Comparison of Adjuvant Chemotherapy Regimens in Treating Stage II/III Rectal Cancer

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.

1. Group I (Pre-operative) Registration

Inclusion Criteria:

- Patients must have histologically proven adenocarcinoma of the rectum with no
distant metastases. Clinical staging is required (T3N0M0, T4N0M0, TanyN1-3M0).

- Patients must not have evidence of tumor outside of the pelvis including liver
metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy.

- The distal border of the tumor must be at or below the peritoneal reflection,
defined as within 12 cm of anal verge by proctoscopic examination. In addition,
patients who have had a portion of their tumors confirmed to be below the
peritoneal reflection at the time of surgery are eligible regardless of the
distance determined by endoscopy.

- Transmural penetration of tumor through the muscularis propria must be
demonstrated by CT scan, endo-rectal ultrasound or MRI.

- Tumors must be defined prospectively by the surgeon as clinically resectable or
not.

- Clinically resectable tumors will be defined by the surgeon as not fixed and
completely resectable with negative margins based on the routine examination
of the non-anesthetized patient.

- Before pre-op treatment, the surgeon should estimate and record the type of
resection anticipated: APR, LAR or LAR/coloanal anastomosis.

- The tumor may be clinically fixed or initially not completely resectable,
clinical stage T4 N0-2 M0 based on the presence of at least one of the following
criteria:

- Clinically fixed tumors on rectal examination with tumor adherent to the
pelvic sidewall or sacrum.

- Hydronephrosis on CT scan or IVP or ureteric or bladder invasion as
documented by cystoscopy and cytology or biopsy, or invasion into prostate.

- Vaginal or uterine involvement.

- Patients must not have a previous or concurrent malignancy, with the exception
of:

- Nonmelanoma skin cancer or in situ cervical cancer.

- Treated non-pelvic cancer from which the patient has been continuously
disease-free for >5 years.

- Patients must have ECOG performance status 0-1.

- Patients must be > 18 years of age.

- All females of childbearing potential must have a blood or urine test within 2
weeks prior to registration to rule out pregnancy.

- Sexually-active women of childbearing potential and sexually active males are
strongly advised to use an accepted and effective method of contraception

Exclusion Criteria:

- Patients have received prior chemotherapy or pelvic irradiation therapy.

- Female patients must not be pregnant or breast-feeding.

- Patients have an active inflammatory bowel disease or other serious medical
illness which might limit the ability of the patient to receive protocol therapy.

2. Group II (Post-operative) Registration

Inclusion Criteria:

- Patients must have had histologically proven adenocarcinoma of the rectum with no
distant metastases. Pathologic staging is required (T3N0M0, T4N0M0, TanyN1-3M0).

- Patients must not have evidence of tumor outside of the pelvis including liver
metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy.

- The distal border of the tumor must have been at or below the peritoneal
reflection, defined as within 12 centimeters of anal verge by proctoscopic
examination. In addition, patients who have had a portion of their tumors
confirmed to be below the peritoneal reflection at the time of the surgery are
eligible regardless of the distance determined by endoscopy.

- Patients must not have received prior chemotherapy or pelvic irradiation therapy.

- Patients must not have a previous or concurrent malignancy, with the exception
of:

- Non-melanoma skin cancer or in situ cervical cancer.

- Treated non-pelvic cancer from which the patient has been continuously
disease-free for >5 years.

- Patients must have ECOG performance status 0-1.

- Patients must be > 18 years of age.

- All females of childbearing potential must have a blood or urine test within 2
weeks prior to registration to rule out pregnancy.

- Sexually active women of childbearing potential and sexually active males are
strongly advised to use an accepted and effective method of contraception.

Exclusion Criteria:

- Patients have an active inflammatory bowel disease or other serious medical
illness which might limit the ability of the patient to receive protocol therapy.

- Female patients are pregnant or breast-feeding.

3. Randomization (Groups I and II)

Inclusion Criteria:

- Patients must have a completely resected tumor and be within 21-56 days from the date
of surgery.

- Patients who received combination chemotherapy/XRT prior to randomization (Group I)
must have had a minimum radiation dose of 50.4 Gy.

- Patients must have ECOG performance status 0-1.

- Patients must have adequate renal function (creatinine < 1.5 x ULN) obtained < 4 weeks
prior to randomization.

- Patients must have adequate hepatic function (bilirubin < 1.5 x ULN, SGOT (AST) < 3 x
ULN) obtained < 4 weeks prior to randomization).

- Patients must have absolute neutrophil count > 1500/mm3 and platelet count >
100,000/mm3 < 4 weeks prior to randomization.

Exclusion Criteria:

• Patients have an active inflammatory bowel disease or other serious medical illness which
might limit the ability of the patient to receive protocol therapy.