Optimization of radiation dosing schedules for proneural glioblastoma

Abstract

Glioblastomas are the most aggressive primary brain tumor. Despite treatment with surgery, radiation and chemotherapy, these tumors remain uncurable and few significant increases in survival have been observed over the last half-century. We recently employed a combined theoretical and experimental approach to predict the effectiveness of radiation administration schedules, identifying two schedules that led to superior survival in a mouse model of the disease (Leder et al., Cell 156 (3):603-616, 2014). Here we extended this approach to consider fractionated schedules to best minimize toxicity arising in early-and late-responding tissues. To this end, we decomposed the problem into two separate solvable optimization tasks: (i) optimization of the amount of radiation per dose, and (ii) optimization of the amount of time that 123 H. Badri et al. passes between radiation doses. To ensure clinical applicability, we then considered the impact of clinical operating hours by incorporating time constraints consistent with operational schedules of the radiology clinic. We found that there was no significant loss incurred by restricting dosage to an 8:00 a.m. to 5:00 p.m. window. Our flexible approach is also applicable to other tumor types treated with radiotherapy.Keywords Brain tumors · Radiotherapy · Nonlinear programming · Linear-quadratic model Mathematics Subject Classification 90C11 · 90C26 · 90C30 · 90C90 · 65K05

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Mathematical Modeling in Radiation Oncology

“…This enables adaptive fractionation schemes that are tailored to the response of the tumor (Unkelbach et al 2014b) or that include dose to multiple normal tissues (Saberian et al 2016). Badri et al (2015) have taken this approach to apply a mathematical optimization for glioblastoma and demonstrate improved tumor control after mathematical model-predicted improved response to an alternative treatment regime in which the treatment fractions were temporally optimized to minimize toxicity to early and late responding normal tissues. The treatment plans suggested by Badri et al were also constrained by the 8 a.m.-5 p.m. clinical workday, to provide a practical dosing schedule that could be performed in the clinic.…”