Affiliations: [a] Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA | [b] Roche Laboratories Inc, Nutley, NJ, USA | [c] Hoffman-La Roche, Nutley, NJ, USA
Correspondence:
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Corresponding author: Tiffany A. Traina, MD, Breast Cancer Medicine Service Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY 10065, USA. Tel.: +1 646 888 4558; Fax: +1 646 888 4917; E-mail: trainat@mskcc.org
Abstract: Background:To hasten and improve anticancer drug development, we created a novel approach to generating and analyzing preclinical dose-scheduling data so as to optimize benefit-to-toxicity ratios. Methods:We applied mathematical methods based upon Norton-Simon growth kinetic modeling to tumor-volume data from breast cancer xenografts treated with capecitabine (Xeloda®, Roche) at the conventional schedule of 14 days of treatment followed by a 7-day rest (14-7). Results:The model predicted that 7 days of treatment followed by a 7-day rest (7-7) would be superior. Subsequent preclinical studies demonstrated that this biweekly capecitabine schedule allowed for safe delivery of higher daily doses, improved tumor response, and prolonged animal survival. Conclusions:We demonstrated that the application of Norton-Simon modeling to the design and analysis of preclinical data predicts an improved capecitabine dosing schedule in xenograft models. This method warrants further investigation and application in clinical drug development.
