Study protocol: PreOperative Brain Irradiation in Glioblastoma (POBIG) - A phase I trial.

Background: Glioblastoma is a high-grade aggressive neoplasm whose outcomes have not changed in decades. In the current treatment pathway, tumour growth continues and remains untreated for several weeks post-diagnosis. Intensified upfront therapy could target otherwise untreated tumour cells and improve the treatment outcome. POBIG will evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma, assessed by the maximum tolerated dose (MTD) and maximum tolerated irradiation volume (MTIV). Methods: POBIG is an open-label, dual-centre phase I dose and volume escalation trial that has received ethical approval. Patients with a new radiological diagnosis of glioblastoma will be screened for eligibility. This is deemed sufficient due to the high accuracy of imaging and to avoid treatment delay. Eligible patients will receive a single fraction of preoperative radiotherapy ranging from 6 to 14 Gy followed by their standard of care treatment comprising maximal safe resection and postoperative chemoradiotherapy (60 Gy/30 fr) with concurrent and adjuvant temozolomide). Preoperative radiotherapy will be directed to the part of the tumour that is highest risk for remaining as postoperative residual disease (hot spot). Part of the tumour will remain unirradiated (cold spot) and sampled separately for diagnostic purposes. Dose/volume escalation will be guided by a Continual Reassessment Method (CRM) model. Translational opportunities will be afforded through comparison of irradiated and unirradiated primary glioblastoma tissue. Discussion: POBIG will help establish the role of radiotherapy in preoperative modalities for glioblastoma. Trial registration: NCT03582514 (clinicaltrials.gov).

Visualising spatial heterogeneity in glioblastoma using imaging habitats.

Glioblastoma is a high-grade aggressive neoplasm characterised by significant intra-tumoral spatial heterogeneity. Personalising therapy for this tumour requires non-invasive tools to visualise its heterogeneity to monitor treatment response on a regional level. To date, efforts to characterise glioblastoma's imaging features and heterogeneity have focussed on individual imaging biomarkers, or high-throughput radiomic approaches that consider a vast number of imaging variables across the tumour as a whole. Habitat imaging is a novel approach to cancer imaging that identifies tumour regions or 'habitats' based on shared imaging characteristics, usually defined using multiple imaging biomarkers. Habitat imaging reflects the evolution of imaging biomarkers and offers spatially preserved assessment of tumour physiological processes such perfusion and cellularity. This allows for regional assessment of treatment response to facilitate personalised therapy. In this review, we explore different methodologies to derive imaging habitats in glioblastoma, strategies to overcome its technical challenges, contrast experiences to other cancers, and describe potential clinical applications.

The impact of anatomical changes during photon or proton based radiation treatment on tumor dose in glioblastoma dose escalation trials.

PURPOSE/OBJECTIVE: Most dose-escalation trials in glioblastoma patients integrate the escalated dose throughout the standard course by targeting a specific subvolume. We hypothesize that anatomical changes during irradiation may affect the dose coverage of this subvolume for both proton- and photon-based radiotherapy. MATERIAL AND METHODS: For 24 glioblastoma patients a photon- and proton-based dose escalation treatment plan (of 75 Gy/30 fr) was simulated on the dedicated radiotherapy planning MRI obtained before treatment. The escalated dose was planned to cover the resection cavity and/or contrast enhancing lesion on the T1w post-gadolinium MRI sequence. To analyze the effect of anatomical changes during treatment, we evaluated on an additional MRI that was obtained during treatment the changes of the dose distribution on this specific high dose region. RESULTS: The median time between the planning MRI and additional MRI was 26 days (range 16-37 days). The median time between the planning MRI and start of radiotherapy was relatively short (7 days, range 3-11 days). In 3 patients (12.5%) changes were observed which resulted in a substantial deterioration of both the photon and proton treatment plans. All these patients underwent a subtotal resection, and a decrease in dose coverage of more than 5% and 10% was observed for the photon- and proton-based treatment plans, respectively. CONCLUSION: Our study showed that only for a limited number of patients anatomical changes during photon or proton based radiotherapy resulted in a potentially clinically relevant underdosage in the subvolume. Therefore, volume changes during treatment are unlikely to be responsible for the negative outcome of dose-escalation studies.

Predicting and implications of target volume changes of brain metastases during fractionated stereotactic radiosurgery.

OBJECTIVE: To study the impact of target volume changes in brain metastases during fractionated stereotactic radiosurgery (fSRS) and identify patients that benefit from MRI guidance. MATERIAL AND METHODS: For 15 patients (18 lesions) receiving fSRS only (fSRSonly) and 19 patients (20 lesions) receiving fSRS postoperatively (fSRSpostop), a treatment planning MRI (MR0) and repeated MRI during treatment (MR1) were acquired. The impact of target volume changes on the target coverage was analyzed by evaluating the planned dose distribution (based on MR0) on the planning target volume (PTV) during treatment as defined on MR1. The predictive value of target volume changes before treatment (using the diagnostic MRI (MRD)) was studied to identify patients that experienced the largest changes during treatment. RESULTS: Target volume changes during fSRS did result in large declines of the PTV dose coverage up to -34.8% (median = 3.2%) for fSRSonly patients. For fSRSpostop the variation and declines were smaller (median PTV dose coverage change = -0.5% (-4.5% to 1.9%)). Target volumes changes did also impact the minimum dose in the PTV (fSRSonly; -2.7 Gy (-16.5 to 2.3 Gy), fSRSpostop; -0.4 Gy (-4.2 to 2.5 Gy)). Changes in target volume before treatment (i.e. seen between the MRD and MR0) predicted which patients experienced the largest dose coverage declines during treatment. CONCLUSION: Target volume changes in brain metastases during fSRS can result in worsening of the target dose coverage. Patients benefiting the most from a repeated MRI during treatment could be identified before treatment.

Significant tumor shift in patients treated with stereotactic radiosurgery for brain metastasis.

INTRODUCTION: Linac-based stereotactic radiosurgery (SRS) for brain metastases may be influenced by the time interval between treatment preparation and delivery, related to risk of anatomical changes. We studied tumor position shifts and its relations to peritumoral volume edema changes over time, as seen on MRI. METHODS: Twenty-six patients who underwent SRS for brain metastases in our institution were included. We evaluated the occurrence of a tumor shift between the diagnostic MRI and radiotherapy planning MRI. For 42 brain metastases the tumor and peritumoral edema were delineated on the contrast enhanced T1weighted and FLAIR images of both the diagnostic MRI and planning MRI examinations. Centre of Mass (CoM) shifts and tumor borders were evaluated. We evaluated the influence of steroids on peritumoral edema and tumor volume and the correlation with CoM and tumor border changes. RESULTS: The median values of the CoM shifts and of the maximum distances between the tumor borders obtained from the diagnostic MRI and radiotherapy planning MRI were 1.3 mm (maximum shift of 5.0 mm) and 1.9 mm (maximum distance of 7.4 mm), respectively. We found significant correlations between the absolute change in edema volume and the tumor shift of the CoM (p < 0.001) and tumor border (p = 0.040). Patients who received steroids did not only had a decrease in peritumoral edema, but also had a median decrease in tumor volume of 0.02 cc while patients who did not receive steroids had a median increase of 0.06 cc in tumor volume (p = 0.035). CONCLUSION: Our results show that large tumor shifts of brain metastases can occur over time. Because shifts may have a significant impact on the local dose coverage, we recommend minimizing the time between treatment preparation and delivery for Linac based SRS.