Brainstem Necrosis Research Articles

RADT-07. CLINICAL RESULTS, ACUTE AND EARLY LATE TOXICITY AFTER PROTON RADIOTHERAPY FOR PEDIATRIC MEDULLOBLASTOMA, RETROSPECTIVE ANALYSIS

Abstract Craniospinal irradiation with boost to primary tumor site (and metastatic sites) is current radiotherapy standard for most patients diagnosed with medulloblastoma (MB). This treatment is effective, but survivors frequently develop long-term toxicity affecting the quality of life. Proton radiotherapy has the same efficacy compared to conventional photon-based techiques, but might achieve lower risk of toxicity. We retrospectivelly analyzed our cohort of patients irradiated for MB in our institution, using IMPT (intensity modulated proton therapy). Between May 2013 and December 2023 eighty patients (50 male, 30 female, median age at radiotherapy 8 years/range 3-17/) with primary or recurrent MB (not previously irradiated) were treated and included into analysis. 36 patients were treated for high-risk MB (mostly metastatic), 44 pts for SR disease. Neoadjuvant, concurrent and adjuvant systemic treatment was applied according to the protocol selected by the pediatric oncologist. All but one patients completed their treatment, acute toxicity including hematological was mild and lead to treatment interruption in seven cases. With a median of follow-up 39,6 months (range 3-119) 62 pts were in complete remission, 3 pts alive with disease, 14 died from disease progression and one died from complication (intracranial hemorrhage). We were able to identify two secondary malignancies potentially associated with IMPT (thyroid cancer, radiation induced high-grade glioma). Most common endocrinopathy observed in our patients was hypothyroidism and growth-hormon decifit. Due to lack of data, we were not able to analyze cognitive functions and quality of life. There was one case of severe brainstem necrosis with persistent neurological deficit, treated with corticosteroids and bevacizumab. Proton radiotherapy using IMPT for craniospinal irradiation in MB is feasible, treatment outcomes and toxicity are encouraging, although a longer follow-up is needed.

847: Voxel-based analysis of symptomatic brainstem necrosis following paediatric proton therapy

847: Voxel-based analysis of symptomatic brainstem necrosis following paediatric proton therapy

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review

Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.

Linear energy transfer-inclusive models of brainstem necrosis following proton therapy of paediatric ependymoma.

Radiation-induced brainstem necrosis after proton therapy is a severe toxicity with potential association to uncertainties in the proton relative biological effectiveness (RBE). A constant RBE of 1.1 is assumed clinically, but the RBE is known to vary with linear energy transfer (LET). LET-inclusive predictive models of toxicity may therefore be beneficial during proton treatment planning. Hence, we aimed to construct models describing the association between brainstem necrosis and LET in the brainstem. A matched case-control cohort (n=28, 1:3 case-control ratio) of symptomatic brainstem necrosis was selected from 954 paediatric ependymoma brain tumour patients treated with passively scattered proton therapy. Dose-averaged LET (LETd) parameters in restricted volumes (L50%, L10% and L0.1cm3, the cumulative LETd) within high-dose thresholds were included in linear- and logistic regression normal tissue complication probability (NTCP) models. A 1keV/µm increase in L10% to the brainstem volume receiving dose over 54Gy(RBE) led to an increased brainstem necrosis risk [95% confidence interval] of 2.5 [0.0, 7.8] percentage points. The corresponding logistic regression model had area under the receiver operating characteristic curve (AUC) of 0.76, increasing to 0.84 with the anterior pons substructure as a second parameter. 19 [7, 350] patients with toxicity were required to associate the L10% (D>54Gy(RBE)) and brainstem necrosis with 80% statistical power. The established models of brainstem necrosis illustrate a potential impact of high LET regions in patients receiving high doses to the brainstem, and thereby support LET mitigation during clinical treatment planning.

Does Size Matter? On the Role of Stereotactic Radiosurgery for Large Vestibular Schwannomas as Seen in an Institutional Experience of Gamma Knife Radiosurgery for High-Grade Tumors.

Management of large vestibular schwannoma (VS) is controversial. Surgery has historically been the treatment of choice, but emerging literature suggests that definitive stereotactic radiosurgery is feasible. We report our institutional experience of control and morbidity outcomes treating Koos grade 3-4 VS with Gamma Knife radiosurgery (GKRS). An institutional review board-approved database compiled outcomes of Koos grade 3-4 VS treated by GKRS from March 2014 to January 2021 with >6 months' follow-up. Baseline symptoms per Common Terminology Criteria for Adverse Events definitions were recorded. Control rates, toxicities, and post-treatment volumetric changes were analyzed. Aggregate impairment scores (AIs) were defined by the sum of relevant Common Terminology Criteria for Adverse Events grades to categorize symptomatic burdens. Baseline and post-treatment AIs were tested for association with definitive versus adjuvant strategies. In total, 34 patients with Koos grade 3-4 VS were identified, 19 treated with definitive GKRS (GKRS-D) and 15 with adjuvant GKRS (GKRS-A). Median follow-up was 34.2 months for GKRS-D and 48.8 months for GKRS-A. Patients who received GKRS-A had greater AIs at presentation (3.73 vs. 2.11, P= 0.017). Irrespective of treatment approach, tumor control rates were 100% without instances of brainstem necrosis or shunt placement. Six of 19 patients who received GKRS-D had improved post-treatment AI, and 63% of patients who received GKRS-D and 66% of patients who received GKRS-A had tumor shrinkage >20%. In well-selected patients with Koos grade 3-4 VS, definitive stereotactic radiosurgery may be an appropriate strategy with excellent control and minimal toxicity. Our data suggest that the need for surgical decompression should be considered based on pretreatment symptom burden rather than tumor size.

Hypofractionated stereotactic radiotherapy for large vestibular schwannomas and the impact of pre-radiation debulking surgery on dosimetry and clinical outcomes

Abstract Introduction: This study was aimed to evaluate the outcomes of patients with large (>2 cm in great diameter) vestibular schwannomas (VSs) treated with hypofractionated stereotactic radiotherapy (HFSRT) compared to small (<2 cm) ones and the impact of debulking surgery prior to radiation for large VSs. Methods: Fifty-nine patients with VSs treated with HFSRT (25 Gy in 5 fractions) were evaluated by tumour size and surgical status. Patients were divided based on tumour size: small VSs (n = 42) and large VSs (n = 17). The large group was further divided into the groups of pre-treatment debulking surgery (n = 8) and no surgery (n = 9). Rates of tumour control, brainstem necrosis and neurologic dysfunction were assessed following treatment. Pre-surgical magnetic resonance imaging (MRI) were used to generate hypothetical HFSRT plans to compare the effect of debulking surgery on dosimetry. Normal tissue complication probability (NTCP) modelling was performed to compare toxicity probabilities with and without surgical debulking in large VSs. Results: There was no statistical difference of tumour control rate between small and large VSs with 100% for small tumours and 94·1% for large tumours (p = 0·12), respectively. In large VSs patient, the tumour control rate of HFSRT was 100% (8/8) for surgically debulked patients and 89% (8/9) for non-surgically debulked patients (p = 0·35). There were no patients who experienced brainstem necrosis or progression of facial and trigeminal nerve symptoms after HFSRT in the entire groups of patients. Surgical debulking large VSs did not change the maximum point dose of brainstem (p = 0·98), but significantly decreased volumes of VSs and changed the minimum dose to the hottest 0·5 cc of tumour (p = 0·016) as well as the volume receiving at least 23 Gy (p = 0·023). NTCP modelling revealed very low rates (average < 1%) of brainstem toxicity with or without surgical debulking, but there was a significant difference favoring surgery (p < 0·05). Conclusions: HFSRT is a safe and effective treatment for both small and large VSs and is a viable option for patients with large VSs who cannot undergo surgery, if NTCP of pre-debulking HFSRT dosimetry is lower.

Brain and Brainstem Necrosis after Re-Irradiation for Recurrent Childhood Central Nervous System (CNS) Tumors: A Report from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Task Force

<h3>Purpose/Objective(s)</h3> Re-irradiation is increasingly used in children, adolescents and young adults (AYA) with recurrent CNS tumors. The PENTEC re-irradiation task force reports the results on the risk of symptomatic necrosis following cranial re-irradiation, and its dependence on cumulative dose. <h3>Materials/Methods</h3> A systematic literature search for peer-reviewed articles 1975 to 2021 identified 1183 studies on re-irradiation and 92 studies on re-irradiation for recurrent CNS tumors. Studies on predominantly adult populations and re-irradiation for secondary neoplasms were excluded (n=49). Data from the remaining 43 studies were captured. 17 studies (n=449), reporting brain and brainstem necrosis were used for analysis. While all studies mentioned techniques and range of doses used for re-irradiation, they lacked details on significant dose-volume metrics (e.g., percentage of re-irradiation treatment volume overlapping with primary radiotherapy, mean and maximum cumulative equivalent dose in 2Gy fractions, with alpha-beta ratio=2 (EQD2/2) to organs at risk) necessary for a dose-response modelling. We, therefore, estimated the incidence of necrosis with an exact 95% confidence interval (CI) and provided a qualitative description of the data. <h3>Results</h3> Treated cancers included ependymoma (n=279;7 studies), medulloblastoma (n=98; 6 studies), any CNS tumors (n=62: 3 studies) and supratentorial high-grade gliomas (n=10: 1 study). The median interval between initial and re-irradiation was 2.3 years (range 1.2-4.75). The median cumulative EQD2/2 prescription dose was 103.8 Gy (range 79.7-141.3). Among 449 children/AYA treated with re-irradiation, 22 (4.9%, 95% CI 3.1-7.3%) developed brain necrosis and 14 (3.1%, 95% CI 1.7-5.2%) brainstem necrosis. The median cumulative prescription EQD2/2 was 111.4 Gy (range 79.7-141.3) for development of any necrosis, 107.7 Gy (range 79.7-141.3) for brain necrosis and 112.1 Gy (range 100.2-117) for brainstem necrosis. In 6 studies (n=176) of conventionally fractionated (≤2 Gy per fractions) re-irradiation, 7 patients developed brain necrosis (3.9%) and 4 brainstem necrosis (1.7). In the 5 studies (n=160) of hypofractionated (4-24 Gy per fraction) re-irradiation, 9 patients developed brain necrosis (5.6%) and 10 brainstem necrosis (6.9%). Though there were more necroses in the hypofractionated group, it was not statistically significant (Fisher's exact test 2-tailed p value=0.4664). The remaining six studies (n=113) used a range of fraction size (1.8-24 Gy). No studies reported cumulative dosing for individual organs at risk. <h3>Conclusion</h3> Existing literature suggests that in children and AYA with recurrent brain tumors, re-irradiation results in less than 5-7% incidence of brain/brainstem necrosis with conventional prescription doses after a median follow-up of 2.3 years. A uniform approach for reporting dosimetric endpoints is recommended to derive a robust predictive model of late toxicities following re-irradiation.

Incidence and Dosimetric Parameters of Brainstem Toxicity in Pediatric Patients after Photon Irradiation for Posterior Fossa Tumors

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) is a crucial component of multimodal therapy for central nervous system (CNS) tumors in pediatric patients. Brainstem necrosis is a serious complication of radiotherapy, and currently, data on the incidence of and factors that predict brainstem necrosis after photon therapy to posterior fossa tumors remain lacking. To better understand the true incidence of brainstem injury and the appropriate dosimetric guidelines to limit this adverse event after photon irradiation, we investigated pediatric patients who received photon irradiation to the brainstem for primary tumors at our institution to determine the incidence and associated predictors of brainstem toxicity. <h3>Materials/Methods</h3> Retrospective chart review was conducted for 74 pediatric patients who were treated with photon radiotherapy for posterior fossa tumors from 2000-2016. Patients were excluded if they received a maximum dose to the brainstem <50.4 Gy or had tumor with brainstem involvement. Central imaging review of all MRI scans pre- and post-radiation were reviewed. Brainstem toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. <h3>Results</h3> Median clinical and imaging follow-up after completion of first radiation treatment was 4.2 years (Range: 0.1-12.7) and 4.0 years (range: 0.1-12.7). Median age at diagnosis was 8.0 years (range: 0.25-19.8). Most of the patients were treated for medulloblastoma (69.3%) and ependymoma (22.7%). Median prescribed total dose was 54.0 Gy (range: 50.4-59.4), median D50% to the brainstem was 55.6 Gy (range: 12.7- 61.9), and median brainstem V50 Gy and V55 Gy were 97.0% (range: 5.7-100) and 68.6% (range: 0-100), respectively. D1cc to the brainstem was 56.8 Gy (range: 50.8 – 64.9 Gy). The crude incidence rate of grade ≥1 brainstem necrosis was 5.4% (4/74), and grade ≥2 brainstem necrosis was 2.7% (2/74). No clinical, treatment or dosimetric variables were associated with patients with brainstem necrosis or brainstem toxicity. <h3>Conclusion</h3> These data suggest that photon therapy leads to low rates of brainstem necrosis. Future studies with longer follow-up are necessary to further examine the rates of brainstem toxicity, including necrosis, after photon and proton radiotherapy, and larger cohort studies are needed to identify variables that may predict toxicity as these events remain rare.

Comparing biological effectiveness guided plan optimization strategies for cranial proton therapy: potential and challenges

BackgroundTo introduce and compare multiple biological effectiveness guided (BG) proton plan optimization strategies minimizing variable relative biological effectiveness (RBE) induced dose burden in organs at risk (OAR) while maintaining plan quality with a constant RBE.MethodsDose-optimized (DOSEopt) proton pencil beam scanning reference treatment plans were generated for ten cranial patients with prescription doses ≥ 54 Gy(RBE) and ≥ 1 OAR close to the clinical target volume (CTV). For each patient, four additional BG plans were created. BG objectives minimized either proton track-ends, dose-averaged linear energy transfer (LETd), energy depositions from high-LET protons or variable RBE-weighted dose (DRBE) in adjacent serially structured OARs. Plan quality (RBE = 1.1) was assessed by CTV dose coverage and robustness (2 mm setup, 3.5% density), dose homogeneity and conformity in the planning target volumes and adherence to OAR tolerance doses. LETd, DRBE (Wedenberg model, α/βCTV = 10 Gy, α/βOAR = 2 Gy) and resulting normal tissue complication probabilities (NTCPs) for blindness and brainstem necrosis were derived. Differences between DOSEopt and BG optimized plans were assessed and statistically tested (Wilcoxon signed rank, α = 0.05).ResultsAll plans were clinically acceptable. DOSEopt and BG optimized plans were comparable in target volume coverage, homogeneity and conformity. For recalculated DRBE in all patients, all BG plans significantly reduced near-maximum DRBE to critical OARs with differences up to 8.2 Gy(RBE) (p < 0.05). Direct DRBE optimization primarily reduced absorbed dose in OARs (average ΔDmean = 2.0 Gy; average ΔLETd,mean = 0.1 keV/µm), while the other strategies reduced LETd (average ΔDmean < 0.3 Gy; average ΔLETd,mean = 0.5 keV/µm). LET-optimizing strategies were more robust against range and setup uncertaintes for high-dose CTVs than DRBE optimization. All BG strategies reduced NTCP for brainstem necrosis and blindness on average by 47% with average and maximum reductions of 5.4 and 18.4 percentage points, respectively.ConclusionsAll BG strategies reduced variable RBE-induced NTCPs to OARs. Reducing LETd in high-dose voxels may be favourable due to its adherence to current dose reporting and maintenance of clinical plan quality and the availability of reported LETd and dose levels from clinical toxicity reports after cranial proton therapy. These optimization strategies beyond dose may be a first step towards safely translating variable RBE optimization in the clinics.

Long-Term Outcomes of Pediatric Patients with Chordomas Treated with Proton Beam Radiation Therapy

<h3>Purpose/Objective(s)</h3> Chordomas are rare tumors that arise from embryonic remnants of the notochord and can arise anywhere along the spine or the base of skull. This condition is even more uncommon within the pediatric population, and standard of care treatment includes maximal safe resection with subsequent radiation. The use of proton radiation allows for a conformal delivery of radiation dose that potentially minimizes the exposure of sensitive nearby structures to harmful treatment effects. The purpose of this study is to evaluate the long-term survival and toxicity of pediatric patients with base of skull or cervical spine chordomas treated at this institution with proton-based radiation therapy. <h3>Materials/Methods</h3> This IRB-approved single-institution study examines a cohort of 36 pediatric patients (≤ 18 years old) with 39 lesions treated with proton radiation between 1994 and 2016. Patients were included if they were treated with definitive intent and had at least five years of time since completing radiation treatment. Median age at treatment of patients was 10.9 years old. 79% of lesions received subtotal resection, while 21% received gross total resection. 10 patients received chemotherapy. The vast majority of tumors was treated to 72-77.4Gy in 40-43 fractions. Two patients were treated to 66.6Gy in 37 fractions. <h3>Results</h3> Median follow-up time was 100 months. The 5-year overall survival for the entire cohort was 26/36 (72%), further stratified by gender to reveal 68% in the female cohort and 75% in the male cohort. Seven patients (19%) developed distant metastases and subsequent passed away from their disease. GTV over size of 25cc and poorly differentiated histology were associated with decreased overall survival and local control. Of the 30 patients with base of skull lesions, at most recent follow-up, 15 patients (50%) had ototoxicity with 12 of those cases related to adjuvant treatment. 17 patients had confirmed pituitary dysfunction or required pituitary hormone replacement at some timepoint after treatment, 7 patients had no dysfunction, 5 patients died without evidence of pituitary dysfunction, 1 patient did not have pituitary function tests available. No instances of brain or brainstem necrosis were seen. Of the 21 survivors, 20 were either in school or employed with no cognitive or learning disabilities present. <h3>Conclusion</h3> This single-institution experience shows the efficacy and safety of proton radiation in pediatric patients with chordomas. Limitations include small number of patients and retrospective nature of the study. Future directions include analysis at 10-year follow-up and further evaluation of long-term toxicity.

Changes in the Symptomatic Burden of High Koos Grade Vestibular Schwannomas Following Definitive and Adjuvant Stereotactic Radiosurgery

<h3>Purpose/Objective(s)</h3> Emerging literature suggests definitive SRS is an option for large vestibular schwannomas with brainstem compression. We investigate our institutional experience of SRS on the Gamma Knife platform (GKRS) in both the definitive and post-operative settings and report control and morbidity outcomes. <h3>Materials/Methods</h3> An IRB-approved institutional database compiled clinical, radiographic, and treatment planning data for Koos grade 3-4 vestibular schwannomas treated by GKRS in our institution from March 2014 to January 2021 with minimum of 6-month follow-up, stratified by definitive (GKRS-D cohort) vs. adjuvant (GKRS-A cohort) treatment approaches. Baseline symptoms per CTCAE definitions were recorded for all patients prior to SRS (pre-SRS) and after SRS (post-SRS). For the adjuvant cohort, pre-operative symptoms were also recorded (pre-op). Hearing function was excluded due to inconsistent availability of audiometric records. Outcomes of tumor control, treatment toxicity, and changes in individual and aggregate symptomatic burdens as sums of relevant CTCAE grades (aggregate impairment; AI) were analyzed. AI was tested for association with definitive vs. adjuvant treatment parameters on presentation and post treatment. <h3>Results</h3> 34 patients were identified, of whom 19 were GKRS-D and 15 GKRS-A. Tumor control rates were 100% with median follow-up 34.2 months for GKRS-D (range: 6-74) and 48.6 months for GKRS-A (range: 6-84). Rates of brainstem necrosis or prolonged steroid use were 0%. No patients required shunt placement or developed clinical hydrocephalus post-GKRS. GKRS-A had greater symptom burden both at pre-op presentation and pre-GKRS than GKRS-D (AI 3.73 vs 2.11, p=0.017; AI 3.40 vs. 2.11, p=0.093). Symptom burden improved following treatment in both groups (mean AI Δ = -1.13 and -0.47 for GKRS-A and GKRS-D, p=0.243). In the GKRS-A cohort, symptom burden improved both with surgical intervention (mean Δ = -0.33), and following GKRS (mean Δ = -0.80.) Following definitive GKRS, 6 subjects had improvement in AI (mean Δ = -2.00), 3 subjects had worsening in AI (mean Δ = +1.00), and 10 subjects had no change. 1 subject had improvement in CNVII weakness (Δ = -2.00) and the remainder had no change. Following subtotal resection and adjuvant GKRS, 11 subjects had improvement in AI (mean Δ = -2.09) and 4 had worsening in AI (mean Δ = +1.50). 1 subject had improvement in CNVII weakness (Δ = -1.00), 6 had worsening (mean Δ = -1.33), and 8 had no change. <h3>Conclusion</h3> In well-selected patients with Koos grade 3 or 4 vestibular schwannomas, definitive SRS without surgical decompression has demonstrated excellent local control and minimal toxicity, with significant numbers of patients demonstrating an improvement in their baseline symptoms post-treatment. We increasingly select surgical intervention based on pre-treatment clinical symptoms rather than tumor volume or Koos grade alone. Larger prospective data are needed to confirm our experience.

RONC-01. A 10 year, single institution experience of re-irradiation for paediatric intracranial tumours

INTRODUCTION: Re-irradiation has become integral in the management of relapsed and recurrent intracranial tumours in children. It is used as salvage therapy for a number of tumours including; diffuse intrinsic pontine glioma (DIPG), high grade glioma (HGG), ependymoma and medulloblastoma. We report the patient demographics, dose, outcomes and toxicity for patients treated with re-irradiation at our institute. METHODS: 33 patients with a diagnosis of DIPG (n=11, 33%), ependymoma (n=11, 33%), HGG (n=4, 12%) or medulloblastoma/sPNET (n=7, 21%), treated with intracranial re-irradiation since 2012 were analysed in this retrospective study. Statistical survival analysis was performed. RESULTS: The median follow-up was 19 months (range 0–216 months). The median age at re-irradiation was 10 years (2-20 years). The median time from first radiation to re-radiation was 34 months (range 3–113 months). Re-irradiation techniques included; photons (n=26), protons (n=2) and stereotactic radiotherapy (n=6). The median re-irradiation dose was 36.37Gy EQD2 (range 20-95.05Gy), given in dose per fraction between 1.8Gy–2Gy. The median overall survival (OS) and progression free survival (PFS) for the cohort was 15.68 months and 7 months respectively. For DIPG, the median OS and PFS were 6.12 months and 4 months respectively. At 2 years, the OS and PFS rates for the cohort were 34.37% and 32.45% respectively. For the non-DIPG cohort, the 2 year OS and PFS rates were 55.37% and 48.13% respectively. In the DIPG cohort, 88% (n=7) had a reported symptomatic benefit from re-irradiation. A stable or improved radiological response was reported in majority of patients (78%, n=18). No acute or late toxicities ≥ grade 3 were reported within the cohort, specifically, there were no reports of brainstem necrosis. CONCLUSION: Re-irradiation for paediatric intracranial tumours is safe and offers a benefit to patients. Further work is ongoing to evaluate cumulative brainstem doses and predictive variables.

Brainstem Toxicity in Pediatric Patients Treated with Protons Using a Single-vault Synchrocyclotron System

PurposeCranial radiation therapy remains an integral component of curative treatment for pediatric patients with brain tumors. Proton beam radiation therapy (PBT) can limit collateral radiation dose to surrounding normal tissue, thus reducing off-target exposure while maintaining appropriate tumor coverage. While PBT offers significant advantages over photon therapy for pediatric patients with intracranial malignancies, cases of brainstem necrosis after PBT have raised concerns that PBT may pose an increased risk of necrosis over photon therapy. We investigated the incidence of brainstem necrosis at our institution in children treated with PBT for intracranial malignancies.Patients and MethodsPatients with pediatric brain tumor treated with passively scattered PBT, using a gantry-mounted, synchrocyclotron single-vault system between 2013 and 2018, were retrospectively reviewed. Inclusion criteria included patients 21 years of age or younger who received a minimum 0.1 cm3 maximum brainstem dose of 50 Gray relative biological effectiveness (GyRBE). Patients were assessed for “central nervous system necrosis” in the brainstem per the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (US National Cancer Institute, Bethesda, Maryland) criteria.ResultsFifty-eight patients were included for analysis. The median age was 10.3 years. Twenty-one (36.2%) patients received craniospinal irradiation. Thirty-four (58.6%) patients received chemotherapy. The median prescription radiation dose was 54 GyRBE. Regarding published dosimetric constraints used at 3 separate proton centers, the goal brainstem D50% <52 GyRBE was exceeded in 23 (40%) patients, but the brainstem Dmax <58 GyRBE was not exceeded in any patients. No patient experienced grade ≥2 brainstem injury. One patient demonstrated radiographic changes consistent with grade 1 toxicity. This patient had myeloablative chemotherapy with tandem stem cell rescue before PBT.ConclusionOur data demonstrates a low risk of any brainstem injury in children treated with passively scattered PBT using a single-vault synchrocyclotron.

Dosimetric analysis of radiation-induced brainstem necrosis for nasopharyngeal carcinoma treated with IMRT

BackgroundRadiation-induced brainstem necrosis (RIBN) is a late life-threatening complication that can appear after treatment in patients with nasopharyngeal carcinoma (NPC). However, the relationship between RIBN and radiation dose is not still well-defined.MethodsDuring January 2013 and December 2017, a total of 1063 patients with NPC were treated at Sichuan cancer hospital with IMRT. A total of 479 patients were eligible for dosimetric analysis. Dosimetric parameters of the RIBN, Dmax(the maximum dose), D0.1c (maximum average dose delivered to a 0.1-cc volume), D1cc, D2cc, D3cc, D5cc, D10cc and Dmean (mean does) were evaluated and recorded. ROC curve was used to analyze the area under curve (AUC) and cutoff points. Logistic regression for screening dose-volume parameter and logistic dose response model were used to predict the incidence of brainstem necrosis.ResultsAmong the 479 patients with NPC, 6 patients were diagnosed with RIBN, the incidence of RIBN was 1.25% (6/479), and the median time to RIBN after treatment was 28.5 months (range 18–48 months). The dose of the brainstem in patients with RIBN were higher than that in patients without necrosis. ROC curve showed that the area under the curve (AUC) of Dmax was the largest (0.987). Moreover, logistic stepwise regression indicated that Dmax was the most important dose factor. The RIBN incidence at 5% over 5 years (TD5/5) and 50% incidence over 5 years (TD50/5) was 69.59 Gy and76.45 Gy, respectively.ConclusionsBrainstem necrosis is associated with high dose irritation. Dmax is the most significant predictive dosimetric factor for RIBN. Dmax of brainstem should be considered as the dose limitation parameter. We suggest that the limitation dose for brainstem was Dmax < 69.59 Gy.

Normal tissue complication probability modeling to guide individual treatment planning in pediatric cranial proton and photon radiotherapy.

Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT). Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio. IMPT plans resulted in lower NTCP compared to IMRT across all models (p<0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (>20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p<0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p<0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p<0.0001). Due to the scarcity of pediatric NTCP data available, sensitivity analyses were performed using plausible ranges based on published adult data. In the clinical scenario where, if female pediatric patients were 20% more radiosensitive (lower TD50 value), they could be up to twice as likely to experience side-effects of brainstem necrosis and cochlea tinnitus compared to males, highlighting the need for considering the sex in NTCP models. Based on our sensitivity analyses, age and sex of a pediatric patient could significantly affect the resultant NTCP from cranial radiotherapy, especially at higher α/β values.

Incidence of Symptomatic Brain Injury Following Pencil Beam Scanning Proton Beam Therapy for Management of Central Nervous System Tumors

Although proton beam therapy (PBT) results in decreased dose to non-target tissue compared to modern photon therapy, there are concerns of rare CNS injury occurring following PBT due in part to RBE/LET uncertainties. Such uncertainties can be further exacerbated when delivering PBT using pencil beam scanning (PBS) technology. The primary objective of this study was to report the incidence of CNS toxicities in a large cohort of adult brain tumor patients treated with PBS at a single academic proton center. We hypothesized that PBS can be safely delivered for treatment of CNS tumors.A single-institution retrospective IRB-approved analysis was conducted of all patients with CNS tumors treated with PBT at our institution between February 2016 and April 2020. Patients were excluded if follow up was less than one month. Kaplan-Meier estimates of treatment toxicities were calculated, accounting for death and local recurrence as competing risks. Multivariate analysis (MVA) was performed using the Cox proportional hazard model to determine risk factors associated with symptomatic toxicity.A total of 283 consecutive patients with CNS toxicities (116 [41%] males, 167 [59%] females) completed a course of definitive-intent PBT; 116 patients had meningiomas/pituitary adenomas, 92 patients had gliomas/GBM, and 75 patients had other histologies (chordoma, paraganglioma, ependymoma, medulloblastoma, pineal tumor). Median age was 52 years old (range 18-91). Median dose of PBT was 51.3 Gy (RBE = 1.1, [range 20.4 - 78.8 Gy RBE]). Median dose per fraction was 1.8 Gy/fx (range 1.1-3.8 Gy/fx). Sixty patients [21%] had received some form of prior intracranial RT. Concurrent systemic therapy was delivered in 49 patients [17%]. Median follow-up time was 20 months. The 2-year incidence of symptomatic-treatment toxicity was 8.7%. Symptomatic radiation necrosis occurred in 13 patients including optic neuritis [N = 2], seizure [N = 3], neurologic deficit [N = 9], stroke [N = 1] and brainstem necrosis [N = 2]. Two patients had symptoms with no radiation-related imaging changes including stroke [N = 1] and seizure [N = 1]. MVA identified prior intracranial irradiation (HR 3.901, 95% CI 1.42, 10.73, P = 0.008) and increasing EQD2 of proton radiation (HR 1.077 per Gray, 95% CI 1.00, 1.15, P = 0.036) as predictive factors for increased incidence of adverse events including symptomatic toxicity and asymptomatic radiation necrosis. No PBT treatment planning parameters were found to correlate with toxicity risk.This is the largest series to date reporting outcomes for patients with CNS tumors treated with pencil beam scanning PBT. Our analysis indicates that pencil beam scanning PBT in this setting is well-tolerated with a toxicity profile similar to modern photon therapy. Future studies correlating toxicity-risk with LET are warranted.B. Savla: None. G.S. Alexander: None. K. Sun: None. S.M. Bentzen: Travel Expenses; University of Copenhagen. S. Mossahebi: None. Y. Kwok: None. W.F. Regine: None. M.V. Mishra: Employee; Orthofix. Research Grant; ASTRO, Keep Punching. Advisory Board; Patient Centers Outcomes Research Institute (PCORI. Travel Expenses; Patient Centers Outcomes Research Institute (PCORI.

Quantifying the Risk and Dosimetric Variables of Symptomatic Brainstem Injury After Proton Beam Radiation in Pediatric Brain Tumors

Brainstem toxicity after radiation is a devastating complication and a particular concern with proton radiation (RT), given the biological differences and range uncertainties at the distal edge of proton beam. Data from St. Jude's found a 3.7% risk of brainstem necrosis after photon-based RT, while the incidence with protons ranges from 0.7% - 31% across studies. We investigated the incidence and clinical correlates of brainstem injury in pediatric brain tumors treated with proton therapy.All patients < 18 years with infratentorial brain and pineal tumors, treated with proton beam RT at our institution from 2007 - 2019, with a brainstem Dmean of > 30 Gy and/or Dmax > 50.4 Gy were included. We excluded patients with primary brainstem tumors. Symptomatic brainstem injury (SBI) was defined as any new or progressive cranial neuropathy, ataxia, dysmetria and/or motor weakness with corresponding radiographic abnormality within the brainstem and was graded per the NCI Common Terminology Criteria for Adverse Events v5.0 (Grade 2: moderate symptoms, corticosteroids indicated; Grade 3: severe symptoms, medical intervention indicated; Grade 4: life-threatening; urgent intervention; and Grade 5: death).A total of 595 patients were reviewed and 362 (medulloblastoma = 209, ependymoma = 86, ATRT = 43, pineoblastoma = 9, others = 15) met our inclusion criteria. Median age at RT was 5 years (range 0.7 - 17.9 years) and median prescribed RT dose was 54 CGyE (range 39.6 - 59.4 CGyE). Median follow up was 40 months (range 1 - 152). Ten patients (2.7%) developed SBI, at a median of 4 months after RT (range 1-6). Grades 2,3,4 and 5 brainstem injuries were seen in 3, 4, 2 and 1 patient respectively. Mean brainstem Dmax in SBI and non-SBI patients was 55.9 Gy and 54.8 Gy (P = 0.30), while the mean Dmean was 43.3 Gy and 43.2 Gy (P = 0.48) respectively. Most common symptoms of SBI were ataxia, slurred speech, 6th cranial nerve palsy and bulbar palsy. All SBI patients required steroids for 1-5 months, while grade 3-5 injuries were also treated with bevacizumab and/or hyperbaric oxygen therapy. Asymptomatic imaging changes within brainstem were seen in 47 patients (13%) at a median of 4 months after RT, most common findings being increased T2 flair, focal enhancement and encephalomalacia. In 2014, our institution started using strict brainstem dose constraints (Dmax ≤ 57 Gy, Dmean ≤ 52.4 Gy and V54 ≤ 10%). The incidence of SBI has decreased from 4.2% (2007-2013) to 0.7% (2014-2019) (P = 0.047) while asymptomatic imaging changes remain similar (11.6% vs 15.1%, P = 0.33). Patients with SBI had a higher V45, V50-52 and D15 -D50; while the Dmax, Dmean, V53-60 and D1- D10 were similar.Our results suggest that there is a low risk of SBI after proton therapy for pediatric brain tumors. A lower incidence of SBI was seen after the use of strict brainstem dose constraints. Volumetric doses to brainstem may play a significant role in determining the risk of SBI and developing a dose response nomogram is warranted.

Proton range uncertainty reduction benefits for skull base tumors in terms of normal tissue complication probability (NTCP) and healthy tissue doses.

Proton therapy allows for more conformal dose distributions and lower organ at risk and healthy tissue doses than conventional photon-based radiotherapy, but uncertainties in the proton range currently prevent proton therapy from making full use of these advantages. Numerous developments therefore aim to reduce such range uncertainties. In this work, we quantify the benefits of reductions in range uncertainty for treatments of skull base tumors. The study encompassed 10skull base patients with clival tumors. For every patient, six treatment plans robust to setup errors of 2mm and range errors from 0% to 5% were created. The determined metrics included the brainstem and optic chiasm normal tissue complication probability (NTCP) with the endpoints of necrosis and blindness, respectively, as well as the healthy tissue volume receiving at least 70% of the prescription dose. A range uncertainty reduction from the current level of 4% to a potentially achievable level of 1% reduced the probability of brainstem necrosis by up to 1.3 percentage points in the nominal scenario in which neither setup nor range errors occur and by up to 2.9 percentage points in the worst-case scenario. Such a range uncertainty reduction also reduced the optic chiasm NTCP with the endpoint of blindness by up to 0.9 percentage points in the nominal scenario and by up to 2.2 percentage points in the worst-case scenario. The decrease in the healthy tissue volume receiving at least 70% of the prescription dose ranged from -7.8 to 24.1cc in the nominal scenario and from -3.4 to 38.4cc in the worst-case scenario. The benefits quantified as part of this study serve as a guideline of the OAR and healthy tissue dose benefits that range monitoring techniques may be able to achieve. Benefits were observed between all levels of range uncertainty. Even smaller range uncertainty reductions may therefore be beneficial.

Dosimetric Assessment of a High Precision System for Mouse Proton Irradiation to Assess Spinal Cord Toxicity.

The uncertainty associated with the relative biological effectiveness (RBE) in proton therapy, particularly near the Bragg peak (BP), has led to the shift towards biological-based treatment planning. Proton RBE uncertainty has recently been reported as a possible cause for brainstem necrosis in pediatric patients treated with proton therapy. Despite this, in vivo studies have been limited due to the complexity of accurate delivery and absolute dosimetry. The purpose of this investigation was to create a precise and efficient method of treating the mouse spinal cord with various portions of the proton Bragg curve and to quantify associated uncertainties for the characterization of proton RBE. Mice were restrained in 3D printed acrylic boxes, shaped to their external contour, with a silicone insert extending down to mold around the mouse. Brass collimators were designed for parallel opposed beams to treat the spinal cord while shielding the brain and upper extremities of the animal. Up to six animals may be accommodated for simultaneous treatment within the restraint system. Two plans were generated targeting the cervical spinal cord, with either the entrance (ENT) or the BP portion of the beam. Dosimetric uncertainty was measured using EBT3 radiochromic film with a dose-averaged linear energy transfer (LETd) correction. Positional uncertainty was assessed by collecting a library of live mouse scans (n = 6 mice, two independent scans per mouse) and comparing the following dosimetric statistics from the mouse cervical spinal cord: Volume receiving 90% of the prescription dose (V90); mean dose to the spinal cord; and LETd. Film analysis results showed the dosimetric uncertainty to be ±1.2% and ±5.4% for the ENT and BP plans, respectively. Preliminary results from the mouse library showed the V90 to be 96.3 ± 4.8% for the BP plan. Positional uncertainty of the ENT plan was not measured due to the inherent robustness of that treatment plan. The proposed high-throughput mouse proton irradiation setup resulted in accurate dose delivery to mouse spinal cords positioned along the ENT and BP. Future directions include adapting the setup to account for weight fluctuations in mice undergoing fractionated irradiation.

Proton Therapy for Pediatric Ependymoma: Mature Results From a Bicentric Study

To report the long-term efficacy and toxicity of proton therapy for pediatric ependymoma. Between 2000 and 2019, 386 children with nonmetastatic grade 2/3 intracranial ependymoma received proton therapy at 1 of 2 academic institutions. Median age at treatment was 3.8 years (range, 0.7-21.3); 56% were male. Most (72%) tumors were in the posterior fossa and classified as World Health Organization grade 3 (65%). Eighty-five percent had a gross total or near total tumor resection before radiation therapy; 30% received chemotherapy. Median radiation dose was 55.8 Gy relative biologic effectiveness (RBE) (range, 50.4-59.4). Median follow-up was 5.0 years (range, 0.4-16.7). The 7-year local control, progression-free survival, and overall survival rates were 77.0% (95% confidence interval [CI], 71.9%-81.5%), 63.8% (95% CI, 58.0%-68.8%), and 82.2% (95% CI, 77.2%-86.3%), respectively. Subtotal resection was associated with inferior local control (59% vs 80%; P < .005), progression-free survival (48% vs 66%; P < .001), and overall survival (70% vs 84%; P < .05). Male sex was associated with inferior progression-free (60% vs 69%; P < .05) and overall survival (76% vs 89%; P < .05). Posterior fossa tumor site was also associated with inferior progression-free (59% vs 74%; P < .05) and overall survival (79% vs 89%; P < .01). Twenty-one patients (5.4%) required hearing aids; of these, 13 received cisplatin, including the 3 with bilateral hearing loss. Forty-five patients (11.7%) required hormone replacement, typically growth hormone (38/45). The cumulative incidence of grade 2+ brain stem toxicity was 4% and occurred more often in patients who received >54 GyRBE. Two patients (0.5%) died of brain stem necrosis. The second-malignancy rate was 0.8%. Proton therapy offers disease control commensurate with modern photon therapy without unexpected toxicity. The high rate of long-term survival justifies efforts to reduce radiation exposure in this young population. Independent of radiation modality, this large series confirms extent of resection as the most important modifiable factor for survival.