A script-enabled interactive checklist document for efficient management of electronic devices in a busy multimodality radiotherapy clinic.

PURPOSE: Develop an efficient, interactive, and instructive checklist document for the management of implanted electronic medical devices in a multimodality radiotherapy clinic. METHODS: The built-in scripting and interactivity of a popular commercial word processor was used to develop an interactive document that changes the information presented to the user based on drop-down selections. The interactivity and scripting were compatible with the radiation oncology information system (ROIS) which allows the document to be accessible by all team members and serve as a permanent record in a patient's electronic chart. RESULTS: The final interactive document, which was clinically deployed after beta testing with a group consisting of nurses and medical physicists, presents information and action plans to the user based on multiple departmental medical device decision trees that are specific to the combination of device, treatment modality, rhythm-pacing dependence for cardiac devices, and distance from the device to the treatment volume. CONCLUSION: A script-enabled interactive document was developed for a busy multimodality clinic, condensing multiple comprehensive departmental guidelines spanning multiple device types and treatment modalities into a single interactive checklist accessible within the ROIS. Given the wide accessibility of the commercial word processor, this approach could be adopted by other clinics to streamline their own respective workflows.

Initial results of a phase II trial of 18F-DOPA PET-guided re-irradiation for recurrent high-grade glioma.

PURPOSE: In-field high-grade glioma (HGG) recurrence is a common challenge with limited treatment options, including re-irradiation. The radiotracer 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) crosses the blood brain barrier and demonstrates high uptake in tumor, but low uptake in normal tissue. This study investigated whether 18F-DOPA positron emission tomography (PET) and MRI guided re-irradiation for recurrent HGG may improve progression free survival (PFS). METHODS: Adults with recurrent or progressive HGG previously treated with radiation were eligible. The primary endpoint was a 20% improvement from the historical control PFS at 3 months (PFS3) of 20% with systemic therapy alone. Re-RT dose was 35 Gy in 10 fractions. The target volume was MRI T1 contrast-enhancement defined tumor plus 18F-DOPA PET defined tumor. RESULTS: Twenty patients completed treatment per protocol. Diagnosis was most commonly glioblastoma, IDH-wildtype (60%). MRI-defined volumes were expanded by a median 43% (0-436%) by utilizing 18F-DOPA PET. PFS3 was 85% (95% CI 63.2-95.8%), meeting the primary endpoint of PFS3 ≥ 40%. With 9.7 months median follow-up, 17 (85%) had progressed and 15 (75%) had died. Median OS from re-RT was 8.8 months. Failure following re-RT was within both the MRI and PET tumor volumes in 75%, MRI only in 13%, PET only in 0%, and neither in 13%. Four (20%) patients experienced grade 3 toxicity, including CNS necrosis (n = 2, both asymptomatic with bevacizumab initiation for radiographic findings), seizures (n = 1), fatigue (n = 1), and nausea (n = 1). No grade 4-5 toxicities were observed. CONCLUSION: 18F-DOPA PET-guided re-irradiation for progressive high-grade glioma appears safe and promising for further investigation.

Prospective trial evaluating the sensitivity and specificity of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET and MRI in patients with recurrent gliomas.

Treatment-related changes can be difficult to differentiate from progressive glioma using MRI with contrast (CE). The purpose of this study is to compare the sensitivity and specificity of 18F-DOPA-PET and MRI in patients with recurrent glioma. Thirteen patients with MRI findings suspicious for recurrent glioma were prospectively enrolled and underwent 18F-DOPA-PET and MRI for neurosurgical planning. Stereotactic biopsies were obtained from regions of concordant and discordant PET and MRI CE, all within regions of T2/FLAIR signal hyperintensity. The sensitivity and specificity of 18F-DOPA-PET and CE were calculated based on histopathologic analysis. Receiver operating characteristic curve analysis revealed optimal tumor to normal (T/N) and SUVmax thresholds. In the 37 specimens obtained, 51% exhibited MRI contrast enhancement (M+) and 78% demonstrated 18F-DOPA-PET avidity (P+). Imaging characteristics included M-P- in 16%, M-P+ in 32%, M+P+ in 46% and M+P- in 5%. Histopathologic review of biopsies revealed grade II components in 16%, grade III in 43%, grade IV in 30% and no tumor in 11%. MRI CE sensitivity for recurrent tumor was 52% and specificity was 50%. PET sensitivity for tumor was 82% and specificity was 50%. A T/N threshold > 2.0 altered sensitivity to 76% and specificity to 100% and SUVmax > 1.36 improved sensitivity and specificity to 94 and 75%, respectively. 18F-DOPA-PET can provide increased sensitivity and specificity compared with MRI CE for visualizing the spatial distribution of recurrent gliomas. Future studies will incorporate 18F-DOPA-PET into re-irradiation target volume delineation for RT planning.

Treatment planning for metals using an extended CT number scale.

Metal implants which saturate the CT number scale may require dosimetrist and physicist involvement to manually contour and assign an appropriate value to the metal for accurate dose calculation. This study investigated dose calculation based directly on extended CT scale images for different metals and geometries. The aim was to evaluate extended CT accuracy as a suitable alternative to standard CT methods in the presence of high-Z materials and artifacts, despite the reduced HU resolution of extended CT. Gafchromic film measurements were made for comparison to calculated doses. The method of direct dose calculation on extended CT scale was compared to our institution's standard method of manually contouring and assigning metal values on saturated CT images for each of the metal samples. Clinical patient plans with metal implants were investigated and DVHs were compared between standard CT and extended CT dose calculations. Dose calculations showed agreement within 2% between the two methods of metal characterization and the film measurement in the case of the strongest metal attenuator, cobalt-chromium. In the clinical treatment plans, the greatest dose discrepancy between the two methods was 1.2%. This study suggests that direct dose calculation on an extended scale CT image in the presence of metal implants can produce accurate clinically viable treatment plans, thereby improving efficiency of clinical workflow and eliminating a potential source of human error by manual CT number assignment.

Evaluation of RANO response criteria compared to clinician evaluation in WHO grade III anaplastic astrocytoma: implications for clinical trial reporting and patterns of failure.

The utility of current response criteria has not been established in anaplastic astrocytoma (AA). We retrospectively reviewed MR images for 20 patients with AA and compared RANO-based approaches to clinician impression described as follow: (1) standard RANO-based criteria met by growth of or development of new enhancing lesion (RANO-C), (2) RANO criteria for progression based on significant FLAIR increase (RANO-F) and (3) clinical progression usually resulting in change of treatment (Clinical). Patterns of failure (POF) were analyzed utilizing all proposed progression MRIs fused with the patients' radiotherapy treatment plan. With an overall median survival of 24.3 months, development of new enhancing lesion was the most common determinant of progression (70 % of patients). Median time to RANO-C, RANO-F and Clinical progression was 9.2, 9.2 and 11.76 months respectively. RANO-C and RANO-F preceded Clinical in 70 and 55 % of patients, respectively. In six patients (30 %) Clinical was concurrent with RANO-F; four of six also met RANO-C. POF for FLAIR component differed based on time point used to determine progression. FLAIR POF was more often marginal or distant when progression was defined clinically compared to either RANO-C or RANO-F criteria. Central POF based on FLAIR at Clinical determination of progression was associated with significantly poorer OS (9.8 vs. 34.4 months). Clinical progression occurs later than progression determined by RANO-based criteria. Evaluation of POF based on FLAIR signal abnormality at the time of clinical progression suggests central recurrences are associated with worse survival.

The role of LAT1 in (18)F-DOPA uptake in malignant gliomas.

Positron emission tomography (PET) imaging with the amino acid tracer 6-(18)F-fluoro-L-3,4-dihydroxy-phenylalanine ((18)F-DOPA) may provide better spatial and functional information in human gliomas than CT or MRI alone. The L-type amino acid transporter 1 (LAT1) is responsible for membrane transport of large neutral amino acids in normal cells. This study assessed the relationship between LAT1 expression and (18)F-DOPA uptake in human astrocytomas. Endogenous LAT1 expression was measured in established glioblastoma (GBM) cell lines and primary GBM xenografts using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Uptake of (18)F-DOPA was approximated in vitro using (3)H-L-DOPA as an analog. Uptake of (3)H-L-DOPA was assessed in cells expressing LAT1 shRNA or LAT1 siRNA and compared to non-targeted (NT) control shRNA or siRNA sequences, respectively. To demonstrate the clinical relevance of these findings, LAT1 immunofluorescence staining was compared with corresponding regions of (18)F-DOPA PET uptake in patients with newly diagnosed astrocytomas. LAT1 mRNA and protein expression varies in GBM, and the extent of (3)H-L-DOPA uptake was positively correlated with endogenous LAT1 expression. Stable shRNA-mediated LAT1 knockdown in T98 and GBM28 reduced (3)H-L-DOPA uptake relative to NT shRNA by 57 (P < 0.0001) and 52 % (P < 0.001), respectively. Transient siRNA-mediated LAT1 knockdown in T98 reduced (3)H-L-DOPA uptake relative to NT siRNA up to 68 % (P < 0.01). In clinical samples, LAT1 expression positively correlated with (18)F-DOPA PET uptake (P = 0.04). Expression of LAT1 is strongly associated with (3)H-L-DOPA uptake in vitro and (18)F-DOPA uptake in patient biopsy samples. These results define LAT1 as a key determinant of (18)F-DOPA accumulation in GBM.

Dosimetric patterns of failure in the era of novel chemoradiotherapy in newly-diagnosed glioblastoma patients.

BACKGROUND: Patterns of failure (POF) may provide an alternative quantitative endpoint to overall survival for evaluation of novel chemoradiotherapy regimens with glioblastoma. MATERIALS AND METHODS: POF of 109 newly-diagnosed glioblastoma patients per 2016 WHO classification who received conformal radiotherapy with concomitant and adjuvant temozolomide were reviewed. Seventy-five of those patients also received an investigational chemotherapy agent (everolimus, erlotinib, or vorinostat). Recurrence volumes were defined with MRI contrast enhancement. POF at protocol (POFp), initial (POFi), and RANO (POFRANO) progression timepoints were characterized by the percentage of recurrence volume within the 95% dose region. POFp, POFi, and POFRANO of each patient were categorized (central, non-central, or both). RESULTS: POF of the temozolomide-only control cohort were unchanged (79% central, 12% non-central, and 9% both) across protocol, initial, and RANO progression timepoints. Unlike the temozolomide-only cohort, POF of the collective novel chemotherapy cohort appeared increasingly non-central when comparing POFi with POFp, with a non-central component increasing from 16% to 29% (p = 0.078). POF did not correlate with overall survival or time to progression. CONCLUSION: POF of patients receiving a novel chemotherapy appeared to be influenced by the timepoint of analysis and were increasingly non-central at protocol progression as compared with initial recurrence, suggesting that recurrence originates from the central region. Addition of everolimus and vorinostat appeared to influence POF, despite similar survival outcomes with the temozolomide-only control group. In studies dealing with novel therapeutic agents, robust and properly-timed dosimetric POF analysis may be helpful to evaluate biologic aspects of novel agents.

Evaluation of a New, Highly Flexible Radiofrequency Coil for MR Simulation of Patients Undergoing External Beam Radiation Therapy.

PURPOSE: To evaluate the performance of a new, highly flexible radiofrequency (RF) coil system for imaging patients undergoing MR simulation. METHODS: Volumetric phantom and in vivo images were acquired with a commercially available and prototype RF coil set. Phantom evaluation was performed using a silicone-filled humanoid phantom of the head and shoulders. In vivo assessment was performed in five healthy and six patient subjects. Phantom data included T1-weighted volumetric imaging, while in vivo acquisitions included both T1- and T2-weighted volumetric imaging. Signal to noise ratio (SNR) and uniformity metrics were calculated in the phantom data, while SNR values were calculated in vivo. Statistical significance was tested by means of a non-parametric analysis of variance test. RESULTS: At a threshold of p = 0.05, differences in measured SNR distributions within the entire phantom volume were statistically different in two of the three paired coil set comparisons. Differences in per slice average SNR between the two coil sets were all statistically significant, as well as differences in per slice image uniformity. For patients, SNRs within the entire imaging volume were statistically significantly different in four of the nine comparisons and seven of the nine comparisons performed on the per slice average SNR values. For healthy subjects, SNRs within the entire imaging volume were statistically significantly different in seven of the nine comparisons and eight of the nine comparisons when per slice average SNR was tested. CONCLUSIONS: Phantom and in vivo results demonstrate that image quality obtained from the novel flexible RF coil set was similar or improved over the conventional coil system. The results also demonstrate that image quality is impacted by the specific coil configurations used for imaging and should be matched appropriately to the anatomic site imaged to ensure optimal and reproducible image quality.

Single and Multifraction Spine Stereotactic Body Radiation Therapy and the Risk of Radiation Induced Myelopathy.

Purpose: This study reports on the risk of radiation-induced myelitis (RM) of the spinal cord from a large single-institutional experience with 1 to 5 fraction stereotactic body radiation therapy (SBRT) to the spine. Methods and Materials: A retrospective review of patients who received spine SBRT to a radiation naïve level at or above the conus medullaris between 2007 and 2019 was performed. Local failure determination was based on SPIne response assessment in Neuro-Oncology criteria. RM was defined as neurologic symptoms consistent with the segment of cord irradiated in the absence of neoplastic disease recurrence and graded by Common Toxicity Criteria for Adverse Events, version 4.0. Rates of adverse events were estimated and dose-volume statistics from delivered treatment plans were extracted for the planning target volumes and spinal cord. Results: A total of 353 lesions in 277 patients were identified that met the specified criteria, for which 270, 70, and 13 lesions received 1-, 3-, and 5-fraction treatments, respectively, with a median follow-up of 46 months (95% confidence interval [CI], 41-52 months) for all surviving patients. The median overall survival was 33.0 months (95% CI, 29-43). The median D0.03cc to the spinal cord was 11.7 Gy (interquartile range [IQR], 10.5-12.4), 16.7 Gy (IQR, 12.8-20.6), and 26.0 Gy (IQR, 24.1-28.1), for 1-, 3-, 5-fractions. Using an a/b = 2Gy for the spinal cord, the median single-fraction equivalent-dose (SFED2) was 11.7 Gy (IQR, 10.2-12.5 Gy) and the normalized biological equivalent dose (nBED2/2) was 19.9 Gy (IQR, 15.4-22.8 Gy). One patient experienced grade 2 RM after a single-fraction treatment. The cumulative probability of RM was 0.3% (95% CI, 0%-2%). Conclusions: Spine SBRT is safe while limiting the spinal cord (as defined on treatment planning magnetic resonance imaging or computed tomography myelogram) D0.03cc to less than 14 Gy, 21.9 Gy, and 30 Gy, for 1, 3, and 5-fractions, consistent with standard guidelines.

Phase II Evaluation of Stereotactic Ablative Radiotherapy (SABR) and Immunity in 11C-Choline-PET/CT-Identified Oligometastatic Castration-Resistant Prostate Cancer.

PURPOSE: Outcomes for resistant metastatic castration-resistant prostate cancer (CRPC) are poor. Stereotactic ablative radiotherapy (SABR) induces antitumor immunity in clinical and preclinical studies, but immunologic biomarkers are lacking. PATIENTS AND METHODS: Eighty-nine patients with oligometastatic CRPC were identified by 11C-Choline-PET (Choline-PET) from August 2016 to December 2019 and treated with SABR. Prespecified coprimary endpoints were 2-year overall survival (OS) and PSA progression. Secondary endpoints included 2-year SABR-treated local failure and 6-month adverse events. Correlative studies included peripheral blood T-cell subpopulations before and after SABR. RESULTS: 128 lesions in 89 patients were included in this analysis. Median OS was 29.3 months, and 1- and 2-year OS were 96% and 80%, respectively. PSA PFS was 40% at 1 year and 21% at 2 years. Local PFS was 84.4% and 75.3% at 1 and 2 years, respectively, and no grade ≥3 AEs were observed. Baseline high levels of tumor-reactive T cells (TTR; CD8+CD11ahigh) predicted superior local, PSA, and distant PFS. Baseline high levels of effector memory T cells (TEM; CCR7-CD45RA-) were associated with improved PSA PFS. An increase in TTR at day 14 from baseline was associated with superior OS. CONCLUSIONS: This is the first comprehensive effector T-cell immunophenotype analysis in a phase II trial before and after SABR in CRPC. Results are favorable and support the incorporation of immune-based markers in the design of future randomized trials in patients with oligometastatic CRPC treated with SABR.

Prediction of MGMT Status for Glioblastoma Patients Using Radiomics Feature Extraction From 18F-DOPA-PET Imaging.

PURPOSE: Methylation of the O6-methylguanine methyltransferase (MGMT) gene promoter is associated with improved treatment response and survival in patients with glioblastoma (GB), but the necessary pathologic specimen can be nondiagnostic. In this study, we assessed whether radiomics features from pretreatment 18F-DOPA positron emission tomography (PET) imaging could be used to predict pathologic MGMT status. METHODS AND MATERIALS: This study included 86 patients with newly diagnosed GB, split into 3 groups (training, validating, and predicting). We performed a radiomics analysis on 18F-DOPA PET images by extracting features from 2 tumor-based contours: a "Gold" contour of all abnormal uptake per expert nuclear medicine physician and a high-grade glioma (HGG) contour based on a tumor-to-normal hemispheric ratio >2.0, representing the most aggressive components. Feature selection was performed by comparing the weighted feature importance and filtering with bivariate analysis. Optimization of model parameters was explored using grid search with selected features. The stability of the model with increasing input features was also investigated for model robustness. The model predictions were then applied by comparing the overall survival probability of the patients with GB and unknown MGMT status versus those with known MGMT status. RESULTS: A radiomics signature was constructed to predict MGMT methylation status. Using features extracted from HGG contour alone with a random forest model, we achieved 80% ± 10% accuracy for 95% confidence level in predicting MGMT status. The prediction accuracy was not improved with the addition of the Gold contour or with more input features. The model was applied to the patients with unknown MGMT methylation status. The prediction results are consistent with what is expected using overall survival as a surrogate. CONCLUSIONS: This study suggests that 3 features from radiomics modeling of 18F-DOPA PET imaging can predict MGMT methylation status with reasonable accuracy. These results could provide valuable therapeutic guidance for patients in whom MGMT testing is inconclusive or nondiagnostic.

Carbon Fiducial Image Guidance Increases the Accuracy of Lumpectomy Cavity Localization in Radiation Therapy for Breast Cancer.

PURPOSE: We investigated the feasibility and accuracy of using carbon fiducials to localize the lumpectomy cavity with 2-dimensional kV imaging for early stage breast cancer radiation therapy. METHODS AND MATERIALS: Carbon fiducials were placed intraoperatively in the periphery of the lumpectomy cavity. Nine patients received whole breast irradiation with a boost, and 2 patients received 3-dimensional conformal partial breast irradiation. A total of 89 fractions were assessed for setup errors relative to a predefined gold standard, cone beam computed tomography (CBCT) match to the lumpectomy cavity, using the following 4 setup methods: (1) Align skin tattoos with lasers; (2) match bone with 2-dimensional-2-dimensional (2D/2D) kV onboard imaging (OBI); (3) match the whole breast with CBCT; and (4) match carbon fiducials with 2D/2D kV OBI. The margin for the planning target volume (PTV) was calculated by 2 standard deviations of the setup errors, and compared among the 4 setup methods. Setup errors for patients treated with free breathing and patients with deep inspiration breath hold were also compared. RESULTS: The carbon fiducials were sufficiently visible on OBI for matching and introduced minimal artifacts. Of the 4 alignment methods, 2D/2D OBI match to fiducials resulted in the smallest setup errors. The PTV margin was 12 mm for aligning skin tattoos using lasers, 9.2 mm for matching bone on OBI, 6.5 mm for matching breast on CBCT, and 3.5 mm for matching fiducials on 2D/2D OBI. Compared with free breathing, deep inspiration breath hold generally reduced the standard deviations of the setup errors, but further investigation would be needed. CONCLUSIONS: Matching to carbon fiducials increased the localization accuracy to the lumpectomy cavity. This reduces residual setup error and PTV margins, facilitating tissue sparing without diminishing treatment efficacy.

Optimization of internal margin to account for dosimetric effects of respiratory motion.

PURPOSE: Use of internal margins to account for respiratory motion of the target volumes is a common strategy in radiotherapy of mobile tumors. Although efficient for tumor coverage, this expansion also risks increased toxicity to nearby healthy organs and therefore requires a careful selection of appropriate margins. In this study, we demonstrate an optimization of the internal margin used to account for respiration motion. METHODS AND MATERIALS: Three-dimensional conformal treatment plans for phantom spherical target volumes as well as clinical treatment plans of 11 patients were evaluated retrospectively for optimum internal margin selection. A software-based simulation of respiration motion was performed for all cases. Moreover, the interplay with treatment setup uncertainties and corresponding margins was investigated in the phantom study. RESULTS: Optimum internal margins in both phantom and patient studies were found to be substantially smaller than the actual target displacement due to respiration. The optimal internal margin was also observed to be approximately independent of the setup margins. Furthermore, no statistically significant dependence on target size and shape was observed in the group of 11 patients. CONCLUSIONS: These findings present significant implications for treatment planning of mobile targets, such as tumors found in the lung and upper abdomen. We conclude that the full motion amplitude for the internal margin is overly conservative, and optimization of the internal margin provides improved sparing of nearby organs at risk without sacrificing dosimetric coverage for the target.

An investigation of temporal resolution parameters in cine-mode four-dimensional computed tomography acquisition.

The accuracy of four-dimensional computed tomography (4DCT) imaging depends on temporal characteristics of the acquisition protocol--for example, the temporal spacing of the reconstructed images (also known as cine duration between images) and the gantry rotation speed. These parameters affect the temporal resolution of 4DCT images, and a single default acquisition protocol, as commonly used in most clinics, may be suboptimal for a subset of respiratory motion characteristics. It could lead to substantial inaccuracies in target delineation. The aim of the present study was to evaluate the interplay between parameters affecting temporal resolution and the accuracy of the resulting images. We acquired 4DCT images of cylindrical phantoms under repetitive motion induced by a translation platform. Acquisition settings varied with respect to temporal spacing, gantry rotation speed, and motion period of the phantoms. Reconstructed images were sorted into 10 phase bins and were compared to static phantom images acquired at corresponding positions of the respiration phase. Acquisitions with different temporal spacing did not play a significant role in the amount of motion observed in full-cycle maximum intensity projection images. Target delineation accuracy at end-of-inhalation phase was observed to be constant up to a threshold in the value of the reconstruction interval, beyond which it varied arbitrarily. This threshold was found to be correlated with the number of phase bins and the motion period. No observable variations were noted with images from the end of exhalation when temporal spacing was varied. Target delineation accuracy was observed to be enhanced in acquisitions using faster gantry rotation speeds. An evaluation of the acquisition parameters needs to be performed depending on the period of the motion and limiting factors such as the availability of acquisition settings, X-ray tube workload, image storage, and processing power.

Dosimetric impact of amino acid positron emission tomography imaging for target delineation in radiation treatment planning for high-grade gliomas.

BACKGROUND AND PURPOSE: The amino-acid positron emission tomography (PET) tracer 3,4-dihydroxy-6-[18F] fluoro-l-phenylalanine (18F-DOPA) has increased sensitivity for detecting regions of biologically aggressive tumors compared to T1 contrast-enhanced (T1-CE) magnetic resonance imaging (MRI). We performed dosimetric evaluation of treatment plans prepared with and without inclusion of 18F-DOPA-based biological target volume (BTV) evaluating its role in guiding radiotherapy of grade III/IV gliomas. MATERIALS AND METHODS: Eight patients (five T1-CE, three non-contrast-enhancing [NCE]) were included in our study. MRI only-guided anatomic plans and MRI+18FDOPA-PET-guided biologic plans were prepared for each patient, and dosimetric data for target volumes and organs at risk (OAR) were compared. High-dose BTV60Gy was defined as regions with tumor to normal brain (T/N) >2.0, while low-dose BTV51Gy was initially based on T/N >1.3, but refined per Nuclear Medicine expert. RESULTS: For T1-CE tumors, planning target volumes (PTV) were larger than MRI-only anatomic target volumes. Despite increases in size of both gross target volumes and PTV, with volumetric-modulated arc therapy planning, no increase of dose to OAR was observed while maintaining similar target dose coverage. For NCE tumors, MRI+18F-DOPA PET biologic imaging identified a sub-region of the large, T2-FLAIR abnormal signal which may allow a smaller volume to receive the high dose (60 Gy) radiation. CONCLUSIONS: For T1-CE tumors, PTVs were larger than MRI-only anatomic target volumes with no increase of dose to OARs. Therefore, MRI+18F-DOPA PET-based biologic treatment planning appears feasible in patients with high-grade gliomas.

Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data.

The blood-brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.

Incidence of radiation pneumonitis after thoracic irradiation: Dose-volume correlates.

PURPOSE: To define clinical and dosimetric parameters correlated with the risk of clinically relevant radiation pneumonitis (RP) after thoracic radiotherapy. METHODS AND MATERIALS: Records of consecutive patients treated with definitive thoracic radiotherapy were retrospectively reviewed for the incidence of RP of Grade 2 or greater by the Common Toxicity Criteria. Dose-volume histograms using total lung volume (TL) and TL minus gross tumor volume (TL-G) were created with and without heterogeneity corrections. Mean lung dose (MLD), effective lung volume (V(eff)), and percentage of TL or TL-G receiving greater than or equal to 10, 13, 15, 20, and 30 Gy (V10-V30, respectively) were analyzed by logistic regression. Receiver operating characteristic (ROC) curves were generated to estimate RP predictive values. RESULTS: Twelve cases of RP were identified in 92 eligible patients. Mean lung dose, V10, V13, V15, V20, and V(eff) were significantly correlated to RP. Combinations of MLD, V(eff), V20, and V30 lost significance using TL-G and heterogeneity corrections. Receiver operating characteristic analysis determined V10 and V13 as the best predictors of RP risk, with a decrease in predictive value above those volumes. CONCLUSIONS: Intrathoracic radiotherapy should be planned with caution when using radiotherapy techniques delivering doses of 10 to 15 Gy to large lung volumes.

Cadaveric verification of the Eclipse AAA algorithm for spine SBRT treatments with titanium hardware.

PURPOSE: To assess the accuracy of the Eclipse Analytical Anisotropic Algorithm when calculating dose for spine stereotactic body radiation therapy treatments involving surgically implanted titanium hardware. METHODS AND MATERIALS: A human spine was removed from a cadaver, cut sagittally along the midline, and then separated into thoracic and lumbar sections. The thoracic section was implanted with titanium stabilization hardware; the lumbar section was not implanted. Spine sections were secured in a water phantom and simulated for treatment planning using both standard and extended computed tomography (CT) scales. Target volumes were created on both spine sections. Dose calculations were performed using (1) the standard CT scale with relative electron density (RED) override of image artifacts and hardware, (2) the extended CT scale with RED override of image artifacts only, and (3) the standard CT scale with no RED overrides for hardware or artifacts. Plans were delivered with volumetric modulated arc therapy using a 6-MV beam with and without a flattening filter. A total of 3 measurements for each plan were made with Gafchromic film placed between the spine sections and compared with Eclipse dose calculations using gamma analysis with a 2%/2 mm passing criteria. A single measurement in a homogeneous phantom was made for each plan before actual delivery. RESULTS: Gamma passing rates for measurements in the homogeneous phantom were 99.6% or greater. Passing rates for measurements made in the lumbar spine section without hardware were 99.3% or greater; measurements made in the thoracic spine containing titanium were 98.6 to 99.5%. CONCLUSIONS: Eclipse Analytical Anisotropic Algorithm can adequately model the effects of titanium implants for spine stereotactic body radiation therapy treatments using volumetric modulated arc therapy. Calculations with standard or extended CT scales give similarly accurate results.

Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma.

BACKGROUND: Targeting drug delivery to invasive glioma cells is a particularly difficult challenge because these cells lie behind an intact blood-brain barrier (BBB) that can be observed using multimodality imaging. BBB-associated efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) influence drug distribution to these cells and may negatively impact efficacy. To test the hypothesis that efflux transporters influence brain pharmacokinetics/pharmacodynamics of molecularly targeted agents in glioma treatment, we assessed region-specific penetrance and molecular-targeting capacity for a PI3K/mTOR kinase inhibitor that has high substrate affinity for efflux transporters (GDC-0980) and an analog (GNE-317) that was purposely designed to have reduced efflux. METHODS: Brain tumor penetrance of GDC-0980 and GNE-317 was compared between FVB/n wild-type mice and Mdr1a/b(-/-)Bcrp(-/-) triple-knockout mice lacking P-gp and BCRP. C57B6/J mice bearing intracranial GL261 tumors were treated with GDC-0980, GNE-317, or vehicle to assess the targeted pharmacokinetic/pharmacodynamic effects in a glioblastoma model. RESULTS: Animals treated with GNE-317 demonstrated 3-fold greater penetrance in tumor core, rim, and normal brain compared with animals dosed with GDC-0980. Increased brain penetrance correlated with decreased staining of activated p-Akt, p-S6, and p-4EBP1 effector proteins downstream of PI3K and mTOR. CONCLUSIONS: GDC-0980 is subject to active efflux by P-gp and BCRP at the BBB, while brain penetrance of GNE-317 is independent of efflux, which translates into enhanced inhibition of PI3K/mTOR signaling. These data show that BBB efflux by P-gp and BCRP is therefore an important determinant in both brain penetrance and molecular targeting efficacy in the treatment of invasive glioma cells.