Model‐based evaluation of image‐guided fractionated whole‐brain radiation therapy in pediatric diffuse intrinsic pontine glioma xenografts

Radiation therapy (RT) is currently the standard treatment for diffuse intrinsic pontine glioma (DIPG), the most common cause of death in children with brain cancer. A pharmacodynamic model was developed to describe the radiation‐induced tumor shrinkage and overall survival in mice bearing DIPG. CD1...

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Published in:CPT: pharmacometrics and systems pharmacology 2021-06, Vol.10 (6), p.599-610
Main Authors: Husband, Hillary R., Campagne, Olivia, He, Chen, Zhu, Xiaoyan, Bianski, Brandon M., Baker, Suzanne J., Shelat, Anang A., Tinkle, Christopher L., Stewart, Clinton F.
Format: Article
Language:English
Subjects:
Animals
Brain cancer
Brain Stem Neoplasms - pathology
Brain Stem Neoplasms - radiotherapy
Computer Simulation
Cranial Irradiation
Drug dosages
Drug interactions
Glioma
Glioma - pathology
Glioma - radiotherapy
Growth models
Heterografts
Humans
Laboratory animals
Mice
Mice, Nude
Models, Biological
Pediatrics
Pharmacodynamics
Pharmacokinetics
Radiation therapy
Radiotherapy, Image-Guided
Tumors
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Summary:Radiation therapy (RT) is currently the standard treatment for diffuse intrinsic pontine glioma (DIPG), the most common cause of death in children with brain cancer. A pharmacodynamic model was developed to describe the radiation‐induced tumor shrinkage and overall survival in mice bearing DIPG. CD1‐nude mice were implanted in the brain cortex with luciferase‐labeled patient‐derived orthotopic xenografts of DIPG (SJDIPGx7 H3F3AWT/K27 M and SJDIPGx37 H3F3AK27M/K27M). Mice were treated with image‐guided whole‐brain RT at 1 or 2 Gy/fraction 5‐days‐on 2‐days‐off for a cumulative dose of 20 or 54 Gy. Tumor progression was monitored with bioluminescent imaging (BLI). A mathematical model describing BLI and overall survival was developed with data from mice receiving 2 Gy/fraction and validated using data from mice receiving 1 Gy/fraction. BLI data were adequately fitted with a logistic tumor growth function and a signal distribution model with linear radiation‐induced killing effect. A higher tumor growth rate in SJDIPGx37 versus SJDIPGx7 xenografts and a killing effect decreasing with higher tumor baseline (p 
ISSN:2163-8306
2163-8306
DOI:10.1002/psp4.12627