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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Colorectal Cancer, Metastatic Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: FOLFOX regimen
* Drug: fluorouracil
* Drug: leucovorin calcium
* Drug: oxaliplatin
* Procedure: conventional surgery
* Procedure: radiofrequency ablation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: bevacizumab|nan|
|Drug: FOLFOX regimen|nan|
|Drug: fluorouracil|nan|
|Drug: leucovorin calcium|nan|
|Drug: oxaliplatin|nan|
|Procedure: conventional surgery|nan|
|Procedure: radiofrequency ablation|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival rate as measured by Kaplan Meier method at 30 months |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver metastases, stage IV colon cancer, stage IV rectal cancer