Optimizing chemotherapy dose and schedule by Norton-Simon mathematical modeling.
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.
Traina
Tiffany A
TA
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. trainat@mskcc.org
Dugan
Ute
U
Higgins
Brian
B
Kolinsky
Kenneth
K
Theodoulou
Maria
M
Hudis
Clifford A
CA
Norton
Larry
L
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D008962:Models, Theoretical; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil