BACKGROUND: Proton therapy may reduce cognitive deficits after radiotherapy among brain tumor survivors, although current data are limited to retrospective comparisons between historical cohorts. The authors compared intelligence quotient scores within a case-matched cohort of children with medulloblastoma treated with proton radiation (PRT) or photon radiation (XRT) over the same time period. METHODS: Among 88 consecutive patients with standard-risk medulloblastoma treated with PRT or XRT at 2 institutions from 2000 to 2009, 50 were matched 1:1 (25 with PRT and 25 with XRT) according to age, gender, date of diagnosis, histology, radiation boost, and craniospinal irradiation dose. One-way analyses of variance were performed to compare the Full-Scale Intelligence Quotient (FSIQ) and associated index scores between the 2 cohorts. RESULTS: Neurocognitive data were available for 37 survivors (17 with PRT and 20 with XRT) from the matched cohort. The mean age was 8.5 years (SD, 4.14 years). The median follow-up was 5.3 years (range, 1.0-11.4 years) and 4.6 years (range, 1.1-11.2 years) for the PRT and XRT cohorts, respectively (P =.193). Patients treated with PRT had significantly higher mean FSIQ (99.6 vs 86.2; P =.021), verbal (105.2 vs 88.6; P =.010), and nonverbal scores (103.1 vs 88.9; P =.011) than the XRT-treated cohort. Differences in processing speed (82.9 vs 77.2; P =.331) and working memory (97.0 vs 92.7; P =.388) were not statistically significant. CONCLUSIONS: Radiotherapy-associated cognitive effects appear to be more attenuated after proton therapy. Comprehensive prospective studies are needed to appropriately evaluate the neurocognitive advantages of proton therapy.

Introduction  Atypical meningiomas (AM) are meningiomas that are more aggressive than their grade-I counterparts and have a higher rate of recurrence. The effect of adjuvant radiotherapy (ART) on AM of the skull base is not defined. Methods  A retrospective review of all AM's of the skull base primarily resected at our institution from 1996 to 2018 was completed. ART was defined as radiotherapy (RT) that occurred within 6 months of initial resection, regardless of Simpson's grade. Minimum time length of follow-up after resection was 2 years. Statistical analysis was performed using SAS. Results  There were a total of 59 skull base-located (SBL) AMs resected at our institution from 1996 to 2018. The average age of our cohort was 53.2 years. Gross total resection, defined as Simpson's grades I to III resection, was achieved in 36 (61%) of cases. Thirty-five of 59 (59%) patients received ART. Recurrence was observed in 14 patients (24%), and mean time to recurrence was 63.8 months. Patients who received ART had a lower observed rate of recurrence (8 vs. 46%); however, time to recurrence was not significantly different between the two populations. Conclusion  We observe that AM in the skull base location have higher recurrence rates than we would expect from grade-I meningioma. These data suggest that ART may offer benefit to the overall observed frequency of recurrence of SBL AM; however, the time to recurrence between patients who received ART and those who did not was not statistically significant in survival analysis.

Purpose: Proton vertebral body sparing craniospinal irradiation (CSI) treats the thecal sac while avoiding the anterior vertebral bodies in an effort to reduce myelosuppression and growth inhibition. However, robust treatment planning needs to compensate for proton range uncertainty, which contributes unwanted doses within the vertebral bodies. This work aimed to develop an early in vivo radiation damage quantification method using longitudinal magnetic resonance (MR) scans to quantify the dose effect during fractionated CSI. Methods and Materials: Ten pediatric patients were enrolled in a prospective clinical trial of proton vertebral body sparing CSI, in which they received 23.4 to 36 Gy. Monte Carlo robust planning was used, with spinal clinical target volumes defined as the thecal sac and neural foramina. T1/T2-weighted MR scans were acquired before, during, and after treatments to detect a transition from hematopoietic to less metabolically active fatty marrow. MR signal intensity histograms at each time point were analyzed and fitted by multi-Gaussian models to quantify radiation damage. Results: Fatty marrow filtration was observed in MR images as early as the fifth fraction of treatment. Maximum radiation-induced marrow damage occurred 40 to 50 days from the treatment start, followed by marrow regeneration. The mean damage ratios were 0.23, 0.41, 0.59, and 0.54, corresponding to 10, 20, 40, and 60 days from the treatment start. Conclusions: We demonstrated a noninvasive method for identifying early vertebral marrow damage based on radiation-induced fatty marrow replacement. The proposed method can be potentially used to quantify the quality of CSI vertebral sparing and preserve metabolically active hematopoietic bone marrow.

Locally advanced cholangiocarcinoma has a poor prognosis, with long-term survival only for patients where complete surgical resection is achieved. Median overall survival with chemotherapy alone is less than 1 year. Novel strategies combining conventional chemotherapy and radiotherapy followed by targeted agents can lead to durable treatment responses and are applicable to cholangiocarcinoma management. Pediatric cholangiocarcinoma is exceedingly rare, with an estimate of 15-22 cases reported in the last 40 years. As such, no standard therapeutic regimen exists. We present a case of a 16-year-old previously healthy patient with unresectable cholangiocarcinoma whose tumor genetic sequencing revealed a novel, actionable neuregulin-1 (NRG1) gene translocation. The patient underwent standard systemic chemotherapy with gemcitabine and cisplatin followed by hypofractionated proton radiation therapy for local control. The patient then started an oral pan-ERBB (erythroblastic B receptor tyrosine kinases including ErbB1/EGFR, ErbB2/HER2, ErbB3/HER3, ErbB4/HER4) family inhibitor as a maintenance medication, remaining with stable disease and excellent quality of life for over 2 years. This case highlights a novel NRG1 fusion in a rare clinical entity that provided an opportunity to utilize a multimodal therapeutic strategy in the pediatric setting.

Background: Adjuvant radiotherapy (RT) can help achieve local control (LC) and reduce hormonal overexpression for pituitary adenomas (PAs). Prior reports involved Gamma Knife or older linear accelerator (LINAC) techniques. The aim of this study was to report long-term outcomes for modern LINAC RT. Methods: Institutional retrospective review of LINAC RT for PAs with minimum 3 years of magnetic resonance imaging follow-up was performed. Hormonal control was defined as biochemical remission in absence of medications targeting hormone excess. LC defined using Response Evaluation Criteria in Solid Tumors on surveillance magnetic resonance imaging. Progression-free survival defined as time alive with LC without return of or worsening hormonal excess from secretory PA. Kaplan-Meier and Cox proportional hazard models used. Results: From 2003 to 2017, 140 patients with PAs (94 nonsecretory, 46 secretory) were treated with LINAC RT (105 fractionated RT, 35 radiosurgery) with median follow-up of 5.35 years. Techniques included fixed gantry intensity-modulated radiotherapy (51.4%), dynamic conformal arcs (9.3%), and volumetric modulated arc therapy (39.3%). Progression-free survival at 5 years was 95.3% for secretory tumors and 94.8% for nonsecretory tumors. Worse progression-free survival was associated with larger planning target volume on multivariable analysis (hazard ratio 2.87, 95% confidence interval 1.01–8.21, P = 0.049). Hormonal control at 5 years was 50.0% and associated with higher dose to tumor (hazard ratio 1.05, 95% confidence interval 1.02–1.09, P = 0.005) and number of surgeries (hazard ratio 1.74, 95% confidence interval 1.05–2.89, P = 0.032). Patients requiring any pituitary hormone replacement increased from 57.9% to 70.0% after RT. Conclusions: Modern LINAC RT for patients with PAs was safe and effective for hormonal control and LC. No difference in LC was noted for functional versus nonfunctional tumors, possibly owing to higher total dose and daily image guidance.

Radiation therapy (RT) is a critical part of definitive therapy for pediatric high-grade glioma (pHGG). RT is designed to treat residual tumor defined on conventional MRI (cMRI), though pHGG lesions may be ill-characterized on standard imaging. Spectroscopic MRI (sMRI) measures endogenous metabolite concentrations in the brain, and Choline (Cho)/N-acetylaspartate (NAA) ratio is a highly sensitive biomarker for metabolically active tumor. We provide a preliminary report of our study introducing a novel treatment approach of whole brain sMRI-guided proton therapy for pHGG. An observational cohort (c1 = 10 patients) receives standard of care RT; a therapeutic cohort (c2 = 15 patients) receives sMRI-guided proton RT. All patients undergo cMRI and sMRI, a high-resolution 3D whole-brain echo-planar spectroscopic imaging (EPSI) sequence (interpolated resolution of 12 µL) prior to RT and at several follow-up timepoints integrated into diagnostic scans. Treatment volumes are defined by cMRI for c1 and by cMRI and Cho/NAA ≥ 2x for c2. A longitudinal imaging database is used to quantify changes in lesion and metabolite volumes. Four subjects have been enrolled (c1 = 1/c2 = 3) with sMRI imaging follow-up of 4–18 months. Preliminary data suggest sMRI improves identification of pHGG infiltration based on abnormal metabolic activity, and using proton therapy to target sMRI-defined high-risk regions is safe and feasible.

OBJECTIVE: Here, we report musculoskeletal outcomes and the impact of radiotherapy dose on vertebral body growth for an institutional series of long-term survivors of high-risk neuroblastoma. METHODS: We conducted a retrospective study of 23 patients who were disease-free and at least 36 months from the end of treatment. The patients were initially treated from July 2003 to May 2012. Patient records were reviewed for growth percentiles (obtained at approximately 6-month intervals from onset of treatment to the last follow-up) and musculoskeletal comorbidities. RT plans and most recent surveillance CT scans were reviewed for locations of in-field vertebral bodies and corresponding vertebral growth patterns. RESULTS: The median follow-up was 7.93 years. The median prescribed radiation dose was 21.6 Gy. Musculoskeletal abnormalities included scoliosis (5 patients), muscular hypoplasia (3), and hypodontia (1). The median growth percentile at treatment onset was 35.5 (range, 4.7-100) versus 10 (0-94.1) at the last follow-up. The median numbers of vertebral bodies encompassed (by at least half of their volume) by the 5-, 10-, 15-, and 20-Gy isodose lines were 7 (mean, 6.78), 7 (6.56), 6 (6.17), and 6 (5.52), respectively. Sixteen patients (70.0%) had in-field abnormalities in vertebral body growth, manifesting as stretches of successive vertebral bodies at the same height, while normally there is a gradual vertebral body height increase progressing caudally down the spinal column. CONCLUSIONS: Musculoskeletal abnormalities, below average height, and stunted in-field vertebral body growth are routine in long-term survivors of high-risk neuroblastoma. Sparing vertebral bodies when feasible may lead to improvement in patient growth trajectories.

Background and purpose: Limited data exist detailing the role of salvage reirradiation following local-regional recurrence (LR) in previously irradiated pediatric patients with rhabdomyosarcoma (RMS). Materials and methods: We evaluated outcomes and prognostic factors in a multi-institutional cohort of 23 patients with LR-only (N = 19) or LR with distant failure (N = 4) RMS managed with (N = 12) or without (N = 11) re-irradiation who were treated from 1996 to 2012. Results: At a median follow-up of 4.6 years from LR, 7 (30%) patients were alive and 5 (22%) had no evidence of disease. Median OS and PFS from LR were 19.3 and 16.9 months, respectively. LFFS and DFFS at 3 years from relapse were 54% and 56%, respectively. Salvage re-irradiation occurred in 12 (52%) patients, with 9 (75%) receiving resection before re-irradiation. Patients classified as low-risk at diagnosis with favorable primary tumor location had improved 3-year PFS 80% (95% CI 51.6–100%) vs. 47.1% (95% CI 27.3–81.2%), p = 0.066], and OS 80% [(95% CI 22.4–100%) vs. 47.1% (95% CI 27.3–81.3%), p = 0.051] following LR. Median LFFS and OS in unirradiated vs. re-irradiated patients was 12.4 vs. 19.6 (p = 0.1) and 18.8 vs. 26.1 months (p = 0.46). No patients experienced ≥grade 4 acute toxicity from re-irradiation. LR failure was a component of cancer-related death in 60% vs. 40% of the unirradiated and re-irradiated group (p = 0.02). Conclusion: Salvage re-irradiation appears tolerable with acceptable morbidity and may reduce the risk of subsequent LR as a component of death in patients with LR RMS.

Background: Glioblastomas (GBMs) are aggressive brain tumors despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Spectroscopic magnetic resonance imaging (sMRI), which measures levels of specific brain metabolites, can delineate regions at high risk for GBM recurrence not visualized on contrast-enhanced (CE) MRI. We conducted a clinical trial to assess the feasibility, safety, and efficacy of sMRI-guided RT dose escalation to 75 Gy for newly diagnosed GBMs. Methods: Our pilot trial (NCT03137888) enrolled patients at 3 institutions (Emory University, University of Miami, Johns Hopkins University) from September 2017 to June 2019. For RT, standard tumor volumes based on T2-FLAIR and T1w-CE MRIs with margins were treated in 30 fractions to 50.1 and 60 Gy, respectively. An additional high-risk volume based on residual CE tumor and Cho/NAA (on sMRI) ≥2× normal was treated to 75 Gy. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. Results: Thirty patients were treated in the study. The median age was 59 years. 30% were MGMT promoter hypermethylated; 7% harbored IDH1 mutation. With a median follow-up of 21.4 months for censored patients, median overall survival (OS) and progression-free survival were 23.0 and 16.6 months, respectively. This regimen appeared well-tolerated with 70% of grade 3 or greater toxicity ascribed to TMZ and 23% occurring at least 1 year after RT. Conclusion: Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for patients with newly diagnosed GBMs. OS outcome is promising and warrants additional testing. Based on these results, a randomized phase II trial is in development.

Purpose: Quality assurance computed tomography (QACT) is the current clinical practice in proton therapy to evaluate the needs for replan. QACT could falsely indicate replan because of setup issues that would be solved on the treatment machine. Deforming the treatment planning CT (TPCT) to the pretreatment CBCT may eliminate this issue. We investigated the performance of replan evaluation based on deformed TPCT (TPCTdir) for proton head and neck (H&N) therapy. Methods and materials: Twenty-eight H&N datasets along with pretreatment CBCT and QACT were used to validate the method. The changes in body volume were analyzed between the no-replan and replan groups. The dose on the TPCTdir, the deformed QACT (QACTdir), and the QACT were calculated by applying the clinical plans to these image sets. Dosimetric parameters’ changes, including ΔD95, ΔDmean, and ΔD1 for the clinical target volumes (CTVs) were calculated. Receiver operating characteristic curves for replan evaluation based on ΔD95 on QACT and TPCTdir were calculated, using ΔD95 on QACTdir as the reference. A threshold for replan based on ΔD95 on TPCTdir is proposed. The specificities for the proposed method were calculated. Results: The changes in the body contour were 95.8 ± 83.8 cc versus 305.0 ± 235.0 cc (p < 0.01) for the no-replan and replan groups, respectively. The ΔD95, ΔDmean, and ΔD1 are all comparable for all the evaluations. The differences between TPCTdir and QACTdir evaluations were 0.30% ± 0.86%, 0.00 ± 0.22 Gy, and −0.17 ± 0.61 Gy for CTV ΔD95, ΔDmean, and ΔD1, respectively. The corresponding differences between the QACT and QACTdir were 0.12% ± 1.1%, 0.02 ± 0.32 Gy, and −0.01 ± 0.71 Gy. CTV ΔD95 > 2.6% in TPCTdir was chosen as the threshold to trigger QACT/replan. The corresponding specificity was 94% and 98% for the clinical practice and the proposed method, respectively. Conclusions: The replan evaluation based on TPCTdir provides better specificity than that based on the QACT.