SMARTc Unit, Inserm S_911 CRO2, Aix-Marseille University, Marseille, France.
Multidisciplinary Oncology and Therapeutic Innovations Department, Assistance Publique Hôpitaux de Marseille, Marseille, France.
CPT Pharmacometrics Syst Pharmacol. 2018 Jan;7(1):42-50. doi: 10.1002/psp4.12265. Epub 2017 Dec 7.
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.
贝伐珠单抗联合培美曲塞和顺铂是治疗晚期非鳞状非小细胞肺癌（NSCLC）的常用方法。贝伐珠单抗给药后血管正常化可能会短暂增强药物输送，提示序贯给药可提高疗效。为了研究最佳方案，我们在 NSCLC 荷瘤小鼠中进行了一项研究。首先，实验表明贝伐珠单抗和化疗的序贯给药比同时给药效果更好。将这些数据与治疗下肿瘤生长的数学模型结合起来，考虑到正常化效应，我们预测贝伐珠单抗和化疗之间的最佳延迟时间为 2.8 天。这一预测在实验中得到了证实，与同时给药相比，肿瘤生长减少了 38%，生存时间延长（74 天 vs. 70 天）。8 天的交替给药方案未能达到类似的疗效增加，因此强调了模型支持以确定最佳方案的实用性。该模型也可以在临床上作为一种有用的工具，根据个人情况定制方案序列。
