Brainstem Toxicity Research Articles

Brainstem Toxicity Following Proton Beam Radiation Therapy in Pediatric Brain Tumors: A Systematic Review and Meta-Analysis.

Background: Proton beam radiation therapy (PBRT) is an advanced cancer treatment modality that utilizes the distinctive physical properties of protons to precisely deliver radiation to tumor targets while sparing healthy tissue. This cannot be obtained with photon radiation. In this systematic review and meta-analysis, we aimed to comprehensively assess the risk of brainstem toxicity in pediatric brain tumor patients undergoing PBRT. Methods: With adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a predetermined search strategy was used to identify eligible articles from PubMed, Web of Science, Scopus, and Cochrane Library through July 2024. Results: The current study included a total of 11 eligible articles. The pooled prevalence of patients who suffered from brainstem toxicity was 1.8% (95% CI: 1%, 2.6%). The pooled prevalences of patients with Grade 1 to Grade 5 brainstem toxicity were found to be 10.6% (95% CI: 8.8%, 30%), 1.5% (95% CI: 0.6%, 2.5%), 0.7% (95% CI: 0.3%, 1.1%), 0.4% (95% CI: 0.1%, 0.7%), and 0.4% (95% CI: 0.1%, 0.8%), respectively, with an overall pooled prevalence of 0.7% (95% CI: 0.4%, 1%). Conclusions: This study revealed a relatively low incidence of symptomatic brainstem toxicity and its related mortality in the pediatric population undergoing PBRT. However, further research is encouraged to study the broader effects of PBRT and to explore various factors that may influence the risk of brainstem toxicity in patients treated with PBRT.

Evolution of Proton Radiation Therapy Brainstem Constraints on the Pediatric Proton/Photon Consortium Registry

Increasing concern that brainstem toxicity incidence after proton radiation therapy might be higher than with photons led to a 2014 University of Florida (UF) landmark paper identifying its risk factors and proposing more conservative dose constraints. We evaluated how practice patterns changed among the Pediatric Proton/Photon Consortium Registry (PPCR). This prospective multicenter cohort study gathered data from patients under the age of 22 years enrolled on the PPCR, treated between 2002 and 2019 for primary posterior fossa brain tumors. After standardizing brainstem contours, we garnered dosimetry data and correlated those meeting the 2014 proton-specific brainstem constraint guidelines by treatment era, histology, and extent of surgical resection. A total of 467 patients with evaluable proton radiation therapy plans were reviewed. Median age was 7.1 years (range: <1-21.9), 63.0% (n = 296) were men, 76.0% (n = 357) were White, and predominant histology was medulloblastoma (55.0%, n = 256), followed by ependymoma (27.0%, n = 125). Extent of resection was mainly gross total resection (GTR) (67.0%, n = 312), followed by subtotal resection (STR) or biopsy (20.0%, n = 92), and near total resection (NTR) (9.2%, n = 43). The UF brainstem constraint metrics most often exceeded were the goal D50% of 52.4 gray relative biological equivalents (43.3%, n = 202) and maximal D50% of 54 gray relative biological equivalents (12.6%, n = 59). The compliance rate increased after the new guidelines (2002-2014: 64.0% vs 2015-2019: 74.6%, P = .02), except for ependymoma (46.3% pre- vs 50.0% post-guidelines, P = .86), presenting lower compliance (48.8%) in comparison to medulloblastoma/ primitive neuroectodermal tumors/pineoblastoma (77.7%), glioma (89.1%), and atypical teratoid/rhabdoid tumors (90.9%) (P < .001). Degree of surgical resection did not affect compliance rates (GTR/NTR 71.0% vs STR/biopsy 72.8%, P = .45), even within the ependymoma subset (GTR/NTR 50.5% vs STR/biopsy 38.1%, P = .82). Since the publication of the UF guidelines, the pediatric proton community has implemented more conservative brainstem constraints in all patients except those with ependymoma, irrespective of residual disease after surgery. Future work will evaluate if this change in practice is associated with decreased rates of brainstem toxicity.

RADT-08. BASAL GANGLIA TOXICITY FOLLOWING PROTON THERAPY OF THE PINEAL REGION WITH BILATERAL ACTION-INDUCED MYOCLONUS

Abstract INTRODUCTION We sought to evaluate the toxicity profile for children receiving 54Gy to the pineal region with a significant dose delivered to posterior thalamus and basal ganglia. METHODS We performed a retrospective review of patients treated at a single institution with intensity modulated proton therapy (IMPT) receiving 54Gy to the pineal region. Multiple beam angles were utilized for planning. Patient characteristics and dosimetric data were correlated with late-toxicity and imaging. RESULTS From 2021-2023, six children were treated, and at a median follow-up of 13 months [9-26], all patients remain disease-free. Three patients had non-germinomatous germ cell tumors, 1 low-grade glioma, 1 atypical teratoid rhabdoid tumor (ATRT), and 1 embryonal tumor with multilayered rosettes. Age range was 2.4 to 16.8 years. All patients received chemotherapy prior to IMPT. Neuropsychological evaluation indicated range of intellectual functioning (mean = 98.3 [83-118]). One patient, a 4-year-old female with ATRT, developed T2 changes within the globus pallidus and thalamus on 3 month follow-up. At 5 months, she developed bilateral action-induced myoclonus with corresponding enhancing lesions in the globus pallidus bilaterally. Neuropsychological evaluation at 5 months post-treatment indicated memory impairments. She was treated with dexamethasone without improvement. Between 912 months post-treatment, tremors improved with physical therapy and imaging showed near complete resolution of enhancement within globus pallidus. CONCLUSION One of six children developed grade 3 toxicity manifesting as bilateral action-induced myoclonus with imaging changes in the globus pallidus bilaterally following IMPT and exhibited related neuropsychological deficits. While brainstem toxicity from IMPT is well documented, globus pallidus toxicity is not well characterized. Given the contiguous neuronal tracts with the brainstem, it is logical to apply similar treatment planning techniques, i.e. minimizing hotspots within the globus pallidus and thalamic “core” structures, and being cognizant of LET/RBE effects for treatment involving the pineal region in young children.

Radiochirurgie des névralgies trigéminales avec accélérateur linéaire dédié sans cadre invasif : de la mise en service de l’appareil aux premiers résultats cliniques

PurposeRadiosurgery for the treatment of trigeminal neuralgia delivers a very high dose in a single fraction, over a few millimeters, at a single isocenter placed along the nerve. We present here the different steps that have been performed to validate small beams by conical collimators, and report the clinical results of the first patients treated on Novalis Tx®, frameless. Material and methodsFirst, the geometric accuracy of 4 and 6mm conical collimators was evaluated using Winston-Lutz tests; then dosimetric data acquisition was performed using high spatial resolution detectors (PTW 60019 microdiamond and a PTW 60017 E-diode). The corrective factors of the TRS 483 report were applied to calculate the collimator aperture factors. These dosimetric data were then compared with the data implemented in the iPlan® treatment planning system. Then end-to-end tests were performed to control the entire treatment process using an anthropomorphic phantom “STEEV”. Between 2020 and 2022, 18 patients were treated for refractory trigeminal neuralgia on Novalis Tx®, frameless, with Exactrac® repositioning. A total of 17 patients were evaluated (one was lost to follow-up) using the BNI score for pain assessment and MRI with a median follow-up of 12 months. ResultsThe quality criteria of geometric and dosimetric accuracy were met for the 6-mm cone but not for the 4-mm cone. All patients were treated with a 6-mm cone with a dose of 90Gy prescribed at the isocenter at the root entry zone. Initial pain control was obtained in 70.5% of our patients, and 53% maintained pain control with a median follow-up of 12 months. All recurrences occurred within 3 to 6 months after radiosurgery. No brainstem toxicity was observed. Six patients had non-disabling facial hypoesthesia, half of whom already had pretreatment hypoesthesia. ConclusionThe treatment of trigeminal neuralgia on a dedicated linear accelerator is a highly technical treatment whose accuracy and safety are paramount. The physical measurements allowed the commissioning of the technique with a 6mm cone. Our first clinical results are in accordance with the literature.

Brainstem toxicity after proton or photon therapy in children and young adults with localized intracranial ependymoma: A French retrospective study

Background and purposeEpendymoma is the third most frequent childhood braintumor. Standard treatment is surgery followed by radiation therapy including proton therapy (PBT). Retrospective studies have reported higher rates of brainstem injury after PBT than after photon therapy (XRT). We report a national multicenter study of the incidence of brainstem injury after XRT versus PBT, and their correlations with dosimetric data. Material and methodsWe included all patients aged < 25 years who were treated with PBT or XRT for intracranial ependymoma at five French pediatric oncology reference centers between 2007 and 2020. We reviewed pre-irradiation MRI, follow-up MRIs over the 12 months post-treatment and clinical data. ResultsOf the 83 patients, 42 were treated with PBT, 37 with XRT, and 4 with both (median dose: 59.4 Gy, range: 53‑60). No new or progressive symptomatic brainstem injury was found. Four patients presented asymptomatic radiographic changes (punctiform brainstem enhancement and FLAIR hypersignal), with median onset at 3.5 months (range: 3.0‑9.4) after radiation therapy, and median offset at 7.6 months (range: 3.7‑7.9). Two had been treated with PBT, one with XRT, and one with mixed XRT-PBT. Prescribed doses were 59.4, 55.8, 59.4 and 54 Gy. ConclusionAsymptomatic radiographic changes occurred in 4.8% of patients with ependymoma in a large national series. There was no correlation with dose or technique. No symptomatic brainstem injury was identified.

Stereotactic Radiosurgery for Vestibular Schwannoma With Radiographic Brainstem Compression.

The safety of single-treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression but without motor deficit is controversial. Data on linear accelerator (linac)-based SRS in this setting are scarce. We address this with an outcomes report from an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS. We included 139 patients with unilateral VS (any size) with radiographic brainstem compression (all without serious brainstem neurological deficits). The SRS prescription dose was 12.5Gy (single fraction) using 6MV linac-produced photon beams, delivered with a multiple arc technique. Inclusion criteria required at least 1 year of radiographic follow-up with magnetic resonance imaging. The primary endpoint was freedom from serious brainstem toxicity (≥grade 3 Common Terminology Criteria for Adverse Events v5); the secondary was freedom from enlargement (tumor progression or any requiring intervention). We assessed serious cranial nerve complications, excluding hearing loss, defined as Common Terminology Criteria for Adverse Events v5 grade 3 toxicity. Median magnetic resonance imaging follow-up time was 5 years, and median tumor size was 2.5cm in greatest axial dimension and 5ml in volume. The median brainstem D0.03ml=12.6Gy and median brainstem V10Gy=0.4ml. At 5 years, the actuarial freedom from serious brainstem toxicity was 100%, and freedom from tumor enlargement (requiring surgery and/or due to progression) was 90%. Severe facial nerve damage in patients without tumor enlargement was 0.9%. Linac-based SRS, as delivered in our series for VS with radiographic brainstem compression, is safe and effective.

RADT-22. STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMA WITH RADIOGRAPHIC BRAINSTEM COMPRESSION

Abstract BACKGROUND The safety of single treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression- but without motor deficit- is controversial. Data on linac-based SRS in this setting are scarce. We address this deficit in the literature with a report of outcome of an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS our institution. METHODS We included patients with unilateral VS of any size with radiographic brainstem compression at the time of SRS. All patients were without serious brainstem neurologic deficits at the time of SRS. The SRS prescription dose was 12.5 Gy in a single fraction using 6MV photon beams produced by a linear accelerator and delivered with a multiple arc technique. Inclusion in this study required at least 1 year of radiographic follow-up with magnetic resonance imaging (MRI). The primary endpoint was freedom from serious brainstem toxicity (CTCAEv5 grade &amp;gt;3); secondary endpoint was freedom from tumor enlargement considered to represent tumor progression, or any type of enlargement requiring surgical intervention. We also assessed serious cranial nerve complications, excluding hearing loss, defined as CTCAEv5 grade 3 toxicity. RESULTS Among 139 patients, the median MRI follow-up time was 5 years and the median tumor size was 2.5 cm greatest axial dimension and 5cc in volume. The median brainstem D0.03cc = 12.6 Gy, and the median brainstem V10Gy = 0.4cc. At 5 years, the actuarial freedom from serious brainstem toxicity was 100% (zero cases), and freedom from tumor enlargement, either requiring surgery or due to progression, was 90%. The rate of grade 3 facial nerve damage in patients without tumor enlargement was 0.9% (1/113). CONCLUSION Linac-based SRS as delivered in our series for VS with radiographic brainstem compression is safe and effective.

Feasibility and Safety of Single-Isocenter/Multi-Lesion (SIML) HyperArc Brain SRT: Clinical Implementation and Early Outcomes

Patients with multiple brain metastases may not tolerate relatively longer treatment times for traditional stereotactic radiation therapy (SRT) with individual isocenter plans for each lesion due to discomfort or co-morbidities. SRT using a single-isocenter/multi-lesion (SIML) HyperArc volumetric modulated arc therapy (VMAT) plan with flattening filter free (FFF) beam could significantly shorten overall treatment time, and improve patient comfort, compliance, and clinic efficiency. We report early clinical results of treating multiple brain metastases with SIML HyperArc SRT. Twenty-three patients with multiple brain metastatic tumors (range, 2-9 lesions; total treated lesions, n = 96) were simulated using Encompass support and Q-fix mask, and treated with a highly-conformal SIML VMAT SRT plans via non-coplanar HyperArc geometry. Mean tumor distance to isocenter was 5.3 cm, maximum up to 7 cm. Common prescriptions were 25-30 Gy/5 fractions, 24-27 Gy/3 fractions, and 20 Gy/1 fraction prescribed to each planning target volume (PTV) using 2 mm margin around standard gross tumor volume (GTV) delineated on contrasted enhanced MP-RAGE MRI fusion. Acuros dose calculation for 6MV-FFF beam was used for tissue heterogeneity corrections. Alliance A071801 criteria was used for dose constraints to organs at risk (OAR) and target conformality. Treatment was delivered every other day with CBCT-guidance, adjustments made with 6DOF couch corrections on a medical linear accelerator, and treatment delivery time within 15 minutes. Local control rates were reported, and toxicity profile rated based on CTCAE v5.0 for brain radionecrosis, optic neuropathy, and brainstem dysfunction. All plans met Alliance A071801 requirements for each tumor coverage, dose to OAR including optic apparatus, brainstem, and spinal cord. Mean GTV and PTV volume were 9.4 cc (range, 0.3-54.8 cc) and 16.13 cc (range, 1.0-80.2 cc). Patient-specific quality assurance results were 98.3% for gamma passing criteria of 2%/2mm. Independent in-house Monte Carlo physics second check agreed with HyperArc plans by ±3.0%. Mean follow up was 6 months (range, 0.0-18.6 months). Of the 23 patients treated, 17 (74%) had post-treatment MRI imaging to assess local control and toxicity. Local control was achieved in 69/73 (95%) of treated and followed lesions. CTCAE grade 2 radionecrosis occurred in 2 patients and were managed with dexamethasone. No CTCAE grade 3+ events of radionecrosis, optic pathway dysfunction, or brainstem toxicity were observed. SIML HyperArc Brain SRT for multiple brain metastases has excellent local control and low toxicity profile in our patients. It can significantly reduce treatment delivery time as compared to traditional multiple-isocenter brain SRT or chronologically separate treatment courses and thus, help to improve patient comfort, compliance, ease of care, and clinic workflow. Longer median follow up of SIML brain SRT on larger patient cohort is warranted.

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 (&gt;2 cm in great diameter) vestibular schwannomas (VSs) treated with hypofractionated stereotactic radiotherapy (HFSRT) compared to small (&lt;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 &lt; 1%) of brainstem toxicity with or without surgical debulking, but there was a significant difference favoring surgery (p &lt; 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.

Brainstem toxicity after proton or photon therapy in children with localized intracranial ependymoma

Objectives Children's ependymomas achieve a 5-years local control rate of 50% with a standard post-operative dose of 59.4 Gy. To decrease the dose to normal tissue, proton bean therapy (PBT) is preferred when available. Recently, retrospective studies reported higher rates of radionecrosis on the brainstem after PBT than photon radiation therapy (XRT), leading several teams to decrease the dose to 54 Gy in PBT for posterior fossa ependymomas under 3 years old. The benefit-risk's balance of the dose reduction is unclear especially since the real incidence of clinically relevant brainstem's toxicity appears low.This prompt us to compare the incidence of clinical and imaging brainstem toxicity between XRT and PBT and to correlate them to the dosimetric datas in the retrospective PEPPI French cohort. Methods From 2001 to 2021, we studied the MRI brainstem's modification and clinical brainstem toxicity for patients ≤ 22 years old from 5 reference French centers treated with surgery and radiation therapy (RT) for a localized intracranial ependymoma. Pre operative, post operative and follow-up MRI during 18 months after RT were analyzed. Post-gadolinium T1, T2, FLAIR and diffusion weighted imaging were used. Results Eighty-three patients were included in the study, 42 patients were treated with PBT, 37 with XRT and 4 with both. Median follow-up was 5.6 years [95%CI: 4.8-6.2], the 5-years overall survival and progression free survival rates were respectively 86.1% [95%CI: 75.7-92.3] and 68.7% [95%CI: 56.4-78.3]. Neither clinical or MRI brainstem radionecrosis nor new or progressive brainstem symptoms were found. Four patients (whose two had received PBT) presented a punctiform brainstem enhancement with a median time of onset of 3.5 months [3.0-9.4] after RT and a median time of disappearance of 7.6 months [3.7-7.9]. Median brainstem mean dose was 47.2 Gy [45.3-53.2] for them and 48.5 Gy for the cohort. Conclusion Brainstem imaging change occurred in 4,8% of children in a large series including PBT. No radionecrosis nor symptomatic MRI change was found within the brainstem. The pursue of the study with the others French centers will strengthen our results. Children's ependymomas achieve a 5-years local control rate of 50% with a standard post-operative dose of 59.4 Gy. To decrease the dose to normal tissue, proton bean therapy (PBT) is preferred when available. Recently, retrospective studies reported higher rates of radionecrosis on the brainstem after PBT than photon radiation therapy (XRT), leading several teams to decrease the dose to 54 Gy in PBT for posterior fossa ependymomas under 3 years old. The benefit-risk's balance of the dose reduction is unclear especially since the real incidence of clinically relevant brainstem's toxicity appears low.This prompt us to compare the incidence of clinical and imaging brainstem toxicity between XRT and PBT and to correlate them to the dosimetric datas in the retrospective PEPPI French cohort. From 2001 to 2021, we studied the MRI brainstem's modification and clinical brainstem toxicity for patients ≤ 22 years old from 5 reference French centers treated with surgery and radiation therapy (RT) for a localized intracranial ependymoma. Pre operative, post operative and follow-up MRI during 18 months after RT were analyzed. Post-gadolinium T1, T2, FLAIR and diffusion weighted imaging were used. Eighty-three patients were included in the study, 42 patients were treated with PBT, 37 with XRT and 4 with both. Median follow-up was 5.6 years [95%CI: 4.8-6.2], the 5-years overall survival and progression free survival rates were respectively 86.1% [95%CI: 75.7-92.3] and 68.7% [95%CI: 56.4-78.3]. Neither clinical or MRI brainstem radionecrosis nor new or progressive brainstem symptoms were found. Four patients (whose two had received PBT) presented a punctiform brainstem enhancement with a median time of onset of 3.5 months [3.0-9.4] after RT and a median time of disappearance of 7.6 months [3.7-7.9]. Median brainstem mean dose was 47.2 Gy [45.3-53.2] for them and 48.5 Gy for the cohort. Brainstem imaging change occurred in 4,8% of children in a large series including PBT. No radionecrosis nor symptomatic MRI change was found within the brainstem. The pursue of the study with the others French centers will strengthen our results.

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.

A case-control study of linear energy transfer and relative biological effectiveness related to symptomatic brainstem toxicity following pediatric proton therapy

A fixed relative biological effectiveness (RBE) of 1.1 (RBE1.1) is used clinically in proton therapy even though the RBE varies with properties such as dose level and linear energy transfer (LET). We therefore investigated if symptomatic brainstem toxicity in pediatric brain tumor patients treated with proton therapy could be associated with a variable LET and RBE. 36 patients treated with passive scattering proton therapy were selected for a case-control study from a cohort of 954 pediatric brain tumor patients. Nine children with symptomatic brainstem toxicity were each matched to three controls based on age, diagnosis, adjuvant therapy, and brainstem RBE1.1 dose characteristics. Differences across cases and controls related to the dose-averaged LET (LETd) and variable RBE-weighted dose from two RBE models were analyzed in the high-dose region. LETd metrics were marginally higher for cases vs. controls for the majority of dose levels and brainstem substructures. Considering areas with doses above 54Gy(RBE1.1), we found a moderate trend of 13% higher median LETd in the brainstem for cases compared to controls (P=.08), while the difference in the median variable RBE-weighted dose for the same structure was only 2% (P=.6). Trends towards higher LETd for cases compared to controls were noticeable across structures and LETd metrics for this patient cohort. While case-control differences were minor, an association with the observed symptomatic brainstem toxicity cannot be ruled out.

The incidence of brainstem toxicity following high-dose conformal proton therapy for adult skull-base malignancies

Background Dose escalation for skull-based malignancies often presents risks to critical adjacent neural structures, including the brainstem. We report the incidence of brainstem toxicity following fractionated high-dose conformal proton therapy and associated dosimetric parameters. Material and methods We performed a single-institution review of patients with skull-base chordoma or chondrosarcoma who were treated with proton therapy between February 2007 and January 2020 on a prospective outcomes-tracking protocol. The primary endpoint was grade ≥2 brainstem toxicity. No patients received concurrent chemotherapy, and brainstem toxicity was censored for analysis if it coincided with local disease progression. Results We analyzed 163 patients who received a minimum of 45 GyRBE to 0.03 cm3 of the brainstem. Patients were treated to a median total dose of 73.8 (range 64.5–74.4) GyRBE at 1.8 GyRBE per fraction with 17 patients undergoing twice-daily treatment at 1.2 GyRBE per fraction. With a median follow-up of 4 years, the 5-year cumulative incidence of grade ≥2 brainstem injury was 1.3% (95% CI 0.25–4.3%). There was one grade 2, one grade 3, and no grade 4 or 5 events, with all patients recovering function with medical management. Conclusion In delivering curative-intent radiotherapy for skull-base chordoma and chondrosarcoma in adults, small volumes of the brainstem can safely receive at least 64 GyRBE with minimal risk of serious brainstem injury.

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.

OC-0091 Brainstem toxicity after proton or photon therapy in children with localized intracranial ependymoma

OC-0091 Brainstem toxicity after proton or photon therapy in children with localized intracranial ependymoma

OC-0455 RBE models of brainstem toxicity from proton therapy of paediatric ependymoma

OC-0455 RBE models of brainstem toxicity from proton therapy of paediatric ependymoma

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.

PO-1801 Regional variation in relative biological effectiveness and pediatric brainstem toxicity

PO-1801 Regional variation in relative biological effectiveness and pediatric brainstem toxicity

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.

RONC-24. PROTON THERAPY FOR PEDIATRIC EPENDYMOMA: MATURE OUTCOMES FROM THE UNIVERSITY OF FLORIDA AND MASSACHUSETTS GENERAL HOSPITAL

OBJECTIVEReport long-term efficacy and toxicity of proton therapy for pediatric ependymoma.MATERIALS AND METHODSBetween 2000–2017, 318 children with nonmetastatic grade II/III intracranial ependymoma received proton therapy at Massachusetts General Hospital and the University of Florida. Median age was 3.5 years (range, 0.7–21.3 years); 56% were male. Most (69%) tumors were in the posterior fossa and classified as WHO grade III (64%). Eighty-four percent had a gross total or near total tumor resection before radiotherapy and 30% received chemotherapy. Median radiation dose was 55.8 CGE (range, 50.4–59.4 CGE).RESULTSMedian follow-up was 6 years (range, 0.6–19.2 years). Seven-year local control, progression-free survival, and overall survival rates were 77.1% (95% CI 71.7–81.7%), 64.4% (95% CI 58.6–69.8%), and 82% (76.9–86.2%), respectively. Subtotal resection was associated with inferior local control (60% vs 80%; p<0.01), progression-free survival (49% vs 67%; p<0.01), and overall survival (69% vs 84%; p<0.05). Male gender was associated with inferior progression-free (59% vs 71%; p<0.01) and overall survival (77% vs 89%; p<0.05). Twenty patients (6.2%) require hearing aids; of these, 12/20 received cisplatin. Grade 3+ brainstem toxicity rate was 1.6% and more common in patients who received >54 CGE. The rate of second malignancy was 0.9%.CONCLUSIONProton therapy offers commensurate disease control to modern photon therapy without unexpected toxicity. The high rate of long-term survival justifies efforts to reduce radiation exposure in this young population with brain tumors. Independent of modality, this large series confirms extent of resection as the most important modifiable factor for survival.