Tania Kaprealian

Feasibility of extreme dose escalation for glioblastoma multiforme using 4π radiotherapy.

BackgroundGlioblastoma multiforme (GBM) frequently recurs at the same location after radiotherapy. Further dose escalation using conventional methods is limited by normal tissue tolerance. 4π non-coplanar radiotherapy has recently emerged as a new potential method to deliver highly conformal radiation dose using the C-arm linacs. We aim to study the feasibility of very substantial GBM dose escalation while maintaining normal tissue tolerance using 4π.Methods11 GBM patients previously treated with volumetric modulated arc therapy (VMAT/RapidArc) on the NovalisTx™ platform to a prescription dose of either 59.4 Gy or 60 Gy were included. All patients were replanned with 30 non-coplanar beams using a 4π radiotherapy platform, which inverse optimizes both beam angles and fluence maps. Four different prescriptions were used including original prescription dose and PTV (4πPTVPD), 100 Gy to the PTV and GTV (4πPTV100Gy), 100 Gy to the GTV only while maintaining prescription dose to the rest of the PTV (4πGTV100Gy), and a 5 mm margin expansion plan (4πPTVPD+5mm). OARs included in the study are the normal brain (brain – PTV), brainstem, chiasm, spinal cord, eyes, lenses, optical nerves, and cochleae.ResultsThe 4π plans resulted in superior dose gradient indices, as indicated by >20% reduction in the R50, compared to the clinical plans. Among all of the 4π cases, when compared to the clinical plans, the maximum and mean doses were significantly reduced (p < 0.05) by a range of 47.01-98.82% and 51.87-99.47%, respectively, or unchanged (p > 0.05) for all of the non-brain OARs. Both the 4πPTVPD and 4π GTV100GYplans reduced the mean normal brain mean doses.Conclusions4π non-coplanar radiotherapy substantially increases the dose gradient outside of the PTV and better spares critical organs. Dose escalation to 100 Gy to the GTV or additional margin expansion while meeting clinical critical organ dose constraints is feasible. 100 Gy to the PTV result in higher normal brain doses but may be tolerated when delivered in proportionally increased treatment fractions. Therefore, 4π non-coplanar radiotherapy on C-arm gantry may provide an accessible tool to improve the outcome of GBM radiotherapy through extreme dose escalation.

Incorporating Cancer Stem Cells in Radiation Therapy Treatment Response Modeling and the Implication in Glioblastoma Multiforme Treatment Resistance

PURPOSE To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model. METHODS AND MATERIALS The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non-small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated. RESULTS Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations. CONCLUSION The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from stereotactic ablative radiation therapy. The DLQ model also predicted the remarkable GBM radioresistance, a result that is highly consistent with clinical observations. The radioresistance putatively stemmed from accelerated DCC regrowth that rapidly restored compartmental equilibrium between CSCs and DCCs.

Predictors of recurrence following resection of intracranial chordomas

Management of intracranial chordomas remains challenging, despite improvements in microsurgical techniques and radiotherapy. Here, we analyzed the prognostic factors associated with improved rates of tumor control in patients with intracranial chordomas, who received either gross (GTR) or subtotal resections (STR). A retrospective review was performed to identify all patients who were undergoing resection of their intracranial chordomas at the Ronald Reagan University of California Los Angeles Medical Center from 1990 to 2011. In total, 57 patients undergoing 81 resections were included. There were 24 females and 33 males with a mean age of 44.6 years, and the mean tumor diameter was 3.36 cm. The extent of resection was not associated with recurrence. For all 81 operations, the 1 and 5 year progression free survival (PFS) was 87.5 and 40.4%, and 88.0 and 33.6% for STR and GTR, respectively (p=0.90). Adjuvant radiotherapy was associated with improved rates of PFS (hazard ratio [HR] 0.20; p=0.009). Additionally, age >45 years (HR 5.88; p=0.01) and the presence of visual deficits (HR 7.59; p=0.03) were associated with worse rates of tumor control. Tumor size, sex, tumor histology, and recurrent tumors were not predictors of recurrence. Younger age, lack of visual symptoms on presentation and adjuvant radiotherapy were associated with improved rates of tumor control following surgery. However, GTR and STR produced comparable rates of tumor control. The surgical management of intracranial chordomas should take a conservative approach, with the aim of maximal but safe cytoreductive resection with adjuvant radiation therapy, and a major focus on quality of life.

Accuracy of UTE-MRI-based patient setup for brain cancer radiation therapy.

PURPOSE Radiation therapy simulations solely based on MRI have advantages compared to CT-based approaches. One feature readily available from computed tomography (CT) that would need to be reproduced with MR is the ability to compute digitally reconstructed radiographs (DRRs) for comparison against on-board radiographs commonly used for patient positioning. In this study, the authors generate MR-based bone images using a single ultrashort echo time (UTE) pulse sequence and quantify their 3D and 2D image registration accuracy to CT and radiographic images for treatments in the cranium. METHODS Seven brain cancer patients were scanned at 1.5 T using a radial UTE sequence. The sequence acquired two images at two different echo times. The two images were processed using an in-house software to generate the UTE bone images. The resultant bone images were rigidly registered to simulation CT data and the registration error was determined using manually annotated landmarks as references. DRRs were created based on UTE-MRI and registered to simulated on-board images (OBIs) and actual clinical 2D oblique images from ExacTrac™. RESULTS UTE-MRI resulted in well visualized cranial, facial, and vertebral bones that quantitatively matched the bones in the CT images with geometric measurement errors of less than 1 mm. The registration error between DRRs generated from 3D UTE-MRI and the simulated 2D OBIs or the clinical oblique x-ray images was also less than 1 mm for all patients. CONCLUSIONS UTE-MRI-based DRRs appear to be promising for daily patient setup of brain cancer radiotherapy with kV on-board imaging.

Overall survival benefit associated with adjuvant radiotherapy in WHO grade II meningioma

Background Adjuvant radiotherapy (RT) after surgical resection of World Health Organization (WHO) grade II meningioma, also known as atypical meningioma (AM), is a topic of controversy. The purpose of this study is to compare overall survival (OS) with or without adjuvant RT after subtotal resection (STR) or gross total resection (GTR) in AM patients diagnosed according to the 2007 WHO classification. Methods The National Cancer Database was used to identify 2515 patients who were diagnosed with AM between 2009 and 2012 and underwent STR or GTR with or without adjuvant RT. Propensity score matching was first applied to balance covariates including age, year of diagnosis, sex, race, histology, and tumor size in STR or GTR cohorts stratified by adjuvant RT status. Multivariate regression according to the Cox proportional hazards model and Kaplan-Meier survival plots with log-rank test were then used to evaluate OS difference associated with adjuvant RT. Results GTR is associated with improved OS compared with STR. In the subgroup analysis, adjuvant RT in patients who underwent STR demonstrated significant association with improved OS compared with no adjuvant RT (adjusted hazard ratio [AHR] 0.590, P = .045); however, adjuvant RT is not associated with improved OS in patients who underwent GTR (AHR 1.093, P = .737). Conclusions Despite the lack of consensus on whether adjuvant RT reduces recurrence after surgical resection of AM, our study observed significantly improved OS with adjuvant RT compared with no adjuvant RT after STR.

Adjuvant Stereotactic Radiosurgery and Radiation Therapy for the Treatment of Intracranial Chordomas.

Objective Chordomas are locally aggressive, highly recurrent tumors requiring adjuvant radiotherapy following resection for successful management. We retrospectively reviewed patients treated for intracranial chordomas with adjuvant stereotactic radiosurgery (SRS) and stereotactic radiation therapy (SRT). Methods A total of 57 patients underwent 83 treatments at the UCLA Medical Center between February 1990 and August 2011. Mean follow-up was 57.8 months. Mean tumor diameter was 3.36 cm. Overall, 8 and 34 patients received adjuvant SRS and SRT, and the mean maximal dose of radiation therapy was 1783.3 cGy and 6339 cGy, respectively. Results Overall rate of recurrence was 51.8%, and 1- and 5-year progression-free survival (PFS) was 88.2% and 35.2%, respectively. Gross total resection was achieved in 30.9% of patients. Adjuvant radiotherapy improved outcomes following subtotal resection (5-year PFS 62.5% versus 20.1%; p = 0.036). SRS and SRT produced comparable rates of tumor control (p = 0.28). Higher dose SRT (> 6,000 cGy) (p = 0.013) and younger age (< 45 years) (p = 0.03) was associated with improved rates of tumor control. Conclusion Adjuvant radiotherapy is critical following subtotal resection of intracranial chordomas. Adjuvant SRT and SRS were safe and improved PFS following subtotal resection. Higher total doses of SRT and younger patient age were associated with improved rates of tumor control.

Systematic Analysis of Clinical Outcomes Following Stereotactic Radiosurgery for Central Neurocytoma

Central neurocytoma (CN) typically presents as an intraventricular mass causing obstructive hydrocephalus. The first line of treatment is surgical resection with adjuvant conventional radiotherapy. Stereotactic radiosurgery (SRS) was proposed as an alternative therapy for CN because of its lower risk profile. The objective of this systematic analysis is to assess the efficacy of SRS for CN. A systematic analysis for CN treated with SRS was conducted in PubMed. Baseline patient characteristics and outcomes data were extracted. Heterogeneity and publication bias were also assessed. Univariate and multivariate linear regressions were used to test for correlations to the primary outcome: local control (LC). The estimated cumulative rate of LC was 92.2% (95% confidence interval: 86.5-95.7%, p<0.001). Mean follow-up time was 62.4 months (range 3-149 months). Heterogeneity and publication bias were insignificant. The univariate linear regression models for both mean tumor volume and mean dose were significantly correlated with improved LC (p<0.001). Our data suggests that SRS may be an effective and safe therapy for CN. However, the rarity of CN still limits the efficacy of a quantitative analysis. Future multi-institutional, randomized trials of CN patients should be considered to further elucidate this therapy.

Diffusion tractography imaging–guided frameless linear accelerator stereotactic radiosurgical thalamotomy for tremor: case report

Essential tremor and Parkinsons disease-associated tremor are extremely prevalent within the field of movement disorders. The ventral intermediate (VIM) nucleus of the thalamus has been commonly used as both a neuromodulatory and neuroablative target for the treatment of these forms of tremor. With both deep brain stimulation and Gamma Knife radiosurgery, there is an abundance of literature regarding the surgical planning, targeting, and outcomes of these methodologies. To date, there have been no reports of frameless, linear accelerator (LINAC)-based thalomotomies for tremor. The authors report the case of a patient with tremor-dominant Parkinsons disease, with poor tremor improvement with medication, who was offered LINAC-based thalamotomy. High-resolution 0.9-mm isotropic MR images were obtained, and simulation was performed via CT with 1.5-mm contiguous slices. The VIM thalamic nucleus was determined using diffusion tensor imaging (DTI)-based segmentation on FSL using probabilistic tractography. The supplemental motor and premotor areas were the cortical target masks. The authors centered their isocenter within the region of the DTI-determined target and treated the patient with 140 Gy in a single fraction. The DTI-determined target had coordinates of 14.2 mm lateral and 8.36 mm anterior to the posterior commissure (PC), and 3 mm superior to the anterior commissure (AC)-PC line, which differed by 3.30 mm from the original target determined by anatomical considerations (15.5 mm lateral and 7 mm anterior to the PC, and 0 mm superior to the AC-PC line). There was faint radiographic evidence of lesioning at the 3-month follow-up within the target zone, which continued to consolidate on subsequent scans. The patient experienced continued right upper-extremity resting tremor improvement starting at 10 months until it was completely resolved at 22 months of follow-up. Frameless LINAC-based thalamotomy guided by DTI-based thalamic segmentation is a feasible method for achieving radiosurgical lesions of the VIM thalamus to treat tremor.

Distortion-free diffusion MRI using an MRI-guided Tri-Cobalt 60 radiotherapy system: Sequence verification and preliminary clinical experience

Purpose: Monitoring tumor response during the course of treatment and adaptively modifying treatment plan based on tumor biological feedback may represent a new paradigm for radiotherapy. Diffusion MRI has shown great promises in assessing and predicting tumor response to radiotherapy. However, the conventional diffusion‐weighted single‐shot echo‐planar‐imaging (DW‐ssEPI) technique suffers from limited resolution, severe distortion, and possibly inaccurate ADC at low field strength. The purpose of this work was to develop a reliable, accurate and distortion‐free diffusion MRI technique that is practicable for longitudinal tumor response evaluation and adaptive radiotherapy on a 0.35 T MRI‐guided radiotherapy system. Methods: A diffusion‐prepared turbo spin echo readout (DP‐TSE) sequence was developed and compared with the conventional diffusion‐weighted single‐shot echo‐planar‐imaging sequence on a 0.35 T MRI‐guided radiotherapy system (ViewRay). A spatial integrity phantom was used to quantitate and compare the geometric accuracy of the two diffusion sequences for three orthogonal orientations. The apparent diffusion coefficient (ADC) accuracy was evaluated on a diffusion phantom under both 0 °C and room temperature to cover a diffusivity range between 0.40 × 10−3 and 2.10 × 10−3 mm2/s. Ten room temperature measurements repeated on five different days were conducted to assess the ADC reproducibility of DP‐TSE. Two glioblastoma (GBM) and six sarcoma patients were included to examine the in vivo feasibility. The target registration error (TRE) was calculated to quantitate the geometric accuracy where structural CT or MR images were co‐registered to the diffusion images as references. ADC maps from DP‐TSE and DW‐ssEPI were calculated and compared. A tube phantom was placed next to patients not treated on ViewRay, and ADCs of this reference tube were also compared. Results: The proposed DP‐TSE passed the spatial integrity test (< 1 mm within 100 mm radius and < 2 mm within 175 mm radius) under the three orthogonal orientations. The detected errors were 0.474 ± 0.355 mm, 0.475 ± 0.287 mm, and 0.546 ± 0.336 mm in the axial, coronal, and sagittal plane. DW‐ssEPI, however, failed the tests due to severe distortion and low signal intensity. Noise correction must be performed for the DW‐ssEPI to avoid ADC quantitation errors, whereas it is optional for DP‐TSE. At 0 °C, the two sequences provided accurate quantitation with < 3% variation with the reference. In the room temperature study, discrepancies between ADCs from DP‐TSE and the reference were within 4%, but could be as high as 8% for DW‐ssEPI after the noise correction. Excellent ADC reproducibility with a coefficient of variation < 5% was observed among the 10 measurements of DP‐TSE, indicating desirable robustness for ADC‐based tumor response assessment. In vivo TRE in DP‐TSE was less than 1.6 mm overall, whereas it could be greater than 12 mm in DW‐ssEPI. For GBM patients, the CSF and brain tissue ADCs from DP‐TSE were within the ranges found in literature. ADC differences between the two techniques were within 8% among the six sarcoma patients. For the reference tube that had a relatively low diffusivity, the two diffusion sequences provided matched measurements. Conclusion: A diffusion technique with excellent geometric fidelity, accurate, and reproducible ADC measurement was demonstrated for longitudinal tumor response assessment using a low‐field MRI‐guided radiotherapy system.

Hypo-fractionated stereotactic radiotherapy of five fractions with linear accelerator for vestibular schwannomas: a systematic review and meta-analysis

Vestibular schwannomas (VS) are benign tumors stemming from the eighth cranial nerve. Treatment options for VS include conservative management, microsurgery, stereotactic radiosurgery, and fractionated radiotherapy. Though microsurgery has been the standard of care for larger lesions, hypo-fractionated stereotactic radiotherapy (hypo-FSRT) is an emerging modality. However, its clinical efficacy and safety have yet to be established. We conducted a systematic review and meta-analysis of manuscripts indexed in PubMed, Scopus, Web of Science, Embase, and Cochrane databases reporting outcomes of VS cases treated with hypo-FSRT. Five studies representing a total of 228 patients were identified. Across studies, the pooled rates of tumor control, hearing, facial nerve, and trigeminal nerve preservation were 95%, 37%, 97%, and 98%. No instances of malignant induction were observed at median follow-up of 34.8 months. Complications included trigeminal neuropathy (n = 3), maxillary paresthesia (n = 1), neuralgia (n = 1), vestibular dysfunction (n = 1), radionecrosis (n = 1), and hydrocephalus (n = 1). Hypo-FSRT may be another useful approach to manage VS, but studies with extended follow-up times are required to establish long-term safety.