Combination Chemotherapy With or Without Cetuximab Before and After Surgery in Treating Patients With Resectable Liver Metastases Caused By Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, fluorouracil, leucovorin, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving combination chemotherapy together with monoclonal antibodies before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. It is not yet known whether combination chemotherapy is more effective with or without cetuximab in treating liver metastases caused by colorectal cancer. PURPOSE: This randomized phase III trial is studying combination chemotherapy to compare how well it works when given with or without cetuximab before and after surgery in treating patients with resectable liver metastases caused by colorectal cancer.

Detailed Description
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OBJECTIVES: Primary Compare progression-free survival of patients with resectable colorectal liver metastases treated with neoadjuvant and adjuvant combination chemotherapy with vs without cetuximab. Secondary Compare the overall survival of patients treated with these regimens. Compare the quality of life of patients treated with these regimens. Compare the cost effectiveness of these regimens in these patients. OUTLINE: This is a prospective, randomized, multicenter, open-label study. Patients are stratified according to participating center and assigned chemotherapy regimen. Patients are randomized to 1 of 2 treatment arms. Neoadjuvant therapy: Arm I: Patients receive 1 of the following chemotherapy regimens: OxMdG: Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. CAPOX: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-14. Treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive 1 of the following regimens: OxMdG + cetuximab: Patients receive cetuximab IV over 1-2 hours on day 1 and OxMdG chemotherapy as in arm I. Treatment repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. CAPOX + cetuximab: Patients receive cetuximab IV over 1-2 hours on days 1, 8, and 15 and CAPOX chemotherapy as in arm I. Treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Surgery: Beginning 2-6 weeks after completion of chemotherapy, patients in both arms undergo liver resection. Adjuvant therapy: Beginning 4-8 weeks after completion of surgery, patients receive treatment (OxMdG or CAPOX with or without cetuximab) as in arm I or II of neoadjuvant therapy. Arm I: Treatment with OxMdG repeats every 2 weeks for up to 6 courses and treatment with CAPOX repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Arm II: Treatment with OxMdG + cetuximab repeats every 2 weeks for up to 6 courses and treatment with CAPOX + cetuximab repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, every 12 weeks during chemotherapy, at completion of study treatment, every 3 months for 1 year, and then every 6 months thereafter. Cost per life year and per quality-adjusted life year is assessed at baseline, every 12 weeks during treatment, and then at 3, 5, and 10 years. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years. Peer Reviewed and Funded or Endorsed by Cancer Research UK

Official Title
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A Prospective Randomised Open Label Trial of Oxaliplatin/Fluoropyrimidine Versus Oxaliplatin/Fluoropyrimidine Plus Cetuximab Pre and Post Operatively in Patients With Resectable Colorectal Liver Metastasis Requiring Chemotherapy

Conditions
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Colorectal Cancer, Metastatic Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: capecitabine
* Drug: fluorouracil
* Drug: leucovorin calcium
* Drug: oxaliplatin
* Other: study of socioeconomic and demographic variables
* Procedure: adjuvant therapy
* Procedure: neoadjuvant therapy
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically* or radiologically confirmed primary adenocarcinoma of the colon or rectum Advanced and/or metastatic disease NOTE: *Liver metastases should not be biopsied Must have potentially resectable liver metastases present, as defined by any of the following: Metachronous metastases AND complete resection of the primary tumor without gross or microscopic evidence of residual disease (R0) Synchronous metastases AND R0 resection of the primary tumor > 1 month before study entry Synchronous metastases with sufficient evidence (e.g., by CT scan or diagnostic laparoscopy) that both the primary tumor and the liver metastases can be completely resected during the same procedure and resection of primary tumor can be delayed for 3-4 months Suboptimally resectable disease (i.e., potentially resectable disease with compromise of the resection margins) No detectable extrahepatic tumor that cannot be completely resected Unidimensionally measurable disease No brain metastases PATIENT CHARACTERISTICS: WHO performance status 0-2 WBC ≥ 4,000/mm³ ANC ≥ 1,500/mm³ Platelet count > 150,000/mm³ Bilirubin ≤ 1.25 times upper limit of normal (ULN) Alkaline phosphatase ≤ 5 times ULN AST or ALT ≤ 3 times ULN Creatinine clearance > 50 mL/min OR glomerular filtration rate > 50 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment No psychiatric or neurological condition that would preclude study compliance No partial or complete bowel obstruction No preexisting neuropathy > grade 1 No other prior or concurrent malignant disease that, in the opinion of the investigator, would preclude study treatment No concurrent severe uncontrolled medical illness (including poorly-controlled angina or myocardial infarction within the past 3 months) that would preclude study treatment No known hypersensitivity reaction to any of the components of the study drugs PRIOR CONCURRENT THERAPY: No prior systemic chemotherapy for metastatic disease More than 6 months since prior adjuvant chemotherapy comprising fluorouracil, leucovorin calcium, capecitabine, or irinotecan hydrochloride More than 1 month since prior rectal chemoradiotherapy comprising fluorouracil and leucovorin calcium No concurrent contraindicated medication

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: OxMdG / IrMdG chemotherapy<br>OxMdG / IrMdG chemotherapy for 12 weeks Followed by surgery OxMdG / IrMdG chemotherapy for 12 weeks | Drug: capecitabine<br> <br> Drug: fluorouracil<br> <br> Drug: leucovorin calcium<br> <br> Drug: oxaliplatin<br> <br> Other: study of socioeconomic and demographic variables<br> <br> Procedure: adjuvant therapy<br> <br> Procedure: neoadjuvant therapy<br> <br> Procedure: quality-of-life assessment<br> <br> |
| Experimental: OxMdG / IrMdG chemotherapy with cetuximab<br>OxMdG / IrMdG chemotherapy with cetuximab for 12 weeks Followed by Surgery OxMdG / IrMdG chemotherapy with cetuximab for 12 weeks | Biological: cetuximab<br> <br> Drug: capecitabine<br> <br> Drug: fluorouracil<br> <br> Drug: leucovorin calcium<br> <br> Drug: oxaliplatin<br> <br> Other: study of socioeconomic and demographic variables<br> <br> Procedure: adjuvant therapy<br> <br> Procedure: neoadjuvant therapy<br> <br> Procedure: quality-of-life assessment<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | end of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate before surgery as assessed by RECIST criteria |  | end of study | 
| Pathological resection status |  | end of study | 
| Overall survival |  | end of study | 
| Toxicity |  | end of study | 
| Quality of life as assessed by the EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LMC21 |  | end of study | 
| Cost effectiveness |  | end of study | 
| Safety |  | end of study | 

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