Citations

Abstract Purpose/Objective(s) To report outcomes for disseminated Medulloblastoma (stage M1-M3) who received radiation (RT) on the Pediatric Proton/Photon Consortium Registry (PPCR). Materials/Methods 71 patients were included with either M1 (6), M2 (21), or M3 (44) Medulloblastoma on PPCR. Survival (OS, Overall; EFS, Event Free) analyses were performed using the Kaplan Meier method and log rank p-values from RT start. Median follow up was calculated using the reverse Kaplan Meier method. Results Median age at RT was 7.5 years (range 2.4-21.89) and the median follow up was 4.3 years. Histology was classic (52), diffuse anaplasia (12), focal anaplasia (5), desmoplastic nodular (1), or other (1). Treatment included surgery, chemotherapy with or without stem cell support, and RT. 54 patients had gross total resection (GTR) or near total resection (NTR); 14 had subtotal resection (STR). Pre-RT chemotherapy was given in 69 (97.1%) patients; 23 had myeloablative chemotherapy with stem cell support. The 5 and 10-year OS of the entire cohort were 73% and 65%, and 5 and 10-year EFS were 65% and 59%. Patients with progression prior to RT (10 patients) had inferior OS (5-year OS 44%) compared to patients without progression pre-RT (5-year OS 78%, p = 0.045). There was a trend for better OS (p = 0.07) and improved EFS (p = 0.043) for M2 stage. GTR/NTR did not impact OS (p = 0.75) or EFS (p = 0.97) compared to STR. Craniospinal (CSI) radiation (70 patients, 99%) doses were: £ 23.4Gy (11.4%), 23.5Gy-36Gy (11.4%), or ³ 36Gy (74.3%). Patients receiving CSI ³ 36Gy had superior OS (p = 0.043), with 5 and 10-year OS of 82% and 71% compared to 5 and 10-year OS of 52% and 52% for lower dose CSI. Conclusion Full dose CSI (36Gy) for M1-M3 medulloblastoma was associated with excellent long-term survival this series, whereas lower dose CSI and progression prior to RT had inferior outcomes.

Abstract BACKGROUND CNS ependymal tumors rarely demonstrate mixed subependymal and ependymal pathology. The clinical course of these tumors is difficult to predict, but prior studies have identified TERT mutations and loss of chromosome 6 as poor prognostic factors in these tumors when located in the posterior fossa. METHODS In this retrospective single-institution study, patients with a diagnosis of mixed subependymoma/ependymoma were identified and chart reviewed to describe demographics, pathological findings, treatment courses and clinical outcomes. RESULTS Eleven patients (median age 57, 2 female, 9 male) were identified. Ten tumors were in the posterior fossa and 1 in the cervical spine. At diagnosis, 2 underwent gross total resection, 8 underwent subtotal resection, and 1 was only biopsied. Radiotherapy was administered to 5 patients at initial diagnosis (54Gy in 30 fractions). Systemic therapy (temozolomide and bevacizumab) was administered at recurrence to 2 patients. Loss of chromosome 6 was present in 5 /11 patients and TERT mutations were present in 4/11 patients, with both present in 3/11 patients. Median progression-free survival (mPFS) was 90.1 months (95% CI: 90.1–NA), with 3 progression events observed at 22, 90, and 107 months. Median follow-up duration was 27.9 months. Receiving radiotherapy had a longer mPFS (98 vs 22 months, p=0.15), although non-significant. At the time of data cut-off none of the patients were deceased. CONCLUSIONS Mixed subependymoma/ependymoma is a rare diagnosis with varying clinical outcomes. Our case series demonstrated that the majority of patients did not exhibit the previously identified poor prognostic factors. Although non-significant due to limited case numbers, radiotherapy was suggestive of longer mPFS.

Background: Post-treatment prognosis and monitoring are critical for determining the timing of salvage treatment in glioblastoma patients but has been challenging due to difficulties differentiating progression from treatment effects in conventional images. This exploratory study aimed to establish the correlation of radiomics image features from time series of amino acid tracer 18F-DOPA PET images, with outcomes, using machine learning and dimension reduction analysis. Methods: 18F-DOPA PET images were collected for a patient cohort with wild-type IDH and unmethylated MGMT who underwent dose-escalated radiation therapy. Quantitative features were derived from the high uptake region (T/N > 2.0) in pre- and post-radiation therapy follow-up 18F-DOPA PET images. A customized workflow was utilized for pre-selecting predictive features, followed by manifold learning. Machine learning algorithms were employed to establish associations between imaging features and remaining survival (RS), defined as the time between a follow-up scan and date of death. Results: The ML models exhibited 81–83% ROC_AUC in predicting RS evaluated on an independent test dataset. A RS map is proposed for monitoring tumor alterations through serial 18F-DOPA PET scans, demonstrating superior sensitivity and better correlation with survival compared to the RANO criteria. Conclusions: Our study demonstrates that ML models utilizing FU 18F-DOPA PET images have the potential to effectively predict future survival outcomes in patients with glioblastoma treated with dose-escalated radiation therapy. The capability to assess changes in tumor over time through imaging can potentially assist in patient stratification and the selection of salvage treatments, while also aiding in distinguishing treatment effects from genuine tumor progression.

Abstract Background Spatially fractionated radiation therapy (SFRT) is a technique that delivers heterogenous dose distributions consisting of alternating regions of high dose “peaks” and low dose “valleys”. Current delivery methods for SFRT using megavoltage x‐rays usually treat large and bulky tumors with brass grid or volumetric modulated arc therapy (VMAT) lattice techniques. The size and spacing of high dose regions in these approaches are typically on the order of centimeters. However, multiple studies have suggested that decreasing these dimensions may improve the therapeutic ratio. Furthermore, a more compact approach to SFRT would allow for a greater number of high dose regions within the tumor, as well as application to smaller and more irregularly shaped targets thereby increasing the number of patients that could benefit from SFRT. Purpose This study describes the commissioning and first patient treatment using mini‐lattice radiation therapy (MLRT). MLRT uses a clinical linear accelerator and decreases the size and spacing of standard lattice SFRT by using individual multileaf collimator (MLC) leaves to deliver 5 mm wide high dose regions. Methods MLRT plans were created in the Varian Eclipse treatment planning system for a Varian Truebeam equipped with Millennium 120 MLCs. MLRT uses 6 MV Flattening Filter Free high dose rate and the width of individual MLCs to define 5 mm by 5 mm openings separated by closed MLCs to deliver alternating opened and blocked regions. Dynamic conformal arcs were used to conform MLCs to 4 mm spherical mini‐lattice structures in the gross tumor volume (GTV). A MLRT‐specific beam model was commissioned to accurately model the small MLRT fields. Film measurements were performed to assess the accuracy of MLRT plans calculations. Plans for seven treatment sites in different parts of the body for retrospective patient candidates were created with varying numbers of mini‐lattices and separation distances to assess the impact of varying these parameters on treatment dose metrics. MLRT was used for the first time to treat a patient with two fractions of MLRT. Results The AcurosXB calculation algorithm with modified x and y spot sizes, dosimetric leaf gap, transmission factor, and output factor table was used to generate a beam model for accurate MLRT calculations. The MLRT‐specific beam model resulted in gamma passing rates (1%/0.5 mm criteria) of 90%–99% for retrospective patient MLRT film measurements. Dose volume histogram statistics, equivalent uniform dose, and mean dose showed a higher number of mini‐lattices with smaller separation increased the dose to the GTV and surrounding tissue. Separation distances between mini‐lattices did not impact plan heterogeneity as measured by D10%/D90%. The first patient treated with the MLRT technique reported pain relief, had stable disease, and no acute toxicities following both fractions. Conclusions MLRT is feasible using clinical linear accelerators and existing radiation oncology infrastructure. It enables targeting smaller tumors with SFRT, allows for a greater number of high dose regions within the target compared to standard VMAT lattice techniques, and may be a useful technique for challenging treatment scenarios.

ABSTRACTIntroductionProton beam therapy (PT) offers a targeted approach to treating pediatric tumors by minimizing radiation exposure to surrounding healthy tissue. However, the specific toxicity profile associated with it remains underexplored. This study aims to investigate the incidence and risk factors of acute and late treatment‐related toxicities following PT in pediatric patients with pelvic tumors.MethodsUsing data from the Pediatric Proton Consortium Registry (PPCR), we analyzed 126 pediatric patients who underwent PT for pelvic tumors. We assessed the incidence of gastrointestinal (GI), genitourinary (GU), and musculoskeletal (MSK) toxicities at baseline, during treatment, and across follow‐up intervals.ResultsAcute toxicities were observed in 61.9% of patients posttreatment, with new GI, GU, and MSK toxicities occurring in 54.3%, 9.7%, and 7.0% of baseline toxicity‐free patients, respectively. Follow‐up indicated that 20.6%, 22.2%, and 13.5% of patients developed late GI, GU, and MSK toxicities, respectively. Use of passive scattering proton therapy and radiation to the abdomen were significant predictors of GI toxicity development, while higher radiation dose was associated with MSK toxicity development.ConclusionOur findings demonstrate the safety profile of PT among pediatric patients while identifying specific risk factors, such as passive scattering proton therapy and abdominal irradiation, that contribute to increased GI toxicity. While proton therapy appears to be a well‐tolerated treatment option, the observed toxicity rates highlight the need for continued monitoring and long‐term follow‐up.

Abstract Background Dasatinib is an oral inhibitor of the Src kinase family, with preclinical data indicating impact on gliomagenesis, tumor invasion, and radiosensitivity. Methods North Central Cancer Treatment Group N0877 is a phase 1 dose escalation and phase II randomized study evaluating the maximum tolerated dose (MTD), safety, and efficacy of dasatinib with radiation and temozolomide (TMZ) for glioblastoma. Following identification of the MTD, adult patients with a histologic diagnosis of glioblastoma were randomized 2:1 between dasatinib given with standard concurrent and adjuvant TMZ, versus placebo with standard concurrent and adjuvant TMZ. Radiation dose was 60 Gy in 30 fractions. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), toxicity, and quality of life. Results Thirteen patients were enrolled in the phase I component and established the MTD and phase II dose of 150 mg given daily. A total of 204 patients were enrolled in the phase II component. OS was not different between arms (median OS 15.6 months for dasatinib compared to 19.3 months for placebo, hazard ratio:1.21 favoring placebo, 95% CI: 0.88–1.65, log-rank P-value: .238). Similarly, PFS was not significantly different between the dasatinib and placebo arms. There was a significant increase in anemia, nausea, and creatinine elevation with dasatinib, but significantly more grade 3 lymphopenia with placebo. Conclusions The addition of dasatinib to standard chemoradiation did not improve outcomes for patients with glioblastoma. Clinical Trial Identifier NCT00869401.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) is increasingly used as a primary treatment modality for intracranial meningiomas. We aim to describe clinical outcomes after single-fraction SRS for sporadic intracranial meningiomas. METHODS: A prospectively maintained database was reviewed for patients with sporadic meningiomas who underwent SRS (Gamma Knife) as primary treatment modality from April 1997 to February 2022. Primary outcomes included progression-free survival (PFS) and treatment-related complications. RESULTS: Six hundred sixteen patients (653 tumors) underwent SRS with median follow-up of 6.3 years (interquartile range [IQR] 3.1-10.5 years). The median tumor volume was 4.5 cm 3 (IQR 2.0-8.0 cm 3 ). The median margin dose was 15.0 Gy (IQR 14.0-16.0). In-field progression was noted in 7 tumors (1.1%) and marginal progression in 2 tumors (0.3%) for a raw failure rate of 1.4%. PFS estimates at 5, 10, and 15 years were 99.8%, 99.0%, and 93.2%, respectively. Factors associated with reduced PFS on univariable analysis included older age (hazards ratio [HR] 1.14, 95% CI, 1.05-1.22, P < .001), male sex (HR 5.44, 95% CI, 1.45-20.4, P = .010), increasing tumor volume (HR 1.06, 95% CI, 0.99-1.13, P = .028), and lower tumor margin dose (HR 0.65, 95% CI, 0.43-0.97, P = .006). Treatment-related complications were noted in 56 patients (9.1%), of which 45 (7.3%) were temporary, 5 (0.8%) were minor, and 6 (1.0%) were permanent and/or required intervention. Radiosurgical parameters associated with treatment-related complications included increased number of isocenters (odds ratio [OR] 1.09, 95% CI, 1.04-1.14, P < .001), higher 12-Gy volume (OR 1.06, 95% CI, 1.03-1.09, P < .001), larger tumor volume (OR 1.06, 95% CI, 1.02-1.10, P < .001), and lower maximal dose (OR 0.90, 95% CI, 0.82-0.98, P = .11). CONCLUSION: SRS is effective as a primary treatment modality for sporadic, small-volume to medium-volume intracranial meningiomas. Pre-emptive SRS should be discussed as a safe management strategy compared with observation alone for incidentally discovered meningiomas.

AbstractPatients with resectable Ewing sarcoma (ES) in select sites, such as the pelvis or chest wall, have a higher risk of positive microscopic margins following surgery. AEWS1031 was the first North American/Australasia ES cooperative group trial allowing standardized preoperative radiotherapy, intended to minimize the morbidity of combined modality local tumor control as well as improve the likelihood of clear surgical margins. In this study, we found that the use of low‐dose preoperative radiation to a smaller target volume resulted in a high rate of R0 resection. The robust pathologic response rate strengthens existing evidence illustrating the radiosensitivity of Ewing sarcoma.

ABSTRACT Purpose Pulmonary toxicity (PT) remains a concern following total body irradiation (TBI). This study describes the incidence and factors associated with PT in a cohort of patients homogeneously treated with the lateral opposed fields technique. Methods Medical records of 61 patients ≤21 years of age treated with TBI as a component of stem cell transplantation from 1993–2017 were retrospectively reviewed. The incidences of PT, graft‐versus‐host disease (GVHD), and other toxicities were recorded for each patient. PT was subdivided into its etiologies, and symptomatic PT was established by clinical diagnosis. The association of PT with other variables was examined using chi‐square tests, and overall survival (OS) was estimated using Kaplan–Meier. Results Three‐year OS was 65% (54%–79%). Median TBI dose rate was 7.7 cGy/min (4.0–10 cGy/min). PT occurred in 20 patients (33%). A higher rate of PT was observed in patients with GVHD (65% vs. 35%, p ≤ 0.01). TBI dose rate (</≥ 7.7 cGy/min) was not associated with the risk of PT; however, on continuous analysis, a higher dose rate increased the risk of PT (HR = 1.9, p = 0.04). PT (HR = 3.4, p = 0.01), noninfectious PT (HR = 5.0, p ≤ 0.01), and pneumonitis (HR = 4.3, p = 0.01) were associated with inferior OS. Conclusions This cohort of patients treated with a low dose rate, bilateral technique, and total dose of 1000–1320 cGy experienced an acceptable incidence of PT, comparable to other published studies. Because PT correlated with reduced survival, current practice should seek to address factors associated with PT by aiming to prevent GVHD and by choosing low dose rates, such as in the range of 4.0–10 cGy/min.

Abstract Purpose: Embryonal tumor with multilayered rosettes (ETMR) is a rare pediatric CNS embryonal tumor with poor survival. The Pediatric Proton/Photon Consortium Registry (PPCR) was queried for outcomes data from prospectively consenting pediatric patients with ETMR treated with proton radiation therapy (RT). Methods: 20 patients (2013-2021) at 9 institutions had ETMR; 2 with prior RT were excluded from statistical analyses (PPCR ETMR, N=18). Overall Survival (OS) and Event Free Survival (EFS) analyses were performed using the Kaplan-Meier method and log-rank values. Median follow-up was calculated using the reverse Kaplan-Meier method. Results: Median age at RT was 3.0 years (1.7-12.2); median follow-up was 55.5 months (2.6-119.4). 8 patients (44%) expired and 6 patients (33%) are surviving ≥55 months. 11 (61%) patients received systemic therapy with stem cell support. The majority (89%) had focal RT, while 2 patients received craniospinal irradiation (CSI). 4-year OS and EFS were 59.6% and 54.2%, respectively. Local control (LC) at 4 years was 81%. No differences in OS or EFS were observed for receipt of systemic therapy with stem cell support (p=0.361, p=0.57), progression prior to RT (p=0.127, p=0.18), or surgery to RT ≥200 days (p=0.35, p=0.254). Symptomatic radionecrosis was not reported. Conclusion: Focal proton RT provided effective local control as part of multimodality therapy for ETMR, with encouraging survival for this rare and often infant age tumor. Outcomes for CSI were limited to 2 patients treated upfront, and 1 patient receiving salvage CSI for disseminated relapse after focal RT who is surviving >1 year. Trial: DFCI protocol 12-103, clinicaltrials.gov NCT01696721, date of registration 9/27/2012