Leucovorin and Fluorouracil With or Without Oxaliplatin Compared to Capecitabine With or Without Oxaliplatin in Treating Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as leucovorin, fluorouracil, capecitabine, and oxaliplatin, use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known whether leucovorin and fluorouracil with or without oxaliplatin is more effective than capecitabine with or without oxaliplatin in treating patients who have metastatic colorectal cancer. PURPOSE: This randomized phase III trial is studying four different chemotherapy regimens to compare how well they work in treating patients with metastatic colorectal cancer.

Detailed Description
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OBJECTIVES: Primary Compare the progression-free survival of patients with metastatic colorectal adenocarcinoma treated with leucovorin calcium and fluorouracil with vs without oxaliplatin or capecitabine with vs without oxaliplatin. Compare the quality of life of patients treated with these fluorouracil-based vs capecitabine-based regimens. Secondary Compare the failure-free and overall survival of patients treated with these regimens. Compare the toxic effects and adverse events associated with these regimens in these patients. Compare the limited health assessments of patients treated with these regimens. Compare the health economics associated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 4 treatment arms and receive 12 weeks of therapy. Arm I (MdG regimen): Patients receive leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression during or within 8 weeks of the completion of this regimen may cross over and receive second-line therapy on arm II. Arm II (OxMdG regimen): Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression during or within 8 weeks of the completion of this regimen may receive second-line therapy or supportive care off-study. Arm III (Cap regimen): Patients receive oral capecitabine twice daily on days 1-15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression during or within 8 weeks of the completion of this regimen may cross over and receive second-line therapy on arm IV. Arm IV (OxCap regimen): Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients with disease progression during or within 8 weeks of the completion of this regimen may receive second-line therapy or supportive care off-study. All patients are then re-evaluated at least every 6 weeks and begin another 12 weeks of therapy at any evidence (e.g., clinical, radiological, or tumor marker) of disease progression. Patients with chemo-sensitive disease may repeat alternating 12-week therapy sessions and evaluation periods indefinitely. Quality of life is assessed at baseline, at 12-14 weeks, at 24 weeks, and then every 3 months thereafter. Patients are followed every 3 months. Peer Reviewed and Funded or Endorsed by Cancer Research UK PROJECTED ACCRUAL: A total of 460 patients (115 per treatment arm) will be accrued for this study within 2 years.

Official Title
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Drug Treatment for Bowel Cancer: Making the Best Choices When a Milder Treatment is Needed

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: FOLFOX regimen
* Drug: capecitabine
* Drug: fluorouracil
* Drug: leucovorin calcium
* Drug: oxaliplatin
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of colorectal adenocarcinoma, defined by 1 of the following: Prior or current histologically confirmed primary adenocarcinoma of the colon or rectum with clinical/radiological evidence of advanced/metastatic disease Histologically or cytologically confirmed metastatic adenocarcinoma with clinical/radiological evidence of colorectal primary tumor Unidimensionally measurable disease Unfit and unsuitable for full-dose combination chemotherapy, which would include 1 of the following circumstances: Unsuitable or unwilling to be entered into any full-dose chemotherapy protocol Ineligible or unsuitable for first-line standard combination as per National Institute of Clinical Excellence guidance PATIENT CHARACTERISTICS: Age Not specified Performance status WHO 0-2 Life expectancy Not specified Hematopoietic WBC greater than 3,000/mm^3 Platelet count greater than 100,000/mm^3 Hepatic Bilirubin no greater than 3 times upper limit of normal (ULN) AST or ALT no greater than 2.5 times ULN Renal Creatinine clearance greater than 50 mL/min OR Glomerular filtration rate greater than 30 mL/min Cardiovascular No uncontrolled angina No recent myocardial infarction Other Not pregnant Negative pregnancy test Fertile patients must use effective contraception No partial or complete bowel obstruction No concurrent severe uncontrolled medical illness that would preclude study treatment No psychiatric or neurological condition that would preclude giving informed consent or complying with oral study medication No other prior or concurrent malignant disease that would preclude study treatment or assessment of response No prior neuropathy greater than grade 1 PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy More than 4 months since prior adjuvant chemotherapy with fluorouracil with or without leucovorin calcium More than 1 month since prior rectal chemoradiotherapy with fluorouracil with or without leucovorin calcium No prior systemic palliative chemotherapy for metastatic disease Endocrine therapy Not specified Radiotherapy See Chemotherapy Surgery Not specified Other No concurrent brivudine or sorivudine

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 120 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: Single Group Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MdG (modified de Gramont)<br>2 weekly 5FU/FA schedule | Drug: FOLFOX regimen<br> <br> Drug: fluorouracil<br> <br> Drug: leucovorin calcium<br> <br> Procedure: quality-of-life assessment<br> <br> |
| Experimental: OxMdG (80%) for 12 weeks<br>MdG + oxaliplatin | Drug: FOLFOX regimen<br> <br> Drug: fluorouracil<br> <br> Drug: leucovorin calcium<br> <br> Drug: oxaliplatin<br> <br> Procedure: quality-of-life assessment<br> <br> |
| Experimental: Capcitabine<br> | Drug: capecitabine<br> <br> Procedure: quality-of-life assessment<br> <br> |
| Experimental: OxCap<br> | Drug: capecitabine<br> <br> Drug: oxaliplatin<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 |
| --- | --- | --- |
| Compare progression-free survival (PFS) in pts. treated w/ leucovorin calcium + fluorouracil (MdG) vs leucovorin calcium + fluorouracil + oxaliplatin (OxMdG) and in pts. treated w/ capecitabine (Cap) vs capecitabine + oxaliplatin (OxCap) at 1 yr | Compare progression-free survival (PFS) in pts. treated w/ leucovorin calcium + fluorouracil (MdG) vs leucovorin calcium + fluorouracil + oxaliplatin (OxMdG) and in pts. treated w/ capecitabine (Cap) vs capecitabine + oxaliplatin (OxCap) at 1 yr | PFS | 
| Compare health assessment in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 14 weeks | Compare health assessment in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 14 weeks | Baseline and 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare health assessment, including quality of life, in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap at baseline and 14 and 24 weeks | Compare health assessment, including quality of life, in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap at baseline and 14 and 24 weeks | Baseline, 14 and 24 weeks | 
| Compare toxicity/adverse events in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap | Compare toxicity/adverse events in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap | post 24 weeks | 
| Compare overall failure-free survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap | Compare overall failure-free survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap | post 24 weeks | 
| Compare overall survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap | Compare overall survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap | post 24 weeks | 
| Compare health economics in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap | Compare health economics in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap | Baseline, 14 and 24 weeks | 
| Compare health assessment in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap |  | Baseline, 14 and 24 weeks | 
| Compare toxicity/adverse events in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 24 weeks | Compare toxicity/adverse events in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 24 weeks | Baseline and 24 weeks | 
| Compare patients acceptability in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap | Compare patients acceptability in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap | post 24 weeks | 
| Compare PFS in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap | Compare PFS in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap | post 24 weeks | 
| Compare health economics in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap | Compare health economics in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap | Baseline, 14 and 24 weeks | 

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