Multi-fraction Stereotactic Radiosurgery Research Articles

How Does the Number of Brain Metastases Correlate With Normal Brain Exposure in Single-Isocenter Multitarget Multifraction Stereotactic Radiosurgery

PurposeTo investigate the relationship between normal brain exposure in linac-based single-isocenter multi-target multi-fraction stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) and the number or volume of treated brain metastases, especially for high numbers of metastases. Methods and MaterialsA cohort of 44 SRT patients with 709 brain metastases was studied. Renormalizing to a uniform prescription of 27 Gy in 3 fractions, normal brain dose volume indices, including V23Gy (volume receiving >23Gy), V18Gy (volume receiving >18Gy), and mean dose, were evaluated on these plans against the number and the total volume of targets for each plan. To compare with exposures from whole-brain radiotherapy (WBRT), the SRT dose distributions were converted to equivalent dose in 3 Gy fractions (EQD3) using an alpha-beta ratio of 2 Gy. ResultsWith increasing number of targets and increasing total target volume, normal brain exposures to dose ≥18 Gy increases, and so does the mean normal brain dose. The factors of number of targets and total target volume are both significant, though the number of targets has a larger effect on the mean normal brain dose and the total target volume has a larger effect on V23Gy and V18Gy. The EQD3 mean normal brain dose with SRT planning is lower than conventional WBRT. On the other hand, SRT results in higher hot spot (i.e. maximum dose outside of tumor) EQD3 dose than WBRT. ConclusionsBased on clinical SRT plans, our study provides information on correlations between normal brain exposure and the number and total volume of targets. As SRT becomes more greatly utilized for patients with increasingly extensive brain metastases, more clinical data on outcomes and toxicities is necessary to better define the normal brain dose constraints for high-exposure cases and to optimize the SRT management for those patients.

Dosimetric evaluation of LINAC-based single-isocenter multi-target multi-fraction stereotactic radiosurgery with more than 20 targets: comparing MME, HyperArc, and RapidArc

BackgroundTo compare the dosimetric quality of three widely used techniques for LINAC-based single-isocenter multi-target multi-fraction stereotactic radiosurgery (fSRS) with more than 20 targets: dynamic conformal arc (DCA) in BrainLAB Multiple Metastases Elements (MME) module and volumetric modulated arc therapy (VMAT) using RapidArc (RA) and HyperArc (HA) in Varian Eclipse.MethodsTen patients who received single-isocenter fSRS with 20–37 targets were retrospectively replanned using MME, RA, and HA. Various dosimetric parameters, such as conformity index (CI), Paddick CI, gradient index (GI), normal brain dose exposures, maximum organ-at-risk (OAR) doses, and beam-on times were extracted and compared among the three techniques. Wilcoxon signed-rank test was used for statistical analysis.ResultsAll plans achieved the prescribed dose coverage goal of at least 95% of the planning target volume (PTV). HA plans showed superior conformity compared to RA and MME plans. MME plans showed superior GI compared to RA and HA plans. RA plans resulted in significantly higher low and intermediate dose exposure to normal brain compared to HA and MME plans, especially for lower doses of ≥ 8Gy and ≥ 5Gy. No significant differences were observed in the maximum dose to OARs among the three techniques. The beam-on time of MME plans was about two times longer than RA and HA plans.ConclusionsHA plans achieved the best conformity, while MME plans achieved the best dose fall-off for LINAC-based single-isocenter multi-target multi-fraction SRS with more than 20 targets. The choice of the optimal technique should consider the trade-offs between dosimetric quality, beam-on time, and planning effort.

RADT-05. SINGLE VERSUS MULTI-FRACTION STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: RATES OF LOCAL PROGRESSION AND NECROSIS

Abstract PURPOSE For large brain metastases, it is unknown whether single fraction stereotactic radiosurgery (sSRS) or multi-fraction stereotactic radiosurgery (fSRS) is optimal. We aimed to compare rates of local progression and necrosis between sSRS and fSRS for large brain metastases. METHODS Patients with intact or resected brain metastases with a target volume ≥ 4.2 cc (corresponding to a diameter ≥ 2 cm) treated with Gamma Knife (GK) or linear accelerator-based SRS from 2014-2022 were included in this retrospective review. RESULTS A total of 343 large brain metastases in 276 patients were included; 171 lesions were treated with sSRS (96% with GK) and 172 lesions with fSRS (100% with linear accelerator). Median lesion volume was 19.8 cc and 8.4 cc for fSRS and sSRS, respectively. Resection was performed prior to SRS in 228 (66%), with the remaining 115 metastases treated intact. There was no difference in rate of local progression between sSRS versus fSRS, or between resected versus intact targets (p >0.8 for both). Cumulative incidence of local progression (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 24% and 30%, respectively, compared to 22% and 34% for fSRS. FSRS was associated with significantly higher rates of necrosis than sSRS (HR 5.58, 2.38-13.08, p < 0.001). This association remained significant after controlling for target volume. Cumulative incidence of necrosis (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 1% and 3%, respectively, compared to 10% and 18% for fSRS. Necrosis rates were significantly higher with fSRS for both intact and resected targets (P < 0.02 for both). CONCLUSION While local control for large resected or intact brain metastases appears similar after sSRS or fSRS, this retrospective study shows higher rates of necrosis after fSRS. Prospective validation is needed.

Hyperarc Vmat and Vmat planning for stereotactic radiosurgery in multiple brain metastases

Automated treatment planning systems are available for linear accelerator (LINAC) based single and more isocenter multitarget stereotactic radiosurgery (SRS) of brain metastases. HyperArc Volumetric Modulated Arc Therapy (HA-VMAT) is a relatively new isocentric Volumetric Modulated Arc Therapy (VMAT) technique developed specifically for non-coplanar, multileaf collimator (MLC)-based stereotactic radiotherapy with automatic treatment optimization and dose delivery. The HA-VMAT planning approach was developed to accommodate dosing procedures for brain metastases stereotactic radiosurgery. In this study, it was aimed to compare the dosimetric parameters of treatment plans created with single and multi-isocenter retrospectively VMAT and HA-VMAT techniques in patients with lung cancer and multiple brain metastases (4–7) who received single and multi-fraction stereotactic radiosurgery (SRS). Using VMAT and HA-VMAT techniques, two separate treatment plans were created for each case, and tumor target coverage (homogeneity index (HI); conformity index (CI); gradient index (GI)) and organ at risk (OAR) were evaluated dosimetrically. Physical properties and Monitor unit (MU) values of both treatment approaches were compared. Treatment plans were created for study purposes and patients were not treated with these plans. In the study, HI (p = 0.000), CI (p = 0.000) and GI (p = 0.002) values calculated with the HA-VMAT technique are superior to the VMAT technique. Medium-low dose spreads (V4Gy-V16Gy) were significantly reduced in HA-VMAT plans compared to plans with VMAT. HA-VMAT plans result in lower MU than VMAT plans. HA-VMAT planning has significantly less radiation necrosis indicator (V8Gy-V16Gy) compared to VMAT plans. However, there are few studies investigating the ability of the HA-VMAT technique to create high-quality treatment plans for extracranial lesions. HA-VMAT may constitute one of the new options for SRS dose delivery for both single target and multiple targets.

Factors Associated with Stereotactic Radiation Plan Revision in Prospective Peer Review.

Stereotactic radiotherapy (SR) is highly effective but has risks for serious toxicity. We sought to identify risk factors for SR plans requiring revision in a comprehensive, prospective peer review program conducted across a network of affiliated radiation centers. We hypothesized that increased physician experience and SR case volume would be associated with lower rates of SR plan revision. Weekly peer review rounds were conducted to review SR cases for image fusion, contours, plan, and dose constraints, all prior to start of radiation. Cases recommended for revision were recorded and tracked prospectively. Factors potentially associated with case revision including body site, SR type, physician experience, and physician case load were assessed for significance using univariate and multivariable logistic regression. From March 2019 to January 2023, 1,015 SR cases were prospectively reviewed, including 312 brain stereotactic radiosurgery (SRS), 190 multi-fraction brain SRS (fSRS), and 513 stereotactic body radiotherapy (SBRT). Revision was recommended in 177 cases (17%). The yearly revision rate was 21% in 2019, 16% in 2020, 17% in 2021, and 18% in 2022. There were 13 individual treating physicians with a median of 5 years' experience (range: 2-18 years), measured at the time of each SR case review. Physicians were categorized as junior (< = 2 years of experience), mid-career (3-9 years), or senior (> = 10 years). The physician's SR case volume in the preceding 3 months (median 25 cases) was dichotomized as low volume (< = 25) or high volume (>25). Logistic regression results are shown in Table 1. Statistical significance was determined by p <0.05. SR plans utilizing SRS (as opposed to SBRT) and treated by physicians with high case volume had lower revision rates. Junior attendings had higher revision rates. These data imply a high value to peer review for junior attendings and for those with low SR case volume. Adequate case volume may be a critical factor for safe delivery of SR, analogous to surgical literature. Annual revision rates in the program remained stable over time, demonstrating the ongoing importance of an effective peer review program for SR.

Morbidity of single-fraction spine radiosurgery for metastatic disease.

e24116 Background: The optimal management of metastatic spine disease involves radiation therapy, with stereotactic radiosurgery (SRS) utilization having increased in adoption while proving to be efficacious and safe. Spine SRS morbidity (fatigue, dermatitis, nausea and esophagitis) is generally mild and depends on the spinal vertebral level(s) treated. More severe adverse events such as vertebral compression fracture (VCF), radiation-induced myelopathy, and tracheoesophageal (TE) fistula have been documented. The potential benefits of single-fraction SRS (sfSRS) over multi-fraction SRS include increased patient convenience, decreased financial toxicity, and increased treatment completion rates. These benefits may potentially be overshadowed by the morbidity of sfSRS versus multifraction SRS. In this analysis, we perform the first comprehensive examination of sfSRS morbidity in the treatment of spinal lesions. Methods: An extensive search of the PubMed database was undertaken through 2/2/23 to find studies examining spinal sfSRS. Search parameters included the terms “single-fraction, spine, radiation SRS OR SBRT” Articles including multi-fractionated regimens only, reviewed sites outside of the spine, or did not report on clinical outcomes/toxicities were excluded. Results: 17 articles met initial inclusion criteria; 9 were added from references for a total of 26 articles comprising at least 2,699 patients (one study reported the number of tumors, not patients). Dose ranges for single-fraction SRS were 8-26 Gy. Commonly noted toxicities were fatigue, nausea/vomiting, and dermatitis which were no worse than moderate/minimal, not requiring invasive intervention. The overall rate of VCF was 16.2%, with an increased propensity at &gt;20 Gy. The proportion of reported segments requiring surgical intervention (operative stabilization, vertebroplasty/kyphoplasty) for VCF after single-fraction SRS was 20.2% (33/163). The rate of TE fistula at 25 Gy was 8.3%, with an overall rate (dose range = 10-28 Gy) of 1.3% with up to 12-years of follow-up. In patients receiving median dose of 24 Gy, the rate of severe esophagitis was 6.8%, myositis was 1.3% (at 1-year) and 8.3% (at 5-years). The rate of peripheral nervous system injury was 2.5% (at 18-26 Gy) and pain flare was 8% (at 16-24 Gy). The rate of ureteral and esophageal stricture was 1.9% each in patients receiving 12-24 Gy. Conclusions: VCF is the most commonly reported severe adverse events with single-fraction spine SRS, particularly for doses &gt; 20 Gy. 80% of VCFs can be successfully managed without invasive intervention. Other severe adverse events are rare – particularly for &lt; 20 Gy – but require post-SRS monitoring to expediently and efficiently intervene if necessary. These findings indicate that single-fraction spine SRS to &lt; 20 Gy is safe with minimal morbidity. Further study regarding the efficacy of such dosing is being evaluated in ongoing clinical trials.

PO-1125 Multifraction Stereotactic Radiosurgery as a safe therapy for limited brain metastasis

PO-1125 Multifraction Stereotactic Radiosurgery as a safe therapy for limited brain metastasis

Intracranial and Extracranial Progression and Their Correlation With Overall Survival After Stereotactic Radiosurgery in a Multi-institutional Cohort With Brain Metastases

Clinical trials for metastatic malignant neoplasms are increasingly being extended to patients with brain metastases. Despite the preeminence of progression-free survival (PFS) as a primary oncologic end point, the correlation of intracranial progression (ICP) and extracranial progression (ECP) events with overall survival (OS) is poorly understood for patients with brain metastases following stereotactic radiosurgery (SRS). To determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course. This multi-institutional retrospective cohort study was conducted from January 1, 2015, to December 31, 2020. We included patients who completed an initial course of SRS for brain metastases during the study period, including receipt of single and/or multifraction SRS, prior whole-brain radiotherapy, and brain metastasis resection. Data analysis was performed on November 15, 2022. Non-OS end points included intracranial PFS, extracranial PFS, PFS, time to ICP, time to ECP, and any time to progression. Progression events were radiologically defined, incorporating multidisciplinary clinical consensus. The primary outcome was correlation of surrogate end points to OS. Clinical end points were estimated from time of SRS completion via the Kaplan-Meier method, while end-point correlation to OS was measured using normal scores rank correlation with the iterative multiple imputation approach. This study included 1383 patients, with a mean age of 63.1 years (range, 20.9-92.8 years) and a median follow-up of 8.72 months (IQR, 3.25-19.68 months). The majority of participants were White (1032 [75%]), and more than half (758 [55%]) were women. Common primary tumor sites included the lung (757 [55%]), breast (203 [15%]), and skin (melanoma; 100 [7%]). Intracranial progression was observed in 698 patients (50%), preceding 492 of 1000 observed deaths (49%). Extracranial progression was observed in 800 patients (58%), preceding 627 of 1000 observed deaths (63%). Irrespective of deaths, 482 patients (35%) experienced both ICP and ECP, 534 (39%) experienced ICP (216 [16%]) or ECP (318 [23%]), and 367 (27%) experienced neither. The median OS was 9.93 months (95% CI, 9.08-11.05 months). Intracranial PFS had the highest correlation with OS (ρ = 0.84 [95% CI, 0.82-0.85]; median, 4.39 months [95% CI, 4.02-4.92 months]). Time to ICP had the lowest correlation with OS (ρ = 0.42 [95% CI, 0.34-0.50]) and the longest median time to event (median, 8.76 months [95% CI, 7.70-9.48 months]). Across specific primary tumor types, correlations of intracranial PFS and extracranial PFS with OS were consistently high despite corresponding differences in median outcome durations. The results of this cohort study of patients with brain metastases completing SRS suggest that intracranial PFS, extracranial PFS, and PFS had the highest correlations with OS and time to ICP had the lowest correlation with OS. These data may inform future patient inclusion and end-point selection for clinical trials.

Time interval from diagnosis to treatment of brain metastases with stereotactic radiosurgery is not associated with radionecrosis or local failure.

Brain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear. This single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher's exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure. A total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure. An optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.

Patterns of Failure after Stereotactic Radiosurgery vs. Whole Brain Radiotherapy for Resected Brain Metastases: Central Imaging Review of the N107C/CEC.3 (Alliance) Phase III Clinical Trial

<h3>Purpose/Objective(s)</h3> Whole brain radiotherapy (WBRT) has historically been the main instrument to decrease intracranial progression after resection of brain metastases. The previously reported NCCTG N107C/CEC.3 (Alliance) randomized phase III clinical trial of WBRT vs. stereotactic radiosurgery (SRS) demonstrated that overall survival did not significantly differ between arms, while SRS was associated with less cognitive decline than WBRT. However, the initial analysis also showed that local tumor bed control (LC) was significantly worse with SRS than WBRT, with an unexpectedly low 12-month LC rate of 60.5% in patients receiving post-operative SRS. To further investigate LC, a central imaging review was performed. <h3>Materials/Methods</h3> In N107C/CEC.3, 194 patients were randomized to SRS (n=98) or WBRT (n=96). SRS dose was dependent on resection cavity volume and ranged from 12 Gy to 20 Gy all in a single fraction, and WBRT dose was 30 Gy in 10 fractions or 37.5 Gy in 15 fractions. For this analysis, patients with local failure (LF) or leptomeningeal failure that had imaging available were centrally reviewed by two radiation oncologists to verify pattern of failure. Patient and treatment characteristics were assessed for association with updated outcomes after central review using Cox proportional hazards, Pearson's chi-square, or Kruskal-Wallis tests. <h3>Results</h3> Seventy-three patients with LF or leptomeningeal failure determined by their local site were centrally reviewed. After adding patients with no LF or leptomeningeal failure, 185 (95% of total enrolled) patients were included in this analysis as 9 patients with LF did not have imaging available for central review. Of 59 patients initially determined to have LF, 20 were determined on central review to be free of LF. Accordingly, after central review post-operative SRS was no longer associated with significantly lower rates of LC than WBRT (79.2% vs. 86.5% 12-month LC, respectively, p=0.099). After central review, the interrelated variables of tumor diameter, target volume, and prescription dose were associated with risk of LF. Patients with resection cavities > 3 cm had higher rates of LF than those with smaller cavities (23.5% vs. 12.6% 12-month LF rate, respectively; p=0.010). Larger target volume was associated with increased risk of LF (HR: 1.05, 95% CI: 1.01 – 1.09, p=0.008), while higher prescription dose was associated with lower risk of LF (HR: 0.81, 95% CI: 0.67 – 0.96, p=0.018). <h3>Conclusion</h3> In contrast to the initial report, after central review SRS was not associated with significantly higher rates of LF than WBRT. Patients with larger surgical cavities had higher rates of LF, though it is unclear whether this is related to cavity size, biology, or radiation dose. Randomized data comparing single to multifraction SRS in larger surgical cavities is awaited.

Implementation of a Special Medical Physics Consult Process for Re-Irradiation in Patients with Brain Tumors: Planning and Toxicity Outcomes

<h3>Purpose/Objective(s)</h3> We hypothesized that implementation of a systematic approach to re-irradiation (ReRT) using a special medical physics consult (SMPC) process would lead to acceptably low rates of high-grade toxicity associated with planning parameters impacting clinical management. <h3>Materials/Methods</h3> Consecutive patients treated using the ReRT-SMPC process during the first 18 months of its implementation were included. Accuracy of data set registration in the region of treatment was assessed by physics and verified by physician to generate cumulative physical and biologically corrected dose maps (equivalent dose in 2 Gy fractions EQD₂, alpha/beta 2.5 for normal tissue). Standardized dose discounts based on time interval from prior treatment and consistent guidelines for acceptable EQD₂ dose-limits per organ-at-risk (OAR) were used in all cases to provide allowable dose constraints prior to planning. Post-planning physics evaluation highlighted exceeded limits to assist clinical management. Comparison of planning parameters among patients with and without high-grade toxicity (grade 3 or higher) per CTCAE v5.0 was performed using 2-sided t-test and significance level 0.05. <h3>Results</h3> From April 2017 to September 2018, 261 consecutive patients underwent ReRT using this workflow, of whom 55 (21%) had brain tumors. ReRT with conventional fractionation (CFRT) was given to 47% primarily for gliomas (median EQD₂ 47 Gy (IQR, 41-56)), and with single or multi-fraction stereotactic radiosurgery in 53% primarily for brain metastases (median EQD₂ 100 Gy (IQR 57-120)). Median follow-up after ReRT among patients alive at time of analysis was 6.9 months (IQR, 5.3-10.8). No high-grade toxicity was observed in any delineated OAR including brainstem or optic structures. No specific normal brain constraint was employed in the SMPC process, and 5 (9%) patients experienced high-grade toxicity both early (cerebral edema, n=3) and late (necrosis, n=2). Cumulative EQD₂ was lower among patients with vs without toxicity (D0.03cc 87 vs 155 Gy, p=0.047), as 80% of patients with toxicity underwent ReRT with CFRT to larger volumes (39 vs 14 cc). While no constraints were applied for normal brain, recovery factors based on interval from index treatment were applied for all patients. However, no association with time interval was observed in patients with vs without toxicity (p=0.4). In two instances, the ReRT-SMPC analysis resulted in physician decision not to treat due to potential toxicity concerns. <h3>Conclusion</h3> Re-irradiation of primary and metastatic brain tumors using a standardized SMPC process yields low rates of high-grade CNS toxicity and meaningfully impacts physician decision-making. Future planning parameters including normal brain dose will be refined using this systematic process to improve the therapeutic ratio among patients undergoing re-irradiation.

Stereotactic radiosurgery of radioresistant glioblastomas. The ways of overcoming radioresistance of hypoxic tumors

Background. Taking into account high degree of resistance of glioblastoma to radiation therapy, and also low overall survival rates of patients, it is necessary to develop improved methods of treating this pathology, in particular, complex combined treatment with radiation therapy and radiosensitizers.&#x0D; Purpose – to assess the effectiveness of radiosensitization of hypoxic tumors in radiosurgical treatment of glioblastomas; to increase non-recurrent and overall survival rate of patients. Materials and methods. Stereotactic radiosurgery (SRS) of glioblastoma was performed in 106 patients (average age – 53 years), 66 males (62,26%) and 40 females (37,73%). The average dose was 18 Gy in a single-fraction SRS, and 32 Gy (7 Gy per fraction) in multi-fraction SRS. The average volume tumor was 29 cm3 . The treatment group consisted of 66 patients who underwent SRS with radiosensitization. 40 patients made up the control group and underwent SRS without radiosensitization.&#x0D; Results. Median overall survival (MOS) was 20 months in the group with radiosensitization, whereas in the control group it was 12 months. 10-month recurrence-free period after radiosurgery was observed in 95,4% of the patients of the group with radiosensitization and in 70,6% of the patients of the control group. MOS after SRS was similar between the patients with wild-type IDH tumors and patients with tumors with IDH mutation (10,0 months and 11,0 months respectively), and also between the patients with MGMT-methylated tumors and patients with MGMT-nonmethylated tumors (11,2 and 10,2 months respectively). Among all the treated patients, in 20 of them (16,6%) side radiation effects after SRS were observed, and in 9 patients (7,5%) radiation necrosis developed in 3 to 16 months after SRS. The signs of moderate toxicity in the form of vomiting were observed in 6,6% of the patients of the subgroup with metronidazole. There were no signs of toxicity in the subgroup with nimorazole.&#x0D; Conclusions. Radiosensitization improves rates of overall survival by 53,3% and recurrence-free survival by 24,8 % in performing SRS of hypoxic radioresistant glioblastomas. Nimorazole and metronidazole are powerful radiosensitizers which increase radiosensitivity of tumor cells through enhancing oxygen saturation of hypoxic cells. In order to determine indications for performing SRS with radiosensitization and periods for performing an SRS session we must take into consideration the result of an oxygen test (level of oxygen saturation of the tumor), the peak of signal intensity in the zone of active tumor growth and the peak of saturation of the whole tumor volume.

The interim result of a phase I/II study of nivolumab with or without ipilimumab in combination with multi-fraction stereotactic radiosurgery for recurrent, high-grade, radiation-relapsed meningioma.

2068 Background: There is a lack of effective therapy for recurrent high-grade meningiomas who relapsed after prior radiation therapy (RT). ETCTN 10186 is a phase I/II study to evaluate the feasibility and preliminary clinical efficacy of combining reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab for recurrent high-grade meningiomas. The preliminary results from the phase I portion are reported here. Methods: Recurrent grade II-III meningioma patients were treated with radiosurgery plus nivolumab with or without ipilimumab. Key eligibility criteria include age ≥ 18 years; ECOG score ≤ 2; tumor diameter 1-5 cm; prior radiation dose ≤ 70 Gy; normal organ function; no active autoimmunity. During the phase I portion, eligible patients were treated according to treatment-escalation schema following the modified 3+3 design (Table 1). The maximum tolerated combination (MTC) will be the regimen at which ≤ 1/6 patients experience dose-limiting toxicity (DLT) within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. The primary endpoint of the phase I portion is to determine the MTC. Objective radiological responses (ORRs) are defined as per the Macdonald criteria. One cycle of immunotherapy is defined as 4 weeks of nivolumab with or without concurrent ipilimumab. Results: From 7/2019 to 3/2021, 13 patients were enrolled in the phase I, including 6 with regimen A and 7 with regimen B (Table). The median prior RT dose was 56 Gy (18-70) at a median interval of 2.8 years (1.3-13.3). There was no DLT in either cohort, so regimen B was deemed the MTC. The median cycles of immunotherapy completed were not significantly different between cohort A and B (11 vs. 6, p = 0.41, respectively). Three cohort A patients and 2 cohort B patients completed all planned doses of immunotherapy. Most patients stopped due to progression, and only one cohort B patient stopped due to treatment-related toxicity (grade 3 hypophysitis and encephalitis after 6 cycles of immunotherapy). After a median follow-up of 11.1 months, there have been 5 progressions and 4 deaths. The 6 month-PFS and 12 month-PFS rates are 62% and 54%, respectively. Two ORRs have been reported by institutional assessment, and central radiology review is ongoing and will be reported. Conclusions: Reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab are well tolerated for radiation-relapsed high-grade meningiomas. Phase II study of regimen B is currently enrolling. Clinical trial information: NCT03604978. [Table: see text]

RTID-01. PHASE III MULTICENTER RCT OF POST-SURGICAL STEREOTACTIC RADIOTHERAPY VERSUS SURGICALLY TARGETED RADIATION THERAPY FOR THE TREATMENT OF LARGE NEWLY DIAGNOSED BRAIN METASTASES – TRIAL IN PROGRESS

Abstract BACKGROUND Resection (R) followed by single- or multi-fraction stereotactic radiosurgery (SRT) of brain metastases (BMs) lowers resection bed recurrence compared to R alone. Nevertheless, for larger BMs, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiotherapy. STaRT allows rapid, intense localized radiation dose delivery directly to the tumor bed with predictable dosimetry immediately at the time of R, which may confer reduced risk for radiation necrosis compared to other therapies. It is hypothesized that R+ STaRT will increase surgical bed recurrence-free survival (SB-RFS), while reducing impact on functional and neurocognitive status compared to R+SRT. METHODS Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” BMs (≥ 2.5–5cm), and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo R+SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 14 sites. Enrollment opened 03/31/2021. First subject was enrolled 04/07/2021. Primary endpoint is SB-RFS. Secondary endpoints include overall survival, quality of life, neurocognition, functional status, imaging findings and adverse events. Follow-up will be through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures captured will elucidate the potential risks and benefits of these two RT delivery methods in the setting of newly diagnosed BMs. We will present trial accrual progress, available data, experience and lessons learned.

INNV-32. ACCESS TO SPECIALTY RADIATION CARE FOR PATIENTS WITH RESECTABLE BRAIN TUMORS

Abstract INTRODUCTION Many patients with brain tumors face challenges with access to care. For rural patients, prolonged travel times may limit access to appropriate radiotherapy. Radiation centers (RCs) offering specialized brain radiotherapy, e.g., stereotactic radiosurgery (SRS), are geographically limited. Brain brachytherapy at the time of resection offers an option for such patients, but technical challenges have limited the adoption. To address the limitations of traditional brachytherapy, a device with Cs-131 seeds embedded in a bioresorbable collagen tile (GammaTile (GT), GT Medical Technologies, Tempe, AZ) was developed. The device is FDA-cleared for permanent implantation at the time of resection for all recurrent intracranial tumors and newly diagnosed malignant intracranial neoplasms. To investigate if wider availability of this treatment could possibly lower the geographic barrier to access to care, we mapped the US population against existing RCs with brain tumor expertise and neurosurgery centers (NSCs) performing craniotomies. METHODS We analyzed 2018 CMS claims data using CPT codes for single- and multi-fraction SRS to identify RCs with brain tumor treatment expertise and mapped these against the population. Using similar methodology, using CPT codes for craniotomies, we identified NSCs, as any facility performing craniotomies is potentially eligible to implant the device. RESULTS 135 RCs used CPT codes for SRS. 193-, 119-, 82-, and 52-million Americans lived &amp;gt;30-, &amp;gt;60-, &amp;gt;90-, and &amp;gt;120-minutes from one of these centers, respectively. 530 NSCs preform craniotomies, including ≥ 1 in every state, a 4-fold increase over the number of RCs offering SRS. CONCLUSIONS For many patients, substantial travel distances limit access to RCs with brain tumor treatment expertise. In contrast, the 530 craniotomy-performing NSCs have far greater geographic dispersion. The option of undergoing brain radiation with GT implantation at the time of brain tumor craniotomy brings treatment closer to millions, ensures compliance, and reduces additional travel for follow-up radiation treatment.

A phase III multicenter randomized controlled trial of postsurgical stereotactic radiotherapy versus surgically targeted radiation therapy (STaRT) for the treatment of large (&gt;2.5cm) newly diagnosed brain metastases: Trial in progress.

TPS2067 Background: Resection (R) followed by single or multi-fraction stereotactic radiosurgery (SRT) of brain metastases lowers resection bed recurrence compared to R alone. Nevertheless, for larger (&gt;2.5cm) brain metastasis, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile or GT, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiation therapy. It is hypothesized that immediate adjuvant radiotherapy (RT) and/or RT dose intensification could improve outcomes. The device is FDA-cleared for this indication and early commercial use is demonstrating favorable safety and efficacy outcomes. STaRT allows rapid dose delivery of radiation therapy directly to the tumor bed with predictable dosimetry immediately at the time of resection, and an intense but localized radiation treatment, which may confer a reduced risk for radiation necrosis compared to other therapies. The device is easily placed with minimal additional operative time and limited staff radiation exposure. It is hypothesized that R+ STaRT will increase the surgical bed recurrence-free survival, while reducing the impact on functional and neurocognitive status compared to R+SRT. Methods: Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” brain metastases measuring ≥2.5–5 cm, and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo either R+ SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 13 sites. Enrollment will open in Q1. Primary endpoint is surgical bed-recurrence free survival. Secondary endpoints include overall survival, quality of life (Functional Assessment of Cancer Therapy-Brain, Linear Analog Self-Assessment), neurocognition (Hopkins Verbal Learning Test, Trail Making Tests, Controlled Oral Word Association), functional status (Karnofsky Performance Scale, Barthel-ADL), and adverse events. Follow-up will be at 1,3,6,9, and 12 months, then every 6 months through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures will be captured to elucidate the potential risks and benefits of these two differing post-operative RT delivery methods in the setting of newly diagnosed metastatic brain tumors. Clinical trial information: NCT04365374.

Access to radiation oncology centers with brain tumor treatment expertise for patients with resectable brain tumors.

e18509 Background: Many patients with brain tumors face challenges with access to care. For rural patients, prolonged travel times may limit access to appropriate radiotherapy. Radiation centers (RCs) offering specialized brain radiotherapy, e.g., stereotactic radiosurgery (SRS), are geographically limited. Utilization of brain brachytherapy at the time of resection offers an option for such patients, but technical challenges have limited the adoption. To address the limitations of traditional brachytherapy, a device with Cs-131 seeds embedded in a bioresorbable collagen tile (GammaTile, GT Medical Technologies, Tempe, AZ USA) was developed. GammaTile (GT) is FDA-cleared for permanent implantation at the time of resection for all recurrent intracranial tumors and for newly diagnosed malignant intracranial neoplasms. To investigate if wider availability of this treatment could possibly lower the geographic barrier to access to care, we mapped the US population against existing RCs with brain tumor expertise and neurosurgery centers (NSCs) performing craniotomies. Methods: We analyzed 2018 CMS claims data using CPT codes for single- and multi-fraction SRS to identify RCs with brain tumor treatment expertise and mapped these against the population. Using similar methodology, using CPT codes for craniotomies, we identified NSCs, as any facility performing craniotomies is potentially eligible to implant GT. Results: 135 RCs used CPT codes for SRS. 193-, 119-, 82-, and 52-million Americans lived &gt;30-, &gt;60-, &gt;90-, and &gt;120-minutes from one of these centers, respectively. 530 NSCs preform craniotomies, including ≥1 in every state, a 4-fold increase over the number of RCs offering SRS. Conclusions: For many patients, substantial travel distances limit their access to RCs with brain tumor treatment expertise. In contrast, the 530 craniotomy-performing NSCs have far greater geographic dispersion. The option of undergoing brain radiation with GT implantation at the time of brain tumor craniotomy brings treatment closer to millions, ensures compliance, and reduces additional travel for follow-up radiation treatment.[Table: see text]

Single- and Multifraction Stereotactic Radiosurgery Dose/Volume Tolerances of the Brain

As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy investigating normal tissue complication probability (NTCP) after hypofractionated radiation therapy, data from published reports (PubMed indexed 1995-2018) were pooled to identify dosimetric and clinical predictors of radiation-induced brain toxicity after single-fraction stereotactic radiosurgery (SRS) or fractionated stereotactic radiosurgery (fSRS). Eligible studies provided NTCPs for the endpoints of radionecrosis, edema, or symptoms after cranial SRS/fSRS and quantitative dose-volume metrics. Studies of patients with only glioma, meningioma, vestibular schwannoma, or brainstem targets were excluded. The data summary and analyses focused on arteriovenous malformations (AVM) and brain metastases. Data from 51 reports are summarized. There was wide variability in reported rates of radionecrosis. Available data for SRS/fSRS for brain metastases were more amenable to NTCP modeling than AVM data. In the setting of brain metastases, SRS/fSRS-associated radionecrosis can be difficult to differentiate from tumor progression. For single-fraction SRS to brain metastases, tissue volumes (including target volumes) receiving 12 Gy (V12) of 5 cm3, 10 cm3, or >15 cm3 were associated with risks of symptomatic radionecrosis of approximately 10%, 15%, and 20%, respectively. SRS for AVM was associated with modestly lower rates of symptomatic radionecrosis for equivalent V12. For brain metastases, brain plus target volume V20 (3-fractions) or V24 (5-fractions) <20 cm3 was associated with <10% risk of any necrosis or edema, and <4% risk of radionecrosis requiring resection. The risk of radionecrosis after SRS and fSRS can be modeled as a function of dose and volume treated. The use of fSRS appears to reduce risks of radionecrosis for larger treatment volumes relative to SRS. More standardized dosimetric and toxicity reporting is needed to facilitate future pooled analyses that can refine predictive models of brain toxicity risks.

55. A RANDOMIZED, MULTICENTER PHASE III TRIAL OF SURGERY PLUS STEREOTACTIC RADIOSURGERY (SRS) COMPARED WITH SURGERY PLUS PERMANENTLY IMPLANTED COLLAGEN TILE BRACHYTHERAPY (CTBT) FOR RESECTABLE METASTATIC BRAIN TUMORS-PROTOCOL IN PROGRESS

BACKGROUNDResection (R) followed by single or multi-fraction stereotactic radiosurgery (SRS) lowers resection bed recurrence compared to R alone. Nevertheless for larger brain metastasis (>2.5 cm) 12-month recurrence rates after R+SRS can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy (CTBT) device (GammaTile, GT Medical Technologies, Tempe AZ) utilizing Cs-131 was developed, hypothesizing that immediate adjuvant radiotherapy (RT) and/or RT dose intensification could improve outcomes. The device received FDA clearance for this indication, based on a single-arm pre-commercial study and in early commercial use due to the excellent safety and local control of R+CTBT. It is hypothesized that R+CTBT will increase the time to post-resection-recurrence, while prolonging survival and reducing the impact on functional and neurocognitive status compared to R+SRS.STUDY DESIGNMulticenter, randomized, comparison trial. Patients with resectable, previously untreated “index” brain metastases measuring >2.5–5 cm and 0–3 other tumors will be preoperatively randomized 1:1 to undergo either R+ SRS or R+CTBT to the index lesion; unresected tumors in both groups will receive SRS. Planned sample size is 160 from ~5 sites; accrual to start in Q3-2020. Primary endpoint is surgical bed-recurrence free survival. Secondary endpoints include overall survival, quality of life (Functional Assessment of Cancer Therapy-Brain, Linear Analog Self-Assessment), neurocognition (Hopkins Verbal Learning Test, Trail Making Tests, Mini-Mental Status Exam, Controlled Oral Word Association), functional decline (Karnofsky Performance Scale, Barthel-ADL), and adverse events. Follow-up will be at 1,3,6,9, and 12 months, then q 6 months through 5 years.CONCLUSIONSThis will be the first randomized trial comparing R+SRS versus R+CTBT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures will be captured to elucidate the potential risks and benefits of these two differing approaches for patients with metastatic brain tumors.

Multifraction Stereotactic Radiosurgery to Large Brain Metastases: Is This Scheme Effective and Safe?

Many fractionation regimens have been described for the treatment of large brain metastases with stereotactic radiosurgery (SRS). The purpose of this analysis is to demonstrate the efficacy and the tolerance of multifraction stereotactic radiosurgery (mSRS), 3 fractions, in patients with large brain metastases. Were reviewed all patients with brain metastases treated with mSRS (3 fractions) at a single institution. Patients with large brain metastases were the majority population, but patients who were not appropriate candidates for single fraction SRS were treated with mSRS and included as well. Prognostic factors including Ds-GPA, Score Index for Radiosurgery (SIR), number of lesions, systemic disease status, primary site, PTV volume, dose (3 schemes were used due a constraint of the organ at risk - 7 Gy, 8 Gy or 9 Gy/fraction), use of whole brain radiotherapy (WBRT) either pre or post SRS, surgery and the use of systemic therapy were all evaluated. The toxicity was graded using the CTCAE V. 4.0. Kaplan- Mayer and Log-Rank test were used for survival curve calculations. Chi-square test was used for comparative analysis with a significance level of 0.05. Between March 2015 and November 2018, 86 patients were enrolled, of which 2 were excluded due to loss to follow-up and 144 lesions treated. The median follow-up was 9.0 months. The patient characteristics are shown in Table 1. The overall survival (OS) at 12 and 24 months was 43% and 21.6%, respectively, with a median overall survival of 10 months. Death due to neurological failure was 14.5%. Local control at 12 months was 81.3%, with 47.6% developing new lesions after the first mSRS. There wasn’t a correlation between local control and dose/fraction, PTV volume and the other factors. There were 4 patients with acute grade 3 toxicity (paresthesia), reversible with corticosteroids. The most common symptom was headache, grade 1 and 2, (23.5%). Eight patients had grade 1-2 seizures. The radionecrosis rate was 9.5%, and four patients had symptomatic radionecrosis. The PTV volume average was 20.87 cc (1-140 cc). In multivariate analysis, Ds-GPA, SIR, KPS, primary site (melanoma and breast were better) and systemic progression status had a statistically significant effect on OS. The dose/fraction and PTV volume did not correlate with toxicity or radionecrosis. This mSRS scheme of 3 fractions to large brain metastases showed good local control with low complication rates, in the studied population. In our retrospective analysis of 84 patients, we conclude that this 3 fraction mSRS is safe and effective. A prospective trial is warranted to compare and evaluate the best SRS regimens for this approach.Abstract 2160; Table 1Patients CharacteristicsAge (median)54.5 y (22-81)Numb. Lesions: 1 - 3; >3;91.6%/ 8.4%Ds-GPA 0-1; 1.5 - 2.5; >2.5;23.8%/ 29.8%/ 46.4%/Primary Lung; Breast; Melanoma; Others;39.3%/ 28.6%/ 8.3%/ 23.8%Fractionation 7 Gy x 3; 8 Gy x 3; 9 Gy x 3;8.3%/ 29.8%/ 61.9%/WBRT Pre mSRS; Pos mSRS; No;13.1%/ 23.8%/ 63.1%/ Open table in a new tab