Cochlea-sparing acoustic neuroma treatment with 4π radiation therapy.

PurposeThis study investigates whether 4π noncoplanar radiation therapy can spare the cochleae and consequently potentially improve hearing preservation in patients with acoustic neuroma who are treated with radiation therapy.Methods and materialsClinical radiation therapy plans for 30 patients with acoustic neuroma were included (14 stereotactic radiation surgery [SRS], 6 stereotactic radiation therapy [SRT], and 10 intensity modulated radiation therapy [IMRT]). The 4π plans were created for each patient with 20 optimal beams selected using a greedy column generation method and subsequently recalculated in Eclipse for comparison. Organ-at-risk (OAR) doses, homogeneity index, conformity, and tumor control probability (TCP) were compared. Normal tissue complication probability (NTCP) was calculated for sensorineural hearing loss (SNHL) at 3 and 5 years posttreatment. The dose for each plan was then escalated to achieve 99.5% TCP.Results4π significantly reduced the mean dose to both cochleae by 2.0 Gy (32%) for SRS, 3.2 Gy (29%) for SRT, and 10.0 Gy (32%) for IMRT. The maximum dose to both cochleae was also reduced with 4π by 1.6 Gy (20%), 2.2 Gy (15%), and 7.1 Gy (18%) for SRS, SRT, and IMRT plans, respectively. The reductions in mean/maximum brainstem dose with 4π were also statistically significant. Mean doses to other OARs were reduced by 19% to 56% on average. 4π plans had a similar CN and TCP, with a significantly higher average homogeneity index (0.93 vs 0.92) and significantly lower average NTCP for SNHL at both 3 years (30.8% vs 40.8%) and 5 years (43.3% vs 61.7%). An average dose escalation of approximately 116% of the prescription dose achieved 99.5% TCP, which resulted in 32.6% and 43.4% NTCP for SNHL at 3 years and 46.4% and 64.7% at 5 years for 4π and clinical plans, respectively.ConclusionsCompared with clinical planning methods, optimized 4π radiation therapy enables statistically significant sparing of the cochleae in acoustic neuroma treatment as well as lowering of other OAR doses, potentially reducing the risk of hearing loss

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

Irradiation to Improve the Response to Immunotherapeutic Agents in Glioblastomas.

PurposeGlioblastoma (GBM) remains an incurable disease despite extensive treatment with surgical resection, irradiation, and temozolomide. In line with many other forms of aggressive cancers, GBM is currently under consideration as a target for immunotherapy. However, GBM tends to be nonimmunogenic and exhibits a microenvironment with few or no effector T cells, a relatively low nonsynonymous somatic mutational load, and a low predicted neoantigen burden. GBM also exploits a multitude of immunosuppressive strategies.Methods and materialsA number of immunotherapeutic approaches have been tested with disappointing results. A rationale exists to combine immunotherapy and radiation therapy, which can induce an immunogenic form of cell death with T-cell activation and tumor infiltration.ResultsVarious immunotherapy agents, including immune checkpoint modulators, transforming growth factor beta receptor inhibitors, and indoleamine-2,3-dioxygenase inhibitors, have been evaluated with irradiation in preclinical GBM models, with promising results, and are being further tested in clinical trials.ConclusionsThis review aims to present the basic rationale behind this emerging complementary therapeutic approach in GBM, appraise the current preclinical and clinical data, and discuss the future challenges in improving the antitumor immune response

Cochlea-sparing acoustic neuroma treatment with 4π radiation therapy.

PurposeThis study investigates whether 4π noncoplanar radiation therapy can spare the cochleae and consequently potentially improve hearing preservation in patients with acoustic neuroma who are treated with radiation therapy.Methods and materialsClinical radiation therapy plans for 30 patients with acoustic neuroma were included (14 stereotactic radiation surgery [SRS], 6 stereotactic radiation therapy [SRT], and 10 intensity modulated radiation therapy [IMRT]). The 4π plans were created for each patient with 20 optimal beams selected using a greedy column generation method and subsequently recalculated in Eclipse for comparison. Organ-at-risk (OAR) doses, homogeneity index, conformity, and tumor control probability (TCP) were compared. Normal tissue complication probability (NTCP) was calculated for sensorineural hearing loss (SNHL) at 3 and 5 years posttreatment. The dose for each plan was then escalated to achieve 99.5% TCP.Results4π significantly reduced the mean dose to both cochleae by 2.0 Gy (32%) for SRS, 3.2 Gy (29%) for SRT, and 10.0 Gy (32%) for IMRT. The maximum dose to both cochleae was also reduced with 4π by 1.6 Gy (20%), 2.2 Gy (15%), and 7.1 Gy (18%) for SRS, SRT, and IMRT plans, respectively. The reductions in mean/maximum brainstem dose with 4π were also statistically significant. Mean doses to other OARs were reduced by 19% to 56% on average. 4π plans had a similar CN and TCP, with a significantly higher average homogeneity index (0.93 vs 0.92) and significantly lower average NTCP for SNHL at both 3 years (30.8% vs 40.8%) and 5 years (43.3% vs 61.7%). An average dose escalation of approximately 116% of the prescription dose achieved 99.5% TCP, which resulted in 32.6% and 43.4% NTCP for SNHL at 3 years and 46.4% and 64.7% at 5 years for 4π and clinical plans, respectively.ConclusionsCompared with clinical planning methods, optimized 4π radiation therapy enables statistically significant sparing of the cochleae in acoustic neuroma treatment as well as lowering of other OAR doses, potentially reducing the risk of hearing loss

Treating Glioblastoma Multiforme (GBM) with super hyperfractionated radiation therapy: Implication of temporal dose fractionation optimization including cancer stem cell dynamics.

PurposeA previously developed ordinary differential equation (ODE) that models the dynamic interaction and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC) was used to explain the definitive treatment failure in Glioblastoma Multiforme (GBM) for conventionally and hypo-fractionated treatments. In this study, optimization of temporal dose modulation based on the ODE equation is performed to explore the feasibility of improving GBM treatment outcome.MethodsA non-convex optimization problem with the objective of minimizing the total cancer cell number while maintaining the normal tissue biological effective dose (BEDnormal) at 100 Gy, equivalent to the conventional 2 Gy × 30 dosing scheme was formulated. With specified total number of dose fractions and treatment duration, the optimization was performed using a paired simulated annealing algorithm with fractional doses delivered to the CSC and DCC compartments and time intervals between fractions as variables. The recurrence time, defined as the time point at which the total tumor cell number regrows to 2.8×109 cells, was used to evaluate optimization outcome. Optimization was performed for conventional treatment time frames equivalent to currently and historically utilized fractionation schemes, in which limited improvement in recurrence time delay was observed. The efficacy of a super hyperfractionated approach with a prolonged treatment duration of one year was therefore tested, with both fixed regular and optimized variable time intervals between dose fractions corresponding to total number of fractions equivalent to weekly, bi-weekly, and monthly deliveries (n = 53, 27, 13). Optimization corresponding to BEDnormal of 150 Gy was also obtained to evaluate the possibility in further recurrence delay with dose escalation.ResultsFor the super hyperfractionated schedules with dose fraction number equivalent to weekly, bi-weekly, and monthly deliveries, the recurrence time points were found to be 430.5, 423.9, and 413.3 days, respectively, significantly delayed compared with the recurrence time of 250.3 days from conventional fractionation. Results show that optimal outcome was achieved by first delivering infrequent fractions followed by dense once per day fractions in the middle and end of the treatment course, with sparse and low dose treatments in the between. The dose to the CSC compartment was held relatively constant throughout while larger dose fractions to the DCC compartment were observed in the beginning and final fractions that preceded large time intervals. Dose escalation to BEDnormal of 150 Gy was shown capable of further delaying recurrence time to 452 days.ConclusionThe development and utilization of a temporal dose fractionation optimization framework in the context of CSC dynamics have demonstrated that substantial delay in GBM local tumor recurrence could be achieved with a super hyperfractionated treatment approach. Preclinical and clinical studies are needed to validate the efficacy of this novel treatment delivery method

Cochlea-sparing acoustic neuroma treatment with 4π radiation therapy

Purpose: This study investigates whether 4π noncoplanar radiation therapy can spare the cochleae and consequently potentially improve hearing preservation in patients with acoustic neuroma who are treated with radiation therapy. Methods and materials: Clinical radiation therapy plans for 30 patients with acoustic neuroma were included (14 stereotactic radiation surgery [SRS], 6 stereotactic radiation therapy [SRT], and 10 intensity modulated radiation therapy [IMRT]). The 4π plans were created for each patient with 20 optimal beams selected using a greedy column generation method and subsequently recalculated in Eclipse for comparison. Organ-at-risk (OAR) doses, homogeneity index, conformity, and tumor control probability (TCP) were compared. Normal tissue complication probability (NTCP) was calculated for sensorineural hearing loss (SNHL) at 3 and 5 years posttreatment. The dose for each plan was then escalated to achieve 99.5% TCP. Results: 4π significantly reduced the mean dose to both cochleae by 2.0 Gy (32%) for SRS, 3.2 Gy (29%) for SRT, and 10.0 Gy (32%) for IMRT. The maximum dose to both cochleae was also reduced with 4π by 1.6 Gy (20%), 2.2 Gy (15%), and 7.1 Gy (18%) for SRS, SRT, and IMRT plans, respectively. The reductions in mean/maximum brainstem dose with 4π were also statistically significant. Mean doses to other OARs were reduced by 19% to 56% on average. 4π plans had a similar CN and TCP, with a significantly higher average homogeneity index (0.93 vs 0.92) and significantly lower average NTCP for SNHL at both 3 years (30.8% vs 40.8%) and 5 years (43.3% vs 61.7%). An average dose escalation of approximately 116% of the prescription dose achieved 99.5% TCP, which resulted in 32.6% and 43.4% NTCP for SNHL at 3 years and 46.4% and 64.7% at 5 years for 4π and clinical plans, respectively. Conclusions: Compared with clinical planning methods, optimized 4π radiation therapy enables statistically significant sparing of the cochleae in acoustic neuroma treatment as well as lowering of other OAR doses, potentially reducing the risk of hearing loss

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

Essential tremor and Parkinson's 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 Parkinson's 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

Radiosurgical target distance from the root entry zone in the treatment of trigeminal neuralgia

PurposeStereotactic radiosurgery (SRS) provides a noninvasive treatment modality for patients with medically refractory trigeminal neuralgia. The root entry zone (REZ) has been proposed to be an ideal stereotactic target because it is partially composed of centrally produced myelin, conferring a theoretical increased sensitivity to irradiation as well as increased susceptibility to neurovascular conflict, making it the site in which nociceptive signals likely arise. The aim of this study is to determine if there is a statistically and clinically significant difference in pain relief or facial hypesthesia following SRS based on distance of the stereotactic isocenter from REZ.Methods and materialsPatients undergoing Novalis radiosurgery for the treatment of trigeminal neuralgia with at least 3 months' follow-up were included in this study. Postoperative outcomes were stratified by Barrow Neurological Institute (BNI) score for pain relief and BNI facial numbness score for facial hypesthesia.ResultsSixty-seven patients met inclusion criteria and were included in this study. BNI score of I-IIIa was attained in 82% of patients at 3 months and 65% at 1 year following SRS. Distance from isocenter to REZ varied from 0 to 8.6 mm, with a mean of 1.94 ± 1.62 mm. Logistic regression of target-REZ distance against pain relief outcome (patients with score I-IIIa and IIIb-V) was insignificant at 3 months (P = .988), 6 months (P = .925), 9 months (P = .845), and 12 months (P = .547) postoperatively. Furthermore, no significant correlation was found with logistic regression of target-REZ distance with pain relief outcome (patients with score I and score II-IV) (P = .544).ConclusionsThe current analysis suggests that distance from REZ does not correlate with degree of postoperative pain relief or facial hypesthesia; thus, targeting specific regions within the trigeminal nerve in relation to these anatomical characteristics may not afford any advantage from this perspective

Treating Glioblastoma Multiforme (GBM) with super hyperfractionated radiation therapy: Implication of temporal dose fractionation optimization including cancer stem cell dynamics.

PurposeA previously developed ordinary differential equation (ODE) that models the dynamic interaction and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC) was used to explain the definitive treatment failure in Glioblastoma Multiforme (GBM) for conventionally and hypo-fractionated treatments. In this study, optimization of temporal dose modulation based on the ODE equation is performed to explore the feasibility of improving GBM treatment outcome.MethodsA non-convex optimization problem with the objective of minimizing the total cancer cell number while maintaining the normal tissue biological effective dose (BEDnormal) at 100 Gy, equivalent to the conventional 2 Gy × 30 dosing scheme was formulated. With specified total number of dose fractions and treatment duration, the optimization was performed using a paired simulated annealing algorithm with fractional doses delivered to the CSC and DCC compartments and time intervals between fractions as variables. The recurrence time, defined as the time point at which the total tumor cell number regrows to 2.8×109 cells, was used to evaluate optimization outcome. Optimization was performed for conventional treatment time frames equivalent to currently and historically utilized fractionation schemes, in which limited improvement in recurrence time delay was observed. The efficacy of a super hyperfractionated approach with a prolonged treatment duration of one year was therefore tested, with both fixed regular and optimized variable time intervals between dose fractions corresponding to total number of fractions equivalent to weekly, bi-weekly, and monthly deliveries (n = 53, 27, 13). Optimization corresponding to BEDnormal of 150 Gy was also obtained to evaluate the possibility in further recurrence delay with dose escalation.ResultsFor the super hyperfractionated schedules with dose fraction number equivalent to weekly, bi-weekly, and monthly deliveries, the recurrence time points were found to be 430.5, 423.9, and 413.3 days, respectively, significantly delayed compared with the recurrence time of 250.3 days from conventional fractionation. Results show that optimal outcome was achieved by first delivering infrequent fractions followed by dense once per day fractions in the middle and end of the treatment course, with sparse and low dose treatments in the between. The dose to the CSC compartment was held relatively constant throughout while larger dose fractions to the DCC compartment were observed in the beginning and final fractions that preceded large time intervals. Dose escalation to BEDnormal of 150 Gy was shown capable of further delaying recurrence time to 452 days.ConclusionThe development and utilization of a temporal dose fractionation optimization framework in the context of CSC dynamics have demonstrated that substantial delay in GBM local tumor recurrence could be achieved with a super hyperfractionated treatment approach. Preclinical and clinical studies are needed to validate the efficacy of this novel treatment delivery method