Study protocol of the GLOW study: maximising treatment options for recurrent glioblastoma patients by whole genome sequencing-based diagnostics—a prospective multicenter cohort study

Abstract

Background Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence and treatment options are limited. Unfortunately, the results of dedicated trials with new drugs have been very disappointing. The goal of the project is to obtain the evidence for changing standard of care (SOC) procedures to include whole genome sequencing (WGS) and consequently adapt care guidelines for this specific patient group with very poor prognosis by offering optimal and timely benefit from novel therapies, even in the absence of traditional registration trials for this small volume cancer indication. Methods The GLOW study is a prospective diagnostic cohort study executed through collaboration of the Hartwig Medical Foundation (Hartwig, a non-profit organisation) and twelve Dutch centers that perform neurosurgery and/or treat GBM patients. A total of 200 patients with a first recurrence of a glioblastoma will be included. Dual primary endpoint is the percentage of patients who receive targeted therapy based on the WGS report and overall survival. Secondary endpoints include WGS report success rate and number of targeted treatments available based on WGS reports and number of patients starting a treatment in presence of an actionable variant. At recurrence, study participants will undergo SOC neurosurgical resection. Tumour material will then, together with a blood sample, be sent to Hartwig where it will be analysed by WGS. A diagnostic report with therapy guidance, including potential matching off-label drugs and available clinical trials will then be sent back to the treating physician for discussing of the results in molecular tumour boards and targeted treatment decision making. Discussion The GLOW study aims to provide the scientific evidence for changing the SOC diagnostics for patients with a recurrent glioblastoma by investigating complete genome diagnostics to maximize treatment options for this patient group. Trial registration: ClinicalTrials.gov Identifier: NCT05186064.

Repeat surgery of recurrent glioma for molecularly informed treatment in the age of precision oncology: A risk–benefit analysis

“…However, most salvage therapies do not account for possible post-therapeutic changes in tumor biology especially in IDH-mutant glioma and show limited treatment efficacy and inevitable further tumor progression [13][14][15][16][17]. Therefore, sampling of current tumor tissue at progression to inform on relevant molecular alterations for targeted therapy has hence become an increasingly relevant modality of last-line therapy [18].…”

Whole genome sequencing in (recurrent) glioblastoma: challenges related to informed consent procedures and data sharing

“…Currently, NGS is used for diagnosis and identification of molecular alterations with potential therapeutical implications in glioblastoma [ 8 ]. The benefit of routine application of WGS for patients with recurrent glioblastoma is currently being explored in a prospective clinical trial [ 43 ]. WGS provides a wealth of information that could contribute to a better understanding of pathogenesis and to the development of novel therapies, therapy monitoring and treatment optimization [ 25 ].…”