Oxaliplatin, Capecitabine, and Radiation Therapy With or Without Cetuximab in Treating Patients Undergoing Surgery for High-Risk Rectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. 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 chemotherapy and radiation therapy with or without cetuximab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether giving oxaliplatin, capecitabine, and radiation therapy is more effective with or without cetuximab when given before surgery in treating rectal cancer. PURPOSE: This randomized phase II trial is studying oxaliplatin, capecitabine, and radiation therapy to compare how well they work with or without cetuximab in treating patients undergoing surgery for high-risk rectal cancer.

Detailed Description
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OBJECTIVES: Compare the pathological complete response rate at total mesorectal excision in patients with high-risk rectal cancer treated with neoadjuvant therapy comprising oxaliplatin, capecitabine, and radiotherapy with or without cetuximab. OUTLINE: This is a multicenter, open-label, randomized, controlled study. Patients are stratified according to participating center and presence of T4 disease (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Neoadjuvant chemotherapy: Patients receive oxaliplatin IV over 2 hours on days 1, 22, 43, and 64 and oral capecitabine twice daily on days 1-14, 22-35, 43-56, and 64-77. Neoadjuvant chemoradiotherapy: Patients undergo radiotherapy once daily on days 85-89, 92-96, 99-103, 106-110, 113-117, and 120-124 and receive oral capecitabine twice daily on days 85-126. Surgery: Four to six weeks after completion of chemoradiotherapy, patients undergo total mesorectal excision (TME). Adjuvant therapy: Beginning 6-8 weeks after surgery, patients receive oxaliplatin IV over 2 hours on days 1, 22, 43, and 64 and oral capecitabine twice daily on days 1-14, 22-35, 43-56, and 64-77. Arm II: Neoadjuvant therapy: Patients receive oxaliplatin and capecitabine as in arm I neoadjuvant chemotherapy and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Neoadjuvant chemoradiotherapy: Patients undergo radiotherapy and receive capecitabine as in arm I neoadjuvant chemoradiotherapy and cetuximab IV over 1 hour on days 85, 92, 99, 106, 113, and 120. Surgery: Four to six weeks after completion of chemoradiotherapy patients undergo TME as in arm I. Adjuvant therapy: Beginning 6-8 weeks after surgery, patients receive oxaliplatin and capecitabine as in arm I adjuvant chemotherapy and cetuximab IV over 1 hour on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed periodically. After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years. PROJECTED ACCRUAL: A total of 164 patients will be accrued for this study.

Official Title
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A Multicentre Randomised Phase II Clinical Trial Comparing Oxaliplatin (Eloxatin), Capecitabine (Xeloda) and Pre-Operative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision for the Treatment of Patients With Magnetic Resonance Imaging (MRI) Defined High Risk Rectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: capecitabine
* Drug: oxaliplatin
* Procedure: adjuvant therapy
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma or undifferentiated non-small cell carcinoma of the rectum MRI-defined high-risk, operable disease, defined by ≥ 1 of the following: Tumors within 1 mm of mesorectal fascia (i.e., circumferential resection margin threatened or involved) T3 tumors at or below levators Tumors extending ≥ 5 mm into perirectal fat T4 tumors Presence of extramural venous invasion (primary tumor is therefore at least T3) No evidence of metastatic disease by CT scan of the chest and abdomen or, if required, by positron emission tomography scan or biopsy No rectal cancer that is unlikely to be operable even after neoadjuvant treatment (i.e., tumor involving the internal iliac vessels) No T1-2 rectal cancer, in the absence of other high-risk factors T2 tumors within 1 mm of mesorectal fascia allowed No recurrent disease PATIENT CHARACTERISTICS: WHO performance status 0-2 Life expectancy > 3 months WBC > 3,000/mm³ Absolute neutrophil count > 1,500/mm³ Platelet count > 100,000/mm³ Bilirubin < 1.5 times upper limit of normal (ULN) Transaminases < 2.5 times ULN Creatinine normal OR creatinine clearance > 50 mL/min Not pregnant or nursing Fertile patients must use effective contraception No concurrent uncontrolled medical condition No other active malignant disease within the past 10 years except nonmelanoma skin cancer or carcinoma in situ of the cervix No contraindications to MRI (e.g., pacemaker) No medical or psychiatric conditions that would preclude informed consent No known malabsorption syndrome or lack of physical integrity of the upper gastrointestinal tract No clinically significant (i.e., active) cardiac disease, including any of the following: Congestive heart failure Symptomatic coronary artery disease Cardiac dysrhythmia (e.g., atrial fibrillation, even if controlled with medication) Myocardial infarction within the past 12 months No symptoms or history of peripheral neuropathy PRIOR CONCURRENT THERAPY: No prior chemotherapy, radiotherapy, or investigational treatment for rectal cancer No other concurrent cytotoxic agents or investigational drugs No concurrent sorivudine or sorivudine analogues (e.g., brivudine)

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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: cetuximab|nan|
|Drug: capecitabine|nan|
|Drug: oxaliplatin|nan|
|Procedure: adjuvant therapy|nan|
|Procedure: conventional surgery|nan|
|Procedure: neoadjuvant therapy|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rate at time of total mesorectal excision (TME) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological response rates after completion of neoadjuvant therapy |  |  | 
| Complete resection rate (R0 resection) with microscopic clear resection margin (tumor observed > 1 mm from the resection margin), especially circumferential resection margin |  |  | 
| Perioperative measures, including operation time, duration of in-patient stay, perioperative transfusion requirement, and mortality, within 30 days of TME |  |  | 
| Postoperative complications, including wound infection, wound dehiscence, and fistula formation |  |  | 
| Quality of TME as assessed by audit of photographed surgical specimens |  |  | 
| Rate of abdominoperitoneal excision |  |  | 
| Rate of permanent defunctioning colostomies |  |  | 
| Clinical and radiological anastomotic leak rate |  |  | 
| Progression-free survival and patterns of failure |  |  | 
| Overall survival |  |  | 
| Safety |  |  | 
| Quality of life, including long-term bowel function |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the rectum, stage I rectal cancer, stage II rectal cancer, stage III rectal cancer