Radiation Therapy, Chemotherapy, and Cetuximab Followed by Surgery, Chemotherapy, and Cetuximab in Treating Patients With Locally Advanced or Metastatic Rectal Cancer That Can Be Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as capecitabine, oxaliplatin, fluorouracil, and leucovorin, 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 radiation therapy together with combination chemotherapy and cetuximab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy and cetuximab after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II clinical trial is studying how well giving radiation therapy together with chemotherapy and cetuximab followed by surgery, chemotherapy, and cetuximab works in treating patients with locally advanced or metastatic rectal cancer that can be removed by surgery.

Detailed Description
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OBJECTIVES: Primary Determine the complete remission rate at 6 months after neoadjuvant radiotherapy, capecitabine, and oxaliplatin (XELOX), and cetuximab followed by surgery, adjuvant FOLFOX 4, and cetuximab in patients with synchronous locally advanced or metastatic cancer of the rectum with resectable metastases (T3-4 Nx or T2 N+ M1). Secondary Determine progression-free survival. Determine overall survival. Assess toxicities. Evaluate objective response in patients with measurable metastases. Determine the rate of local recurrence. Evaluate the downstaging and downsizing of patients with operable disease. Evaluate surgical complications in patients with operable disease. Evaluate biological markers predictive of response to cetuximab. OUTLINE: This is a multicenter study. Neoadjuvant therapy: Patients undergo radiotherapy for 5 weeks and receive concurrent oral capecitabine twice daily on days 1-5 of each week and oxaliplatin IV over 2 hours on day 1 of each week (XELOX). Patients also receive cetuximab IV on day 1 of the first week and on days 1-7 of weeks 2-5. Surgery: At 6 weeks after completing chemoradiotherapy, patients with resectable disease undergo surgery comprising total mesorectal excision. Patients with progressive disease, nonresectable tumor, or who require R2 surgery are removed from the study. Adjuvant therapy: Patients who undergo surgery, with or without removal of metastases, receive FOLFOX 4, comprising oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours, and leucovorin calcium IV on day 1, and cetuximab IV. Treatment repeats every 2 weeks for up to 6 courses (approximately 3 months). Patients who have not undergone prior surgical resection of metastases may have surgery to remove metastases after completing this second regimen of chemotherapy. After completion of study therapy, patients are followed periodically for up to 5 years.

Official Title
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Phase II Multicenter Study of the Impact of the Therapeutic Sequence of Radiochemotherapy (50 Gy + Capecitabine + Oxaliplatin + Cetuximab) Followed by Total Mesorectal Excision Surgery Then Post-surgery Chemotherapy (FOLFOX 4 + Cetuximab) in Synchronous Locally Advanced or Metastatic Cancers of the Rectum With Metastases Resectable From the Start (T3-4 Nx or T2 N+ M1).

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: capecitabine
* Drug: fluorouracil
* Drug: leucovorin calcium
* 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 of the rectum Locally advanced (T3-4 Nx) or metastatic (T2 N+ M1) synchronous disease Metastases must be resectable Primary tumor examined by endorectal echography and MRI Measurable disease by thoraco-abdomino-pelvic scanner Disease considered susceptible to treatment with radiotherapy and chemotherapy No diffuse metastases considered nonresectable No acute occlusion not caused by colostomy PATIENT CHARACTERISTICS: Inclusion criteria: ECOG performance status 0-2 WBC ≥ 4,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10 g/dL Creatinine ≤ 130 µmol/L Transaminases ≤ 5 times upper limit of normal (ULN) Total bilirubin ≤ 1.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients of must use effective contraception Exclusion criteria: Contraindication to therapy with capecitabine, oxaliplatin, cetuximab, and/or radiotherapy Impossible to perform translational analyses Uncontrolled severe illness Severe renal or hepatic insufficiency Cardiac insufficiency or symptomatic coronary disease Sensitive peripheral neuropathy Uncontrolled diabetes Other malignancy within the past 10 years except previously treated basal cell skin cancer or carcinoma in situ of the cervix Impossible to participate in study due to geographic, social, or psychiatric reasons Patients who are under supervision or incarcerated PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior anticancer chemotherapy or radiotherapy for this cancer No therapy with coumarin anticoagulants, phenytoin, sorivudine, brivudine, antacids, or allopurinol No concurrent participation in another therapeutic study or receiving another experimental drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: cetuximab|nan|
|Drug: capecitabine|nan|
|Drug: fluorouracil|nan|
|Drug: leucovorin calcium|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 |
| --- | --- | --- |
| Complete remission at ≥ 6 months by abdomino-pelvic-thoracic scan and a pelvic MRI |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preoperative clinical response |  |  | 
| Progression-free survival |  |  | 
| Overall survival |  |  | 
| Early toxicity before surgery |  |  | 
| Early toxicity due to surgery (mortality at 30 days, postoperative complications, surgical recovery) |  |  | 
| Late toxicity |  |  | 
| Late radiotherapy toxicity by CTC AE v. 3.0 |  |  | 
| Objective response of measurable metastases by RECIST |  |  | 
| Sexual function |  |  | 
| Downstaging and downsizing of patients with operable disease |  |  | 
| Surgical complications |  |  | 
| Sphincter function |  |  | 
| Predictive biomarkers of response to cetuximab |  |  | 

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