GammaTile® (GT) as a brachytherapy platform for rapidly proliferating glioblastomas: from case series to clinical trials.

PURPOSE: Radiation plays a central role in glioblastoma treatment. Logistics related to coordinating clinic visits, radiation planning, and surgical recovery necessitate delay in radiation delivery from the time of diagnosis. Unimpeded tumor growth occurs during this period, and is associated with poor clinical outcome. Here we provide a pilot experience of GammaTile ® (GT), a collagen tile-embedded Cesium-131 (131Cs) brachytherapy platform for such aggressive tumors. METHODS: We prospectively followed seven consecutive patients (2019-2023) with newly diagnosed (n = 3) or recurrent (n = 4) isocitrate dehydrogenase wild-type glioblastoma that grew > 100% in volume during the 30 days between the time of initial diagnosis/surgery and the radiation planning MRI. These patients underwent re-resection followed by GT placement. RESULTS: There were no surgical complications. One patient developed right hemiparesis prior to re-resection/GT placement and was discharged to rehabilitation, all others were discharged home-with a median hospital stay of 2 days (range: 1-5 days). There was no 30-day mortality and one 30-day readmission (hydrocephalus, requiring ventriculoperitoneal shunting (14%)). With a median follow-up of 347 days (11.6 months), median progression free survival of ≥ 320 days (10.6 months) was achieved for both newly and recurrent glioblastoma patients. The median overall survival (mOS) was 304 and 347 days (10 and 11.5 mo) for recurrent and newly diagnosed glioblastoma patients, respectively. CONCLUSION: Our pilot experience suggests that GT offers favorable local control and safety profile for patients afflicted with rapidly proliferating glioblastomas and lay the foundation for future clinical trial design.

Comparison of Gamma Knife (GK) and Linear Accelerator (LINAC) radiosurgery of brain metastasis resection cavity: a systematic review and proportional meta-analysis.

PURPOSE: Stereotactic radiosurgery (SRS) to the resection cavity is essential in the treatment of brain metastasis (BM) amenable to surgical resection. The two most common platforms for SRS delivery include Gamma Knife (GK) and LINAC. Here we collated the available peer-reviewed literature and performed a meta-analysis on clinical outcomes after GK or LINAC resection cavity SRS. METHODS: Following PRISMA Guidelines, a search on PUBMED and MEDLINE was performed to include all studies evaluating each post-operative SRS modality. Local control, overall survival, radiation necrosis, and leptomeningeal disease were evaluated from the available data. A proportional meta-analysis was performed via R using the metafor package to pool the outcomes of studies and a moderator effect to assess the significance between groups. RESULTS: We identified 21 GK studies (n = 2009) and 28 LINAC studies (n = 2219). The radiosurgery doses employed were comparable between GK and LINAC studies. The pooled estimate of 1-year local control, 1-year overall survival, and risk of leptomeningeal disease were statistically comparable between GK and LINAC (81.7 v 85.8%; 61.4 v 62.7%; 10.6 v 12.5%, respectively). However, the risk of radiation necrosis (RN) was higher for LINAC resection cavity SRS (5.4% vs. 10%, p = 0.036). The volume of the resection cavity was a significant modifying factor for RN in both modalities (p = 0.007) with a 0.5% and 0.7% increase in RN risk with every 1 cm3 increase in tumor volume for GK and LINAC, respectively. CONCLUSIONS: Our meta-analysis suggests that GK and LINAC SRS of resection cavity achieve comparable 1-year local control and survival. However, resection cavity treated with GK SRS was associated with lowered RN risk relative to those treated with LINAC SRS.

Preoperative Versus Postoperative Radiosurgery of Brain Metastases: A Meta-Analysis.

OBJECTIVE: While postoperative resection cavity radiosurgery (post-SRS) is an accepted treatment paradigm for brain metastasis (BM) patients who undergo surgical resection, there is emerging interest in preoperative radiosurgery (pre-SRS) followed by surgical resection as an alternative treatment paradigm. Here, we performed a meta-analysis of the available literature on this matter. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of all studies evaluating pre-SRS and post-SRS was completed. Local recurrence (LR), overall survival (OS), radiation necrosis (RN), and leptomeningeal disease (LMD) were evaluated from the available data. Moderator analysis and pooled effect sizes were performed using a proportional meta-analysis with R using the metafor package. Statistics are presented as mean [95% confidence interval]. RESULTS: We identified 6 pre-SRS and 33 post-SRS studies with comparable tumor volume (4.5-17.6 cm3). There were significant differences in the pooled estimates of LR and LMD, favoring pre-SRS over post-SRS. Pooled aggregate for LR was 11.0% [4.9-13.7] and 17.5% [15.1-19.9] for pre- and post-SRS studies (P = 0.014). Similarly, pooled estimates of LMD favored pre-SRS, 4.4% [2.6-6.2], relative to post-SRS, 12.3% [8.9-15.7] (P = 0.019). In contrast, no significant differences were found in terms of RN and OS. Pooled estimates for RN were 6.4% [3.1-9.6] and 8.9% [6.3-11.6] for pre- and post-SRS studies (P = 0.393), respectively. Pooled estimates for OS were 60.2% [55.8-64.6] and 60.5% [56.9-64.0] for pre- and post-SRS studies (P = 0.974). CONCLUSIONS: This meta-analysis supports further exploration of pre-SRS as a strategy for the treatment of BM.

Comparison of peripheral leukocyte parameters in patients receiving conventionally and hypofractionated radiotherapy schemes for the treatment of newly diagnosed glioblastoma.

Introduction: Treatment for glioblastomas, aggressive and nearly uniformly fatal brain tumors, provide limited long-term success. Immunosuppression by myeloid cells in both the tumor microenvironment and systemic circulation are believed to contribute to this treatment resistance. Standard multi-modality therapy includes conventionally fractionated radiotherapy over 6 weeks; however, hypofractionated radiotherapy over 3 weeks or less may be appropriate for older patients or populations with poor performance status. Lymphocyte concentration changes have been reported in patients with glioblastoma; however, monocytes are likely a key cell type contributing to immunosuppression in glioblastoma. Peripheral monocyte concentration changes in patients receiving commonly employed radiation fractionation schemes are unknown. Methods: To determine the effect of conventionally fractionated and hypofractionated radiotherapy on complete blood cell leukocyte parameters, retrospective longitudinal concentrations were compared prior to, during, and following standard chemoradiation treatment. Results: This study is the first to report increased monocyte concentrations and decreased lymphocyte concentrations in patients treated with conventionally fractionated radiotherapy compared to hypofractionated radiotherapy. Discussion: Understanding the impact of fractionation on peripheral blood leukocytes is important to inform selection of dose fractionation schemes for patients receiving radiotherapy.

GammaTile® (GT) as a brachytherapy platform for rapidly growing brain metastasis.

Background: A subset of brain metastasis (BM) shows rapid recurrence post-initial resection or aggressive tumor growth between interval scans. Here we provide a pilot experience in the treatment of these BM with GammaTile® (GT), a collagen tile-embedded Cesium 131 (131Cs) brachytherapy platform. Methods: We identified ten consecutive patients (2019-2023) with BM that showed either (1) symptomatic recurrence while awaiting post-resection radiosurgery or (2) enlarged by >25% of tumor volume on serial imaging and underwent surgical resection followed by GT placement. Procedural complication, 30-day readmission, local control, and overall survival were assessed. Results: For this cohort of ten BM patients, 3 patients suffered tumor progression while awaiting radiosurgery and 7 showed >25% tumor growth prior to surgery and GT placement. There were no procedural complications or 30-day mortality. All patients were discharged home, with a median hospital stay of 2 days (range: 1-9 days). 4/10 patients experienced symptomatic improvement while the remaining patients showed stable neurologic conditions. With a median follow-up of 186 days (6.2 months, range: 69-452 days), no local recurrence was detected. The median overall survival (mOS) for the newly diagnosed BM was 265 days from the time of GT placement. No patients suffered from adverse radiation effects. Conclusion: Our pilot experience suggests that GT offers favorable local control and safety profile in patients suffering from brain metastases that exhibit aggressive growth patterns and support the future investigation of this treatment paradigm.

Phase II Study of Myeloablative 7-8/8-Matched Allotransplantation with Post-Transplantation Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil.

Graft-versus-host disease (GVHD) is the major toxicity of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that a GVHD prophylaxis regimen of post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) would be associated with incidences of acute and chronic GVHD in patients receiving a matched or single antigen mismatched HCT. This Phase II study was conducted at the University of Minnesota using a myeloablative regimen of either total body irradiation (TBI) at a total dose of 1320 cGy, administered in 165-cGy fractions, twice daily from day -4 to day -1, or busulfan (Bu) 3.2 mg/kg daily (cumulative area under the curve, 19,000 to 21,000 µmol/min/L) plus fludarabine (Flu) 40 mg/m2 once daily on days -5 to -2, followed by a GVHD prophylaxis regimen of PTCy 50 mg/kg on days +3 and +4, Tac, and MMF beginning on day +5. The primary endpoint was the cumulative incidence of chronic GVHD necessitating systemic immunosuppression (IST) at 1 year post-transplantation. Between March 2018 and May 2022, we enrolled 125 pediatric and adult patients, with a median follow-up of 813 days. The incidence of chronic GVHD necessitating systemic IST at 1 year was 5.5%. The rate of grade II-IV acute GVHD was 17.1%, and that of grade III-IV acute GVHD was 5.5%. Two-year overall survival was 73.7%, and 2-year graft-versus-host disease-free, relapse-free survival was 52.2%. The 2-year cumulative incidence of nonrelapse mortality was 10.2%, and the rate of relapse was 39.1%. There was no statistically significant difference in survival outcomes between recipients of matched donor transplants versus recipients of 7/8 matched donor transplants. Our data show that myeloablative HCT with PTCy/Tac/MMF results in an extremely low incidence of severe acute and chronic GVHD in well-matched allogeneic HCT.

Phase II Study of Myeloablative 8/8- or 7/8-Matched Allotransplantation with Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil: Marked Reduction in GVHD Risk Without Increased Relapse Risk Compared to Historical Cyclosporine/Methotrexate.

Introduction: Graft-versus host disease (GVHD) is a major limitation to the success of allogeneic hematopoietic cell transplant (HCT). We hypothesized that the GVHD prophylaxis regimen of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) would reduce the incidence of GVHD in patients receiving a matched or single antigen mismatched HCT without an increase in risk of malignant relapse. Methods: This is a phase II study conducted at the University of Minnesota using a myeloablative regimen of either: (A) total body irradiation (TBI, total dose 1320 cGy, administered in 165 cGy fractions, twice a day from days -4 to -1) or (B) Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 µmol/min/L) plus fludarabine 160mg/m2 days -5 to -2, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppression at 1-year post-transplant. We compared results to our previous myeloablative protocol for matched donors utilizing cyclosporine/methotrexate (CSA/MTX) GVHD prophylaxis. Results: From March 2018 - June 2022, we enrolled and treated 125 pediatric and adult patients with a median follow up of 472 days. Grade II-IV acute GVHD occurred in 16% (95% confidence interval (CI): 9-23%); Grade III-IV acute GVHD was 4% (CI: 0-8%). No patients experienced grade IV GVHD, and there were no deaths due to GVHD before day 100. Only 3 developed chronic GVHD requiring immune suppression, (4%, CI: 0-8%). Two-year overall survival (OS) was 80% (CI: 69-87%), and (graft-versus-host disease-free, relapse-free survival) GRFS 57% (CI: 45-67%), both higher than historical CSA/MTX. The incidence of grade II-IV aGVHD, cGVHD, and NRM were all lower with PTCy/Tac/MMF compared to historical CSA/MTX. One-quarter (25%) experienced relapse (CI: 15-36%) similar to historical CSA/MTX. There was no statistically significant difference in survival outcomes between recipients of matched versus 7/8 donors. Conclusion: Myeloablative HCT with PTCy/Tac/MMF results in extremely low incidence of severe acute or chronic GVHD, the primary endpoint of this clinical trial. Relapse risk is not increased compared to our historical CSA/MTX cohort.

Idiopathic Pneumonitis Syndrome After Total Body Irradiation in Pediatric Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation: A PENTEC Comprehensive Review.

PURPOSE: Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS. METHODS AND MATERIALS: A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data. RESULTS: Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy-1 (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process. CONCLUSIONS: This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.

Resection of disseminated recurrent myxopapillary ependymoma with more than 4-year follow-up: operative nuance for prolonged prone position. Illustrative case.

BACKGROUND: Symptomatic disseminated myxopapillary ependymoma (MPE) in a young person presents a daunting challenge because the risks of prolonged prone positioning and spinal cord injury may outweigh the likelihood of attaining the benefit of gross total resection. OBSERVATIONS: The authors reported the case of a 15-year-old girl with five discrete recurrent spinal cord ependymomas. The patient received a 25-hour surgical procedure for gross total resection of the tumors and fusion over an approximately 33-hour period. She experienced complete resolution of all preoperative neurological symptoms and subsequently received adjuvant radiation therapy. At 52 months after surgery, she was still experiencing neurologically intact, progression-free survival. This case illustrated one of the most extensive recurrent tumor resections for MPE with prolonged disease-free survival reported to date. It may also represent the longest prone position spinal case reported and was notable for a lack of any of the complications commonly associated with the prolonged prone position. LESSONS: The authors discussed the complexity of surgical decision-making in a symptomatic patient with multiple disseminated metastases, technical considerations for resection of intradural and intramedullary spinal cord tumors, and considerations for avoiding complications during prolonged positioning necessary for spinal surgery.

Analysis of dose to the macula, optic disc, and lens in relation to vision toxicities - A retrospective study using COMS eye plaques.

PURPOSE: The aim of this study was to relate common toxicity endpoints with dose to the macula, optic disc, and lens for uveal melanoma patients treated with Iodine-125 Collaborative Ocular Melanoma Study (COMS) eye plaque brachytherapy. METHODS: A cohort of 52 patients treated at a single institution between 2005 and 2019 were retrospectively reviewed. Demographics, dosimetry, and clinical outcomes were recorded. Univariate, relative risk, and Kaplan-Meier analyses were performed to relate dose to toxicity endpoints including retinopathy, vision decline, and cataracts. RESULTS: By the end of follow up (Median = 3.6 years, Range = 0.4 - 13.5 years), 65 % of eyes sustained radiation retinopathy, 40 % demonstrated moderate vision decline (>5 Snellen lines lost), and 56 % developed cataracts. Significant (p < 0.05) risk estimates exist for retinopathy and VA decline for doses >52 Gy to the macula and >42 Gy to the optic disc. Moreover, dose to the lens > 16 Gy showed a significant risk for cataract formation. Kaplan-Meier analysis demonstrated significantly different incidence of radiation retinopathy for > 52 Gy to the macula and > 42 Gy to the optic disc. In addition, the Kaplan-Meier analysis showed significantly different incidence of cataract formation for patients with lens dose > 16 Gy. CONCLUSIONS: Dose-effect relationships exist for the macula and optic disc with respect to the loss of visual acuity and the development of retinopathy. To better preserve vision after treatment, further research is needed to reduce macula, optic disc, and lens doses while maintaining tumor control.

How to Treat Breast Cancer After Childhood Cancer: Management of Oncologic and Cardiovascular Concerns.

•Childhood cancer survivors are at higher risk for the development of breast cancer necessitating early breast cancer screening, often with both breast MRI and mammography.•Risk-stratify breast cancer treatment, taking into account prior radiation fields, surgical procedures, use of anthracyclines, and current comorbidities is essential.•Aggressive management of CV risk factors in collaboration with cardiologists, oncologists, primary care providers, and allied health care providers is needed to provide the best cancer treatment while optimizing CV health.

Stereotactic Laser Ablation (SLA) followed by consolidation stereotactic radiosurgery (cSRS) as treatment for brain metastasis that recurred locally after initial radiosurgery (BMRS): a multi-institutional experience.

INTRODUCTION: The optimal treatment paradigm for brain metastasis that recurs locally after initial radiosurgery remains an area of active investigation. Here, we report outcomes for patients with BMRS treated with stereotactic laser ablation (SLA, also known as laser interstitial thermal therapy, LITT) followed by consolidation radiosurgery. METHODS: Clinical outcomes of 20 patients with 21 histologically confirmed BMRS treated with SLA followed by consolidation SRS and > 6 months follow-up were collected retrospectively across three participating institutions. RESULTS: Consolidation SRS (5 Gy × 5 or 6 Gy × 5) was carried out 16-73 days (median of 26 days) post-SLA in patients with BMRS. There were no new neurological deficits after SLA/cSRS. While 3/21 (14.3%) patients suffered temporary Karnofsky Performance Score (KPS) decline after SLA, no KPS decline was observed after cSRS. There were no 30-day mortalities or wound complications. Two patients required re-admission within 30 days of cSRS (severe headache that resolved with steroid therapy (n = 1) and new onset seizure (n = 1)). With a median follow-up of 228 days (range: 178-1367 days), the local control rate at 6 and 12 months (LC6, LC12) was 100%. All showed diminished FLAIR volume surrounding the SLA/cSRS treated BMRS at the six-month follow-up; none of the patients required steroid for symptoms attributable to these BMRS. These results compare favorably to the available literature for repeat SRS or SLA-only treatment of BMRS. CONCLUSIONS: This multi-institutional experience supports further investigations of SLA/cSRS as a treatment strategy for BMRS.

GammaTile® brachytherapy in the treatment of recurrent glioblastomas.

BACKGROUND: GammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform. Here, we report clinical outcomes for recurrent glioblastoma patients after GT treatment following maximal safe resection. METHODS: We prospectively followed twenty-two consecutive Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients (6 O6-Methylguanine-DNA methyltransferase methylated (MGMTm); sixteen MGMT unmethylated (MGMTu)) who underwent maximal safe resection of recurrent tumor followed by GT placement. RESULTS: The cohort consisted of 14 second and eight third recurrences. In terms of procedural safety, there was one 30-day re-admission (4.5%) for an incisional cerebrospinal fluid leak, which resolved with lumbar drainage. No other wound complications were observed. Six patients (27.2%) declined in Karnofsky Performance Score (KPS) after surgery due to worsening existing deficits. One patient suffered a new-onset seizure postsurgery (4.5%). There was one (4.5%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. The mean follow-up was 733 days (range 279-1775) from the time of initial diagnosis. Six-month local control (LC6) and twelve-month local control (LC12) were 86 and 81%, respectively. Median progression-free survival (PFS) was comparable for MGMTu and MGMTm patients (~8.0 months). Median overall survival (OS) was 20.0 months for the MGMTu patients and 37.4 months for MGMTm patients. These outcomes compared favorably to data in the published literature and an independent glioblastoma cohort of comparable patients without GT treatment. CONCLUSIONS: This clinical experience supports GT brachytherapy as a treatment option in a multi-modality treatment strategy for recurrent glioblastomas.

Rapid Interval Recurrence of Glioblastoma Following Gross Total Resection: A Possible Indication for GammaTileⓇ Brachytherapy.

Glioblastoma recurrence between initial resection and standard-of-care adjuvant chemoradiotherapy (CRT) is a negative prognostic factor in an already highly aggressive disease. Re-resection with GammaTileⓇ(GT Medical Technologies Inc., Tempe, AZ) placement affords expedited adjuvant radiation to mitigate the likelihood of such growth. Here, we report a glioblastoma patient who underwent re-resection and GammaTileⓇ (GT) placement within two months of the initial gross total resection due to regrowth that reached the size of the original presenting tumor. The patient subsequently received concurrent temozolomide and 60 Gy external beam to regions outside of the brachytherapy range, fulfilling the generally accepted Stupp regimen. The patient tolerated the treatment without complication. The dosimetrics and implications of the case presentation are reviewed.

Pulmonary Toxicity After Total Body Irradiation - Critical Review of the Literature and Recommendations for Toxicity Reporting.

INTRODUCTION: Total body irradiation is an effective conditioning regimen for allogeneic stem cell transplantation in pediatric and adult patients with high risk or relapsed/refractory leukemia. The most common adverse effect is pulmonary toxicity including idiopathic pneumonia syndrome (IPS). As centers adopt more advanced treatment planning techniques for TBI, total marrow irradiation (TMI), or total marrow and lymphoid irradiation (TMLI) there is a greater need to understand treatment-related risks for IPS for patients treated with conventional TBI. However, definitions of IPS as well as risk factors for IPS remain poorly characterized. In this study, we perform a critical review to further evaluate the literature describing pulmonary outcomes after TBI. MATERIALS AND METHODS: A search of publications from 1960-2020 was undertaken in PubMed, Embase, and Cochrane Library. Search terms included "total body irradiation", "whole body radiation", "radiation pneumonias", "interstitial pneumonia", and "bone marrow transplantation". Demographic and treatment-related data was abstracted and evidence quality supporting risk factors for pulmonary toxicity was evaluated. RESULTS: Of an initial 119,686 publications, 118 met inclusion criteria. Forty-six (39%) studies included a definition for pulmonary toxicity. A grading scale was provided in 20 studies (17%). In 42% of studies the lungs were shielded to a set mean dose of 800cGy. Fourteen (12%) reported toxicity outcomes by patient age. Reported pulmonary toxicity ranged from 0-71% of patients treated with TBI, and IPS ranged from 1-60%. The most common risk factors for IPS were receipt of a TBI containing regimen, increasing dose rate, and lack of pulmonary shielding. Four studies found an increasing risk of pulmonary toxicity with increasing age. CONCLUSIONS: Definitions of IPS as well as demographic and treatment-related risk factors remain poorly characterized in the literature. We recommend routine adoption of the diagnostic workup and the definition of IPS proposed by the American Thoracic Society. Additional study is required to determine differences in clinical and treatment-related risk between pediatric and adult patients. Further study using 3D treatment planning is warranted to enhance dosimetric precision and correlation of dose volume histograms with toxicities.

Utilization of CBCT to improve the delivery accuracy of Gamma Knife radiosurgery with G-frame.

PURPOSE: To quantify the G-frame based stereotactic coordinate definition accuracy of Leksell coordinate G-frame-based Gamma Knife radiosurgery (GKRS) by the on-board cone-beam CT (CBCT) and establish remedial action rules to minimize the delivery errors. METHODS: We analyzed the data of 108 patients (a total of 201 tumors) treated by GKRS with G-frame for head fixation. After co-registering the CBCT images and plan reference images, the Leksell GammaPlan (LGP) treatment planning system provided the amount of geometric translation and rotation required to minimize the position difference between the plan and treatment. The software also calculated maximum displacement, which characterizes the position shift more clearly. We studied how much these predicted dosimetric quantities changed if the treatment was delivered without correcting the patient's position. RESULTS: The maximum displacement of the patient position obtained from the co-registration of CBCT and plan reference images was 0.81 ± 0.38 mm (0.24-2.03 mm). The target coverage decreased by 3.3 ± 7.0% on average (-48.5% to +35.7%). The decrease of the target coverage, however, became smaller as the target volume increased. In particular, if the volume was greater than 2 cm3 , the %change in target coverage was always less than -5%. CONCLUSIONS: The position differences reported by the registration module of LGP were within the accuracy limit of image registration for most clinical cases, but the errors could be larger in some cases. Therefore, we propose the following decision process. We do not advise position adjustment for G-frame based GKRS if the maximum displacement is less than 1 mm. When this limit is exceeded, however, another criterion should be applied to the decision making by considering the tumor size (or the treatment volume) together with the acceptable change of the tumor coverage.

A radiomics-based model for predicting local control of resected brain metastases receiving adjuvant SRS.

PURPOSE: Adjuvant radiosurgery to the cavities of surgically resected brain metastases provides excellent local tumor control while reducing the risk of deleterious cognitive decline associated with whole brain radiotherapy. A subset of these patients, however, will develop disease recurrence following radiosurgery. In this study, we sought to assess the predictive capability of radiomic-based models, as compared with standard clinical features, in predicting local tumor control. METHODS: We performed a retrospective chart review of patients treated with adjuvant radiosurgery for resected brain metastases at the "Institution" from 2009 to 2019. Shape, intensity and texture based radiomics features of the cavities were extracted from the pre-radiosurgery treatment planning MRI scans and trained using a gradient boosting technique with K-fold cross validation. RESULTS: In total, 71 cavities from 67 treated patients were included for analysis. The 6 and 12 month local control estimates were 86% and 76%, respectively. The 6 and 12 month overall survival was 78% and 55%, respectively. Thirty-six patients developed intracranial failures outside of the surgical cavity. The predictive model for local control trained on imaging features from the whole cavity achieved an area-under-the-curve (AUC) of 0.73 on the validation set versus an AUC of 0.40 for the clinical features. CONCLUSIONS: Here we report a single institutional experience using radiomic-based predictive modeling of local tumor control following adjuvant Gamma Knife radiosurgery for resected brain metastases. We found the radiomics features to provide more robust predictive models of local control rates versus clinical features alone. Such techniques could potentially prove useful in the clinical setting and warrant further investigation.

First clinical implementation of GammaTile permanent brain implants after FDA clearance.

PURPOSE: GammaTile cesium-131 (131Cs) permanent brain implant has received Food and Drug Administration (FDA) clearance as a promising treatment for certain brain tumors. Our center was the first institution in the United States after FDA clearance to offer the clinical use of GammaTile brachytherapy outside of a clinical trial. The purpose of this work is to aid the medical physicist and radiation oncologist in implementing this collagen carrier tile brachytherapy (CTBT) program in their practice. METHODS: A total of 23 patients have been treated with GammaTile to date at our center. Treatment planning system (TPS) commissioning was performed by configuring the parameters for the 131Cs (IsoRay Model CS-1, Rev2) source, and doses were validated with the consensus data from the American Association of Physicists in Medicine TG-43U1S2. Implant procedures, dosimetry, postimplant planning, and target delineations were established based on our clinical experience. Radiation safety aspects were evaluated based on exposure rate measurements of implanted patients, as well as body and ring badge measurements. RESULTS: An estimated timeframe of the GammaTile clinical responsibilities for the medical physicist, radiation oncologist, and neurosurgeon is presented. TPS doses were validated with published dose to water for 131Cs. Clinical aspects, including estimation of the number of tiles, treatment planning, dosimetry, and radiation safety considerations, are presented. CONCLUSION: The implementation of the GammaTile program requires collaboration from multiple specialties, including medical physics, radiation oncology, and neurosurgery. This manuscript provides a roadmap for the implementation of this therapy.

Biological Principles of Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiation Surgery (SRS): Indirect Cell Death.

PURPOSE: To review the radiobiological mechanisms of stereotactic body radiation therapy stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). METHODS AND MATERIALS: We reviewed previous reports and recent observations on the effects of high-dose irradiation on tumor cell survival, tumor vasculature, and antitumor immunity. We then assessed the potential implications of these biological changes associated with SBRT and SRS. RESULTS: Irradiation with doses higher than approximately 10 Gy/fraction causes significant vascular injury in tumors, leading to secondary tumor cell death. Irradiation of tumors with high doses has also been reported to increase the antitumor immunity, and various approaches are being investigated to further elevate antitumor immunity. The mechanism of normal tissue damage by high-dose irradiation needs to be further investigated. CONCLUSIONS: In addition to directly killing tumor cells, high-dose irradiation used in SBRT and SRS induces indirect tumor cell death via vascular damage and antitumor immunity. Further studies are warranted to better understand the biological mechanisms underlying the high efficacy of clinical SBRT and SRS and to further improve the efficacy of SBRT and SRS.

GammaTile®: Surgically targeted radiation therapy for glioblastomas.

Glioblastoma is the most common primary malignant neoplasm of the central nervous system in adults. Standard of care is resection followed by chemo-radiation therapy. Despite this aggressive approach, >80% of glioblastomas recur in proximity to the resection cavity. Brachytherapy is an attractive strategy for improving local control. GammaTile® is a newly US FDA-cleared device which incorporates 131Cs radiation emitting seeds in a resorbable collagen-based carrier tile for surgically targeted radiation therapy to achieve highly conformal radiation at the time of surgery. Embedding encapsulated 131Cs radiation emitter seeds in collagen-based tiles significantly lowers the technical barriers associated with traditional brachytherapy. In this review, we highlight the potential of surgically targeted radiation therapy and the currently available data for this novel approach.