Colorectal Cancer, Metastatic Cancer
Conditions
Keywords
adenocarcinoma of the colon, stage IV colon cancer, adenocarcinoma of the rectum, stage IV rectal cancer, liver metastases, recurrent colon cancer, recurrent rectal cancer
Brief summary
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
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
Interventions
BIOLOGICALcetuximab
DRUGcapecitabine
DRUGfluorouracil
DRUGleucovorin calcium
DRUGoxaliplatin
OTHERstudy of socioeconomic and demographic variables
PROCEDUREadjuvant therapy
PROCEDUREneoadjuvant therapy
PROCEDUREquality-of-life assessment
Sponsors
University Hospital Southampton NHS Foundation Trust
University of Southampton
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Progression-free survival | end of study |
Secondary
| Measure | Time frame |
|---|---|
| Quality of life as assessed by the EQ-5D, EORTC QLQ-C30, and EORTC QLQ-LMC21 | end of study |
| Response rate before surgery as assessed by RECIST criteria | end of study |
| Pathological resection status | end of study |
| Toxicity | end of study |
| Cost effectiveness | end of study |
| Safety | end of study |
| Overall survival | end of study |
Countries
United Kingdom
Contacts
Primary ContactLouisa Little
Outcome results
None listed