Diffusion-weighted imaging on an MRI-linear accelerator to identify adversely prognostic tumour regions in glioblastoma during chemoradiation.

BACKGROUND AND PURPOSE: 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). MATERIALS AND METHODS: 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). RESULTS: 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). CONCLUSION: 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.

Chemical Exchange Saturation Transfer MRI for Differentiating Radiation Necrosis From Tumor Progression in Brain Metastasis-Application in a Clinical Setting.

BACKGROUND: High radiation doses of stereotactic radiosurgery (SRS) for brain metastases (BM) can increase the likelihood of radiation necrosis (RN). Advanced MRI sequences can improve the differentiation between RN and tumor progression (TP). PURPOSE: To use saturation transfer MRI methods including chemical exchange saturation transfer (CEST) and magnetization transfer (MT) to distinguish RN from TP. STUDY TYPE: Prospective cohort study. SUBJECTS: Seventy patients (median age 60; 73% females) with BM (75 lesions) post-SRS. FIELD STRENGTH/SEQUENCE: 3-T, CEST imaging using low/high-power (saturation B1  = 0.52 and 2.0 µT), quantitative MT imaging using B1  = 1.5, 3.0, and 5.0 µT, WAter Saturation Shift Referencing (WASSR), WAter Shift And B1 (WASABI), T1 , and T2 mapping. All used gradient echoes except T2 mapping (gradient and spin echo). ASSESSMENT: Voxel-wise metrics included: magnetization transfer ratio (MTR); apparent exchange-dependent relaxation (AREX); MTR asymmetry; normalized MT exchange rate and pool size product; direct water saturation peak width; and the observed T1 and T2 . Regions of interests (ROIs) were manually contoured on the post-Gd T1 w. The mean (of median ROI values) was compared between groups. Clinical outcomes were determined by clinical and radiologic follow-up or histopathology. STATISTICAL TESTS: t-Test, univariable and multivariable logistic regression, receiver operating characteristic, and area under the curve (AUC) with sensitivity/specificity values with the optimal cut point using the Youden index, Akaike information criterion (AIC), Cohen's d. P < 0.05 with Bonferroni correction was considered significant. RESULTS: Seven metrics showed significant differences between RN and TP. The high-power MTR showed the highest AUC of 0.88, followed by low-power MTR (AUC = 0.87). The combination of low-power CEST scans improved the separation compared to individual parameters (with an AIC of 70.3 for low-power MTR/AREX). Cohen's d effect size showed that the MTR provided the largest effect sizes among all metrics. DATA CONCLUSION: Significant differences between RN and TP were observed based on saturation transfer MRI. EVIDENCE LEVEL: 3 Technical Efficacy: Stage 2.

Accuracy and precision of apparent diffusion coefficient measurements on a 1.5 T MR-Linac in central nervous system tumour patients.

BACKGROUND AND PURPOSE: MRI linear accelerators (MR-Linacs) may allow treatment adaptation to be guided by quantitative MRI including diffusion-weighted imaging (DWI). The aim of this study was to evaluate the accuracy and precision of apparent diffusion coefficient (ADC) measurements from DWI on a 1.5 T MR-Linac in patients with central nervous system (CNS) tumours through comparison with a diagnostic scanner. MATERIALS AND METHODS: CNS patients were treated using a 1.5 T Elekta Unity MR-Linac. DWI was acquired during MR-Linac treatment and on a Philips Ingenia 1.5 T. The agreement between the two scanners on median ADC over the gross tumour/clinical target volumes (GTV/CTV) and in brain regions (white/grey matter, cerebrospinal fluid (CSF)) was computed. Repeated scans were used to estimate ADC repeatability. Daily changes in ADC over the GTV of high-grade gliomas were characterized from MR-Linac scans. RESULTS: DWI from 59 patients was analyzed. MR-Linac ADC measurements showed a small bias relative to Ingenia measurements in white matter, grey matter, GTV, and CTV (bias: -0.05 ± 0.03, -0.08 ± 0.05, -0.1 ± 0.1, -0.08 ± 0.07 µm2/ms). ADC differed substantially in CSF (bias: -0.5 ± 0.3 µm2/ms). The repeatability of MR-Linac ADC over white/grey matter was similar to previous reports (coefficients of variation for median ADC: 1.4%/1.8%). MR-Linac ADC changes in the GTV were detectable. CONCLUSIONS: It is possible to obtain ADC measurements in the brain on a 1.5 T MR-Linac that are comparable to those of diagnostic-quality scanners. This technical validation study adds to the foundation for future studies that will correlate brain tumour ADC with clinical outcomes.

Chemical exchange saturation transfer MRI in central nervous system tumours on a 1.5 T MR-Linac.

PURPOSE: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system. METHODS: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTRAmide), nuclear Overhauser effect (NOE) MTR (MTRNOE) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours. RESULTS: The gross tumour volume (GTV) exhibited lower MTRAmide and MTRNOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease. CONCLUSION: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols.

Multi-institutional Analysis of Prognostic Factors and Outcomes After Hypofractionated Stereotactic Radiotherapy to the Resection Cavity in Patients With Brain Metastases.

IMPORTANCE: For brain metastases, the combination of neurosurgical resection and postoperative hypofractionated stereotactic radiotherapy (HSRT) is an emerging therapeutic approach preferred to the prior practice of postoperative whole-brain radiotherapy. However, mature large-scale outcome data are lacking. OBJECTIVE: To evaluate outcomes and prognostic factors after HSRT to the resection cavity in patients with brain metastases. DESIGN, SETTING, AND PARTICIPANTS: An international, multi-institutional cohort study was performed in 558 patients with resected brain metastases and postoperative HSRT treated between December 1, 2003, and October 31, 2019, in 1 of 6 participating centers. Exclusion criteria were prior cranial radiotherapy (including whole-brain radiotherapy) and early termination of treatment. EXPOSURES: A median total dose of 30 Gy (range, 18-35 Gy) and a dose per fraction of 6 Gy (range, 5-10.7 Gy) were applied. MAIN OUTCOMES AND MEASURES: The primary end points were overall survival, local control (LC), and the analysis of prognostic factors associated with overall survival and LC. Secondary end points included distant intracranial failure, distant progression, and the incidence of neurologic toxicity. RESULTS: A total of 558 patients (mean [SD] age, 61 [0.50] years; 301 [53.9%] female) with 581 resected cavities were analyzed. The median follow-up was 12.3 months (interquartile range, 5.0-25.3 months). Overall survival was 65% at 1 year, 46% at 2 years, and 33% at 3 years, whereas LC was 84% at 1 year, 75% at 2 years, and 71% at 3 years. Radiation necrosis was present in 48 patients (8.6%) and leptomeningeal disease in 73 patients (13.1%). Neurologic toxic events according to the Common Terminology Criteria for Adverse Events grade 3 or higher occurred in 16 patients (2.8%) less than 6 months and 24 patients (4.1%) greater than 6 months after treatment. Multivariate analysis identified a Karnofsky Performance Status score of 80% or greater (hazard ratio [HR], 0.61; 95% CI, 0.46-0.82; P < .001), 22 to 33 days between resection and radiotherapy (HR, 1.50; 95% CI, 1.07-2.10; P = .02), and a controlled primary tumor (HR, 0.69; 95% CI, 0.52-0.90; P = .007) as prognostic factors associated with overall survival. For LC, a single brain metastasis (HR, 0.57; 95% CI, 0.35-0.93; P = .03) and a controlled primary tumor (HR, 0.59; 95% CI, 0.39-0.92; P = .02) were significant in the multivariate analysis. CONCLUSIONS AND RELEVANCE: To date, this cohort study includes one of the largest series of patients with brain metastases and postoperative HSRT and appears to confirm an excellent risk-benefit profile of local HSRT to the resection cavity. Additional studies will help determine radiation dose-volume parameters and provide a better understanding of synergistic effects with systemic and immunotherapies.