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Background: The radiotherapy process relies on several metrics in determining a notion of "distance" from one three‐dimensional region‐of‐interest (ROI) to another. The majority are symmetric (or commutative) and do not contain information pertaining to directionality. Growth versus regression, for example, is not inherently distinguished by these metrics. Purpose: The purpose of this work was to formalize a unidirectional distance metric, motivated by radiotherapy margin concepts, which we term the migration distance. Informally, the migration distance from ROI X$X$ to Y$Y$ is the minimum isotropic expansion of X$X$ such that Y$Y$ is completely encompassed by the expansion. If Y$Y$ is contained within X$X$, the migration distance is negative with magnitude equal to the maximum isotropic contraction of X$X$ such that Y$Y$ remains contained within contraction. The metric is demonstrated by quantifying glioblastoma interfraction target changes. Methods: An explicit mathematical formulation of the migration distance is presented and contrasted with the related Hausdorff distance. The results are demonstrated for the gross tumor volume (GTV) dynamics of a glioblastoma cohort consisting of 111 patients that underwent standard chemoradiotherapy with offline MR imaging at planning, fraction 10, fraction 20, and 1‐month post radiotherapy. Results: The mean ± SD of the GTV migration distance relative to planning was 5.9 ± 3.9 mm at fraction 10, 6.2 ± 4.4 mm at fraction 20, and 7.9 ± 7.1 mm at 1‐month post radiotherapy. The maximum GTV migration distance across all patients at the same timepoints was 20.4, 20.7, and 45.5 mm, respectively. Conclusions: We have proposed and demonstrated a unidirectional distance metric. The migration distance may have applications in the quantification of anatomical changes, planning target volume designs, and dosimetric radiotherapy plan assessment. [ABSTRACT FROM AUTHOR]

Background and Purpose: To quantitatively compare the recurrence patterns of glioblastoma (isocitrate dehydrogenase-wild type) versus grade 4 isocitrate dehydrogenase-mutant astrocytoma (wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase, respectively) following primary chemoradiation. Materials and Methods: A retrospective matched cohort of 22 wild type isocitrate dehydrogenase and 22 mutant isocitrate dehydrogenase patients were matched by sex, extent of resection, and corpus callosum involvement. The recurrent gross tumor volume was compared to the original gross tumor volume and clinical target volume contours from radiotherapy planning. Failure patterns were quantified by the incidence and volume of the recurrent gross tumor volume outside the gross tumor volume and clinical target volume, and positional differences of the recurrent gross tumor volume centroid from the gross tumor volume and clinical target volume. Results: The gross tumor volume was smaller for wild type isocitrate dehydrogenase patients compared to the mutant isocitrate dehydrogenase cohort (mean ± SD: 46.5 ± 26.0 cm3 vs 72.2 ± 45.4 cm3, P =.026). The recurrent gross tumor volume was 10.7 ± 26.9 cm3 and 46.9 ± 55.0 cm3 smaller than the gross tumor volume for the same groups (P =.018). The recurrent gross tumor volume extended outside the gross tumor volume in 22 (100%) and 15 (68%) (P =.009) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively; however, the volume of recurrent gross tumor volume outside the gross tumor volume was not significantly different (12.4 ± 16.1 cm3 vs 8.4 ± 14.2 cm3, P =.443). The recurrent gross tumor volume centroid was within 5.7 mm of the closest gross tumor volume edge for 21 (95%) and 22 (100%) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively. Conclusion: The recurrent gross tumor volume extended beyond the gross tumor volume less often in mutant isocitrate dehydrogenase patients possibly implying a differential response to chemoradiotherapy and suggesting isocitrate dehydrogenase status might be used to personalize radiotherapy. The results require validation in prospective randomized trials. [ABSTRACT FROM AUTHOR]

• Simplified IVIM metrics from MRIs taken during chemoradiation have prognostic value. • Nonenhancing T2-FLAIR regions have important prognostic value. Prediction of early progression in glioblastoma may provide an opportunity to personalize treatment. Simplified intravoxel incoherent motion (IVIM) MRI offers quantitative estimates of diffusion and perfusion metrics. We investigated whether these metrics, during chemoradiation, could predict treatment outcome. 38 patients with newly diagnosed IDH-wildtype glioblastoma undergoing 6-week/30-fraction chemoradiation had standardized post-operative MRIs at baseline (radiation planning), and at the 10th and 20th fractions. Non-overlapping T1-enhancing (T1C) and non-enhancing T2-FLAIR hyperintense regions were independently segmented. Apparent diffusion coefficient (ADC T1C , ADC T2-FLAIR) and perfusion fraction (f T1C , f T2-FLAIR) maps were generated with simplified IVIM modelling. Parameters associated with progression before or after 6.9 months (early vs late progression, respectively), overall survival (OS) and progression-free survival (PFS) were investigated. Higher ADC T2-FLAIR at baseline [Odds Ratio (OR) = 1.06, 95% CI 1.01–1.15, p = 0.025], lower f T2-FLAIR at fraction 10 (OR = 2.11, 95% CI 1.04–4.27, p = 0.018), and lack of increase in ADC T2-FLAIR at fraction 20 compared to baseline (OR = 1.12, 95% CI 1.02–1.22, p = 0.02) were associated with early progression. Combining ADC T2-FLAIR at baseline, f T2-FLAIR at fraction 10, ECOG and MGMT promoter methylation status significantly improved AUC to 90.3% compared to a model with only ECOG and MGMT promoter methylation status (p = 0.001). Using multivariable analysis, neither IVIM metrics were associated with OS but higher f T2-FLAIR at fraction 10 (HR = 0.72, 95% CI 0.56–0.95, p = 0.018) was associated with longer PFS. ADC T2-FLAIR at baseline, its lack of increase from baseline to fraction 20, or f T2-FLAIR at fraction 10 significantly predicted early progression. f T2-FLAIR at fraction 10 was associated with PFS. [ABSTRACT FROM AUTHOR]

Background: We study the changes in organs‐at‐risk (OARs) morphology as contoured on serial MRIs during chemoradiation therapy (CRT) of glioblastoma (GBM). The dosimetric implication of assuming non‐deformable OAR changes and the accuracy and feasibility of semi‐automatic OAR contour propagation are investigated. Methods: Fourteen GBM patients who were treated with adjuvant CRT for GBM prospectively underwent MRIs on fractions 0 (i.e., planning), 10, 20, and 1 month post last fraction of CRT. Three sets of OAR contours — (a) manual, (b) rigidly registered (static), and (c) semi‐automatically propagated — were compared using Dice similarity coefficient (DSC) and Hausdorff distance (HD). Dosimetric impact was determined by comparing the minimum dose to the 0.03 cc receiving the highest dose (D0.03 cc) on a clinically approved reference, non‐adapted radiation therapy plan. Results: The DSC between the manual contours and the static contours decreased significantly over time (fraction 10: [mean ± 1 SD] 0.78 ± 0.17, post 1 month: 0.76 ± 0.17, P = 0.02) while the HD (P = 0.74) and the difference in D0.03cc did not change significantly (P = 0.51). Using the manual contours as reference, compared to static contours, propagated contours have a significantly higher DSC (propagated: [mean ± 1 SD] 0.81 ± 0.15, static: 0.77 ± 0.17, P < 0.001), lower HD (propagated: 3.77 ± 1.8 mm, static: 3.96 ± 1.6 mm, P = 0.002), and a significantly lower absolute difference in D0.03cc (propagated: 101 ± 159 cGy, static: 136 ± 243 cGy, P = 0.019). Conclusions: Nonrigid changes in OARs over time lead to different maximum doses than planned. By using semi‐automatic OAR contour propagation, OARs are more accurately delineated on subsequent fractions, with corresponding improved accuracy of the reported dose to the OARs. [ABSTRACT FROM AUTHOR]

Purpose: Integrated MRI-linear accelerator (MR-Linac) technology allows for daily soft tissue visualization, online adaptive replanning and potential for safe margin reduction. We report preliminary findings of weekly tumor reduction in a consecutive series of MGMTmethylated glioblastoma (GBM) patients treated on the MR-Linac (MRL). Methods and materials: UNITED (NCT04726397) is a phase II trial investigating the safety and feasibility of margin reduced MR-guided adaptive radiotherapy in GBM using the MRL. Patients treated with 60 Gy in 30 fractions or 40 Gy in 15 fractions with concomitant temolozomide (TMZ) are eligible. A 5 mm clinical target volume (CTV) expansion is applied to the gross tumor volume (GTV), which is extended to include abnormal T2-FLAIR. Patients undergo weekly on-line adaptive replanning based on a contrast-enhanced T1 and T2- FLAIR MRL-MRI taken in the treatment position. Results: The first five consecutive MGMT-methylated patients are reported. All patients had IDH wild-type GBM and the mean age was 60 years (range: 44- 76 years). Compared to the Day 1 MRL plan, weekly average GTV changes at fraction 6, 11, 16, 21, and 26 were -7.8% (range, +1.1% to -14.0%), -17.6% (range, -3.7% to -24.3%), -15.5% (range, -5.8% to -25.0%), -20.4% (range, -7.4% to -38.1%) and -22.0% (range, -3.6% to -35.7%), respectively. Average CTV reductions were 4.3%, 11.6%, 7.6%, 14.0% and 14.0% at the same respective time points. In comparison, the first five treated unmethylated patients exhibited consistent weekly growth patterns in the GTV during RT. Conclusions: Our preliminary findings support a treatment adaptation protocol for GBM, in particular for patients with methylated GBM, given the volume reductions observed. Clinical outcomes from the UNITED clinical trial will inform endpoints including failure patterns, quality of life, and treatment tolerance. [ABSTRACT FROM AUTHOR]

Purpose Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study. [ABSTRACT FROM AUTHOR]

Purpose: Magnetic resonance image (MRI) guided radiation therapy has the potential to improve outcomes for glioblastoma by adapting to tumor changes during radiation therapy. This study quantifies interfraction dynamics (tumor size, position, and geometry) based on sequential magnetic resonance imaging scans obtained during standard 6-week chemoradiation.Methods and Materials: Sixty-one patients were prospectively imaged with gadolinium-enhanced T1 (T1c) and T2/FLAIR axial sequences at planning (Fx0), fraction 10 (Fx10), fraction 20 (Fx20), and 1 month after the final fraction of chemoradiation therapy (P1M). Gross tumor volumes (GTVs) and clinical target volumes (CTVs) were contoured at all time points. Target dynamics were quantified by absolute volume (V), volume relative to Fx0 (Vrel), and the migration distance (dmigrate; the linear displacement of the GTV or CTV relative to Fx0). Temporal changes were assessed using a linear mixed-effects model.Results: Median volumes at Fx0, Fx10, Fx20, and P1M for the GTV were 18.4 cm3 (range, 1.1-110.5 cm3), 14.7 cm3 (range, 0.9-115.1 cm3), 13.7 cm3 (range, 0.6-174.2 cm3), and 13.0 cm3 (range, 0.9-76.3 cm3), respectively, with corresponding median Vrel of 0.88 at Fx10, 0.77 at Fx20, and 0.71 at P1M relative to Fx0 (P < .001 for all). The GTV (CTV) migration distances were greater than 5 mm in 46% (54%) of patients at Fx10, 50% (58%) of patients at Fx20, and 52% (57%) of patients at P1M. Dynamic tumor morphologic changes were observed, with 40% of patients exhibiting a decreased GTV (Vrel ≤1) with a dmigrate >5 mm during chemoradiation therapy.Conclusions: Clinically meaningful tumor dynamics were observed during chemoradiation therapy for glioblastoma, supporting evaluation of daily MRI guided radiation therapy and treatment plan adaptation. [ABSTRACT FROM AUTHOR]

[Display omitted] • MR-Linac diffusion MRI (DWI) changes in glioblastoma are prognostic. • DWI changes correlate with survival two to five weeks from radiotherapy start. • DWI changes show greater survival correlation than gross tumour volume changes. Survival in glioblastoma might be extended by escalating the radiotherapy dose to treatment-resistant tumour and adapting to tumour changes. Diffusion-weighted imaging (DWI) on MRI-linear accelerators (MR-Linacs) could be used to identify a dose escalation target, but its prognostic value must be demonstrated. The purpose of this study was to determine whether MR-Linac DWI can assess treatment response in glioblastoma and whether changes in DWI show greater prognostic value than changes in the contrast-enhancing gross tumour volume (GTV). Seventy-five patients with glioblastoma were treated with chemoradiotherapy, of which 32 were treated on a 1.5 T MRI-linear accelerator (MR-Linac). Patients were imaged with simulation MRI scanners (MR-sim) at treatment planning and weeks 2, 4, and 10 after treatment start. Twenty-eight patients had additional MR-Linac DWI sequences. Cox modelling was used to evaluate the correlation of overall and progression-free survival (OS and PFS) with clinical variables and volumetric changes in the GTV and low-ADC regions (ADC < 1.25 µm2/ms within GTV). In total, 479 MR-Linac DWI and 289 MR-sim DWI datasets were analyzed. MR-Linac low-ADC changes between weeks 2 and 5 inclusive were prognostic for OS (hazard ratio lower limits ≥ 1.2, p-values ≤ 0.02). MR-sim low-ADC changes showed greater correlation with OS and PFS than GTV changes (e.g., OS hazard ratio at week 2 was 3.4 (p <0.001) for low-ADC versus 2.0 (p = 0.022) for GTV). MR-Linac DWI can measure low-ADC tumour volumes that correlate with OS and PFS better than contrast-enhancing GTV. Low-ADC regions could serve as dose escalation targets. [ABSTRACT FROM AUTHOR]