Open AccessRevisiting Bevacizumab + Cytotoxics Scheduling Using Mathematical Modeling: Proof of Concept Study in Experimental Non‐Small Cell Lung Carcinoma
Author(s) -
Imbs DianeCharlotte,
El Cheikh Raouf,
Boyer Arnaud,
Ciccolini Joseph,
Mascaux Céline,
Lacarelle Bruno,
Barlesi Fabrice,
Barbolosi Dominique,
Benzekry Sébastien
Publication year - 2018
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12265
Subject(s) - bevacizumab , concomitant , oncology , lung cancer , medicine , regimen , normalization (sociology) , chemotherapy , computer science , sociology , anthropology
Concomitant administration of bevacizumab and pemetrexed‐cisplatin is a common treatment for advanced nonsquamous non‐small cell lung cancer (NSCLC). Vascular normalization following bevacizumab administration may transiently enhance drug delivery, suggesting improved efficacy with sequential administration. To investigate optimal scheduling, we conducted a study in NSCLC‐bearing mice. First, experiments demonstrated improved efficacy when using sequential vs. concomitant scheduling of bevacizumab and chemotherapy. Combining this data with a mathematical model of tumor growth under therapy accounting for the normalization effect, we predicted an optimal delay of 2.8 days between bevacizumab and chemotherapy. This prediction was confirmed experimentally, with reduced tumor growth of 38% as compared to concomitant scheduling, and prolonged survival (74 vs. 70 days). Alternate sequencing of 8 days failed in achieving a similar increase in efficacy, thus emphasizing the utility of modeling support to identify optimal scheduling. The model could also be a useful tool in the clinic to personally tailor regimen sequences.