Originally published as JCO Early Release 10.1200/JCO.2006.08.6652 on April 30 2007

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Neurotoxicity From Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: NSABP C-07

Stephanie R. Land, Jacek A. Kopec, Reena S. Cecchini, Patricia A. Ganz, H. Samuel Wieand, Linda H. Colangelo, Kate Murphy, J. Philip Kuebler, Thomas E. Seay, Burton M. Needles, James D. Bearden, III, Lauren K. Colman, Keith S. Lanier, Eduardo R. Pajon, Jr, David Cella, Roy E. Smith, Michael J. O'Connell, Joseph P. Costantino, Norman Wolmark

From the National Surgical Adjuvant Breast and Bowel Project Operations Office and Biostatistical Center; University of Pittsburgh Graduate School of Public Health, Department of Biostatistics, Pittsburgh; The Regional Cancer Center, Erie; and Allegheny General Hospital, Pittsburgh, PA; Department of Health Care and Epidemiology, University of British Columbia, Vancouver, BC, Canada; University of California, Los Angeles, Schools of Medicine and Public Health, and the Jonsson Comprehensive Cancer Center, Los Angeles, CA; Colorectal Cancer Coalition, Skaneateles, NY; Clinical Community Oncology Program, Columbus, OH; Atlanta Regional Community Clinical Oncology Program (CCOP), Atlanta, GA; St John's Mercy Medical Center, St Louis, MO; Upstate Carolina CCOP, Spartanburg, SC; Northwest CCOP, Tacoma, WA; Columbia River Oncology Program, Portland, OR; Colorado Cancer Research Program, Denver Veterans Medical Center, Denver, CO; and the Evanston Northwestern Healthcare, Evanston, IL
Deceased

Address reprint requests to Stephanie R. Land, PhD, NSABP Biostatistical Center, 201 N Craig St, Suite 350, Pittsburgh, PA 15213; e-mail: land{at}pitt.edu

Purpose: The randomized, multicenter, phase III protocol C-07 compared the efficacy of adjuvant bolus fluorouracil and leucovorin (FULV) versus FULV with oxaliplatin (FLOX) in stage II or III colon cancer. Definitive analysis revealed an increase in 4-year disease-free survival from 67.0% to 73.2% in favor of FLOX. This study compares neurotoxicity between the treatments.

Patients and Methods: Neurotoxicity was recorded for all patients using standard adverse event reporting. Patients at select institutions completed a neurotoxicity questionnaire through 18 months of follow-up.

Results: A total of 2,492 patients enrolled onto C-07 and 400 patients enrolled onto the patient-reported substudy. Mean patient-reported neurotoxicity was higher with oxaliplatin throughout the 18 months of study (P < .0001). During therapy, patients receiving oxaliplatin experienced significantly more hand/foot toxicity (eg, "quite a bit" of cold-induced hand/foot pain 26% FLOX v 2.6% FULV) and overall weakness (eg, moderate weakness in 27.4% FLOX v 16.2% FULV). At 18 months, hand neuropathy had diminished, but patients who received oxaliplatin experienced continued foot discomfort (eg, moderate foot numbness and tingling for 22.1% FLOX v 4.6% FULV). Observer-reported neurotoxicity was low grade and primarily neurosensory rather than neuromotor. Sixty-eight percent in the FLOX group v 8% in the FULV group had neurotoxicity at their first on-treatment assessment. Time to resolution was significantly longer for those receiving oxaliplatin, and continued beyond 2 years for more than 10% in the oxaliplatin group.

Conclusion: Oxaliplatin causes significant neurotoxicity. It is experienced primarily in the hands during therapy and in the feet during follow-up. In a minority of patients the neurotoxicity is long lasting.

published online ahead of print at www.jco.org on April 30, 2007.

Supported by Grants No. U10-CA-69951 and U10-CA-12027 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and Michael Smith Foundation for Health Research (J.A.K.).

Trial Registry: ClinicalTrials.gov ID#: NCT00004931; url: http://clinicaltrial.gov/ct/shows/NCT00004931?order=1.

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

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