Celecoxib, Fluorouracil, and Radiation Therapy in Treating Patients With Stage II or Stage III Rectal Cancer That Can Be Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Celecoxib may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, 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. Celecoxib may make tumor cells more sensitive to radiation therapy. Giving celecoxib together with fluorouracil and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying how well giving celecoxib together with fluorouracil and radiation therapy works in treating patients with stage II or stage III rectal cancer that can be removed by surgery.

Detailed Description
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OBJECTIVES: Determine cyclo-oxygenase-2 (COX-2) overexpression in patients with resectable stage II or III rectal cancer treated with neoadjuvant celecoxib, fluorouracil, and radiotherapy. Determine whether administration of celecoxib, a COX-2 inhibitor, results in changes in tumor (COX-2 overexpressing) levels of eicosanoids but not in the surrounding normal tissue. Determine if there is a greater change in protein and gene expression in post-treatment biopsies when compared to pretreatment biopsies that are greater for tumor (COX-2 overexpression) than in surrounding normal tissue. Determine whether patients who express the greatest degree of change in gene and protein expression are those most likely to respond to therapy. Assess the toxicities of concurrent treatment with celecoxib, fluorouracil, and radiotherapy. OUTLINE: This is a pilot study. Patients receive oral celecoxib twice daily beginning 5 days prior to radiotherapy and continuing until completion of radiotherapy. Patients undergo radiotherapy 5 days a week for 5 weeks. Patients also receive concurrent fluorouracil IV continuously for 5 weeks. Patients undergo radical resection 4-10 weeks after completion of chemoradiotherapy. Patients undergo tumor biopsy at baseline and then at the time of surgical resection. Patients also undergo blood and urine collection at baseline, 5 days after initiation of celecoxib, 7 days after initiation of celecoxib in combination with fluorouracil and radiotherapy, and at the time of surgical resection. The specimens are evaluated for COX-2 expression, eicosanoid production, and gene and protein expression using immunohistochemistry, microarray, and mass spectrometry. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: Approximately 28 patients will be accrued for this study.

Official Title
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Phase II Pilot Study of Pre-Operative Celecoxib (Celebrex) in Combination With Prolonged Venous Infusion 5FU and Radiation Therapy for Patients With Stage II/III Resectable Rectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: celecoxib
* Drug: fluorouracil
* Procedure: conventional surgery
* Radiation: radiation therapy
* Procedure: tumor biopsy
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary adenocarcinoma of the rectum Stage II or III disease Distal border of tumor must be at or below the peritoneal reflection Distal border of the tumor must be within 12 cm of the anal verge by proctoscopic exam Tumor must be clinically resectable Transmural penetration beyond muscularis propria by transrectal ultrasound No high-grade obstruction No evidence of metastatic disease PATIENT CHARACTERISTICS: Karnofsky performance status 60-100% WBC ≥ 4,000/mm³ Platelet count ≥ 150,000/mm³ Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other serious medical illness or psychiatric condition that would preclude study treatment No history of allergy to celecoxib or any other NSAIDs No history of allergy to sulfonamides No prior or concurrent malignancy except inactive noninvasive cervical carcinoma or skin cancer (excluding melanoma) or other cancer that has been disease free for ≥ 5 years PRIOR CONCURRENT THERAPY: No prior radiotherapy to the pelvis At least 7 days since prior and no other concurrent COX-2 inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) No concurrent warfarin except low-dose warfarin (1 mg/day)

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment intervention<br> | Drug: celecoxib<br>* twice daily beginning 5 days prior to radiotherapy and continuing until completion of radiotherapy<br>Drug: fluorouracil<br>* Patients receive concurrent fluorouracil IV continuously for 5 weeks.<br>Procedure: conventional surgery<br>* 4-10 weeks after completion of chemoradiotherapy<br>Radiation: radiation therapy<br>* Patients undergo radiotherapy 5 days a week for 5 weeks<br>Procedure: tumor biopsy<br>* at baseline and then at the time of surgical resection<br>Other: laboratory biomarker analysis<br>* blood and urine collected at baseline, 5 days after initiation of celecoxib, 7 days after initiation of celecoxib in combination with fluorouracil and radiotherapy, and at the time of surgical resection. specimens are evaluated for COX-2 expression, eicosanoid production, and gene and protein expression using immunohistochemistry, microarray, and mass spectrometry.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response rate |  | at time of surgery, day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete resection rate |  | at time of surgery, day 5 | 
| Patterns of failure |  | during study, beginning day 5 forward | 
| Survival |  | at time of death | 
| Toxicity |  | 5 days before surgery & 5 days after surgery | 

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