Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

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.

Further Study Information

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

Trial Contact Information

Trial Lead Organizations/Sponsors

European Organization for Research and Treatment of Cancer

Theo Ruers

Wolf O. Bechstein

Study Chair

Jonathan A. Ledermann

Study Chair

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00043004
Information obtained from ClinicalTrials.gov on January 10, 2012

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