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Purpose: To assess whether reirradiation (re-RT) and concurrent bevacizumab (BEV) improve overall survival (OS) and/or progression-free survival (PFS), compared with BEV alone in recurrent glioblastoma (GBM). The primary objective was OS, and secondary objectives included PFS, response rate, and treatment adverse events (AEs) including delayed CNS toxicities., Methods: NRG Oncology/RTOG1205 is a prospective, phase II, randomized trial of re-RT and BEV versus BEV alone. Stratification factors included age, resection, and Karnofsky performance status (KPS). Patients with recurrent GBM with imaging evidence of tumor progression ≥ 6 months from completion of prior chemo-RT were eligible. Patients were randomly assigned 1:1 to re-RT, 35 Gy in 10 fractions, with concurrent BEV IV 10 mg/kg once in every 2 weeks or BEV alone until progression., Results: From December 2012 to April 2016, 182 patients were randomly assigned, of whom 170 were eligible. Patient characteristics were well balanced between arms. The median follow-up for censored patients was 12.8 months. There was no improvement in OS for BEV + RT, hazard ratio, 0.98; 80% CI, 0.79 to 1.23; P = .46; the median survival time was 10.1 versus 9.7 months for BEV + RT versus BEV alone. The median PFS for BEV + RT was 7.1 versus 3.8 months for BEV, hazard ratio, 0.73; 95% CI, 0.53 to 1.0; P = .05. The 6-month PFS rate improved from 29.1% (95% CI, 19.1 to 39.1) for BEV to 54.3% (95% CI, 43.5 to 65.1) for BEV + RT, P = .001. Treatment was well tolerated. There were a 5% rate of acute grade 3+ treatment-related AEs and no delayed high-grade AEs. Most patients died of recurrent GBM., Conclusion: To our knowledge, NRG Oncology/RTOG1205 is the first prospective, randomized multi-institutional study to evaluate the safety and efficacy of re-RT in recurrent GBM using modern RT techniques. Overall, re-RT was shown to be safe and well tolerated. BEV + RT demonstrated a clinically meaningful improvement in PFS, specifically the 6-month PFS rate but no difference in OS.

Rationale and Objectives: Glioblastoma image evaluation utilizes Magnetic Resonance Imaging contrast-enhanced, T1-weighted, and noncontrast T2-weighted fluid-attenuated inversion recovery (FLAIR) acquisitions. Disease progression assessment relies on changes in tumor diameter, which correlate poorly with survival. To improve treatment monitoring in glioblastoma, we investigated serial voxel-wise comparison of anatomically-aligned FLAIR signal as an early predictor of GBM progression., Materials and Methods: We analyzed longitudinal normalized FLAIR images (rFLAIR) from 52 subjects using voxel-wise Parametric Response Mapping (PRM) to monitor volume fractions of increased (PRM rFLAIR+ ), decreased (PRM rFLAIR- ), or unchanged (PRM rFLAIR0 ) rFLAIR intensity. We determined response by rFLAIR between pretreatment and 10 weeks posttreatment. Risk of disease progression in a subset of subjects (N = 26) with stable disease or partial response as defined by Response Assessment in Neuro-Oncology (RANO) criteria was assessed by PRM rFLAIR between weeks 10 and 20 and continuously until the PRM rFLAIR+ exceeded a defined threshold. RANO defined criteria were compared with PRM-derived outcomes for tumor progression detection., Results: Patient stratification for progression-free survival (PFS) and overall survival (OS) was achieved at week 10 using RANO criteria (PFS: p <0.0001; OS: p <0.0001), relative change in FLAIR-hyperintense volume (PFS: p = 0.0011; OS: p <0.0001), and PRM rFLAIR+ (PFS: p <0.01; OS: p <0.001). PRM rFLAIR+ also stratified responding patients' progression between weeks 10 and 20 (PFS: p <0.05; OS: p = 0.01) while changes in FLAIR-volume measurements were not predictive. As a continuous evaluation, PRM rFLAIR+ exceeding 10% stratified patients for PFA after 5.6 months (p<0.0001), while RANO criteria did not stratify patients until 15.4 months (p <0.0001)., Conclusion: PRM rFLAIR may provide an early biomarker of disease progression in glioblastoma., (Copyright © 2020 The Association of University Radiologists. All rights reserved.)

Purpose: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response., Methods and Materials: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m 2 , 8.4 mg/m 2 , 16.5 mg/m 2 , 27.5 mg/m 2 ). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume., Results: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01)., Conclusions: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: We evaluated whether dose-intensified chemoradiation alters patterns of failure and is associated with favorable survival in the temozolomide era., Materials and Methods: Between 2003 and 2015, 82 patients with newly diagnosed glioblastoma were treated with 66-81 Gy in 30 fractions using conventional magnetic resonance imaging. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Factors associated with improved PFS, OS, and time to progression were assessed using multivariate Cox model and linear regression., Results: Median follow-up was 23 months (95% CI 4-124 months). Sixty-one percent of patients underwent subtotal resection or biopsy, and 38% (10/26) of patients with available data had MGMT promoter methylation. Median PFS was 8.4 months (95% CI 7.3-11.0) and OS was 18.7 months (95% CI 13.1-25.3). Only 30 patients (44%) experienced central recurrence, 6 (9%) in-field, 16 (23.5%) marginal and 16 (23.5%) distant. On multivariate analysis, younger age (HR 0.95, 95% CI 0.93-0.97, p = 0.0001), higher performance status (HR 0.39, 95% CI 0.16-0.95, p = 0.04), gross total resection (GTR) versus biopsy (HR 0.37, 95% CI 0.16-0.85, p = 0.02) and MGMT methylation (HR 0.25, 95% CI 0.09-0.71, p = 0.009) were associated with improved OS. Only distant versus central recurrence (p = 0.03) and GTR (p = 0.02) were associated with longer time to progression. Late grade 3 neurologic toxicity was rare (6%) in patients experiencing long-term survival., Conclusion: Dose-escalated chemoRT resulted in lower rates of central recurrence and prolonged time to progression compared to historical controls, although a significant number of central recurrences were still observed. Advanced imaging and correlative molecular studies may enable targeted treatment advances that reduce rates of in- and out-of-field progression.

Background and Importance: This report illustrates a case of a low-grade glioma that showed significant disease progression during pregnancy, and then subsequent regression spontaneously in the postpartum period without treatment. This is a rare case of spontaneous glioma regression in the postpartum period, and may suggest underlying mechanisms of hormonal influences upon glioma progression., Clinical Presentation: The patient is a 27-yr-old female who underwent placement of a right-sided ventriculoperitoneal shunt for aqueductal stenosis at 8 wk of age. At the age of 24 yr, she was evaluated for chronic headaches and was found on magnetic resonance imaging (MRI) for the first time to have a small nonenhancing tectal glioma that remained stable on follow-up MRI. At the age of 25 yr, she returned for annual follow-up after giving birth and reported a significant increase in headache frequency and severity during the pregnancy. Repeat imaging now showed a larger, contrast-enhancing lesion. A decision was made to pursue radiosurgery, but during the pretreatment planning phase, the lesion and symptoms regressed spontaneously, and the lesion has remained stable on repeat MRI studies over a 30-mo period since delivery of her child., Conclusion: A young woman with a tectal glioma developed symptomatic disease progression during pregnancy, and subsequently had regression of the lesion and symptoms in the postpartum period without treatment. This case supports watchful waiting in select cases and suggests a potential role of hormones in glioma progression., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Noninvasive imaging methods are sought to objectively predict early response to therapy for high-grade glioma tumors. Quantitative metrics derived from diffusion-weighted imaging, such as apparent diffusion coefficient (ADC), have previously shown promise when used in combination with voxel-based analysis reflecting regional changes. The functional diffusion mapping (fDM) metric is hypothesized to be associated with volume of tumor exhibiting an increasing ADC owing to effective therapeutic action. In this work, the reference fDM-predicted survival (from previous study) for 3 weeks from treatment initiation (midtreatment) is compared to multiple histogram-based metrics using Kaplan-Meier estimator for 80 glioma patients stratified to responders and nonresponders based on the population median value for the given metric. The ADC histogram metric reflecting reduction in midtreatment volume of solid tumor (ADC < 1.25 × 10 -3 mm 2 /s) by >8% population-median with respect to pretreatment is found to have the same predictive power as the reference fDM of increasing midtreatment ADC volume above 4%. This study establishes the level of correlation between fDM increase and low-ADC tumor volume shrinkage for prediction of early response to radiation therapy in patients with glioma malignancies.

Purpose: Glioblastoma (GBM) remains incurable, despite state-of-the-art treatment involving surgical resection, chemotherapy, and radiation. GBM invariably recurs as a highly invasive and aggressive phenotype, with the majority of recurrences within the radiation therapy treatment field. Although a large body of literature reporting on primary GBM exists, comprehensive studies of how prior irradiation alters recurrent tumor growth are lacking. An animal model that replicates the delayed effects of radiation therapy on the brain microenvironment, and its impact on the development of recurrent GBM, would be a significant advance., Methods and Materials: Cohorts of mice received a single fraction of 0, 20, 30, or 40 Gy Gamma Knife irradiation. Naïve, nonirradiated mouse GBM tumor cells were implanted into the ipsilateral hemisphere 6 weeks postirradiation. Tumor growth was measured by magnetic resonance imaging, and animal survival was assessed by monitoring weight loss. Magnetic resonance imaging results were supported by hemotoxylin and eosin histology., Results: Tumorous lesions generated from orthotopic implantation of nonirradiated mouse GBM tumor cells into irradiated mouse brain grew far more aggressively and invasively than implantation of these same cells into nonirradiated brain. Lesions in irradiated brain tissue were significantly larger, more necrotic, and more vascular than those in control animals with increased invasiveness of tumor cells in the periphery, consistent with the histologic features commonly observed in recurrent high-grade tumors in patients., Conclusions: Irradiation of normal brain primes the targeted cellular microenvironment for aggressive tumor growth when naïve (not previously irradiated) cancer cells are subsequently introduced. The resultant growth pattern is similar to the highly aggressive pattern of tumor regrowth observed clinically after therapeutic radiation therapy. The mouse model offers an avenue for determining the cellular and molecular basis for the aggressiveness of recurrent GBM., (Copyright © 2018. Published by Elsevier Inc.)

We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan-Meier methods and the log-rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60-100) and median age was 67 years (range 60-81), with 29 patients ≥ 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9-11.0) and OS was 12.7 months (95% CI 9.7-14.1). Patients age ≥ 70 with KPS ≥ 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8-0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1-0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3-0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment.

Purpose: Blood-tumor barrier is a limiting factor for effectiveness of systemic therapy to brain metastases. This study aimed to assess the extent and time course of BTB opening in BM following whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) to determine optimal timing for systemic therapy., Materials and Method: 30 patients received WBRT or SRS and a total of 64 metastatic lesions were analyzed. Dynamic contrast-enhanced MRI were acquired, to quantify a transfer constant (K trans ), pre-RT, 1-2weeks after starting RT (Wk1-2), and 1-month post-RT (1M post-RT). Lesions were categorized as either low or high permeability based upon the pre-RT percentage volume of a lesion with K trans >0.005min -1 (%V all ) less or greater than 50%. Time-course changes of %V all after RT were analyzed., Results: Fifty-seven lesions had high-permeability and seven had low-permeability at baseline. Intra-patient and inter-lesion heterogeneity was observed in six patients who had both low- (n=7) and high-permeability lesions (n=10). Also, lesion permeability showed a significant size-effect at baseline. For high-permeability lesions, either received WBRT (n=43) or SRS (n=14), %V all decreased non-significantly following RT (from 85.4% pre-RT to 76.9% 1M post-RT). For low-permeability lesions (n=7, all received WBRT), %V all increased from 5.6% pre-RT to 30.2% at Wk1-2 and to 52.6% 1M-post (p=0.01)., Conclusion: Our preliminary results suggest that 2-4weeks after RT, when BTB opening is high for both low- and high-permeability brain metastatic lesions, could be optimal time to start systemic therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

To investigate the utilization and overall survival (OS) impact of concurrent chemotherapy in combination with radiation therapy (RT) for elderly glioblastoma (GBM) patients. Elderly patients (age >70) with supratentorial and nonmetastatic GBM who received RT of 20-75 Gy with concurrent single-agent chemotherapy (ChemoRT) or without (RT alone) during 2004-2012 were identified from the National Cancer Data Base (NCDB). The Cochran-Armitage test was used for trend analysis. Hazard ratios (HR) and 95% confidence intervals (CIs) were determined using Cox proportional hazards. Propensity score analysis was performed to reduce selection bias in treatment allocation. A total of 5252 patients were identified (RT alone: n = 1389; ChemoRT: n = 3863). There was increasing utilization of chemotherapy during this period (45-80%, P < .001). A similar trend was also observed for the subset of age >80 (25-68%, P < .001). ChemoRT was associated with significantly better OS than RT alone (HR 0.79, 95% CI 0.70-0.89, P < .001) on multivariate analysis, and similar OS benefit was demonstrated with 1202 pairs of propensity-matched patients (HR 0.79, 95% CI 0.73-0.86, P < .001). For the matched pair, the median OS was 5.8 months with ChemoRT and 5.0 months with RT alone; the 2-year OS rate was 9% with ChemoRT and 4% with RT alone (P < .001). Concurrent chemotherapy has been administered with RT for the majority of elderly GBM patients. Addition of chemotherapy to RT for elderly GBM patients is associated with significantly improve OS in routine clinical practice.

During the 6 month period following chemoradiotherapy, gliomas frequently develop new areas of contrast enhancement, which are due to treatment effect rather than tumor progression. We sought to characterize this phenomenon in oligodendrogliomas (OG) and mixed oligoastrocytomas (MOA). We reviewed the imaging findings from 143 patients with a WHO grade II or III OG or MOA for evidence of pseudoprogression (PsP) or early tumor progression. We characterized these cases for 1p/19q codeletions by FISH, IDH1 R132H mutation by immunohistochemistry, and TP53, ATRX, and EGFR mutations by next generation sequencing. We then reviewed the pathologic specimens of the patient cases in which a re-resection was performed. We found that OG and MOA that are 1p/19q intact developed PsP at a higher rate than tumors that are 1p/19q codeleted (27 vs. 8 %). Moreover, IDH1 wild-type (WT) tumors developed PsP at a higher rate than IDH1 R132H cases (27 vs. 11 %). Patients with ATRX or TP53 mutations developed PsP at an intermediate rate of 21 %. Ten patients in our cohort underwent a re-resection for early contrast enhancement; these tumors were predominantly 1p/19q intact (90 %) and had a low rate of IDH1 R132H mutation (50 %). 8 of 10 tumors demonstrated primarily treatment effects, while the remaining 2 of 10 demonstrated recurrent/residual tumor of the same grade. Early contrast enhancement that develops during the first 6 months after chemoradiotherapy is typically due to PsP and occurs primarily in OG and MOA that are 1p/19q intact and IDH WT.

Purpose/objectives: Radiation injury to parahippocampal cingulum white matter is associated with cognitive decline. Diffusion tensor imaging (DTI) detects micropathologic changes in white matter. Increased radial diffusion (RD) and decreased axial diffusion (AD) correspond to demyelination and axonal degeneration/gliosis respectively. We aimed to develop a predictive model for radiation-induced cognitive changes based upon DTI changes., Materials/methods: Twenty-seven adults with benign or low-grade tumors received partial brain radiation therapy (RT) to a median dose of 54Gy. Patients underwent DTI before RT, during RT, and at the end of RT. Cognitive testing was performed before RT, and 6 and 18months after RT. Parahippocampal cingulum white matter was contoured to obtain mean values of AD and RD., Results: By univariate analysis, decreasing AD and increasing RD during RT predicted declines in verbal memory and verbal fluency. By multivariate analysis, baseline neurocognitive score was the only clinical variable predicting verbal memory change; no clinical variables predicted verbal fluency change. In a multivariate model, increased RD at the end of RT significantly predicted decline in verbal fluency 18months after RT., Conclusions: Imaging biomarkers of white matter injury contributed to predictive models of cognitive function change after RT., Competing Interests: Statement None of the authors have any real or potential conflicts of interest to disclose., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate the tolerability and efficacy of gemcitabine plus radiation therapy (RT) in this phase 1 study of patients with newly diagnosed malignant glioma (HGG)., Patients and Methods: Between 2004 and 2012, 29 adults with HGG were enrolled. After any extent of resection, RT (60 Gy over 6 weeks) was given concurrent with escalating doses of weekly gemcitabine. Using a time-to-event continual reassessment method, 5 dose levels were evaluated starting at 500 mg/m(2) during the last 2 weeks of RT and advanced stepwise into earlier weeks. The primary objective was to determine the recommended phase 2 dose of gemcitabine plus RT. Secondary objectives included progression-free survival, overall survival (OS), and long-term toxicity., Results: Median follow-up was 38.1 months (range, 8.9-117.5 months); 24 patients were evaluable for toxicity. After 2005 when standard practice changed, patients with World Health Organization grade 4 tumors were no longer enrolled. Median progression-free survival for 22 patients with grade 3 tumors was 26.0 months (95% confidence interval [CI] 15.6-inestimable), and OS was 48.5 months (95% CI 26.8-inestimable). In 4 IDH mutated, 1p/19q codeleted patients, no failures occurred, with all but 1 alive at time of last follow-up. Seven with IDH mutated, non-codeleted tumors with ATRX loss had intermediate OS of 73.5 months (95% CI 32.8-inestimable). Six nonmutated, non-codeleted patients had a median OS of 26.5 months (95% CI 25.4-inestimable). The recommended phase 2 dose of gemcitabine plus RT was 750 mg/m(2)/wk given the last 4 weeks of RT. Dose reductions were most commonly due to grade 3 neutropenia; no grade 4 or 5 toxicities were seen., Conclusions: Gemcitabine concurrent with RT is well-tolerated and yields promising outcomes, including in patients with adverse molecular features. It is a candidate for further study, particularly for poor-prognosis patient subgroups with HGG., (Published by Elsevier Inc.)

Purpose: Use of conventional magnetic resonance imaging (MRI) for target definition may expose glioblastomas (GB) to inadequate radiation dose coverage of the nonenhanced hypercellular subvolume. This study aimed to develop a technique to identify the hypercellular components of GB by using high b-value diffusion-weighted imaging (DWI) and to investigate its relationship with the prescribed 95% isodose volume (PDV) and progression-free survival (PFS)., Methods and Materials: Twenty-one patients with GB underwent chemoradiation therapy post-resection and biopsy. Radiation therapy (RT) treatment planning was based upon conventional MRI. Pre-RT DWIs were acquired in 3 orthogonal directions with b-values of 0, 1000, and 3000 s/mm(2). Hypercellularity volume (HCV) was defined on the high b-value (3000 s/mm(2)) DWI by a threshold method. Nonenhanced signified regions not covered by the Gd-enhanced gross tumor volume (GTV-Gd) on T1-weighted images. The PDV was used to evaluate spatial coverage of the HCV by the dose plan. Association between HCV and PFS or other clinical covariates were assessed using univariate proportional hazards regression models., Results: HCVs and nonenhanced HCVs varied from 0.58 to 67 cm(3) (median: 9.8 cm(3)) and 0.15 to 60 cm(3) (median: 2.5 cm(3)), respectively. Fourteen patients had incomplete dose coverage of the HCV, 6 of whom had >1 cm(3) HCV missed by the 95% PDV (range: 1.01-25.4 cm(3)). Of the 15 patients who progressed, 5 progressed earlier, within 6 months post-RT, and 10 patients afterward. Pre-RT HCVs within recurrent GTVs-Gd were 78% (range: 65%-89%) for the 5 earliest progressions but lower, 53% (range: 0%-85%), for the later progressions. HCV and nonenhanced HCV were significant negative prognostic indicators for PFS (P<.002 and P<.01, respectively). The hypercellularity subvolume not covered by the 95% PDV was a significant negative predictor for PFS (P<.05)., Conclusions: High b-value DWI identifies the hypercellular components of GB and could aid in RT target volume definition. Future studies will allow us to investigate the role of high b-value DWI in identifying radiation boost volumes and diagnosing progression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Diffusion MRI, although having the potential to be a biomarker for early assessment of tumor response to therapy, could be confounded by edema and necrosis in or near the brain tumors. This study aimed to develop and investigate the ability of the diffusion abnormality index (DAI) to be a new imaging biomarker for early assessment of brain metastasis response to radiation therapy (RT)., Methods: Patients with either radiosensitive or radioresistant brain metastases that were treated by whole brain RT alone or combined with bortezomib as a radiation sensitizer had diffusion-weighted (DW) MRI pre-RT and 2 weeks (2W) after starting RT. A patient-specific diffusion abnormality probability function (DAProF) was created to account for abnormal low and high apparent diffusion coefficients differently, reflecting respective high cellularity and edema/necrosis. The DAI of a lesion was then calculated by the integral of DAProF-weighted tumor apparent diffusion coefficient histogram. The changes in DAI from pre-RT to 2W were evaluated for differentiating the responsive, stable, and progressive tumors and compared with the changes in gross tumor volume and conventional diffusion metrics during the same time interval., Results: In lesions treated with whole brain RT, the DAI performed the best among all metrics in predicting the posttreatment response of brain metastases to RT. In lesions treated with whole brain RT + bortezomib, although DAI was the best predictor, the performance of all metrics worsened compared with the first group., Conclusions: The ability of DAI for early assessment of brain metastasis response to RT depends upon treatment regimes.

Purpose: To develop a pharmacokinetic modelfree framework to analyze the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data for assessment of response of brain metastases to radiation therapy., Methods: Twenty patients with 45 analyzable brain metastases had MRI scans prior to whole brain radiation therapy (WBRT) and at the end of the 2-week therapy. The volumetric DCE images covering the whole brain were acquired on a 3T scanner with approximately 5 s temporal resolution and a total scan time of about 3 min. DCE curves from all voxels of the 45 brain metastases were normalized and then temporally aligned. A DCE matrix that is constructed from the aligned DCE curves of all voxels of the 45 lesions obtained prior to WBRT is processed by principal component analysis to generate the principal components (PCs). Then, the projection coefficient maps prior to and at the end of WBRT are created for each lesion. Next, a pattern recognition technique, based upon fuzzy-c-means clustering, is used to delineate the tumor subvolumes relating to the value of the significant projection coefficients. The relationship between changes in different tumor subvolumes and treatment response was evaluated to differentiate responsive from stable and progressive tumors. Performance of the PC-defined tumor subvolume was also evaluated by receiver operating characteristic (ROC) analysis in prediction of nonresponsive lesions and compared with physiological-defined tumor subvolumes., Results: The projection coefficient maps of the first three PCs contain almost all response-related information in DCE curves of brain metastases. The first projection coefficient, related to the area under DCE curves, is the major component to determine response while the third one has a complimentary role. In ROC analysis, the area under curve of 0.88 ± 0.05 and 0.86 ± 0.06 were achieved for the PC-defined and physiological-defined tumor subvolume in response assessment., Conclusions: The PC-defined subvolume of a brain metastasis could predict tumor response to therapy similar to the physiological-defined one, while the former is determined more rapidly for clinical decision-making support.

Ipilimumab, an antibody that enhances T-cell activation, may augment immunogenicity of tumor cells that are injured by radiation therapy. We hypothesized that patients with melanoma brain metastasis treated with both ipilimumab and radiotherapy would have improved overall survival, and that the sequence of treatments may affect disease control in the brain. We analyzed the clinical and radiographic records of melanoma patients with brain metastases who were treated with whole brain radiation therapy or stereotactic radiosurgery between 2005 and 2012. The hazard ratios for survival were estimated to assess outcomes as a function of ipilimumab use and radiation type. Seventy patients were identified, 33 of whom received ipilimumab and 37 who did not. The patients who received ipilimumab had a censored median survival of 18.3 months (95% confidence interval 8.1-25.5), compared with 5.3 months (95% confidence interval 4.0-7.6) for patients who did not receive ipilimumab. Ipilimumab and stereotactic radiosurgery were each significant predictors of improved overall survival (hazard ratio = 0.43 and 0.45, with P = 0.005 and 0.008, respectively). Four of 10 evaluable patients (40.0%) who received ipilimumab prior to radiotherapy demonstrated a partial response to radiotherapy, compared with two of 22 evaluable patients (9.1%) who did not receive ipilimumab. Ipilimumab is associated with a significantly reduced risk of death in patients with melanoma brain metastases who underwent radiotherapy, and this finding supports the need for multimodality therapy to optimize patient outcomes. Prospective studies are needed and are underway., (© 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis., Methods: A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects., Results: Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023)., Conclusions: Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.

Purpose: To develop an image analysis framework to delineate the physiological imaging-defined subvolumes of a tumor in relating to treatment response and outcome., Methods and Materials: Our proposed approach delineates the subvolumes of a tumor based on its heterogeneous distributions of physiological imaging parameters. The method assigns each voxel a probabilistic membership function belonging to the physiological parameter classes defined in a sample of tumors, and then calculates the related subvolumes in each tumor. We applied our approach to regional cerebral blood volume (rCBV) and Gd-DTPA transfer constant (K(trans)) images of patients who had brain metastases and were treated by whole-brain radiation therapy (WBRT). A total of 45 lesions were included in the analysis. Changes in the rCBV (or K(trans))-defined subvolumes of the tumors from pre-RT to 2 weeks after the start of WBRT (2W) were evaluated for differentiation of responsive, stable, and progressive tumors using the Mann-Whitney U test. Performance of the newly developed metrics for predicting tumor response to WBRT was evaluated by receiver operating characteristic (ROC) curve analysis., Results: The percentage decrease in the high-CBV-defined subvolumes of the tumors from pre-RT to 2W was significantly greater in the group of responsive tumors than in the group of stable and progressive tumors (P<.007). The change in the high-CBV-defined subvolumes of the tumors from pre-RT to 2W was a predictor for post-RT response significantly better than change in the gross tumor volume observed during the same time interval (P=.012), suggesting that the physiological change occurs before the volumetric change. Also, K(trans) did not add significant discriminatory information for assessing response with respect to rCBV., Conclusion: The physiological imaging-defined subvolumes of the tumors delineated by our method could be candidates for boost target, for which further development and evaluation is warranted., (Published by Elsevier Inc.)

Purpose: There is little known about how brain white matter structures differ in their response to radiation, which may have implications for radiation-induced neurocognitive impairment. We used diffusion tensor imaging (DTI) to examine regional variation in white matter changes following chemoradiotherapy., Methods: Fourteen patients receiving two or three weeks of whole-brain radiation therapy (RT) ± chemotherapy underwent DTI pre-RT, at end-RT, and one month post-RT. Three diffusion indices were measured: fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). We determined significant individual voxel changes of diffusion indices using tract-based spatial statistics, and mean changes of the indices within fourteen white matter structures of interest., Results: Voxels of significant FA decreases and RD increases were seen in all structures (p<0.05), with the largest changes (20-50%) in the fornix, cingula, and corpus callosum. There were highly significant between-structure differences in pre-RT to end-RT mean FA changes (p<0.001). The inferior cingula had a mean FA decrease from pre-RT to end-RT significantly greater than 11 of the 13 other structures (p<0.00385)., Conclusions: Brain white matter structures varied greatly in their response to chemoradiotherapy as measured by DTI changes. Changes in FA and RD related to white matter demyelination were prominent in the cingula and fornix, structures relevant to radiation-induced neurocognitive impairment. Future research should evaluate DTI as a predictive biomarker of brain chemoradiotherapy adverse effects.

Purpose: To segment fiber tracts in the limbic circuit and to assess their sensitivity to radiation therapy (RT)., Methods: Twelve patients with brain metastases who had received fractionated whole brain radiation therapy to 30 Gy or 37.5 Gy were included in the study. Diffusion weighted images were acquired pre-RT, at the end of RT, and 1-month post-RT. The fornix, corpus callosum, and cingulum were extracted from diffusion weighted images by combining fiber tracking and segmentation methods based upon characteristics of the fiber bundles. Cingulum was segmented by a seed-based tractography, fornix by a region of interests (ROI)-based tractography, and corpus callosum by a level-set segmentation algorithm. The radiation-induced longitudinal changes of diffusion indices of the structures were evaluated., Results: Significant decreases were observed in the fractional anisotropy of the posterior part of the cingulum, fornix, and corpus callosum from pre-RT to end of RT by -14.0%, -12.5%, and -5.2%, respectively (p < 0.001), and from pre-RT to 1-month post-RT by -11.9%, -12.8%, and -6.4%, respectively (p < 0.001). Moreover, significant increases were observed in the mean diffusivity of the corpus callosum and the posterior part of the cingulum from pre-RT to end of RT by 6.8% and 6.5%, respectively, and from pre-RT to 1-month post-RT by 8.5% and 6.3%, respectively. The increase in the radial diffusivity primarily contributed to the significant decrease in the fractional anisotropy, indicating that demyelination is the predominant radiation effect on the white matter structures., Conclusions: Our findings indicate that the fornix and the posterior part of the cingulum are significantly susceptible to radiation damage. We have developed robust computer-aided semiautomatic segmentation and fiber tracking tools to facilitate the ROI delineation of critical structures, which is important for assessment of radiation damage in a longitudinal fashion.

Purpose: To develop an approach for computer-aided detection (CAD) of small brain metastases in post-Gd T1-weighted magnetic resonance imaging (MRI)., Method: A set of unevenly spaced 3D spherical shell templates was optimized to localize brain metastatic lesions by cross-correlation analysis with MRI. Theoretical and simulation analyses of effects of lesion size and shape heterogeneity were performed to optimize the number and size of the templates and the cross-correlation thresholds. Also, effects of image factors of noise and intensity variation on the performance of the CAD system were investigated. A nodule enhancement strategy to improve sensitivity of the system and a set of criteria based upon the size, shape and brightness of lesions were used to reduce false positives. An optimal set of parameters from the FROC curves was selected from a training dataset, and then the system was evaluated on a testing dataset including 186 lesions from 2753 MRI slices. Reading results from two radiologists are also included., Results: Overall, a 93.5% sensitivity with 0.024 of intra-cranial false positive rate (IC-FPR) was achieved in the testing dataset. Our investigation indicated that nodule enhancement was very effective in improving both sensitivity and specificity. The size and shape criteria reduced the IC-FPR from 0.075 to 0.021, and the brightness criterion decreases the extra-cranial FPR from 0.477 to 0.083 in the training dataset. Readings from the two radiologists had sensitivities of 60% and 67% in the training dataset and 70% and 80% in the testing dataset for the metastatic lesions <5 mm in diameter., Conclusion: Our proposed CAD system has high sensitivity and fairly low FPR for detection of the small brain metastatic lesions in MRI compared to the previous work and readings of neuroradiologists. The potential of this method for assisting clinical decision- making warrants further evaluation and improvements., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To determine the maximum-tolerated dose (MTD) of radiation (RT) with concurrent temozolomide in patients with newly diagnosed glioblastoma (GBM), to estimate their progression-free (PFS) and overall survival (OS), and to assess the role of (11)C methionine PET (MET-PET) imaging in predicting recurrence., Experimental Design: Intensity-modulated RT (IMRT) doses of 66 to 81 Gy, assigned to patients by the time-to-event continual reassessment method, were delivered over 6 weeks with concurrent daily temozolomide (75 mg/m(2)) followed by adjuvant cyclic temozolomide (200 mg/m(2) d1-5 q28d ×6 cycles). Treatment was based on gadolinium-enhanced MRI. Pretreatment MET-PET scans were obtained for correlation with eventual sites of failure., Results: A total of 38 patients were analyzed with a median follow-up of 54 months for patients who remain alive. Late CNS grade ≥III toxicity was observed at 78 (2 of 7 patients) and 81 Gy (1 of 9 patients). None of 22 patients receiving 75 or less Gy developed RT necrosis. Median OS and PFS were 20.1 (14.0-32.5) and 9.0 (6.0-11.7) months, respectively. Twenty-two of 32 patients with pretreatment MET-PET uptake showed uptake beyond the contrast-enhanced MRI. Patients whose treatment did not include the region of increased MET-PET uptake showed an increased risk of noncentral failure (P < 0.001)., Conclusions: Patients with GBM can safely receive standard temozolomide with 75 Gy in 30 fractions, delivered using IMRT. The median OS of 20.1 months is promising. Furthermore, MET-PET appears to predict regions of high risk of recurrence not defined by MRI, suggesting that further improvements may be possible by targeting metabolically active regions., (© 2011 AACR.)

Although the addition of concurrent and adjuvant temozolomide (TMZ) to standard-dose radiation (60 Gy) improves survival, the pattern of failure continues to be local. Conventional contrast enhanced T1-weighted and T2-weighted magnetic resonance imaging (MRI) used for radiation planning reflect anatomic rather than molecular or functional, properties of the tumor. Functional and metabolic MRI and positron emission tomography are able to detect metabolic and functional abnormalities beyond the tumor volume seen on conventional MRI, assess early response to treatment, and delineate the regions of high risks for failure in high-grade gliomas. This article focuses on the potential of these functional and metabolic imaging techniques to refine our clinical target volumes.

Purpose: To determine whether early assessment of cerebral microvessel injury can predict late neurocognitive dysfunction after brain radiation therapy (RT)., Experimental Design: Ten patients who underwent partial brain RT participated in a prospective dynamic contrast-enhanced magnetic resonance imaging (MRI) study. Dynamic contrast-enhanced MRI was acquired prior to, at weeks 3 and 6 during, and 1 and 6 months after RT. Neuropsychological tests were done pre-RT and at the post-RT MRI follow-ups. The correlations between early delayed changes in neurocognitive functions and early changes in vascular variables during RT were analyzed., Results: No patients had tumor progression up to 6 months after RT. Vascular volumes and blood-brain barrier (BBB) permeability increased significantly in the high-dose regions during RT by 11% and 52% (P<0.05), respectively, followed by a decrease after RT. Changes in both vascular volume and BBB permeability correlated with the doses accumulated at the time of scans at weeks 3 and 6 during RT and 1 month after RT (P<0.03). Changes in verbal learning scores 6 months after RT were significantly correlated with changes in vascular volumes of left temporal (P<0.02) and frontal lobes (P<0.03), and changes in BBB permeability of left frontal lobes during RT (P<0.007). A similar correlation was found between recall scores and BBB permeability., Conclusion: Our data suggest that the early changes in cerebral vasculature may predict delayed alterations in verbal learning and total recall, which are important components of neurocognitive function. Additional studies are required for validation of these findings.

Objective: Differentiation between recurrent neoplasm and postradiation change in patients previously treated for primary brain tumors is often difficult based on imaging features alone. The purpose of this study was to develop a method using alterations in the ratios of standard brain metabolites-choline (Cho), creatine (Cr), and N-acetylaspartate (NAA)-to predict the probability of tumor recurrence in patients previously treated for brain tumors with new contrast-enhancing lesions., Materials and Methods: Thirty-three patients who had undergone treatment for primary brain tumors in whom routine MRI showed new contrast-enhancing lesions were retrospectively studied. The final diagnosis was assigned using histopathology (n = 13) or imaging follow-up (n = 20; range, 2-27 months). Ratios of three metabolites (Cho, Cr, and NAA) were calculated, and the results were correlated with the final diagnosis using a Wilcoxon's rank sum analysis. A logistic regression model was then used to create a prediction model based on the most statistically significant ratio., Results: Elevations of the metabolic ratios Cho/Cr (p < 0.001) and Cho/NAA (p < 0.001) and a decrease in the ratio NAA/Cr (p = 0.018) were found in patients with recurrent tumor (n = 20) versus those with postradiation change (n = 13). A prediction model using the Cho/NAA ratio yielded a sensitivity of 85%, a specificity of 69.2%, and an area under the receiver operating characteristic curve of 0.92., Conclusion: An elevated Cho/NAA ratio correlated with evidence of tumor recurrence and allowed creation of a prediction rule to aid in lesion classification. The results suggest that MR spectroscopy is a useful tool in assigning patients with nonspecific enhancing lesions to either invasive biopsy or conservative management.

Purpose: To quantify the radiation-induced changes in normal-appearing white matter before, during, and after radiotherapy (RT) in cerebral tumor patients., Methods and Materials: Twenty-five patients with low-grade glioma, high-grade glioma, or benign tumor treated with RT were studied using diffusion tensor magnetic resonance imaging. The biologically corrected doses ranged from 50 to 81 Gy. The temporal changes were assessed before, during, and to 45 weeks after the start of RT. The mean diffusivity of water (), fractional anisotropy of diffusion, diffusivity perpendicular (lambdaperpendicular) and parallel (lambda||) to white matter fibers were calculated in normal-appearing genu and splenium of the corpus callosum., Results: In the genu and splenium, fractional anisotropy decreased and , lambda||, lambdaperpendicular increased linearly and significantly with time (p<0.01). At 45 weeks after the start of RT, lambdaperpendicular had increased approximately 30% in the genu and splenium, and lambda|| had increased 5% in the genu and 9% in the splenium, suggesting that demyelination is predominant. The increases in lambdaperpendicular and lambda|| were dose dependent, starting at 3 weeks and continuing to 32 weeks from the start of RT. The dose-dependent increase in lambdaperpendicular and lambda|| was not sustained after 32 weeks, indicating the transition from focal to diffuse effects., Conclusion: The acute and subacute changes in normal-appearing white matter fibers indicate radiation-induced demyelination and mild structural degradation of axonal fibers. The structural changes after RT are progressive, with early dose-dependent demyelination and subsequent diffuse dose-independent demyelination and mild axonal degradation. Diffusion tensor magnetic resonance imaging is potentially a biomarker for the assessment of radiation-induced white matter injury.

Purpose: To determine whether cerebral blood volume (CBV) and cerebral blood flow can predict the response of high-grade gliomas to radiotherapy (RT) by taking into account spatial heterogeneity and temporal changes in perfusion., Methods and Materials: Twenty-three patients with high-grade gliomas underwent conformal RT, with magnetic resonance imaging perfusion before and at Weeks 1-2 and 3-4 during RT. Tumor perfusion was classified as high, medium, or low. The prognostic values of pre-RT perfusion and the changes during RT for early prediction of tumor response to RT were evaluated., Results: The fractional high-CBV tumor volume before RT and the fluid-attenuated inversion recovery imaging tumor volume were identified as predictors for survival (p = 0.01). Changes in tumor CBV during the early treatment course also predicted for survival. Better survival was predicted by a decrease in the fractional low-CBV tumor volume at Week 1 of RT vs. before RT, a decrease in the fractional high-CBV tumor volume at Week 3 vs. Week 1 of RT, and a smaller pre-RT fluid-attenuated inversion recovery imaging tumor volume (p = 0.01)., Conclusion: Early temporal changes during RT in heterogeneous regions of high and low perfusion in gliomas might predict for different physiologic responses to RT. This might also open the opportunity to identify tumor subvolumes that are radioresistant and might benefit from intensified RT.

Diffuse malignant gliomas, the most common type of brain tumor, carry a dire prognosis and are poorly responsive to initial treatment. The response to treatment is typically evaluated by measurements obtained from radiographic images several months after the start of treatment; therefore, an early biomarker of tumor response would be useful for making early treatment decisions and for prognostic information. Thirty-four patients with malignant glioma were examined by diffusion MRI before treatment and 3 weeks later. These images were coregistered, and differences in tumor-water diffusion values were calculated as functional diffusion maps (fDM), which were correlated with the radiographic response, time-to-progression (TTP), and overall survival (OS). Changes in fDM at 3 weeks were closely associated with the radiographic response at 10 weeks. The percentage of the tumor undergoing a significant change in the diffusion of water (V(T)) was different between patients with progressive disease (PD) vs. stable disease (SD) (P < 0.001). Patients classified as PD by fDM analysis at 3 weeks were found to have a shorter TTP compared with SD (median TTP, 4.3 vs. 7.3 months; P < 0.04). By using fDM, early patient stratification also was correlated with shorter OS in the PD group compared with SD patients (median survival, 8.0 vs. 18.2 months; P < 0.01). On the basis of fDM, tumor assessment provided an early biomarker for response, TTP, and OS in patients with malignant glioma. Further evaluation of this technique is warranted to determine whether it may be useful in the individualization of treatment or evaluation of the response in clinical protocols.

Purpose: For chemotherapy to act synergistically and safely with radiation against high-grade gliomas, drugs must pass the endothelial junctions of the blood-tumor barrier (BTB) to reach all tumor cells, and should not pass the blood-brain barrier (BBB) to cause toxicity to normal brain. The objective of this study was to assess BBB/BTB status using magnetic resonance imaging (MRI) during a course of radiotherapy of high-grade gliomas., Patients and Methods: Sixteen patients with grade 3 or 4 supratentorial malignant glioma receiving conformal radiotherapy (RT) underwent contrast-enhanced MRI before, during, and after completion of RT. A gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) uptake index was analyzed with respect to the tumor and RT dose received., Results: In the nonenhanced tumor region, contrast uptake increased significantly after the receipt of approximately 10 Gy (P < .01), and reached a maximum after the receipt of approximately 30 Gy. In the initially contrast-enhanced tumor region, contrast uptake decreased over the course of RT and became significant after completion of RT in patients without progressive disease. The healthy brain showed only nonsignificant changes during and after irradiation., Conclusion: Contrast MRI reveals increases in Gd-DTPA uptake in the initially nonenhanced tumor region but not in the remaining brain during the course of RT, suggesting opening of the BTB. This finding suggests that the effect of conformal radiation is more selective on the BTB than the BBB, and there may be a window extending from 1 week after the initiation of radiotherapy to 1 month after the completion of treatment during which a pharmaceutical agent has maximum access to high-grade gliomas.