SWOG-9304 Chemotherapy Plus Radiation Therapy in Treating Patients With Rectal Cancer That Has Been Surgically Removed

NCT ID: NCT00002551

Last Updated: 2013-04-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1917 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1994-03-31
• Study Completion Date: 2008-10-31

Brief Summary

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.

Detailed Description

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.

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, and then annually until death.

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

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bolus 5-FU, Pelvic XRT + PVI 5-FU, Bolus 5-FU

Bolus 5-FU (fluorouracil) (500mg/m2/day on days 1-5, 29-33), Pelvic XRT + PVI 5-FU, Bolus 5-FU (450mg/m2/day for 5 days beginning 28 days after RT, for 2 cycles on days 1-5 of a 28 days cycle).

Group Type: EXPERIMENTAL

fluorouracil

Intervention Type: DRUG

See arm assignments.

radiation therapy

Intervention Type: RADIATION

See arm assignments.

PVI 5-FU+Pelvic XRT+PVI 5-FU+PVI 5-FU

5-FU (fluorouracil) 300mg/m2/day for 42 days followed by 2 week interruption, Day 57 through XRT will receive 225mg/m2/day of 5-FU followed by 1 month interruption, 4 weeks after completion of XRT 1 8wk cycle of 5-FU 300mg/m2/day.

Group Type: EXPERIMENTAL

fluorouracil

Intervention Type: DRUG

See arm assignments.

radiation therapy

Intervention Type: RADIATION

See arm assignments.

Bol 5-FU+LV+LEV+Pel XRT+Bol 5-FU+LV Bol 5-FU + LV + LEV

5-FU (fluorouracil) 425/mg/m2/day Days 1-5,29-33; LV (leucovorin calcium) 20mg/m2/day Days 1-5,29-33; LEV (levamisole hydrochloride) 150mg/day (50mg TID) for 3 days every 14 days starting after each course of 5-FU. During RT: 5-FU and LV 4 days on wk 1 and wk 5 of RT. LV 20 mg/m2/day IV bolus within 2hrs after completion of that day's radiation therapy, for four days in each cycle. Followed immediately by 5- FU 400 mg/m2/day IV bolus. Treatment will be given on days 57 - 60 and 85 - 88.Treatment post-RT-chemotherapy 28 days after completion of RT consist of 5 days of chemotherapy in 28 day cycles. 5-FU, 380 mg/m2/day on days 1 - 5 and LV given at a dose of 20 mg/m2/day on days 1 - 5 with the 5-FU given immediately after the LV. For 2 post-radiation cycles on days 1 - 5 of a 28 day cycle. Levamisole will be given orally at a dose of 150 mg/day (50 mg tid) for 3 days every 14 days during the 1st 3 days of each cycle of 5-FU, and again 14 days after starting each course of 5-FU.

Group Type: EXPERIMENTAL

fluorouracil

Intervention Type: DRUG

See arm assignments.

leucovorin calcium

Intervention Type: DRUG

See arm assignments.

levamisole hydrochloride

Intervention Type: DRUG

See arm assignments.

radiation therapy

Intervention Type: RADIATION

See arm assignments.

Interventions

fluorouracil

See arm assignments.

Intervention Type: DRUG

leucovorin calcium

See arm assignments.

Intervention Type: DRUG

levamisole hydrochloride

See arm assignments.

Intervention Type: DRUG

radiation therapy

See arm assignments.

Intervention Type: RADIATION

Other Intervention Names

5-FU; leucovorin; LV; LEV

Eligibility Criteria

Inclusion 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

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Eastern Cooperative Oncology Group

NETWORK

Sponsor Role: collaborator

Radiation Therapy Oncology Group

NETWORK

Sponsor Role: collaborator

North Central Cancer Treatment Group

NETWORK

Sponsor Role: collaborator

NCIC Clinical Trials Group

NETWORK

Sponsor Role: collaborator

Cancer and Leukemia Group B

NETWORK

Sponsor Role: collaborator

SWOG Cancer Research Network

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephen R. Smalley, MD

Role: STUDY_CHAIR

University of Kansas

Al B. Benson, MD, FACP

Role: STUDY_CHAIR

Robert H. Lurie Cancer Center

Jaffer A. Ajani, MD

Role: STUDY_CHAIR

M.D. Anderson Cancer Center

Michael J. O'Connell, MD

Role: STUDY_CHAIR

Mayo Clinic

Anthony LA Fields, MD, FRCPC

Role: STUDY_CHAIR

Cross Cancer Institute at University of Alberta

Robert J. Mayer, MD, FACP

Role: STUDY_CHAIR

Dana-Farber Cancer Institute

Locations

CCOP - Scottsdale Oncology Program

Scottsdale, Arizona, United States

CCOP - Colorado Cancer Research Program, Inc.

Denver, Colorado, United States

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Robert H. Lurie Comprehensive Cancer Center, Northwestern University

Chicago, Illinois, United States

Veterans Affairs Medical Center - Chicago (Lakeside)

Chicago, Illinois, United States

CCOP - Evanston

Evanston, Illinois, United States

CCOP - Illinois Oncology Research Association

Peoria, Illinois, United States

CCOP - Carle Cancer Center

Urbana, Illinois, United States

CCOP - Cedar Rapids Oncology Project

Cedar Rapids, Iowa, United States

CCOP - Iowa Oncology Research Association

Des Moines, Iowa, United States

Siouxland Hematology-Oncology

Sioux City, Iowa, United States

CCOP - Ochsner

New Orleans, Louisiana, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

CCOP - Ann Arbor Regional

Ann Arbor, Michigan, United States

CCOP - Kalamazoo

Kalamazoo, Michigan, United States

CCOP - Duluth

Duluth, Minnesota, United States

University of Minnesota Cancer Center

Minneapolis, Minnesota, United States

CCOP - Metro-Minnesota

Saint Louis Park, Minnesota, United States

CCOP - Missouri Valley Cancer Consortium

Omaha, Nebraska, United States

Veterans Affairs Medical Center - East Orange

East Orange, New Jersey, United States

CCOP - Northern New Jersey

Hackensack, New Jersey, United States

Albert Einstein Comprehensive Cancer Center

The Bronx, New York, United States

Quain & Ramstad Clinic, P.C.

Bismarck, North Dakota, United States

CCOP - Merit Care Hospital

Fargo, North Dakota, United States

Altru Health Systems

Grand Forks, North Dakota, United States

Ireland Cancer Center

Cleveland, Ohio, United States

CCOP - Toledo Community Hospital Oncology Program

Toledo, Ohio, United States

CCOP - Geisinger Clinical and Medical Center

Danville, Pennsylvania, United States

Hahnemann University Hospital

Philadelphia, Pennsylvania, United States

Rapid City Regional Hospital

Rapid City, South Dakota, United States

CCOP - Sioux Community Cancer Consortium

Sioux Falls, South Dakota, United States

CCOP - Marshfield Medical Research and Education Foundation

Marshfield, Wisconsin, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Veterans Affairs Medical Center - Milwaukee (Zablocki)

Milwaukee, Wisconsin, United States

Saskatchewan Cancer Agency

Regina, Saskatchewan, Canada

Pretoria Academic Hospital

Pretoria, , South Africa

Countries

United States; Canada; South Africa

References

Ulrich CM, Rankin C, Holmes RS, et al.: Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among stage II or III rectal cancer patients (SWOG 9304). [Abstract] American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, FL. A-309, 2008.

Reference Type: RESULT

Zhang W, Rankin CJ, Danenberg KD, et al.: An update of pharmacogenetic analysis of adjuvant rectal cancer patients treated with 5-fluorouracil and pelvic radiation in a phase III intergroup trial (INT-0144, SWOG 9304). [Abstract] J Clin Oncol 26 (Suppl 15): A-4115, 2008.

Reference Type: RESULT

Zhang W, Rankin C, Nagashima F, et al.: Pharmacogenetic analysis of stage II/III rectal cancer patients treated with 5-fluorouracil and pelvic radiation in a phase III intergroup trial (INT-0144, SWOG 9304). [Abstract] American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, FL. A-300, 2008.

Reference Type: RESULT

Smalley SR, Benedetti JK, Williamson SK, Robertson JM, Estes NC, Maher T, Fisher B, Rich TA, Martenson JA, Kugler JW, Benson AB 3rd, Haller DG, Mayer RJ, Atkins JN, Cripps C, Pedersen J, Periman PO, Tanaka MS Jr, Leichman CG, Macdonald JS. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol. 2006 Aug 1;24(22):3542-7. doi: 10.1200/JCO.2005.04.9544.

Reference Type: RESULT

PMID: 16877719 (View on PubMed)

Smalley SR, Benedetti J, Williamson S, et al.: Intergroup 0144 - phase III trial of 5-FU based chemotherapy regimens plus radiotherapy (XRT) in postoperative adjuvant rectal cancer. Bolus 5-FU vs prolonged venous infusion (PVI) before and after XRT + PVI vs bolus 5-FU + leucovorin (LV) + levamisole (LEV) before and after XRT + bolus 5-FU + LV. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-1006, 2003.

Reference Type: RESULT

Other Identifiers

SWOG-9304

Identifier Type: OTHER

Identifier Source: secondary_id

CAN-NCIC-CO11

Identifier Type: OTHER

Identifier Source: secondary_id

NCCTG-934751

Identifier Type: OTHER

Identifier Source: secondary_id

RTOG-9403

Identifier Type: OTHER

Identifier Source: secondary_id

CLB-C9491

Identifier Type: OTHER

Identifier Source: secondary_id

INT-0144

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA032102

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000063349

Identifier Type: -

Identifier Source: org_study_id