PRIMARY OBJECTIVES:
I. To compare the overall survival of patients treated with irinotecan, 5-FU and leucovorin versus those treated with oxaliplatin, leucovorin and 5-FU versus those treated with leucovorin and 5-FU for patients with stage II and III rectal cancer.
SECONDARY OBJECTIVES:
I. To determine sphincter preservation, tolerance of treatment and patterns of failure.
II. To describe patterns of failures
OTHER PRE-SPECIFIED OBJECTIVES:
I.To prospectively assess rectal function using the Patient Bowel Function/Uniscale questionnaire and the FACT Diarrhea Subscale in patients treated with an adjuvant program of pelvic radiation therapy and chemotherapy.
II. To correlate expression of key targets for 5-FU, leucovorin, oxaliplatin and irinotecan from tumor tissue biopsies with treatment efficacy III. To correlate tumor molecular prognostic markers with survival. IV. To determine physician preference in regard to the radiation-chemotherapy sequence in the Intergroup.
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 I (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 intravenously (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.
