebermetastasen und Tumoren
Institute of Cancer Research, United Kingdom

Investigators

Study Chair: Theo Ruers, MD, Universitair Medisch Centrum St. Radboud - Nijmegen
Study Chair: Wolf O. Bechstein, MD, Arbeitsgruppe Lebermetastasen und Tumoren
Study Chair: Jonathan A. Ledermann, MD, Cancer Research UK