Neo-adjuvant Chemoradiation With Oxaliplatin/5-FU in Rectal Cancer

Study Overview
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Brief Summary
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RATIONALE: 5FU based neoadjuvant chemoradiation (nCRT) is the standard of care for Stage II/III rectal cancer. Pathologic complete response (pCR) and downstaging have been associated with improved outcomes. The addition of oxaliplatin (OXA) to neoadjuvant therapy may reduce distant disease recurrence. Adjuvant treatment with OXA for rectal cancer has been motivated by benefits demonstrated in stage III colon cancer. Objective: To determine the feasibility, toxicity, and efficacy of preoperative OXA/5FU and RT followed by total mesorectal excision (TME) and adjuvant PURPOSE: This phase II trial is studying the side effects and how well giving neo-adjuvant combination chemotherapy with radiation works in treating patients undergoing surgery for rectal cancer.

Detailed Description
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OBJECTIVES: Primary To assess the complete pathologic response rate in patients with rectal cancer treated with radiation, modified neoadjuvant FOLFOX 6 chemotherapy followed by total mesorectal excision and adjuvant modified FOLFOX 6 chemotherapy. Secondary To observe the overall pathologic response rate in these patients. To correlate pathologic staging with preoperative ultrasound and pelvic MRI staging. To assess toxic side effects of these regimens in these patients. To assess patterns of disease relapse, disease-free survival outcomes, and overall survival outcomes of these patients. OUTLINE: Patients with stage II/III rectal cancer were treated with OXA 60mg/m2 weekly continuous infusion 5FU of 225 mg/m2/d d1-5 with pelvic RT of 1.8Gy/d for 28 doses. Adjuvant therapy consisted of 6 cycles of biweekly FOLFOX6. Surgery: Patients undergo total mesorectal excision by anterior resection or an abdominal perineal resection within 4 weeks after completion of neoadjuvant therapy. Adjuvant therapy: Within 4 weeks after surgery, patients receive modified FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium IV over 2 hours on day 1 and continuous fluorouracil IV over 46 hours on days 1-2. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients complete quality of life assessment questionnaires at baseline and at each follow-up visit. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and annually thereafter.

Official Title
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A Phase II Open-labeled, Prospective Study to Determine the Efficacy of Preoperative Chemoradiation With Oxaliplatin/5-FU in Locally Advanced Rectal Cancer Followed by Total Mesorectal Excision and FOLFOX6

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: 5-FU
* Drug: Oxaliplatin
* Drug: leucovorin
* Procedure: mesorectal excision


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically proven adenocarcinoma of the rectum with no distant metastases. T3-4N0M0, TanyN1-3M0 assessed by clinical exam, TRUS, MRI and CT The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 centimeters of the anal verge by protoscopic examination. No prior chemotherapy or pelvic irradiation. ECOG performance status 0-1 Age 18 to 70 years ANC >= 1500/mm3 and platelets >= 100,000/mm3 Serum creatinine <= 1.5 x ULN; bilirubin <= 1.5 x ULN; ALT<= 2.5 x ULN Exclusion Criteria Pregnant or lactating females; patients not practicing active contraception while sexually active. No other serious medical condition A psychiatric disorder that would prohibit the subject from participating fully. Peripheral neuropathy > grade 1 History within the past 5 years of a cancer diagnosis except for non-melanomatous skin cancers or in situ cervix carcinoma. HIV positive patients

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: Preoperative Chemoradiation<br>Preoperative Chemoradiation with oxaliplatin/5-FU followed by mesorectal excision and 5-FU / leucovorin (FOLFOX 6) | Drug: 5-FU<br>* 5-FU: continuous infusion via portable pump during all RT (approximately 33 days)<br>* Other names: fluorouracil;Drug: Oxaliplatin<br>* Oxaliplatin: 50mg/m2 weekly dosing during RT (Day 1)<br>* Other names: Eloxatin;Drug: leucovorin<br>* Folinic Acid (Leucovorin): 400 mg/m2; 2-hour IV infusion simultaneously with oxaliplatin<br>* Other names: Folinic Acid;Procedure: mesorectal excision<br>* mesorectal excision<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Response and Complete Response | Pathologic Response and Complete Response to preoperative therapy will be determined at the time of surgical resection. All grossly visible areas of ulceration and/or induration with be measured and submitted for histological evaluation. The unit of measure is the tumor response rate to preoperative chemoradiation. Pathologic complete response (pCR) is defined as no evidence of invasive tumor cells on pathologic examination of the primary rectal cancer. Tumor regression grade (TRG) will be quantitated into five grades: TRG 1 (complete regression) -absence of residual cancer and fibrosis extending from the site of original tumor through the layers of the rectal wall. TRG 2 characterized by the presence of rare residual cancer cells scattered through the fibrosis. TRG 3 characterized by an increase in the number of residual cancer cells, but fibrosis still predominant. TRG 4 -residual cancer outgrowing fibrosis. TRG 5 characterized by absence of regressive changes. | Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, an average of 3.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Toxicity | Toxicity was assessed weekly during neoadjuvant chemotherapy and radiation therapy, bi-weekly during adjuvant FOLFOX therapy. | Weekly during chemoradiation treatment (3 months). Bi-weekly during adjuvant FOLFOX therapy (3.5 months). | 
| Complete Resectability Rates | Complete resectability rates assessed by circumferential margin. | Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, 3 months after beginning of chemoradiation treatment. | 
| Local Regional Control | subjects were followed for median of 22 months post-surgery | median follow-up 22 months post-TME | 
| Disease-free Survival |  | median 22 months follow-up | 
| Overall Survival |  | median follow-up 22 months | 
| Patterns of Disease Failure, Including Local Recurrence and Distant Metastasis Assessed by CT Scan |  | median follow-up 22 months | 
| Number of Participants With Comparison of Preoperative Stage With Post-treatment Pathologic Stage | Thin-section high resolution pelvic MRI was used to image the tumor prior to chemoradiation and repeated prior to surgery, and then compared to post-treatment pathological stage. | Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, 3 months after beginning of chemoradiation treatment. | 

 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