Official Title: “Intergroup Randomized Phase III Study Of Postoperative Irinotecan, 5-Fluorouracil And Leucovorin Vs Oxaliplatin, 5-Flourouracil And Leucovorin Vs 5-Fluorouracil And Leucovorin For Patients With Stage II or III Rectal Cancer Receiving Either Preoperative Radiation And 5-Fluorouracil Or Postoperative Radiation And 5-Flourouracil”

RATIONALE: Drugs used in chemotherapy, such as irinotecan, fluorouracil, leucovorin, and oxaliplatin, use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known which adjuvant combination chemotherapy regimen is more effective in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for rectal cancer.

PURPOSE: This randomized phase III trial is comparing the effectiveness of three adjuvant combination chemotherapy regimens in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for stage II or stage III rectal cancer.

Study Type: Interventional

Study Design: Treatment, Randomized, Active Control

OBJECTIVES:

Primary - Compare the overall survival of patients with stage II or III rectal cancer receiving preoperative (group 1) or postoperative (group 2) radiotherapy and fluorouracil when additionally treated with adjuvant irinotecan, fluorouracil, and leucovorin calcium vs oxaliplatin, fluorouracil, and leucovorin calcium vs fluorouracil and leucovorin calcium.

Secondary - Determine sphincter preservation, tolerance of treatment, and patterns of failure in patients treated with these regimens. - Determine rectal function in patients treated with postoperative pelvic radiotherapy and chemotherapy. - Correlate tumor molecular prognostic markers (chromosome 18q allelic loss and microsatellite instability) with survival of patients treated with these regimens. - Determine physician preference in regard to the radiotherapy-chemotherapy sequence in these patients. - Correlate p53 gene mutation in tumor tissue with treatment efficacy in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG performance status (0 vs 1), chemotherapy/radiotherapy sequence (preoperative vs postoperative), and risk group (high risk [T3, N+, M0 or T4, any N, M0] vs low risk [T1-2, N+, M0 or T3, N0, M0]). Patients are treated in 1 of 2 groups according to physician preference and then randomized to 1 of 3 treatment arms. - Group 1 (preoperative chemoradiotherapy and additional adjuvant chemotherapy): - Preoperative chemoradiotherapy: Patients receive 1 of 3 treatment regimens, determined by the treating physician. - Regimen A (radiotherapy and fluorouracil): Patients undergo external beam radiotherapy once daily 5 days a week for 5 1/2 weeks (total of 28 fractions).

Patients also receive concurrent fluorouracil IV continuously 7 days a week for 5 1/2 weeks. - Regimen B (radiotherapy, fluorouracil, and leucovorin calcium): Patients undergo external beam radiotherapy as in regimen A. Patients also receive concurrent fluorouracil IV and leucovorin calcium IV continuously for 4 days on weeks 1 and 5. - Regimen C (radiotherapy and capecitabine)*: Patients undergo external beam radiotherapy as in regimen A. Patients also receive concurrent oral capecitabine twice daily for 5 1/2 weeks. NOTE: *Regimen C is allowed only for patients enrolled on protocol NSABP-R-04. - Surgery: Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. - Additional adjuvant chemotherapy: Within 21-56 days after complete surgical resection, patients are randomized to 1 of 3 treatment arms. - Arm I: Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1.

Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. - Arm II: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1.

Treatment repeats every 2 weeks for 8 courses. - Arm III: Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV over 1 hour on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 8 weeks for 3 courses. In all arms, treatment continues in the absence of disease progression or unacceptable toxicity. - Group 2 (postoperative chemoradiotherapy and additional adjuvant chemotherapy): Within 21-56 days after complete surgical resection, patients are randomized to 1 of 3 treatment arms. - Arm I: Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses. - Arm II: Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses. - Arm III: Patients receive leucovorin calcium and fluorouracil as in group 1, arm III for 1 course.

Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemoradiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 3 years, every 6 months for 2 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 3,000 patients (1,000 per treatment arm) will be accrued for this study over 5 years.

Intervention(s) in this Clinical Trial

• Drug: FOLFIRI regimen
• Drug: FOLFOX regimen
• Drug: capecitabine
• Drug: fluorouracil
• Drug: irinotecan hydrochloride
• Drug: leucovorin calcium
• Drug: oxaliplatin
• Procedure: adjuvant therapy
• Procedure: conventional surgery
• Procedure: neoadjuvant therapy
• Radiation: radiation therapy

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the rectum
• Stage II or III (T3-4, N0, M0 or any T, N1-3, M0)
• No distant metastases
• No evidence of tumor outside of the pelvis, including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy
• Distal border of the tumor must be or have been at or below the peritoneal reflection, defined as within 12 cm of anal verge by protoscopic examination* NOTE: *Tumor with a portion confirmed to be below the peritoneal reflection at the time of surgery is allowed regardless of the distance by endoscopy
• Transmural penetration of tumor through the muscularis propria by CT scan, endorectal ultrasound, or MRI (group 1)
• Tumor must be defined prospectively by the surgeon as clinically resectable or not (group 1)
• Tumor may be clinically fixed or initially not completely resectable (clinical stage
• T4, N0-2, M0) based on the presence of at least 1 of the following criteria (group 1):
• Tumor adherent to the pelvic sidewall or sacrum on rectal examination
• Hydronephrosis on CT scan or intravenous pyelogram OR ureteric or bladder invasion by cystoscopy and cytology or biopsy OR invasion into prostate
• Vaginal or uterine involvement

PATIENT CHARACTERISTICS:

• Age
• 18 and over
• Performance status
• ECOG 0-1
• Life expectancy
• Not specified
• Hematopoietic
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hepatic
• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST no greater than 3 times ULN
• Renal
• Creatinine no greater than 1.5 times ULN
• Other
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other prior or concurrent malignancy except nonmelanoma skin cancer, carcinoma in situ of the cervix, or other treated non-pelvic cancer from which the patient has been disease-free for more than 5 years
• No active inflammatory bowel disease
• No other serious medical illness that would preclude study treatment

PRIOR CONCURRENT THERAPY:

• Biologic therapy
• Not specified
• Chemotherapy
• No prior chemotherapy
• Endocrine therapy
• Not specified
• Radiotherapy
• No prior radiotherapy to the pelvis
• No concurrent intraoperative radiotherapy and/or brachytherapy
• Surgery
• See Disease Characteristics

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Eastern Cooperative Oncology Group

Overall Clinical Trial Officials and Contacts

Al B. Benson, MD, FACP Study Chair Robert H. Lurie Cancer Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00068692

Study ID Number: CDR0000327815

ClinicalTrials.gov Identifier: NCT00068692

Health Authority: United States: Federal Government

Clinical trial summary from the National Cancer Institute's PDQ® database