Rules-based Volumetric Segmentation of Multiparametric MRI for Response Assessment in Recurrent High-Grade Glioma.

We report domain knowledge-based rules for assigning voxels in brain multiparametric MRI (mpMRI) to distinct tissuetypes based on their appearance on Apparent Diffusion Coefficient of water (ADC) maps, T1-weighted unenhanced and contrast-enhanced, T2-weighted, and Fluid-Attenuated Inversion Recovery images. The development dataset comprised mpMRI of 18 participants with preoperative high-grade glioma (HGG), recurrent HGG (rHGG), and brain metastases. External validation was performed on mpMRI of 235 HGG participants in the BraTS 2020 training dataset. The treatment dataset comprised serial mpMRI of 32 participants (total 231 scan dates) in a clinical trial of immunoradiotherapy in rHGG (NCT02313272). Pixel intensity-based rules for segmenting contrast-enhancing tumor (CE), hemorrhage, Fluid, non-enhancing tumor (Edema1), and leukoaraiosis (Edema2) were identified on calibrated, co-registered mpMRI images in the development dataset. On validation, rule-based CE and High FLAIR (Edema1 + Edema2) volumes were significantly correlated with ground truth volumes of enhancing tumor (R = 0.85;p < 0.001) and peritumoral edema (R = 0.87;p < 0.001), respectively. In the treatment dataset, a model combining time-on-treatment and rule-based volumes of CE and intratumoral Fluid was 82.5% accurate for predicting progression within 30 days of the scan date. An explainable decision tree applied to brain mpMRI yields validated, consistent, intratumoral tissuetype volumes suitable for quantitative response assessment in clinical trials of rHGG.

Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424.

PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015. RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913.

Background: This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma. Methods: Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities. Results: A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6-methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors. Conclusion: Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

Dosimetric analysis of modulated and hybrid arcs in stereotactic radiosurgery.

PURPOSE: Forward-planned conformal arcs (termed dynamic arcs in the BrainLab iPlan system) have been routinely used in cranial stereotactic radiosurgery (SRS) for many yeras. This study compares dosimetric parameters of the newer, inversely-planned volumetric modulated arc therapy (VMAT) and VMAT-conformal hybrid plans with conformal arc plans. In the hybrid plans, various numbers of conformal arcs in a conformal plan are replaced with VMAT arcs. METHODS: Ten brain cancer cases previously treated on a Novalis accelerator for frameless cranial stereotactic radiosurgery using conformal arcs generated by BrainLab iPlan treatment planning system were retrospectively studied with various numbers of VMAT arcs replacing the conformal arcs. Pure VMAT plans of different numbers of arcs were also generated using the same angle and arc length setup for all or part of the conformal arcs and compared with both the original and hybrid plans. Pinnacle version 9.0 was used for treatment plan generation. SmartArc was used for the VMAT planning for a Novalis accelerator. The conformity index (CI), defined as the ratio of the isodose volume to the isodose covered target volume, gradient index (GI), defined as the ratio of the 50% isodose volume (V50) to the 100% isodose volume, volume covered by 12 Gy isodose (V12), mean dose and standard deviation of dose in target were studied. RESULTS: With one of the conformal arcs replaced with a VMAT arc of the same weighting and geometric setup, the average CI with one standard deviation was improved from 1.35 ± 0.18 to 1.29 ± 0.15 (p-value 0.03), while the average GI degraded from 3.8 ± 1.0 to 4.9 ± 1.5 (p-value < 0.01). The degraded GI in the VMAT plans is due to the absence of beam margin limit in SmartArc planning. Pure VMAT plans usually demonstrated better CI values than the hybrid and conformal arc plans when the number of arcs was greater than 2. The GI value was improved with increasing number of arcs in VMAT plans. For target volumes greater than 1 cc, VMAT plans demonstrated improved CI and smaller V50 and V12 than that in conformal arc plans. Better dose fall-off in normal tissue in VMAT plans is accompanied with higher dose heterogeneity in the target volume. CONCLUSION: VMAT and conformal-VMAT hybrid plans usually offer better target conformity. The dose fall-off in normal tissue is also better in VMAT plans when the number of arcs is greater than 3 and target volume is greater than 1 cc, but compromise the dose homogeneity in target volumes. VMAT plans are the best option for targets that are greater than 1 cc for cranial radiosurgery treatments, while for very small targets, conformal arc technique may still be the better choice based on data of dose fall-off in normal tissues.