PET/CT-Based Absorbed Dose Maps in 90Y Selective Internal Radiation Therapy Correlate with Spatial Changes in Liver Function Derived from Dynamic MRI.

Functional liver parenchyma can be damaged from treatment of liver malignancies with 90Y selective internal radiation therapy (SIRT). Evaluating functional parenchymal changes and developing an absorbed dose (AD)-toxicity model can assist the clinical management of patients receiving SIRT. We aimed to determine whether there is a correlation between 90Y PET AD voxel maps and spatial changes in the nontumoral liver (NTL) function derived from dynamic gadoxetic acid-enhanced MRI before and after SIRT. Methods: Dynamic gadoxetic acid-enhanced MRI scans were acquired before and after treatment for 11 patients undergoing 90Y SIRT. Gadoxetic acid uptake rate (k1) maps that directly quantify spatial liver parenchymal function were generated from MRI data. Voxel-based AD maps, derived from the 90Y PET/CT scans, were binned according to AD. Pre- and post-SIRT k1 maps were coregistered to the AD map. Absolute and percentage k1 loss in each bin was calculated as a measure of loss of liver function, and Spearman correlation coefficients between k1 loss and AD were evaluated for each patient. Average k1 loss over the patients was fit to a 3-parameter logistic function based on AD. Patients were further stratified into subgroups based on lesion type, baseline albumin-bilirubin scores and alanine transaminase levels, dose-volume effect, and number of SIRT treatments. Results: Significant positive correlations (ρ = 0.53-0.99, P < 0.001) between both absolute and percentage k1 loss and AD were observed in most patients (8/11). The average k1 loss over 9 patients also exhibited a significant strong correlation with AD (ρ ≥ 0.92, P < 0.001). The average percentage k1 loss of patients across AD bins was 28%, with a logistic function model demonstrating about a 25% k1 loss at about 100 Gy. Analysis between patient subgroups demonstrated that k1 loss was greater among patients with hepatocellular carcinoma, higher alanine transaminase levels, larger fractional volumes of NTL receiving an AD of 70 Gy or more, and sequential SIRT treatments. Conclusion: Novel application of multimodality imaging demonstrated a correlation between 90Y SIRT AD and spatial functional liver parenchymal degradation, indicating that a higher AD is associated with a larger loss of local hepatocyte function. With the developed response models, PET-derived AD maps can potentially be used prospectively to identify localized damage in liver and to enhance treatment strategies.

Integrating multi-modal imaging in radiation treatments for glioblastoma.

Advances in diagnostic and treatment technology along with rapid developments in translational research may now allow the realization of precision radiotherapy. Integration of biologically informed multimodality imaging to address the spatial and temporal heterogeneity underlying treatment resistance in glioblastoma is now possible for patient care, with evidence of safety and potential benefit. Beyond their diagnostic utility, several candidate imaging biomarkers have emerged in recent early-phase clinical trials of biologically based radiotherapy, and their definitive assessment in multicenter prospective trials is already in development. In this review, the rationale for clinical implementation of candidate advanced magnetic resonance imaging and positron emission tomography imaging biomarkers to guide personalized radiotherapy, the current landscape, and future directions for integrating imaging biomarkers into radiotherapy for glioblastoma are summarized. Moving forward, response-adaptive radiotherapy using biologically informed imaging biomarkers to address emerging treatment resistance in rational combination with novel systemic therapies may ultimately permit improvements in glioblastoma outcomes and true individualization of patient care.

Does Vascular Collapse Occur After Treatment of Hepatocellular Cancer With Stereotactic Body Radiation Therapy?

There is debate about why stereotactic body radiation therapy (SBRT) produces superior control of hepatocellular cancer (HCC) compared to fractionated treatment. Both preclinical and clinical evidence has been presented to support a "classic" biological explanation: the greater BED of SBRT produces more DNA damage and tumor cell kill. More recently, preclinical evidence has supported the concept of a "new biology", particularly radiation-induced vascular collapse, which increases hypoxia and free radical activation. This is hypothesized to cause much greater tumor cell death than was produced by the initial radiation-induced DNA damage to the tumor. We decided to investigate if vascular collapse occurs after standard SBRT for patients with HCC. Eight patients with 10 lesions underwent dynamic contrast enhanced MRI at the time of simulation and either 48 or 96 hours after the first fraction. Only three of 10 tumors showed a decrease in blood flow. These findings suggest that vascular collapse does not typically occur after SBRT for HCC.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation. METHODS AND MATERIALS: This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months. RESULTS: There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P = .018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P = .037) compared with patients receiving standard CRT. CONCLUSIONS: Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption.

Deep learning prediction of post-SBRT liver function changes and NTCP modeling in hepatocellular carcinoma based on DGAE-MRI.

BACKGROUND: Stereotactic body radiation therapy (SBRT) produces excellent local control for patients with hepatocellular carcinoma (HCC). However, the risk of toxicity for normal liver tissue is still a limiting factor. Normal tissue complication probability (NTCP) models have been proposed to estimate the toxicity with the assumption of uniform liver function distribution, which is not optimal. With more accurate regional liver functional imaging available for individual patient, we can improve the estimation and be more patient-specific. PURPOSE: To develop normal tissue complication probability (NTCP) models using pre-/during-treatment (RT) dynamic Gadoxetic Acid-enhanced (DGAE) MRI for adaptation of RT in a patient-specific manner in hepatocellular cancer (HCC) patients who receive SBRT. METHODS: 24 of 146 HCC patients who received SBRT underwent DGAE MRI. Physical doses were converted into EQD2 for analysis. Voxel-by-voxel quantification of the contrast uptake rate (k1) from DGAE-MRI was used to quantify liver function. A logistic dose-response model was used to estimate the fraction of liver functional loss, and NTCP was estimated using the cumulative functional reserve model for changes in Child-Pugh (C-P) scores. Model parameters were calculated using maximum-likelihood estimations. During-RT liver functional maps were predicted from dose distributions and pre-RT k1 maps with a conditional Wasserstein generative adversarial network (cWGAN). Imaging prediction quality was assessed using root-mean-square error (RMSE) and structural similarity (SSIM) metrics. The dose-response and NTCP were fit on both original and cWGAN predicted images and compared using a Wilcoxon signed-rank test. RESULTS: Logistic dose response models for changes in k1 yielded D50 of 35.2 (95% CI: 26.7-47.5) Gy and k of 0.62 (0.49-0.75) for the whole population. The high baseline ALBI (poor liver function) subgroup showed a significantly smaller D50 of 11.7 (CI: 9.06-15.4) Gy and larger k of 0.96 (CI: 0.74-1.22) compared to a low baseline ALBI (good liver function) subgroup of 54.8 (CI: 38.3-79.1) Gy and 0.59 (CI: 0.48-0.74), with p-values of < 0.001 and = 0.008, respectively, which indicates higher radiosensitivity for the worse baseline liver function cohort. Subset analyses were also performed for high/low baseline CP subgroups. The corresponding NTCP models showed good agreement for the fit parameters between cWGAN predicted and the ground-truth during-RT images with no statistical differences for low ALBI subgroup. CONCLUSIONS: NTCP models which incorporate voxel-wise functional information from DGAE-MRI k1 maps were successfully developed and feasibility was demonstrated in a small patient cohort. cWGAN predicted functional maps show promise for estimating localized patient-specific response to RT and warrant further validation in a larger patient cohort.

The Effect of Stereotactic Body Radiation Therapy for Hepatocellular Cancer on Regional Hepatic Liver Function.

PURPOSE: To investigate direct radiation dose-related and inflammation-mediated regional hepatic function losses after stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) and poor liver function. METHODS AND MATERIALS: Twenty-four patients with HCC enrolled on an IRB-approved adaptive SBRT trial had liver dynamic gadoxetic acid-enhanced magnetic resonance imaging and blood sample collections before and 1 month after SBRT. Gadoxetic acid uptake rate (k1) maps were quantified for regional hepatic function and coregistered to both 2-Gy equivalent dose and physical dose distributions. Regional k1 loss patterns from before to after SBRT were analyzed for effects of dose and patient using a mixed-effects model and logistic function and were associated with pretherapy liver-function albumin-bilirubin scores. Plasma levels of tumor necrosis factor α receptor 1 (TNFR1), an inflammation marker, were correlated with mean k1 losses in the lowest dose regions by Spearman rank correlation. RESULTS: The whole group had a k1 loss rate of 0.4%/Gy (2-Gy equivalent dose); however, there was a significant random effect of patient in the mixed-effect model (P < .05). Patients with poor and good liver functions lost 50% of k1 values at 12.5 and 57.2 Gy and 33% and 16% of k1 values at the lowest dose regions (<5 Gy), respectively. The k1 losses at the lowest dose regions of individual patients were significantly correlated with their TNFR1 levels after SBRT (P < .02). CONCLUSIONS: The findings suggest that regional hepatic function losses after SBRT in patients with HCC include both direct radiation dose-dependent and inflammation-mediated effects, which could influence how to manage these patients to preserve their liver function after SBRT.

Randomized Phase II Study of Physiologic MRI-Directed Adaptive Radiation Boost in Poor Prognosis Head and Neck Cancer.

PURPOSE: We conducted a randomized phase II multicenter clinical trial to test the hypothesis that physiologic MRI-based radiotherapy (RT) dose escalation would improve the outcome of patients with poor prognosis head and neck cancer. PATIENTS AND METHODS: MRI was acquired at baseline and at RT fraction 10 to create low blood volume/apparent diffusion coefficient maps for RT boost subvolume definition in gross tumor volume. Patients were randomized to receive 70 Gy (standard RT) or 80 Gy to the boost subvolume (RT boost) with concurrent weekly platinum. The primary endpoint was disease-free survival (DFS) with significance defined at a one-sided 0.1 level, and secondary endpoints included locoregional failure (LRF), overall survival (OS), comparison of adverse events and patient reported outcomes (PRO). RESULTS: Among 81 randomized patients, neither the primary endpoint of DFS (HR = 0.849, P = 0.31) nor OS (HR = 1.19, P = 0.66) was significantly improved in the RT boost arm. However, the incidence of LRF was significantly improved with the addition of the RT boost (HR = 0.43, P = 0.047). Two-year estimates [90% confidence interval (CI)] of the cumulative incidence of LRF were 40% (27%-53%) in the standard RT arm and 18% (10%-31%) in the RT boost arm. Two-year estimates (90% CI) for DFS were 48% (34%-60%) in the standard RT arm and 57% (43%-69%) in the RT boost arm. There were no significant differences in toxicity or longitudinal differences seen in EORTC QLQ30/HN35 subscales between treatment arms in linear mixed-effects models. CONCLUSIONS: Physiologic MRI-based RT boost decreased LRF without a significant increase in grade 3+ toxicity or longitudinal PRO differences, but did not significantly improve DFS or OS. Additional improvements in systemic therapy are likely necessary to realize improvements in DFS and OS.

Gadoxetic Acid Uptake Rate as a Measure of Global and Regional Liver Function as Compared With Indocyanine Green Retention, Albumin-Bilirubin Score, and Portal Venous Perfusion.

Purpose: Global and regional liver function assessments are important for defining the magnitude and spatial distribution of dose to preserve functional liver parenchyma and reduce incidence of hepatotoxicity from radiation therapy for intrahepatic cancer treatment. This individualized liver function-guided radiation therapy strategy is critical for patients with heterogeneous and poor liver function, often observed in cirrhotic patients treated for hepatocellular carcinoma. This study aimed to validate k1 as a measure of global and regional function through comparison with 2 well-regarded global function measures: indocyanine green retention (ICGR) and albumin-bilirubin (ALBI). Methods and Materials: Seventy-nine dynamic gadoxetic acid enhanced magnetic resonance imaging scans were acquired in 40 patients with hepatocellular carcinoma in institutional review board approved prospective protocols. Portal venous perfusion (kpv ) was quantified from gadoxetic acid enhanced magnetic resonance imaging using a dual-input 2-compartment model, and gadoxetic acid uptake rate (k1) was fitted using a linearized single-input 2-compartment model chosen for robust k1 estimation. Four image-derived measures of global liver function were tested: (1) mean k1 multiplied by liver volume (k1VL ) (functional volume), (2) mean k1 multiplied by blood distribution volume (k1Vdis ), (3) mean kpv, and (4) liver volume (VL ). The measure's correlation with corresponding ICGR and ALBI tests was assessed using linear regression. Voxel-wise similarity between k1 and kpv was compared using Spearman ranked correlation. Results: Significant correlations (P < .05) with ICGR and ALBI were found for k1VL, k1Vdis, and VL (in order of strength), but not for mean k pv . The mean ranked correlation coefficient between k1 and kpv maps was 0.09. k1 and kpv maps were predominantly mismatched in patients with poor liver function. Conclusions: The metric combining function and liver volume (k1VL ) was a stronger measure of global liver function compared with perfusion or liver volume alone, especially in patients with poor liver function. Gadoxetic acid uptake rate is promising for both global and regional liver function.

Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: In locally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC), (i) to investigate kinetics of human papillomavirus (HPV) circulating tumor DNA (ctDNA) and association with tumor progression after chemoradiation, and (ii) to compare the predictive value of ctDNA to imaging biomarkers of MRI and FDG-PET. EXPERIMENTAL DESIGN: Serial blood samples were collected from patients with AJCC8 stage III OPSCC (n = 34) enrolled on a randomized trial: pretreatment; during chemoradiation at weeks 2, 4, and 7; and posttreatment. All patients also had dynamic-contrast-enhanced and diffusion-weighted MRI, as well as FDG-PET scans pre-chemoradiation and week 2 during chemoradiation. ctDNA values were analyzed for prediction of freedom from progression (FFP), and correlations with aggressive tumor subvolumes with low blood volume (TVLBV) and low apparent diffusion coefficient (TVLADC), and metabolic tumor volume (MTV) using Cox proportional hazards model and Spearman rank correlation. RESULTS: Low pretreatment ctDNA and an early increase in ctDNA at week 2 compared with baseline were significantly associated with superior FFP (P < 0.02 and P < 0.05, respectively). At week 4 or 7, neither ctDNA counts nor clearance were significantly predictive of progression (P = 0.8). Pretreatment ctDNA values were significantly correlated with nodal TVLBV, TVLADC, and MTV pre-chemoradiation (P < 0.03), while the ctDNA values at week 2 were correlated with these imaging metrics in primary tumor. Multivariate analysis showed that ctDNA and the imaging metrics performed comparably to predict FFP. CONCLUSIONS: Early ctDNA kinetics during definitive chemoradiation may predict therapy response in stage III OPSCC.

Response assessment during chemoradiation using a hypercellular/hyperperfused imaging phenotype predicts survival in patients with newly diagnosed glioblastoma.

BACKGROUND: Adversely prognostic hypercellular and hyperperfused regions of glioblastoma (GBM) predict progression-free survival, and are a novel target for dose-intensified chemoradiation (chemoRT) recently implemented in a phase II clinical trial. As a secondary aim, we hypothesized that dose-intensified chemoRT would induce greater mid-treatment response of hypercellular/hyperperfused tumor regions vs standard chemoradiation, and that early response would improve overall survival (OS). METHODS: Forty-nine patients with newly diagnosed GBM underwent prospective, multiparametric high b value diffusion-weighted MRI (DW-MRI) and perfusion dynamic contrast-enhanced MRI (DCE-MRI) pre-RT and 3-4 weeks into RT. The hypercellular tumor volume (TVHCV, mean contralateral normal brain + 2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal gray matter + 1SD) were generated using automated thresholding. Twenty-six patients were enrolled on a dose-escalation trial targeting TVHCV/TVCBV with 75 Gy in 30 fractions, and 23 non-trial patients comprised the control group. OS was estimated using the Kaplan-Meier method and compared using the log-rank test. The effect of TVHCV/TVCBV and Gd-enhanced tumor volume on OS was assessed using multivariable Cox proportional-hazard regression. RESULTS: Most patients had gross total (47%) or subtotal resection (37%), 25% were MGMT-methylated. Patients treated on the dose-escalation trial had significantly greater reduction in TVHCV/TVCBV (41% reduction, IQR 17%-75%) vs non-trial patients (6% reduction, IQR 6%-22%, P = .002). An increase in TVHCV/TVCBV during chemoRT was associated with worse OS (adjusted hazard ratio [aHR] 1.2, 95%CI 1.0-1.4, P = .02), while pre-treatment tumor volumes (P > .5) and changes in Gd-enhanced volume (P = .9) were not. CONCLUSIONS: Multiparametric MRI permits identification of therapeutic resistance during chemoRT and supports adaptive strategies in future trials.

A Phase 2 Study of Dose-intensified Chemoradiation Using Biologically Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma.

PURPOSE: We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TVHCV) and hyperperfused (TVCBV) tumor volumes would improve outcomes in patients with glioblastoma. METHODS AND MATERIALS: This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TVHCV/TVCBV >1 cm3, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TVHCV/TVCBV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TVHCV/TVCBV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative 11C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test-Revised. RESULTS: Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TVHCV alone, and 13 patients were boosted to both TVHCV/TVCBV. Gross or subtotal resection was performed in 87% of patients; 22% were O6-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TVHCV/TVCBV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TVHCV/TVCBV decreased to less than the median volume (3 cm3) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the 11C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy. CONCLUSIONS: Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy.

Early MRI Blood Volume Changes in Constrictor Muscles Correlate With Postradiation Dysphagia.

PURPOSE: Predicting individual patient sensitivity to radiation therapy (RT) for tumor control or normal tissue toxicity is necessary to individualize treatment planning. In head and neck cancer, radiation doses are limited by many nearby critical structures, including structures involved in swallowing. Previous efforts showed that imaging parameters correlate with RT dose; here, we investigate the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) blood volume (BV) changes in predicting dysphagia. METHODS AND MATERIALS: This study included 32 patients with locally advanced oropharyngeal squamous cell carcinoma treated with definitive chemoradiation on an institutional protocol incorporating baseline and early midtreatment DCE-MRI. BV maps of the pharyngeal constrictor muscles (PCM) were created, and BV increases midtreatment were correlated with the following parameters at 3 and 12 months post-RT: RT dose, Dynamic Imaging Grade of Swallowing Toxicity swallow score, aspiration frequency, European Organisation for Research and Treatment of Cancer HN35 patient-reported outcomes, physician-reported dysphagia, and feeding tube (FT) dependence. RESULTS: The mean BV to the PCMs increased from baseline to fraction 10, which was significant for the superior PCM (P = .006) and middle PCM (P < .001), with a trend in the inferior PCM where lower mean doses were seen (P = .077). The factors associated with FT dependence at 3 months included BV increases in the total PCM (correlation, 0.48; P = .006) and middle PCM (correlation, 0.50; P = .004). A post-RT increase in aspiration was associated with a BV increase in the superior PCM (correlation, 0.44; P = .013),and the increase in the total PCMs was marginally significant (correlation, 0.34; P = .06). The best-performing models of FT dependence (area under the receiver operating curve [AUC] = 0.84) and aspiration increases (AUC = 0.78) included BV increases as well as a mean RT dose to middle PCM. CONCLUSIONS: Our results suggest that midtreatment BV increases derived from DCE-MRI are an early predictor of dysphagia. Further investigation of these promising imaging markers to assess individual patient sensitivity to treatment and the patient's subsequent risk of toxicities is warranted to improve personalization of RT planning.

BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases.

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/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). 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.

Predictive Values of MRI and PET Derived Quantitative Parameters for Patterns of Failure in Both p16+ and p16- High Risk Head and Neck Cancer.

Purpose: FDG-PET adds to clinical factors, such tumor stage and p16 status, in predicting local (LF), regional (RF), and distant failure (DF) in poor prognosis locally advanced head and neck cancer (HNC) treated with chemoradiation. We hypothesized that MRI-based quantitative imaging (QI) metrics could add to clinical predictors of treatment failure more significantly than FDG-PET metrics. Materials and methods: Fifty four patients with poor prognosis HNCs who were enrolled in an IRB approved prospective adaptive chemoradiotherapy trial were analyzed. MRI-derived gross tumor volume (GTV), blood volume (BV), and apparent diffusion coefficient (ADC) pre-treatment and mid-treatment (fraction 10), as well as pre-treatment FDG PET metrics, were analyzed in primary and individual nodal tumors. Cox proportional hazards models for prediction of LRF and DF free survival were used to test the additional value of QI metrics over dominant clinical predictors. Results: The mean ADC pre-RT and its change rate mid-treatment were significantly higher and lower in p16- than p16+ primary tumors, respectively. A Cox model identified that high mean ADC pre-RT had a high hazard for LF and RF in p16- but not p16+ tumors (p = 0.015). Most interesting, persisting subvolumes of low BV (TVbv) in primary and nodal tumors mid-treatment had high-risk for DF (p < 0.05). Also, total nodal GTV mid-treatment, mean/max SUV of FDG in all nodal tumors, and total nodal TLG were predictive for DF (p < 0.05). When including clinical stage (T4/N3) and total nodal GTV in the model, all nodal PET parameters had a p-value of >0.3, and only TVbv of primary tumors had a p-value of 0.06. Conclusion: MRI-defined biomarkers, especially persisting subvolumes of low BV, add predictive value to clinical variables and compare favorably with FDG-PET imaging markers. MRI could be well-integrated into the radiation therapy workflow for treatment planning, response assessment, and adaptive therapy.

Real-Time Quantitative Assessment of Accuracy and Precision of Blood Volume Derived from DCE-MRI in Individual Patients During a Clinical Trial.

Accuracy and precision of quantitative imaging (QI) metrics should be assessed in real time in each patient during a clinical trial to support QI-based decision-making. We developed a framework for real-time quantitative assessment of QI metrics and evaluated accuracy and precision of dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI)-derived blood volume (BV) in a clinical trial for head and neck cancers. Patients underwent DCE-MRI before and after 2 weeks of radiation therapy (2wkRT). A mean as a reference value and a repeatability coefficient (RC) of BV values established from n patients in cerebellum volumes of interest (VOIs), which were normal and affected little by therapy, served as accuracy and precision measurements. The BV maps of a new patient were called accurate and precise if the values in cerebellum VOIs and the difference between the 2 scans agreed with the respective mean and RC with 95% confidence. The new data could be used to update reference values. Otherwise, the data were flagged for further evaluation before use in the trial. BV maps from 62 patients enrolled on the trial were evaluated. Mean BV values were 2.21 (±0.14) mL/100 g pre-RT and 2.22 (±0.17) mL/100 g at 2wkRT; relative RC was 15.9%. The BV maps from 3 patients were identified to be inaccurate and imprecise before use in the clinical trial. Our framework of real-time quantitative assessment of QI metrics during a clinical trial can be translated to different QI metrics and organ-sites for supporting QI-based decision-making that warrants success of a clinical trial.

The Impact of Arterial Input Function Determination Variations on Prostate Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacokinetic Modeling: A Multicenter Data Analysis Challenge, Part II.

This multicenter study evaluated the effect of variations in arterial input function (AIF) determination on pharmacokinetic (PK) analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data using the shutter-speed model (SSM). Data acquired from eleven prostate cancer patients were shared among nine centers. Each center used a site-specific method to measure the individual AIF from each data set and submitted the results to the managing center. These AIFs, their reference tissue-adjusted variants, and a literature population-averaged AIF, were used by the managing center to perform SSM PK analysis to estimate Ktrans (volume transfer rate constant), ve (extravascular, extracellular volume fraction), kep (efflux rate constant), and τi (mean intracellular water lifetime). All other variables, including the definition of the tumor region of interest and precontrast T1 values, were kept the same to evaluate parameter variations caused by variations in only the AIF. Considerable PK parameter variations were observed with within-subject coefficient of variation (wCV) values of 0.58, 0.27, 0.42, and 0.24 for Ktrans, ve, kep, and τi, respectively, using the unadjusted AIFs. Use of the reference tissue-adjusted AIFs reduced variations in Ktrans and ve (wCV = 0.50 and 0.10, respectively), but had smaller effects on kep and τi (wCV = 0.39 and 0.22, respectively). kep is less sensitive to AIF variation than Ktrans, suggesting it may be a more robust imaging biomarker of prostate microvasculature. With low sensitivity to AIF uncertainty, the SSM-unique τi parameter may have advantages over the conventional PK parameters in a longitudinal study.

Developing a Pipeline for Multiparametric MRI-Guided Radiation Therapy: Initial Results from a Phase II Clinical Trial in Newly Diagnosed Glioblastoma.

Quantitative mapping of hyperperfused and hypercellular regions of glioblastoma has been proposed to improve definition of tumor regions at risk for local recurrence following conventional radiation therapy. As the processing of the multiparametric dynamic contrast-enhanced (DCE-) and diffusion-weighted (DW-) magnetic resonance imaging (MRI) data for delineation of these subvolumes requires additional steps that go beyond the standard practices of target definition, we sought to devise a workflow to support the timely planning and treatment of patients. A phase II study implementing a multiparametric imaging biomarker for tumor hyperperfusion and hypercellularity consisting of DCE-MRI and high b-value DW-MRI to guide intensified (75 Gy/30 fractions) radiation therapy (RT) in patients with newly diagnosed glioblastoma was launched. In this report, the workflow and the initial imaging outcomes of the first 12 patients are described. Among all the first 12 patients, treatment was initiated within 6 weeks of surgery and within 2 weeks of simulation. On average, the combined hypercellular volume and high cerebral blood volume/tumor perfusion volume were 1.8 times smaller than the T1 gadolinium abnormality and 10 times smaller than the FLAIR abnormality. Hypercellular volume and high cerebral blood volume/tumor perfusion volume each identified largely distinct regions and showed 57% overlap with the enhancing abnormality, and minimal-to-no extension outside of the FLAIR. These results show the feasibility of implementing a workflow for multiparametric magnetic resonance-guided radiation therapy into clinical trials with a coordinated multidisciplinary team, and the unique and complementary tumor subregions identified by the combination of high b-value DW-MRI and DCE-MRI.

Combining Perfusion and High B-value Diffusion MRI to Inform Prognosis and Predict Failure Patterns in Glioblastoma.

PURPOSE: Advanced imaging modalities such as high b-value diffusion and dynamic contrast enhancement magnetic resonance imaging have the potential to improve the clinical management of glioblastoma by informing prognosis, predicting sites of progression, and guiding dose-escalated radiation to maximize tumor control and minimize toxicity. METHODS AND MATERIALS: Fifty-two patients with de novo glioblastoma underwent magnetic resonance imaging before chemoradiation therapy. Enhanced tumor volumes (TVs), excluding the surgical cavity, hypercellularity (TVHCV) and increased cerebral blood volume (TVCBV) were defined using conventional gadolinium-enhanced T1-weighted images, high b-value (3000 s/mm2) diffusion-weighted images, and cerebral blood volume maps from T1-weighted dynamic contrast enhancement images, respectively. The image-phenotype TVs were analyzed for prediction of progression-free survival (Cox proportional hazard models), and sites of progression (pattern of failure tumor volume). RESULTS: The median progression-free survival (PFS) of the cohort was 13 months. The TVCBV and TVHCV were spatially distinct, with a mean overlap of only 21%. Univariate analysis showed that increasing age, decreasing radiation dose, larger TVHCV, and larger overlap of TVHCV and TVCBV were significantly associated with inferior PFS. Multivariate analysis identified that TVHCV was the most adversely prognostic imaging-defined variable. Enhanced TVs, excluding the surgical cavity, and the union of TVHCV and TVCBV showed a high likelihood of containing the pattern of failure tumor volume, and the volume composed of the intersection of TVHCV and TVCBV had an especially high likelihood of progression. CONCLUSIONS: TVHCV and the overlap of TVHCV and TVCBV are prognostic for PFS. Combinations of gadolinium-enhanced TVs, TVCBV, and TVHCV could predict tumor progression locations better than could individual subvolumes. Radiation dose escalation to these subvolumes could be a promising therapeutic strategy.

Adaptive Boost Target Definition in High-Risk Head and Neck Cancer Based on Multi-imaging Risk Biomarkers.

PURPOSE: Positron emission tomography with 18F-deoxyglucose (FDG), dynamic contrast-enhanced magnetic resonance imaging (MRI), and diffusion-weighted MRI each identify unique risk factors for treatment outcomes in head and neck cancer (HNC). Clinical trials in HNC largely rely on a single imaging modality to define targets for boosting. This study aimed to investigate the spatial correspondence of FDG uptake, perfusion, and the apparent diffusion coefficient (ADC) in HNC and their response to chemoradiation therapy (CRT) and to determine the implications of this overlap or lack thereof for adaptive boosting. METHODS AND MATERIALS: Forty patients with HNC enrolled in a clinical trial underwent FDG positron emission tomography-computed tomography before CRT and underwent dynamic contrast-enhanced and diffusion-weighted MRI scans before and during CRT. The gross tumor volume (GTV) of the primary tumor was contoured on post-gadolinium T1-weighted images. Tumor subvolumes with high FDG uptake, low blood volume (BV), and low ADC were created by using previously established thresholds. Spatial correspondences between subvolumes were analyzed using the Dice coefficient, and those between each pair of image parameters at voxel level were analyzed by Spearman rank correlation coefficients. RESULTS: Prior to CRT, the median subvolumes of high FDG, low BV, and low ADC relative to the primary GTV were 20%, 21%, and 45%, respectively. Spearman correlation coefficients between BV and ADC varied from -0.47 to 0.22; between BV and FDG, from -0.08 to 0.59; and between ADC and FDG, from -0.68 to 0.25. Dice coefficients between subvolumes of FDG and BV, FDG and ADC, and BV and ADC were 10%, 46%, and 15%, respectively. The union of the 3 parameters was 64% of the GTV. The union of the subvolumes of BV and ADC was 56% of the GTV before CRT but was reduced significantly by 57% after 10 fractions of radiation therapy. CONCLUSIONS: High FDG uptake, low BV, and low ADC as imaging risk biomarkers of HNC identify largely distinct tumor characteristics. A single imaging modality may not define the boosting target adequately.

Accuracy, repeatability, and interplatform reproducibility of T1 quantification methods used for DCE-MRI: Results from a multicenter phantom study.

PURPOSE: To determine the in vitro accuracy, test-retest repeatability, and interplatform reproducibility of T1 quantification protocols used for dynamic contrast-enhanced MRI at 1.5 and 3 T. METHODS: A T1 phantom with 14 samples was imaged at eight centers with a common inversion-recovery spin-echo (IR-SE) protocol and a variable flip angle (VFA) protocol using seven flip angles, as well as site-specific protocols (VFA with different flip angles, variable repetition time, proton density, and Look-Locker inversion recovery). Factors influencing the accuracy (deviation from reference NMR T1 measurements) and repeatability were assessed using general linear mixed models. Interplatform reproducibility was assessed using coefficients of variation. RESULTS: For the common IR-SE protocol, accuracy (median error across platforms = 1.4-5.5%) was influenced predominantly by T1 sample (P < 10-6 ), whereas test-retest repeatability (median error = 0.2-8.3%) was influenced by the scanner (P < 10-6 ). For the common VFA protocol, accuracy (median error = 5.7-32.2%) was influenced by field strength (P = 0.006), whereas repeatability (median error = 0.7-25.8%) was influenced by the scanner (P < 0.0001). Interplatform reproducibility with the common VFA was lower at 3 T than 1.5 T (P = 0.004), and lower than that of the common IR-SE protocol (coefficient of variation 1.5T: VFA/IR-SE = 11.13%/8.21%, P = 0.028; 3 T: VFA/IR-SE = 22.87%/5.46%, P = 0.001). Among the site-specific protocols, Look-Locker inversion recovery and VFA (2-3 flip angles) protocols showed the best accuracy and repeatability (errors < 15%). CONCLUSIONS: The VFA protocols with 2 to 3 flip angles optimized for different applications achieved acceptable balance of extensive spatial coverage, accuracy, and repeatability in T1 quantification (errors < 15%). Further optimization in terms of flip-angle choice for each tissue application, and the use of B1 correction, are needed to improve the robustness of VFA protocols for T1 mapping. Magn Reson Med 79:2564-2575, 2018. © 2017 International Society for Magnetic Resonance in Medicine.