Originally published as JCO Early Release 10.1200/JCO.2006.05.6754 on April 24 2006

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Phase I/II Study of Preoperative Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy in Patients With Locally Advanced Rectal Cancer: Cancer and Leukemia Group B 89901

David P. Ryan, Donna Niedzwiecki, Donna Hollis, Brent E. Mediema, Scott Wadler, Joel E. Tepper, Richard M. Goldberg, Robert J. Mayer

From the Massachusetts General Hospital Cancer Center; Dana-Farber Cancer Institute, Boston, MA; Cancer and Leukemia Group B Statistical Center; Duke University Medical Center, Durham, NC; University of North Carolina, Chapel Hill, NC; University of Missouri, Ellis Fischel Cancer Center, Columbia, MO; Weill Medical College of Cornell University, New York, NY

Address reprint requests to David P. Ryan, MD, Massachusetts General Hospital, 100 Blossom St, Cox 640, Boston MA 02114; e-mail: dpryan{at}partners.org

PURPOSE: The addition of oxaliplatin to fluorouracil in patients with advanced colorectal cancer improves survival. This phase I/II study evaluated the addition of weekly oxaliplatin to preoperative continuous infusion fluorouracil (FU) and external-beam radiation therapy (RT) in patients with locally advanced rectal adenocarcinoma.

PATIENTS AND METHODS: Patients with clinical T3/T4 rectal adenocarcinoma and no evidence of metastases were treated with weekly oxaliplatin, continuous infusion FU 200 mg/m² intravenously, and RT. A total of 6 weekly doses of oxaliplatin were planned. RT dose was 1.8 Gy/fraction to a total dose of 50.4 Gy. In the phase I portion, oxaliplatin was escalated from 30 to 60 mg/m².

RESULTS: Forty-four patients were entered onto the study, 18 on the phase I portion and 26 on the phase II portion. The maximum-tolerated dose (MTD) for oxaliplatin was determined to be 60 mg/m². At the MTD, 12 patients experienced grade 3 or 4 diarrhea, two patients experienced grade 3 neutropenia, and one patient experienced grade 3 thrombocytopenia. Fifty-six percent of patients entered at the MTD completed all 6 weeks of oxaliplatin. Eight (25%) of 32 patients enrolled at the phase II dose experienced a pathologic complete response.

CONCLUSION: In this multicenter study, the addition of oxaliplatin to intravenous continuous infusion FU and RT for patients with locally advanced rectal cancer was associated with a high pathologic complete response rate but more toxicity than when FU is used alone. A regimen of weekly oxaliplatin, continuous infusion FU, and radiation therapy is now being evaluated by the National Surgical Adjuvant Breast and Bowel Project.

Supported in part by grants from the National Cancer Institute to the Cancer and Leukemia Group B (Grant No. CA31946; Richard L. Schilsky, MD, Chairman), as well as Grants No. CA12449 (D.P.R.), CA33601 (D.N. and D.H.), CA12046 (B.E.M.), CA07968 (S.W.), CA47559 (J.E.T. and R.M.G.), CA32291 (R.J.M.).

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

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

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