[Paper Review] Mathematical modeling of the treatment response of resection plus combined chemotherapy and different types of radiation therapy in a glioblastoma patient

Farshad Samadifam, Ehsan Ghafourian|arXiv (Cornell University)|Aug 15, 2023

Mathematical Biology Tumor Growth4 citations

TL;DR

This study develops a mathematical model to simulate treatment response in a glioblastoma patient following gross total resection, concurrent chemoradiotherapy with temozolomide, and adjuvant chemotherapy. The model demonstrates that hyperfractionated radiotherapy extends survival by over 3 months at high radiation sensitivity, outperforming conventional radiotherapy due to higher total dose delivery, while MRI detection thresholds limit visible tumor assessment despite treatment effects.

ABSTRACT

Background: Gliomas are the most common brain tumors, which vary from low to high-grade. Despite the improvements in imaging techniques in the last decade, all parts of the tumor are not visible in these images, due to having a threshold of detection often lower than most of the tumor. Method: We simulated a brain domain to model heterogeneous growth plus gross total resection following concurrent chemo- and radiation therapy and adjuvant chemotherapy using temozolomide for a patient, diagnosed with glioblastoma, for different radiobiological alpha parameter as high, medium, and low sensitivity. The extent of difference in the result of treatment, area of the tumor, and survival time relating to those sensitivity parameters were shown. Moreover, based on the threshold of detection of MRI (T1Gd), the area of the tumor visible to this imaging technique was simulated. Furthermore, the extent of difference in the result of treatment for both conventional and hyperfractionated radiotherapy was investigated. Conclusion: The survival time of patient was increased by 2 months and more than 3 months at the lowest and highest sensitivity of radiation therapy, respectively.The result showed hyperfractionated radiotherapy was more effective than conventional radiotherapy in reducing the concentration of cancerous cells,as hyperfractionated method allows administration of higher total dose.

Motivation & Objective

• To simulate the treatment response of glioblastoma patients undergoing resection, concurrent chemoradiotherapy, and adjuvant temozolomide.
• To evaluate the impact of varying radiobiological alpha parameters (high, medium, low sensitivity) on tumor control and survival duration.
• To compare the efficacy of conventional versus hyperfractionated radiotherapy in reducing residual cancer cell concentration.
• To model the visible tumor area based on MRI T1Gd contrast threshold detection limits.
• To quantify the influence of imaging sensitivity on perceived treatment outcomes.

Proposed method

• A 3D brain domain was simulated to represent heterogeneous glioblastoma growth and resection.
• A system of partial differential equations modeled tumor cell dynamics with spatial and temporal resolution.
• Radiation therapy was simulated with varying alpha parameters to reflect differential radiosensitivity (high, medium, low).
• Concurrent chemoradiotherapy and adjuvant temozolomide were modeled using pharmacokinetic and cytotoxicity parameters.
• Hypofractionated and hyperfractionated radiotherapy regimens were compared by adjusting fractionation and total dose.
• MRI detection threshold (T1Gd) was applied to estimate the visible tumor volume, based on minimum detectable cell concentration.

Experimental results

Research questions

• RQ1 How does varying radiobiological alpha parameter affect survival time and residual tumor burden in a glioblastoma patient post-resection and multimodal therapy?
• RQ2 What is the comparative efficacy of hyperfractionated versus conventional radiotherapy in reducing cancer cell concentration?
• RQ3 To what extent does MRI T1Gd detection threshold limit the visibility of residual tumor after treatment?
• RQ4 How does the combination of resection, concurrent chemoradiotherapy, and adjuvant temozolomide influence long-term survival?
• RQ5 Can mathematical modeling predict survival gains from higher total radiation dose delivered via hyperfractionation?

Key findings

• Survival time increased by more than 3 months when radiation therapy was highly effective (high alpha parameter), compared to low sensitivity.
• Hypofractionated radiotherapy was more effective than conventional radiotherapy in reducing cancer cell concentration due to higher total dose delivery.
• The model predicted a 2-month survival gain at the lowest radiation sensitivity (low alpha parameter).
• Visible tumor area based on MRI T1Gd threshold was significantly smaller than actual residual tumor burden, indicating underestimation by imaging.
• The model demonstrated that higher total radiation dose via hyperfractionation improved tumor control, even with similar fractionation schedules.
• Treatment response varied substantially with radiobiological sensitivity, highlighting the importance of patient-specific radiobiological parameters in modeling.