TY - JOUR
T1 - Revisiting Bevacizumab 1 Cytotoxics Scheduling Using Mathematical Modeling
T2 - Proof of Concept Study in Experimental Non-Small Cell Lung Carcinoma
AU - Imbs, Diane Charlotte
AU - Cheikh, Raouf El
AU - Boyer, Arnaud
AU - Ciccolini, Joseph
AU - Mascaux, Celine
AU - Lacarelle, Bruno
AU - Barlesi, Fabrice
AU - Barbolosi, Dominique
AU - Benzekry, Sebastien
N1 - Publisher Copyright:
VC 2017 ASCPT All rights reserved
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041207654&partnerID=8YFLogxK
U2 - 10.1002/psp4.12265
DO - 10.1002/psp4.12265
M3 - Article
C2 - 29218795
AN - SCOPUS:85041207654
SN - 2163-8306
VL - 7
SP - 42
EP - 50
JO - CPT: Pharmacometrics and Systems Pharmacology
JF - CPT: Pharmacometrics and Systems Pharmacology
IS - 1
ER -