RATIONALE: Drugs used in chemotherapy 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 treatment regimen is more effective for rectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of combination chemotherapy plus radiation therapy in treating patients who have rectal cancer that has been surgically removed.

Condition	Treatment or Intervention	Phase
stage III rectal cancer adenocarcinoma of the rectum stage II rectal cancer	Drug: fluorouracil  Drug: leucovorin calcium  Drug: levamisole	Phase III

Further Study Details: 

OBJECTIVES: I. Compare the overall and relapse free survival of patients with stage II or III rectal cancer treated with one of the following three regimens: bolus injections of fluorouracil (5-FU) prior to and following pelvic irradiation plus protracted venous infusion (PVI) 5-FU radiosensitization vs PVI 5-FU prior to and following pelvic irradiation plus PVI 5-FU radiosensitization vs bolus 5-FU with leucovorin calcium and levamisole prior to and following pelvic irradiation.

II. Describe relapse patterns and tolerance associated with these regimens in these patients.

PROTOCOL OUTLINE: This is a randomized, multicenter study. Patients are stratified according to type of prior surgery (abdominoperineal resection vs anterior resection), nodal status (N0 vs N1 vs N2-3), depth of tumor invasion (T1-2 vs T3 vs T4a vs T4b), time from surgery to study entry (20-45 days vs 46-70 days), participating center, and performance status (0-1 vs 2). Patients are randomized to one of three treatment arms.

Arm I: Patients receive fluorouracil (5-FU) IV on days 1-5 and 29-33. 5-FU is then given as a continuous infusion beginning on day 57 and continuing concurrently with radiotherapy for 5 weeks. Following a 28 day break from treatment patients receive 5-FU IV on days 1-5 of a 28 day course. Postradiotherapy treatment repeats for a total of 2 courses in the absence of disease progression or unacceptable toxicity.

Arm II: Patients receive 5-FU IV continuously on days 1-42. 5-FU and radiotherapy are then administered as in arm II.

Arm III: Patients receive leucovorin calcium (CF) IV followed by 5-FU IV on days 1-5 and 29-33. Patients also receive oral levamisole twice daily on days 1-3, 15-17, 29-31, and 43-45. CF IV and 5-FU IV are then given on days 57-60 and 85-88 concurrently with radiotherapy. Following a 28 day break from treatment patients receive CF IV and 5-FU IV on days 1-5 and 29-33 and oral levamisole twice daily on days 1-3, 15-17, 29-31, and 43-45 in the absence of disease progression or unacceptable toxicity.

All patients receive radiotherapy 5 days per week for 5 weeks starting on day 57.

Patients are followed every 4 months for 2 years, then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 1,800 patients (600 per arm) will be accrued for this study.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically proven stage II or III adenocarcinoma of the rectum; Tumor extends through the bowel wall and into perirectal fat or soft tissue (TNM T3-4, N0, M0); Nodes are involved with tumor (TNM T1-4, N1-3, M0)
• Tumor completely resected en bloc with no gross or microscopic evidence of residual disease; Circumferential (radial) margins of resected adherent tumors must be specifically documented free of disease (with the sole exception of extraperitoneal serosal margins)
• No evidence of metastasis; No regional nodal metastases (metastases outside of the pelvis) that cannot be resected en bloc with the primary lesion
• No distant peritoneal metastases (metastases that are not a direct extension from the primary tumor) even if grossly resected (direct extension into another structure permitted)
• Abdominopelvic CT required unless: Bilirubin, SGOT, and alkaline phosphatase are within normal limits, AND Operative report describes liver as normal on exploration
• No tumors of colonic origin, i.e.: Lower edge of the tumor is below the peritoneal reflection or a portion of the tumor is retroperitoneally located (usually posteriorly) as defined by the surgeon at laparotomy OR Lower margin of the tumor is 12 cm or less from the anal verge by proctoscopic exam
• No prior history of rectal cancer
• No stage II or III cancers of the extrapelvic colon within the past 5 years; Complete surgical resection at least 5 years prior to protocol registration allowed provided no other therapy was administered
• Synchronous modified stage I or IIa colorectal cancer (no nodal involvement or penetration through the muscularis propria) that has been completely resected allowed
• Registration between 20 and 70 days after the definitive surgical procedure required; Chemotherapy must begin no later than day 70 following surgery
• Concurrent registration on protocol SWOG-9419 allowed for patients with adequate tissue samples

--Prior/Concurrent Therapy--

• Biologic therapy: No prior immunotherapy
• Chemotherapy: No prior chemotherapy
• Endocrine therapy: Not specified
• Radiotherapy: No prior radiotherapy
• Surgery: See Disease Characteristics
• Other: No other concurrent antineoplastic therapy

--Patient Characteristics--

• Age: Over 18
• Performance status: SWOG 0-2
• Hematopoietic: WBC at least 4,000/mm3; Platelet count normal
• Hepatic: Bilirubin no greater than 2 times upper limit of normal (ULN); SGOT no greater than 2 times ULN; Alkaline phosphatase no greater than 2 times ULN
• Renal: Not specified
• Other: No chronic ulcerative colitis; No other serious medical illness that would preclude protocol therapy; No psychiatric condition that would preclude informed consent; No noncolorectal malignancy within 5 years except: Adequately treated nonmelanomatous skin cancer; Adequately treated carcinoma in situ of the cervix; Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception

Arizona
      CCOP - Scottsdale Oncology Program, Scottsdale,  Arizona,  85259-5404,  United States
Colorado
      CCOP - Colorado Cancer Research Program, Inc., Denver,  Colorado,  80209-5031,  United States
Florida
      H. Lee Moffitt Cancer Center and Research Institute, Tampa,  Florida,  33612,  United States
Illinois
      CCOP - Carle Cancer Center, Urbana,  Illinois,  61801,  United States
      CCOP - Evanston, Evanston,  Illinois,  60201,  United States
      CCOP - Illinois Oncology Research Association, Peoria,  Illinois,  61602,  United States
      Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago,  Illinois,  60611,  United States
      Veterans Affairs Medical Center - Chicago (Lakeside), Chicago,  Illinois,  60611,  United States
Iowa
      CCOP - Cedar Rapids Oncology Project, Cedar Rapids,  Iowa,  52403-1206,  United States
      CCOP - Iowa Oncology Research Association, Des Moines,  Iowa,  50309-1016,  United States
      Siouxland Hematology-Oncology, Sioux City,  Iowa,  51101-1733,  United States
Louisiana
      CCOP - Ochsner, New Orleans,  Louisiana,  70121,  United States
Massachusetts
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States
      Dana-Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States
Michigan
      CCOP - Ann Arbor Regional, Ann Arbor,  Michigan,  48106,  United States
      CCOP - Kalamazoo, Kalamazoo,  Michigan,  49007-3731,  United States
Minnesota
      CCOP - Duluth, Duluth,  Minnesota,  55805,  United States
      CCOP - Metro-Minnesota, Saint Louis Park,  Minnesota,  55416,  United States
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States
Nebraska
      CCOP - Missouri Valley Cancer Consortium, Omaha,  Nebraska,  68131,  United States
New Jersey
      CCOP - Northern New Jersey, Hackensack,  New Jersey,  07601,  United States
      Veterans Affairs Medical Center - East Orange, East Orange,  New Jersey,  07018-1095,  United States
New York
      Albert Einstein Comprehensive Cancer Center, Bronx,  New York,  10461,  United States
North Dakota
      Altru Health Systems, Grand Forks,  North Dakota,  58201,  United States
      CCOP - Merit Care Hospital, Fargo,  North Dakota,  58122,  United States
      Quain & Ramstad Clinic, P.C., Bismarck,  North Dakota,  58501,  United States
Ohio
      CCOP - Toledo Community Hospital Oncology Program, Toledo,  Ohio,  43623-3456,  United States
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5065,  United States
Pennsylvania
      CCOP - Geisinger Clinical and Medical Center, Danville,  Pennsylvania,  17822-2001,  United States
      Hahnemann University Hospital, Philadelphia,  Pennsylvania,  19102-1192,  United States
South Dakota
      CCOP - Sioux Community Cancer Consortium, Sioux Falls,  South Dakota,  57105-1080,  United States
      Rapid City Regional Hospital, Rapid City,  South Dakota,  57709,  United States
Wisconsin
      CCOP - Marshfield Medical Research and Education Foundation, Marshfield,  Wisconsin,  54449,  United States
      Medical College of Wisconsin, Milwaukee,  Wisconsin,  53226,  United States
      Veterans Affairs Medical Center - Milwaukee (Zablocki), Milwaukee,  Wisconsin,  53295,  United States
Canada, Saskatchewan
      Saskatchewan Cancer Agency, Regina,  Saskatchewan,  S4S 6X3,  Canada
South Africa
      Pretoria Academic Hospital, Pretoria,  0001,  South Africa

Study chairs or principal investigators

Charles A. Coltman, Jr.,  Study Chair,  Southwest Oncology Group   
Al Bowen Benson, III,  Study Chair
Walter John Curran, Jr.,  Study Chair
Michael J. O'Connell,  Study Chair
Anthony L.A. Fields,  Study Chair
Robert J. Mayer,  Study Chair

Study ID Numbers:  CDR0000063349; SWOG-9304; CLB-C9491; INT-0144
Record last reviewed:  June 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002551
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08