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.

Condition	Treatment or Intervention	Phase
adenocarcinoma of the rectum stage II rectal cancer stage III rectal cancer	Drug: capecitabine  Drug: fluorouracil  Drug: irinotecan  Drug: leucovorin calcium  Drug: oxaliplatin  Procedure: adjuvant therapy  Procedure: chemotherapy  Procedure: conventional surgery  Procedure: neoadjuvant therapy  Procedure: radiation therapy  Procedure: surgery	Phase III

Further Study Details: 

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.

• 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.
• 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.
• 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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

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

Alabama
      University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham,  Alabama,  35294-3300,  United States
Arizona
      CCOP - Mayo Clinic Scottsdale Oncology Program, Scottsdale,  Arizona,  85259-5404,  United States
California
      City of Hope Comprehensive Cancer Center, Duarte,  California,  91010-3000,  United States
      Stanford Cancer Center at Stanford University Medical Center, Stanford,  California,  94305-5216,  United States
      Veterans Affairs Medical Center - Palo Alto, Palo Alto,  California,  94304-1290,  United States
Colorado
      CCOP - Colorado Cancer Research Program, Incorporated, Denver,  Colorado,  80224,  United States
Delaware
      CCOP - Christiana Care Health Services, Newark,  Delaware,  19713,  United States
District of Columbia
      MBCCOP - Howard University Cancer Center, Washington,  District of Columbia,  20060,  United States
Florida
      H. Lee Moffitt Cancer Center and Research Institute, Tampa,  Florida,  33612,  United States
      Veterans Affairs Medical Center - Gainesville, Gainesville,  Florida,  32608-1197,  United States
      Veterans Affairs Medical Center - Miami, Miami,  Florida,  33125,  United States
      Veterans Affairs Medical Center - Tampa (Haley), Tampa,  Florida,  33612,  United States
Georgia
      Veterans Affairs Medical Center - Atlanta (Decatur), Decatur,  Georgia,  30033,  United States
      Winship Cancer Institute of Emory University, Atlanta,  Georgia,  30322,  United States
Illinois
      CCOP - Carle Cancer Center, Urbana,  Illinois,  61801,  United States
      CCOP - Central Illinois, Decatur,  Illinois,  62526,  United States
      CCOP - Evanston, Evanston,  Illinois,  60201,  United States
      CCOP - Illinois Oncology Research Association, Peoria,  Illinois,  61615-7828,  United States
      Decatur Memorial Hospital Cancer Care Institute, Decatur,  Illinois,  62526,  United States
      Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago,  Illinois,  60611,  United States
      Veterans Affairs Medical Center - Lakeside Chicago, Chicago,  Illinois,  60611-4494,  United States
Indiana
      CCOP - Northern Indiana CR Consortium, South Bend,  Indiana,  46601,  United States
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5289,  United States
      Veterans Affairs Medical Center - Indianapolis (Roudebush), Indianapolis,  Indiana,  46202,  United States
Iowa
      Burgess Health Center, Onawa,  Iowa,  51040,  United States
      CCOP - Cedar Rapids Oncology Project, Cedar Rapids,  Iowa,  52403-1206,  United States
      CCOP - Iowa Oncology Research Association, Des Moines,  Iowa,  50309-1016,  United States
      Des Moines General Hospital, Des Moines,  Iowa,  50309,  United States
      John Stoddard Cancer Center at Iowa Lutheran Hospital, Des Moines,  Iowa,  50316-2301,  United States
      John Stoddard Cancer Center at Iowa Methodist Medical Center, Des Moines,  Iowa,  50309,  United States
      Mercy Cancer Center at Mercy Medical Center - Des Moines, Des Moines,  Iowa,  50314,  United States
Kansas
      CCOP - Wichita, Wichita,  Kansas,  67214-3882,  United States
      Veterans Affairs Medical Center - Wichita, Wichita,  Kansas,  67218,  United States
Louisiana
      CCOP - Ochsner, New Orleans,  Louisiana,  70121,  United States
      MBCCOP - LSU Health Sciences Center, New Orleans,  Louisiana,  70112,  United States
Massachusetts
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States
Michigan
      CCOP - Kalamazoo, Kalamazoo,  Michigan,  49007-3731,  United States
      CCOP - Michigan Cancer Research Consortium, Ann Arbor,  Michigan,  48106,  United States
      West Michigan Cancer Center, Kalamazoo,  Michigan,  49007,  United States
Minnesota
      CCOP - Duluth, Duluth,  Minnesota,  55805,  United States
      CCOP - Metro-Minnesota, Saint Louis Park,  Minnesota,  55416,  United States
      Mayo Clinic Cancer Center, Rochester,  Minnesota,  55905,  United States
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States
      Veterans Affairs Medical Center - Minneapolis, Minneapolis,  Minnesota,  55417-2399,  United States
Nebraska
      CCOP - Missouri Valley Cancer Consortium, Omaha,  Nebraska,  68106,  United States
      Midlands Cancer Center at Midlands Community Hospital, Papillion,  Nebraska,  68128-4157,  United States
      Veterans Affairs Medical Center - Omaha, Omaha,  Nebraska,  68105,  United States
Nevada
      CCOP - Southern Nevada Cancer Research Foundation, Las Vegas,  Nevada,  89106,  United States
New Hampshire
      Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, Lebanon,  New Hampshire,  03756-0002,  United States
New Jersey
      Cancer Institute of New Jersey at Robert Wood Johnson University Hospital, New Brunswick,  New Jersey,  08903,  United States
      CCOP - Northern New Jersey, Hackensack,  New Jersey,  07601,  United States
      Veterans Affairs Medical Center - East Orange, East Orange,  New Jersey,  07018,  United States
New Mexico
      MBCCOP - University of New Mexico HSC, Albuquerque,  New Mexico,  87131,  United States
New York
      Albert Einstein Clinical Cancer Center, Bronx,  New York,  10461,  United States
      MBCCOP-Our Lady of Mercy Cancer Center, Bronx,  New York,  10466,  United States
      NYU School of Medicine's Kaplan Comprehensive Cancer Center, New York,  New York,  10016,  United States
      Veterans Affairs Medical Center - Brooklyn, Brooklyn,  New York,  11209,  United States
      Veterans Affairs Medical Center - New York, New York,  New York,  10010,  United States
North Dakota
      CCOP - Merit Care Hospital, Fargo,  North Dakota,  58122,  United States
Ohio
      CCOP - Columbus, Columbus,  Ohio,  43206,  United States
      CCOP - Toledo Community Hospital, Toledo,  Ohio,  43623-3456,  United States
      Cleveland Clinic Taussig Cancer Center, Cleveland,  Ohio,  44195,  United States
      MetroHealth's Cancer Care Center at MetroHealth Medical Center, Cleveland,  Ohio,  44109,  United States
Oklahoma
      CCOP - Oklahoma, Tulsa,  Oklahoma,  74136,  United States
Pennsylvania
      Abramson Cancer Center of the University of Pennsylvania, Philadelphia,  Pennsylvania,  19104,  United States
      CCOP - Geisinger Clinic and Medical Center, Danville,  Pennsylvania,  17822-2001,  United States
      CCOP - MainLine Health, Wynnewood,  Pennsylvania,  19096,  United States
      Fox Chase Cancer Center, Philadelphia,  Pennsylvania,  19111-2497,  United States
      Hahnemann University Hospital, Philadelphia,  Pennsylvania,  19102-1192,  United States
      Hillman Cancer Center at University of Pittsburgh Cancer Institute, Pittsburgh,  Pennsylvania,  15236,  United States
      Lankenau Cancer Center at Lankenau Hospital, Wynnewood,  Pennsylvania,  19096,  United States
      Penn State Cancer Institute at Milton S. Hershey Medical Center, Hershey,  Pennsylvania,  17033-0850,  United States
      Veterans Affairs Medical Center - Pittsburgh, Pittsburgh,  Pennsylvania,  15240,  United States
South Dakota
      CCOP - Sioux Community Cancer Consortium, Sioux Falls,  South Dakota,  57104,  United States
Tennessee
      Vanderbilt-Ingram Cancer Center at Vanderbilt Medical Center, Nashville,  Tennessee,  37232-6307,  United States
      Veterans Affairs Medical Center - Tennessee Valley Healthcare System - Nashville Campus, Nashville,  Tennessee,  37212-2637,  United States
Texas
      CCOP - Scott and White Hospital, Temple,  Texas,  76508,  United States
Wisconsin
      CCOP - Marshfield Clinic Research Foundation, Marshfield,  Wisconsin,  54449,  United States
      CCOP - St. Vincent Hospital Cancer Center, Green Bay, Green Bay,  Wisconsin,  54307-3453,  United States
      Medical College of Wisconsin Cancer Center, Milwaukee,  Wisconsin,  53226-3596,  United States
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792-0001,  United States
      Veterans Affairs Medical Center - Madison, Madison,  Wisconsin,  53705,  United States
      Veterans Affairs Medical Center - Milwaukee (Zablocki), Milwaukee,  Wisconsin,  53295,  United States
Australia, New South Wales
      Westmead Hospital, Westmead,  New South Wales,  2145,  Australia
Peru
      Instituto de Enfermedades Neoplasicas, Lima,  34,  Peru
Puerto Rico
      MBCCOP - San Juan, San Juan,  00921-3201,  Puerto Rico
      San Juan City Hospital, San Juan,  00936-7344,  Puerto Rico
      Veterans Affairs Medical Center - San Juan, San Juan,  00927-5800,  Puerto Rico
South Africa
      Pretoria Academic Hospital, Pretoria,  0001,  South Africa

Study chairs or principal investigators

Al Bowen Benson, MD, FACP,  Study Chair,  Robert H. Lurie Cancer Center   
Bruce J. Giantonio, MD,  University of Pennsylvania Health Systems   
Neal Jay Meropol, MD,  Fox Chase Cancer Center   

Study ID Numbers:  CDR0000327815; ECOG-E3201; NCT00068692
Record last reviewed:  January 2005
Last Updated:  January 7, 2005
Record first received:  September 10, 2003
ClinicalTrials.gov Identifier:  NCT00068692
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08