A Feasibility Study of Personalized Prescription Schemes for Glioblastoma Patients Using a Proliferation and Invasion Glioma Model

Abstract

Purpose: This study investigates the feasibility of personalizing radiotherapy prescription schemes (treatment margins and fractional doses) for glioblastoma (GBM) patients and their potential benefits using a proliferation and invasion (PI) glioma model on phantoms. Methods and Materials: We propose a strategy to personalize radiotherapy prescription schemes by simulating the proliferation and invasion of the tumor in 2D according to the PI glioma model. We demonstrate the strategy and its potential benefits by presenting virtual cases, where the standard and personalized prescriptions were applied to the tumor. Standard prescription was assumed to deliver 46 Gy in 23 fractions to the initial, gross tumor volume (GTV1) plus a 2 cm margin and an additional 14 Gy in 7 fractions to the boost GTV2 plus a 2 cm margin. The virtual cases include the tumors with a moving velocity of 0.029 (slow-move), 0.079 (average-move), and 0.13 (fast-move) mm/day for the gross tumor volume (GTV) with a radius of 1 (small) and 2 (large) cm. For each tumor size and velocity, the margin around GTV1 and GTV2 was varied between 0–6 cm and 1–3 cm, respectively. Equivalent uniform dose (EUD) to normal brain was constrained to the EUD value obtained by using the standard prescription. Various linear dose policies, where the fractional dose is linearly decreasing, constant, or increasing, were investigated to estimate the temporal effect of the radiation dose on tumor cell-kills. The goal was to find the combination of margins for GTV1 and GTV2 and a linear dose policy, which minimize the tumor cell-surviving fraction (SF) under a normal tissue constraint. The efficacy of a personalized prescription was evaluated by tumor EUD and the estimated survival time. Results: The personalized prescription for the slow-move tumors was to use 3.0–3.5 cm margins for GTV1, and a 1.5 cm margin for GTV2. For the average- and fast-move tumors, it was optimal to use a 6.0 cm margin for GTV1 and then 1.5–3.0 cm margins for GTV2, suggesting a course of whole brain therapy followed by a boost to a smaller volume. It was more effective to deliver the boost sequentially using a linearly decreasing fractional dose for all tumors. Personalized prescriptions led to surviving fractions of 0.001–0.465% compared to the standard prescription, and increased the tumor EUDs by 25.3–49.3% and estimated survival times by 7.6–22.2 months. Conclusions: Personalizing treatment margins based on the measured proliferative capacity of GBM tumor cells can potentially lead to significant improvements in tumor cell kill and related clinical outcomes.

Distinct Tumor Microenvironment at Tumor Edge as a Result of Astrocyte Activation Is Associated With Therapeutic Resistance for Brain Tumor

“…Currently, the prevalent belief among physicians is that tumor hypoxia is generated when tumor growth outpaces vessel formation, and that hypoxia mainly occurs at the tumor core. Therefore, in clinics, higher spatial doses are used to irradiate the tumor core than the tumor edge, in order to avoid damage to normal tissue (40, 49). However, this study reports the existence of hypoxia at tumor edge, which is a distinct type of transient hypoxia in brain tumors and may escape notice during clinical examination and treatment strategy design that may result in tumor recurrence after the therapy.…”

Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: a modeling study based on longitudinal tumor measurements

“…gEUD ranged between 31.3 and 37.5 Gy, whereas the corresponding near minimum dose was between 28.8 and 35.9 Gy (see Supplementary Table S1 for specific total dose per patient). gEUD calculations were performed in MATLAB (version 2020a) using an exponent (Lyman parameter) of − 10 as suggested previously 26 . The gEUD accounts for dose inhomogeneity, whereas the PTV captures geometric delivery uncertainties across the gross tumor volume, providing the basis for volumetric response evaluation.…”

Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: A modelling study based on longitudinal tumor measurements

“…gEUD ranged between 31.3 and 37.0 Gy, whereas the corresponding near minimum dose D 98% was between 28.5 and 35.9 Gy (see Table S1 for specific total dose per patient). gEUD calculations were performed in Matlab (version 2020a) using an exponent (Lyman parameter) of −10 as suggested previously 17 . The gEUD accounts for dose inhomogeneity, whereas the PTV captures geometric delivery uncertainties across the gross tumour volume, providing the basis for volumetric response evaluation.…”