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Phase III Trial of Fluorouracil-Based Chemotherapy Regimens Plus Radiotherapy in Postoperative Adjuvant Rectal Cancer: GI INT 0144

Stephen R. Smalley, Jacqueline K. Benedetti, Stephen K. Williamson, John M. Robertson, Norman C. Estes, Tracy Maher, Barbara Fisher, Tyvin A. Rich, James A. Martenson, John W. Kugler, Al B. Benson, III, Daniel G. Haller, Robert J. Mayer, James N. Atkins, Christine Cripps, John Pedersen, Phillip O. Periman, Michael S. Tanaka, Jr, Cynthia G. Leichman, John S. Macdonald

From the Kansas City Community Clinical Oncology Program (CCOP), Kansas City, KS; Southwest Oncology Group Statistical Center, Seattle, WA; University of Kansas Medical Center, Kansas City, MO; William Beaumont Hospital, Royal Oak, MI; University of Illinois College of Medicine at Peoria; Illinois Oncology Research Association CCOP, Peoria; Northwestern University, Chicago, IL; London Regional Cancer Centre, London, Ontario; Ottawa Health Research Institute, Ottawa, Ontario; Cross Cancer Institute, Edmonton, Alberta, Canada; University of Virginia Health Sciences Center, Charlottesville, VA; Mayo Clinic, Rochester, MN; University of Pennsylvania Cancer Center, Philadelphia, PA; Dana-Farber Cancer Institute, Boston, MA; Wake Forest/Southeast Cancer Control Consortium, Winston-Salem, NC; University of Texas Health, Science Center, San Antonio, TX; University of California, Davis, Sacramento; University of Southern California School of Medicine, Los Angeles, CA; and St Vincent's Comprehensive Cancer Center, New York, NY

Address reprint requests to Southwest Oncology Group (SWOG-9304), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org

PURPOSE: Adjuvant chemoradiotherapy after or before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. We studied three postoperative fluorouracil (FU) radiochemotherapy regimens.

PATIENTS AND METHODS: After resection of T3-4, N0, M0 or T1-4, N1, 2M0 rectal adenocarcinoma, 1,917 patients were randomly assigned to arm 1, with bolus FU in two 5-day cycles every 28 days before and after radiotherapy (XRT) plus FU via protracted venous infusion (PVI) 225 mg/m²/d during XRT; arm 2 (PVI-only arm), with PVI 42 days before and 56 days after XRT + PVI; or arm 3 (bolus-only arm), with bolus FU + leucovorin (LV) in two 5-day cycles before and after XRT, plus bolus FU + LV (levamisole was administered each cycle before and after XRT). Patients were stratified by operation type, T and N stage, and time from surgery.

RESULTS: Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 49% to 55% of the bolus arms versus 4% in the PVI arm. No disease-free survival (DFS) or OS difference was detected (3-year DFS, 67% to 69% and 3-year OS, 81% to 83% in all arms). Locoregional failure (LRF) at first relapse was 8% in arm 1, 4.6% in arm 2, and 7% in arm 3. LRF in T1-2, N1-2, and T3, N0-2 primaries who received low anterior resection (those most suitable for primary resection) was 5% in arm 1, 3% in arm 2, and 5% in arm 3.

CONCLUSION: All arms provide similar relapse-free survival and OS, with different toxicity profiles and central catheter requirements. LRF with postoperative therapy is low, justifying initial resection for T1-2, N0-2 and T3, and N0-2 anterior resection candidates.

Supported by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: Grants No. CA38926, CA32102, CA35176, CA12644, CA21661, CA25224, CA17145, CA32291, CA03927, CA22433, CA46441, CA35113, CA58882, CA67575, CA20319, CA35090, CA14028, CA58861, CA12644, CA35119, CA45377, CA45807, CA35176, CA67663, CA42777, CA63844, CA45450, CA27057, CA58348, CA46282, CA35192, CA049*19, CA37981, CA35178, CA58686, CA58416, CA76429, CA35261, CA12213, CA04920, CA76447, CA03096, CA35262, CA58658, CA52654, CA58415, CA46136, CA63845, CA16385, CA63850, CA28862, CA68183, CA35281, CA45560, CA35996, CA35128, CA46368, CA52772, CA46113, CA13612, CA45461, CA52757, CA74647, and CA76462.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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