RT-29CONDUCTING VIRTUAL CLINICAL TRIALS TO EVALUATE HYPOFRACTIONATED RADIOTHERAPY FOR NEWLY DIAGNOSED GLIOBLASTOMA

PURPOSE: Fractionated photon irradiation is an integral part of the standard-of-care for newly diagnosed glioblastoma (GBM). Radiotherapy (RT) remains an area of active research, as 42 of 56 open interventional clinical trials for newly diagnosed GBMs involve RT. Hingorani et al reviewed several studies involving hypofractionated radiotherapy (HFRT) that suggested improved outcomes with reduced treatment times and neurological complications. However, these studies, along with many others for GBM, suffer from having a small cohort of patients. In this setting, inter-tumoral heterogeneity presents a significant challenge to evaluating therapeutic response and the interpretation of trial outcomes. METHODS: We present a method for conducting virtual clinical trials (VCT) for glioblastoma in the context of HFRT, although the method is applicable to a variety of therapies. For each VCT, we generate multiple virtual small cohorts of GBM patients by sampling tumor growth and response rates from a distribution created from a previously studied population of 63 GBM patients. The virtual cohorts are characterized by growth and response rates with mathematical models which can be determined through clinical imaging. These models are used to simulate four HFRT clinical trial protocols as well as the standard-of-care. Overall survival and dose to non-involved brain were compared for all protocols for each cohort while the standard-of-care is compared to a population-level control. RESULTS: We found that this approach can be used to differentiate experimental treatments in silico. The ability to conduct repeated VCTs for a variety of cohorts is valuable with the limited availability of patients with newly diagnosed GBM for new trials. This method can be viewed as an additional layer to meta-analysis of published trials, or as a preclinical tool to test hypotheses regarding treatment protocols prior to the proposal of a phase II trial, with the goal of selecting more cost-and time-efficient trials.