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Background: Although the FLASH radiotherapy (FLASH) can improve the sparing of organs-at-risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose coverage and the biological FLASH coverage, for which the concept of FLASH effective dose (FED) is needed to quantify the net improvement of FLASH, compared to the conventional radiotherapy (CONV)., Purpose: This work will develop the first-of-its-kind treatment planning method called simultaneous dose and dose rate optimization via dose modifying factor modeling (SDDRO-DMF) for proton FLASH that directly optimizes FED., Methods: SDDRO-DMF models and optimizes FED using FLASH dose modifying factor (DMF) models, which can be classified into two categories: (1) the phenomenological model of the FLASH effect, such as the FLASH effectiveness model (FEM); (2) the mechanistic model of the FLASH radiobiology, such as the radiolytic oxygen depletion (ROD) model. The general framework of SDDRO-DMF will be developed, with specific DMF models using FEM and ROD, as a demonstration of general applicability of SDDRO-DMF for proton FLASH via transmission beams (TB) or Bragg peaks (BP) with single-field or multi-field irradiation. The FLASH dose rate is modeled as pencil beam scanning dose rate. The solution algorithm for solving the inverse optimization problem of SDDRO-DMF is based on iterative convex relaxation method., Results: SDDRO-DMF is validated in comparison with IMPT and a state-of-the-art method called SDDRO, with demonstrated efficacy and improvement for reducing the high dose and the high-dose volume for OAR in terms of FED. For example, in a SBRT lung case of the dose-limiting factor that the max dose of brachial plexus should be no more than 26 Gy, only SDDRO-DMF met this max dose constraint; moreover, SDDRO-DMF completely eliminated the high-dose (V70%) volume to zero for CTV10mm (a high-dose region as a 10 mm ring expansion of CTV)., Conclusion: We have proposed a new proton FLASH optimization method called SDDRO-DMF that directly optimizes FED using phenomenological or mechanistic models of DMF, and have demonstrated the efficacy of SDDO-DMF in reducing the high-dose volume or/and the high-dose value for OAR, compared to IMPT and a state-of-the-art method SDDRO., (© 2024 American Association of Physicists in Medicine.)

Background: In treatment planning, beam angle optimization (BAO) refers to the selection of a subset with a given number of beam angles from all available angles that provides the best plan quality. BAO is a NP-hard combinatorial problem. Although exhaustive search (ES) can exactly solve BAO by exploring all possible combinations, ES is very time-consuming and practically infeasible., Purpose: To the best of our knowledge, (1) no optimization method has been demonstrated that can provide the exact solution to BAO, and (2) no study has validated an optimization method for solving BAO by benchmarking with the optimal BAO solution (e.g., via ES), both of which will be addressed by this work., Methods: This work considers BAO for proton therapy, for example, the selection of 2-4 beam angles for IMPT. The optimal BAO solution is obtained via ES and serves as the ground truth. A new BAO algorithm, namely angle generation (AG) method, is proposed, and demonstrated to provide nearly-exact solutions for BAO in reference to the ES solution. AG iteratively optimizes the angular set via group-sparsity (GS) regularization, until the planning objective does not decrease further., Results: Since GS alone can also solve BAO, AG was validated and compared with GS for 2-angle brain, 3-angle lung, and 4-angle brain cases, in reference to the optimal BAO solutions obtained by ES: the AG solution had the rank (1/276, 1/2024, 4/10 626), while the GS solution had the rank (42/276, 279/2024, 4328/10 626)., Conclusions: A new BAO algorithm called AG is proposed and shown to provide substantially improved accuracy for BAO from current methods with nearly-exact solutions to BAO, in reference to the ground truth of optimal BAO solution via ES., (© 2023 American Association of Physicists in Medicine.)

Purpose: Compared to CONV-RT (with conventional dose rate), FLASH-RT (with ultra-high dose rate) can provide biological dose sparing for organs-at-risk (OARs) via the so-called FLASH effect, in addition to physical dose sparing. However, the FLASH effect only occurs, when both dose and dose rate meet certain minimum thresholds. This work will develop a simultaneous dose and dose rate optimization (SDDRO) method accounting for both FLASH dose and dose rate constraints during treatment planning for pencil-beam-scanning proton therapy., Methods: SDDRO optimizes the FLASH effect (specific to FLASH-RT) as well as the dose distribution (similar to CONV-RT). The nonlinear dose rate constraint is linearized, and the reformulated optimization problem is efficiently solved via iterative convex relaxation powered by alternating direction method of multipliers. To resolve and quantify the generic tradeoff of FLASH-RT between FLASH and dose optimization, we propose the use of FLASH effective dose based on dose modifying factor (DMF) owing to the FLASH effect., Results: FLASH-RT via transmission beams (TB) (IMPT-TB or SDDRO) and CONV-RT via Bragg peaks (BP) (IMPT-BP) were evaluated for clinical prostate, lung, head-and-neck (HN), and brain cases. Despite the use of TB, which is generally suboptimal to BP for normal tissue sparing, FLASH-RT via SDDRO considerably reduced FLASH effective dose for high-dose OAR adjacent to the target. For example, in the lung SBRT case, the max esophageal dose constraint 27 Gy was only met by SDDRO (24.8 Gy), compared to IMPT-BP (35.3 Gy) or IMPT-TB (36.6 Gy); in the brain SRS case, the brain constraint V12Gy≤15cc was also only met by SDDRO (13.7cc), compared to IMPT-BP (43.9cc) or IMPT-TB (18.4cc). In addition, SDDRO substantially improved the FLASH coverage from IMPT-TB, e.g., an increase from 37.2% to 67.1% for lung, from 39.1% to 58.3% for prostate, from 65.4% to 82.1% for HN, from 50.8% to 73.3% for the brain., Conclusions: Both FLASH dose and dose rate constraints are incorporated into SDDRO for FLASH-RT that jointly optimizes the FLASH effect and physical dose distribution. FLASH effective dose via FLASH DMF is introduced to reconcile the tradeoff between physical dose sparing and FLASH sparing, and quantify the net effective gain from CONV-RT to FLASH-RT., (© 2021 American Association of Physicists in Medicine.)

Pencil beam scanning proton radiotherapy (RT) offers flexible proton spot placement near treatment targets for delivering tumoricidal radiation dose to tumor targets while sparing organs-at-risk. Currently the spot placement is mostly based on a non-adaptive sampling (NS) strategy on a Cartesian grid. However, the spot density or spacing during NS is a constant for the Cartesian grid that is independent of the geometry of tumor targets, and thus can be suboptimal in terms of plan quality (e.g. target dose conformality) and delivery efficiency (e.g. number of spots). This work develops an adaptive sampling (AS) spot placement method on the Cartesian grid that fully accounts for the geometry of tumor targets. Compared with NS, AS places (1) a relatively fine grid of spots at the boundary of tumor targets to account for the geometry of tumor targets and treatment uncertainties (setup and range uncertainty) for improving dose conformality, and (2) a relatively coarse grid of spots in the interior of tumor targets to reduce the number of spots for improving delivery efficiency and robustness to the minimum-minitor-unit (MMU) constraint. The results demonstrate that (1) AS achieved comparable plan quality with NS for regular MMU and substantially improved plan quality from NS for large MMU, using merely about 10% of spots from NS, where AS was derived from the same Cartesian grid as NS; (2) on the other hand, with similar number of spots, AS had better plan quality than NS consistently for regular and large MMU., (© 2021 Institute of Physics and Engineering in Medicine.)

Background: Children with chest wall Ewing sarcoma with malignant pulmonary effusion or pleural stranding require hemithorax radiation, often with plans that exceed lung constraints. We investigated disease control and pneumonitis in children requiring hemithorax radiation., Procedure: Eleven children (median age 13 years) received hemithorax radiotherapy. Symptomatic radiation pneumonitis was considered National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 1+ with respiratory symptoms. Mean lung dose (MLD), volume of lung exposed to a dose ≥5 Gy (V5), ≥20 Gy (V20), and ≥35 Gy (V35) were recorded. Adult and pediatric lung constraints were obtained from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines and Children's Oncology Group (COG) protocols, respectively., Results: Median hemithorax dose was 15 Gy (1.5 Gy/fraction). Median total dose was 51 Gy (1.8 Gy/fraction). Most plans delivered both protons and photons. The ipsilateral MLD, V5, and V20 were 27.2 Gy, 100%, and 48.3%; the bilateral MLD, V20, and V35 were 14.1 Gy, 22.8%, and 14.3%, respectively. One hundred percent, 36%, and 91% of treatments exceeded recommended adult ipsilateral lung constraints of V5 <65%, V20 <52%, and MLD of 22 Gy; 64%, 45%, and 82% exceeded COG bilateral lung constraints of V20 <20%, MLD <15 Gy, and MLD <12 Gy, respectively; 82% of treatments exceeded the COG ipsilateral lung constraint of V20 <30%. At a median 36 months (range 12-129), the symptomatic radiation pneumonitis incidence was 0%. Two patients progressed with nonpulmonary metastatic disease and died at a median 12 months following radiotherapy., Conclusions: Existing guidelines may overestimate pneumonitis risk, even among young children receiving multiagent chemotherapy. For children with chest wall Ewing sarcoma and other thoracic malignancies, more data are needed to refine pediatric dose-effect models for pulmonary toxicity., (© 2021 Wiley Periodicals LLC.)

Background & Purpose: In infants with rhabdomyosarcoma, young age is considered an adverse prognostic factor and treatment is often attenuated to reduce side effects. Proton therapy may improve the therapeutic ratio in these patients. We report outcomes in infants with rhabdomyosarcoma treated with proton therapy., Materials & Methods: Between 2009 and 2019, 37 infants <24 months old with non-metastatic rhabdomyosarcoma received proton therapy. Local control (LC), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier product limit. The log-rank test assessed significance between selected prognostic factors. Toxicity was graded per CTCAEv5.0., Results: Median follow-up was 5.1 years. Overall, 76% of patients had an unfavorable primary site. Median dose was 50.4GyRBE. At 5 years, LC, PFS, and OS rates were 83%, 78%, and 83%. On univariate analysis, 5-year LC and OS were inferior for favorable versus unfavorable disease sites (67% vs 89%, 67% vs 89%, respectively; p < .05) and 5-year OS was superior in stage 3 versus stage 1-2 disease (91% vs 69%; p = .05), owing to inclusion of nasal ala patients among stage 1. Of 9 recurrences, 7 were in-field, 4 occurring in infants with nasal ala primaries. Recategorizing nasal ala as an unfavorable site resulted in 100% 5-year LC and OS for favorable sites. Six infants experienced late grade 3 toxicity. None developed grade 4 or 5 late toxicity., Conclusions: Young age alone may not be an adverse prognostic factor provided infants receive local therapy similar to older children. Consideration should be given to classifying nasal ala primaries as an unfavorable site., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Out-of-field neutron dissemination during double-scattered proton therapy has raised concerns of increased second malignancies, disproportionally affecting pediatric patients due to the proportion of body exposed to scatter dose and inherent radiosensitivity of developing tissue. We sought to provide empiric data on the incidence of early second tumors., Methods: Between 2006 and 2019, 1713 consecutive children underwent double-scattered proton therapy. Median age at treatment was 9.1 years; 371 were ≤3 years old. Thirty-seven patients (2.2%) had tumor predisposition syndromes. Median prescription dose was 54 Gy (range 15-75.6). Median follow-up was 3.3 years (range 0.1-12.8), including 6587 total person-years. Five hundred forty-nine patients had ≥5 years of follow-up. A second tumor was defined as any solid neoplasm throughout the body., Results: Eleven patients developed second tumors; the 5- and 10-year cumulative incidences were 0.8% (95% CI, 0.4-1.9%) and 3.1% (95% CI, 1.5-6.2%), respectively. Using age- and gender-specific data from the Surveillance, Epidemiology, and End Results (SEER) program, the standardized incidence ratio was 13.5; the absolute excess risk was 1.5/1000 person-years. All but one patient who developed second tumors were irradiated at ≤5 years old (p < .0005). There was also a statistically significant correlation between patients with tumor predisposition syndromes and second tumors (p < .0001). Excluding patients with tumor predisposition syndromes, 5- and 10-year rates were 0.6% (95% CI, 0.2-1.7%) and 1.7% (95% CI, 0.7-4.0%), respectively, with all five malignant second tumors occurring in the high-dose region., Conclusion: Second tumors are rare within the decade following double-scattered proton therapy, particularly among children irradiated at >5 years old and those without tumor predisposition syndrome., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Purpose: We report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy., Methods: We reviewed 20 adults with medulloblastoma (≥ 22 years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed., Results: Median age at diagnosis was 27 years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44 days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively., Conclusions: Proton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To evaluate the effectiveness of external-beam proton therapy (PT) on local control and survival in patients with skull-base chordoma., Materials and Methods: We reviewed the medical records of patients with skull-base chordoma treated with definitive or adjuvant high-dose PT and updated their follow-up when feasible. We assessed overall survival, disease-specific survival, local control, and freedom from distant metastasis. Radiotherapy toxicities were scored using the Common Terminology Criteria for Adverse Events, version 4.0., Results: A total 112 patients were analyzed, of whom 105 (94%) received PT and 7 (6%) received combined proton-photon therapy between 2007 and 2019. Eighty-seven patients (78%) underwent a subtotal resection, 22 (20%) a gross total resection, and 3 (3%) a biopsy alone. The median radiotherapy dose was 73.8 Gy radiobiologic equivalent (GyRBE; range, 69.6-74.4). Ninety patients (80%) had gross disease at radiotherapy and 7 (6%) were treated for locally recurrent disease following surgery. Median follow-up was 4.4 years (range, 0.4-12.6); for living patients, it was 4.6 years (range, 0.4-12.6), and for deceased patients, 4.1 years (range, 1.2-11.2). At 5 years after radiotherapy, the actuarial overall survival, disease-specific survival, local control, and freedom from distant metastasis rates were 78% (n = 87), 83% (n = 93), 74% (n = 83), and 99% (n = 111), respectively. The median time to local progression was 2.4 years (range, 0.8-7). Local control and disease-specific survival by resection status was 95% versus 70% ( P  = 0.28) and 100% versus 80% ( P  = 0.06) for gross total, versus subtotal, resection or biopsy alone, respectively. There were no serious acute toxicities (grade ≥ 3) related to radiotherapy., Conclusion: High-dose PT alone or after surgical resection for skull-base chordoma reaffirms the favorable 5-year actuarial local control rate compared with conventional techniques with acceptable late-complication-free survival. Outcomes following gross total resection and adjuvant PT were excellent. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities., Competing Interests: Conflicts of Interest: Adam L. Holtzman, MD, has received a speaking honorarium from the American Academy of Insurance Medicine and the American Council of Life Insurers. William M. Mendenhall, MD, is Operating Editor of the International Journal of Particle Therapy., (©Copyright 2021 The Author(s).)

Background & Purpose: Dose escalation for skull-based chordoma and chondrosarcoma can put critical adjacent structures at risk, specifically the anterior optic pathway. We report the incidence of vision loss following high-dose conformal proton-based radiotherapy., Materials and Methods: We reviewed patients with skull-base chordoma or chondrosarcoma treated with proton-based therapy between 2007 and 2018. We analyzed 148 patients and 283 individual eyes with functional vision at baseline who received a minimum 30GyRBE to 0.1 cm 3 of the anterior optic pathway. Eyes were classified as "functionally blind" if visual acuity was 20/200 or worse. Kaplan-Meier and normal tissue complication probability modeling were used to establish the relationship between radiation dose and risk of functional vision loss., Results: At last follow-up, 110 of 148 patients were alive with no evidence of disease progression. With a median follow-up of 4.1 years (range, 0.5-12.8), 5 eyes in 3 patients developed functional blindness, with 2 patients developing bilateral blindness. Median time to blindness was 15.2 months. The 5-year incidence of vision loss was 2.1% (95% CI: 0.9-4.9%). On univariate analysis, development of blindness was associated with presence of multiple medical comorbidities (p = 0.0040). While there were no events with a maximum dose < 60GyRBE delivered to the anterior optic pathway, the crude rate was 3.6% over 60GyRBE, with all events occurring between 60-65GyRBE., Conclusions: Despite the high radiotherapy dose delivered to patients with skull-base chordoma and chondrosarcoma, the rate of vision loss is low and no events occurred in those who received a maximum dose under 60GyRBE., Competing Interests: Declaration of Competing Interest ALH has received honorariums for educational events from the American Academy of Insurance Medicine and the American Council of Life Insurers unrelated to this research., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Due to the location and high dose required for disease control, pediatric chordomas are theoretically well-suited for treatment with proton therapy, but their low incidence limits the clinical outcome data available in the literature. We sought to report the efficacy and toxicity of proton therapy among a single-institution cohort., Methods and Materials: Between 2008 and 2019, 29 patients with a median age of 14.8 years (range, 3.8-21.8) received passive-scattered proton therapy for nonmetastatic chordoma. No patient received prior irradiation. Twenty-four tumors arose in the clivus/cervical spine region and 5 in the lumbosacral spine. Twenty-six tumors demonstrated classic well-differentiated histology and 3 were dedifferentiated or not otherwise specified. Approximately half of the tumors underwent specialized testing: 14 were brachyury-positive and 10 retained INI-1. Three patients had locally recurrent tumors after surgery alone (n = 2) or surgery + chemotherapy (n = 1), and 17 patients had gross disease at the time of radiation. The median radiation dose was 73.8 Gy relative biological effectivness (range, 69-75.6)., Results: With a median follow-up of 4.3 years (range, 1.0-10.7), the 5-year estimates of local control, progression-free survival, and overall survival rates were 85%, 82%, and 86%, respectively. No disease progression was observed beyond 3 years. Excluding 3 patients with dedifferentiated/not-otherwise-specified chordoma, the 5-year local control, progression-free survival, and overall survival rates were 92%, 92%, and 91%, respectively. Serious toxicities included 3 patients with hardware failure or related infection requiring revision surgery, 2 patients with hormone deficiency, and 2 patients with Eustachian tube dysfunction causing chronic otitis media. No patient experienced brain stem injury, myelopathy, vision loss, or hearing loss after radiation., Conclusions: In pediatric patients with chordoma, proton therapy is associated with a low risk of serious toxicity and high efficacy, particularly in well-differentiated tumors. Complete resection may be unnecessary for local control, and destabilizing operations requiring instrumentation may result in additional complications after therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Radiotherapy-related visual decline is a significant concern in survivors of childhood cancer; however, data establishing the dose-response relationship between dose to the optic apparatus and visual acuity decline in children are sparse. We aimed to determine this relationship in a cohort of children treated with proton therapy., Material and Methods: We identified 458 children with 875 eyes at risk treated with proton therapy for intracranial malignancy between December 2006 and September 2018. Eyes were considered at risk if either the ipsilateral optic nerve or optic chiasm received ≥30 GyRBE to 0.1 cm 3 . Kaplan-Meier and Normal Tissue Complication Probability modeling was used to establish the relationship between radiotherapy dose and risk of visual decline., Results: Excluding children with tumor progression, no patient experienced complete vision loss. The actuarial 5-year rate of any visual acuity decline was 2.6% (95% confidence interval [CI]: 1.5%-4.6%). The dose to 0.1 cm 3 of the ipsilateral optic nerve or optic chiasm resulting in a 1%, 5%, and 10% risk of acuity decline were 52.7 GyRBE, 56.6 GyRBE, and 58.3 GyRBE. Visual decline was only seen in children with primary tumors of the optic pathway or suprasellar region., Conclusions: Visual acuity decline following radiotherapy for intracranial malignancies in children is rare. A dose of approximately 56 GyRBE to 0.1 cm 3 results in an approximately 5% risk of visual acuity decline for children with suprasellar or optic pathway tumors. A dose to 0.1 cm 3 of 56 GyRBE appears to be safe for children with tumors elsewhere in the brain.

Purpose: Ewing sarcoma of the pelvis is associated with inferior local control compared with those arising from other primary sites. Despite its increased use, outcome data for treatment with proton therapy remain limited. We report 3-year disease control and toxicity in pediatric patients treated with proton therapy., Methods and Materials: Thirty-five patients aged ≤21 years (median, 14 years) with nonmetastatic pelvic Ewing sarcoma received proton therapy and chemotherapy between 2010 and 2018. Overall survival and tumor control rates were calculated using the Kaplan-Meier method. A log-rank test assessed significance between strata of prognostic factors. Significant toxicity was reported per the Common Terminology Criteria for Adverse Events, version 4.0., Results: Most patients received definitive radiation (n = 26; median dose 55.8 Gy relative biological effectiveness [RBE]; range, 54.0-64.8), 7 received preoperative radiation (50.4 Gy RBE), and 2 received postoperative radiation (45 Gy RBE and 54 Gy RBE). The median primary tumor size was 10.5 cm. With a median follow-up of 3 years (range, 0.3-9.0 years), the 3-year overall survival, progression-free survival, and local control rates were 83% (95% confidence interval [CI], 65%-93%), 64% (95% CI, 45%-79%), and 92% (95% CI, 74%-98%), respectively. There was no association between local control, progression-free survival, or overall survival and tumor size, patient age, radiation dose, or definitive versus pre-/postoperative radiation therapy. Median time to progression was 1 year (range, 0.1-1.9 years). All patients with large tumors (≥8 cm) who underwent definitive proton therapy with a higher dose (≥59.4 Gy RBE) remained free from tumor recurrence (n = 5). Five patients experienced grade ≥2 subacute/late toxicity, all of whom were treated with combined surgery and radiation., Conclusions: Definitive proton therapy offers local control comparable to photon therapy in pediatric patients with pelvic Ewing sarcoma. These data lend preliminary support to radiation dose escalation without significant toxicity, which may contribute to the favorable outcomes. Combined surgery and radiation therapy, particularly preoperative radiation, is associated with postoperative complications, but not survival, compared with radiation alone., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to report on the institutional outcomes after proton therapy for pelvic rhabdomyosarcoma (RMS)., Methods and Materials: Thirty-one children (≤21 years old) with group III pelvic RMS were enrolled on a prospective outcome study and treated between 2007 and 2018. Patients with vaginal/cervical RMS were excluded. The median age was 2.6 years. Twenty-four patients had embryonal RMS. At diagnosis, the median tumor volume was 185 cm 3 and the median maximum diameter was 9.4 cm. Seven patients had N1 disease. Nineteen and 12 patients received European Pediatric Soft Tissue Sarcoma Study Group- and Children's Oncology Group-based chemotherapy, respectively. Fourteen patients underwent resection of the primary tumor after induction chemotherapy, including 6 patients who had a total cystectomy. The median radiation dose was 50.4 Gy relative biological effectiveness., Results: With a median follow-up of 4.2 years, the 5-year local control, progression-free survival, and overall survival rates were 83%, 80%, and 84%, respectively. Patients <3 years old had better local control (100% vs 68%; P = .02), and patients with embryonal histology had better survival (96% vs 54%; P = .02). No other factors were significantly associated with disease control or survival. Specifically, no statistically significant difference was observed in local control, progression-free survival, or overall survival when comparing patients who underwent biopsy versus gross total resection (75% vs 93%, 68% vs 93%, 75% vs 93%, respectively). Excluding patients who underwent cystectomy, urinary toxicity was limited to 2 patients with nocturnal enuresis. Exploratory surgery to address a persistent mass or thickened bladder wall after radiation was the most common source of serious toxicity., Conclusions: This cohort of young children with large pelvic tumors treated with proton therapy demonstrates similar local control with less toxicity than historic reports. Functional bladder preservation is possible in most patients. Exploratory biopsy in the 18 months after radiation should be approached with caution., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Craniopharyngioma is a benign tumor that commonly develops within the suprasellar region. The tumor and treatment can have debilitating consequences for pediatric and adult patients, including vision loss and pituitary/hypothalamic dysfunction. Most craniopharyngioma series focus on treatment of the pediatric population. We evaluated the outcomes of all adult craniopharyngioma patients treated at our institution using proton therapy to report outcomes for disease control, treatment-related toxicity, and tumor response., Methods: We analyzed 14 adult patients (≥ 22 years old). All patients had gross disease at the time of radiotherapy. Five were treated for de novo disease and 9 for recurrent disease. Patients received double-scattered conformal proton therapy to a mean dose of 54 GyRBE in 1.8 GyRBE/fraction (range 52.2-54 GyRBE). Weekly magnetic resonance imaging (MRI) helped to evaluate tumor changes during radiotherapy., Results: With median clinical and radiographic follow-up of 29 and 26 months, respectively, the 3-year local control and overall survival rates were both 100%. There were no grade 3 or greater acute or late radiotherapy-related side effects. There was no radiotherapy-related vision loss or optic neuropathy. No patients required intervention or treatment replanning due to tumor changes during radiotherapy. Two patients experienced transient cyst expansion at their first post-radiotherapy MRI. Both patients were followed closely clinically and radiographically and had subsequent dramatic tumor/cyst regression, requiring no interventions., Conclusions: Our data support the safety and efficacy of proton therapy in the treatment of adult craniopharyngioma as part of primary or salvage treatment. We recommend early consideration of radiotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03224767.

Purpose: Despite the dosimetric advantages of proton therapy, little data exist on patients who receive proton therapy for Ewing sarcoma of the cranium and skull base. This study reports local disease control and toxicity in such patients., Materials/methods: We reviewed 25 patients (≤21 years old) with nonmetastatic Ewing sarcoma of the cranium and skull base treated between 2008 and 2018. Treatment toxicity was graded per the Common Terminology Criteria for Adverse Events v4.0. The Kaplan-Meier product limit method provided estimates of disease control and survival., Results: Median patient age was 5.9 years (range, 1-21.7). Tumor subsites included the skull base (48%), non-skull-base calvarial bones (28%), paranasal sinuses (20%), and nasal cavity (4%). All patients underwent multiagent alkylator- and anthracycline-based chemotherapy; 16% underwent gross total resection (GTR) before radiation. Clinical target volume (CTV) 1 received 45 GyRBE and CTV2 received 50.4 GyRBE following GTR or 54-55.8 GyRBE following biopsy or subtotal resection. Median follow-up was 3.7 years (range, 0.26-8.3); no patients were lost. The 4-year local control, disease-free survival, and overall survival rates were 96%, 86%, and 92%, respectively. Two patients experienced in-field recurrences. One patient experienced bilateral conductive hearing loss requiring aids, two patients developed intracranial vasculopathy, and 6 patients required hormone replacement therapy for neuroendocrine deficits. None developed a secondary malignancy., Conclusion: Proton therapy is associated with a favorable therapeutic ratio in children with large Ewing tumors of the cranium and skull base. Despite its high conformality, we observed excellent local control and no marginal recurrences. Treatment dosimetry predicts limited long-term neurocognitive and neuroendocrine side effects., (© 2019 Wiley Periodicals, Inc.)

Purpose: In survivors of orbital embryonal rhabdomyosarcoma (ERMS), late effects include facial deformation and asymmetry. We sought to quantify orbital asymmetry in ERMS survivors and characterize the dose effect of radiation to the orbital bones., Methods and Materials: We evaluated the most recent follow-up magnetic resonance imaging (MRI) in 17 children (≤21 years old) with stage 1 group III orbital ERMS treated with proton therapy between 2007 and 2018. For all patients, the orbital socket volumes were calculated and compared with the contralateral, unirradiated orbital socket. Patient age, orbital tumor quadrant, and the radiation dose delivered to the major orbital bones (maxillary, frontal, and zygomatic bones) were recorded and correlated with the orbital socket volume difference., Results: The mean age at diagnosis was 5.4 years old (range, 1.1-9.7 years). All patients received a prescription dose of 45 GyRBE. The mean time interval between radiation and MRI was 2.9 years (range, 0.8-3.2 years). The mean age at most recent MRI was 8.4 years (range, 2.3-12.9 years). In 16 of 17 patients, the volume of the ipsilateral orbit was significantly smaller than the contralateral orbit on follow-up MRI (P ≤ .0001). In one patient with nonviable tumor in situ, the irradiated orbit was larger. The volume difference increased with follow-up time and did not correlate with age at treatment or age at MRI. A dose >40 GyRBE to all bones of the orbital rim was associated with a significant decrease in orbital volume (P < .05), but an isolated dose of >40 GyRBE to either the frontal, maxillary, or zygomatic bone was not., Conclusions: Despite the dosimetric precision of proton therapy, orbital asymmetry will develop after >40 GyRBE to multiple bones of the orbital rim. These data may be used to guide treatment planning and counsel patients on expected cosmesis., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: In children treated for nasopharyngeal carcinoma, proton therapy and postchemotherapy target volumes can reduce the radiation dose to developing tissue in the brain and the skull base region. We analyzed outcomes in children with nasopharyngeal carcinoma treated with induction chemotherapy followed by moderate-dose proton therapy., Methods/materials: Seventeen patients with nonmetastatic nonkeratinizing undifferentiated/poorly differentiated nasopharyngeal carcinoma underwent double-scattered proton therapy between 2011 and 2017. Median age was 15.3 years (range, 7-21). The American Joint Committee on Cancer T and N stage distribution included the following: T1, one patient; T2, five patients; T3, two patients; and T4, nine patients; and N1, six patients; N2, nine patients; and N3, two patients. Median radiation dose to the primary target volume and enlarged lymph nodes was 61.2 Gy (range, 59.4-61.2). Uninvolved cervical nodes received 45 Gy (range, 45-46.8). All radiation was delivered at 1.8 Gy/fraction daily using sequential plans. In 11 patients, photon-based intensity-modulated radiotherapy was used for elective neck irradiation to optimize dose homogeneity and improve target conformity. All patients received induction chemotherapy; all but one received concurrent chemotherapy. Five received adjuvant beta-interferon therapy., Results: Median follow-up was 3.0 years (range, 1.6-7.9). No patients were lost to follow-up. Overall survival, progression-free survival, and local control rates were 100%. Fifteen patients developed mucositis requiring enteral feeding (n = 14) or total parenteral nutrition (n = 1) during radiotherapy. Serious late side effects included cataract (n = 1), esophageal stenosis requiring dilation (n = 1), sensorineural hearing loss requiring aids (n = 1), and hormone deficiency (n = 5, including three with isolated hypothyroidism)., Conclusion: Following induction chemotherapy, moderate-dose proton therapy can potentially reduce toxicity in the brain and skull base region without compromising disease control. However, further follow-up is needed to fully characterize and evaluate any reduction in long-term complications., (© 2019 Wiley Periodicals, Inc.)

Purpose: To review the impact of a weekly multidisciplinary neuroradiology imaging review on the management of patients undergoing radiotherapy., Methods: A prospective study of the management of 118 patients (30=head and neck, 40=skull base, central nervous system=48) was conducted over a 12-month period from January 2018 through January 2019. After review of each patient's history and relevant imaging, a radiation oncologist completed a form detailing the changes that were made in diagnosis and management. Imaging source (external and internal examinations), availability of outside reports, report timeliness, the value of reports, changes in interpretation, changes in clinical management, and changes in prognosis were documented. Changes in interpretation and management were designated as major or minor depending on the significance of the change. The managing radiation oncologist indicated whether the imaging review conference substituted for a peer-to-peer consultation with a neuroradiologist., Results: Nearly half (47%) of all patients had a change in interpretation. Of those, 32% of patients had a major change in interpretation, while 14% had a minor change in interpretation. The existence of the multidisciplinary imaging review conference prevented a peer-to-peer consultation (interruption) by the radiation oncologists to the neuroradiologists in 90% of the cases presented. Further analysis was performed., Conclusion: The involvement of neuroradiologists in a joint radiation oncology imaging review conference resulted in changes in diagnostic imaging interpretation that led to significant changes in management, expected prognosis, and workflow., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Rao et al.)

Purpose: Despite widespread concerns of radiotherapy toxicity in children with head and neck tumors, recent Children's Oncology Group (COG) findings suggest that the use of 45 Gy results in an unacceptably high rate of local recurrences in patients with low-risk orbital rhabdomyosarcoma. We therefore evaluated outcomes in our pediatric patients who received 45 GyRBE using proton therapy. Material and methods: To assess disease control and toxicity, we reviewed the medical records of 30 children (≤21 years old) with COG stage 1, group III embryonal orbital rhabdomyosarcoma enrolled on a prospective outcome study and treated with proton therapy between 2007 and 2018. Results: Median age at the time of radiation was 4.8 years old. Twenty-one and nine patients received ifosfamide- and cyclophosphamide-based chemotherapy according to their respective cooperative group regimens. Median duration between the start of induction chemotherapy and radiation was 12 weeks. Two patients had a complete response to induction chemotherapy and two had stable disease. Twenty-six patients had a partial response to induction chemotherapy, with a median volume reduction of 66%. With a median follow-up of 4.0 years (range, 0.5-9.5 years), we observed 1 local failure 6 months following treatment in a patient who had a partial response to cyclosphophomide-based induction chemotherapy. The 5-year local control, progression-free survival, and overall survival rates were 97%, 97%, and 100%, respectively. Serious late toxicities included 18 patients with cataracts, 4 with exposure keratoconjunctivitis resulting in permanently reduced visual acuity, and 1 with chronic sinusitis. Conclusion: 45 GyRBE offers effective local control for most patients with group III orbital rhabdomyosarcoma. The delivery of proton therapy to the postinduction tumor volume plus a small margin can mitigate early- and intermediate-term toxicity, but side effects still occur and long-term data are needed to demonstrate the dosimetric advantage of proton therapy.

Background: We sought to evaluate the effectiveness of definitive or adjuvant external-beam proton therapy on local control and survival in patients with skull-base chondrosarcoma., Methods: We reviewed the medical records of 43 patients with a median age of 49 years (range, 23-80 years) treated with double-scattered 3D conformal proton therapy for skull-base chondrosarcomas between January 2007 and February 2016. Proton therapy-related toxicities were scored using CTCAE v4.0., Results: The median radiotherapy dose was 73.8 Gy(RBE) (range, 64.5-74.4 Gy[RBE]). Thirty-six (84%) and 7 (16%) patients underwent surgical resection or biopsy alone. Tumor grade distribution included: grade 1, 19 (44%) patients; grade 2, 22 (51%); and grade 3, 2 (5%). Forty patients had gross disease at the time of radiotherapy and 7 patients were treated for locally recurrent disease following surgery. The median follow-up was 3.7 years (range, 0.7-10.1 years). There were no acute grade 3 toxicities related to RT. At 4 years following RT, actuarial rates of overall survival, cause-specific survival, local control, and RT-related grade 3 toxicity-free survival were 95%, 100%, 89%, and 95%., Conclusion: High-dose, double-scattered 3D conformal proton therapy alone or following surgical resection for skull-base chondrosarcoma is an effective treatment with a high rate of local control with no acute grade 3 radiation-related toxicity. Further follow-up of this cohort is necessary to better characterize long-term disease control and late toxicities.

Purpose: Dosimetric studies show that proton therapy can reduce the low/intermediate radiation dose to uninvolved tissue in children with low-grade glioma (LGG). For this reason, LGG is the fourth most common pediatric tumor treated with proton therapy, yet clinical outcome data on efficacy and toxicity are limited., Methods and Materials: We reviewed the medical records of 174 children (≤21 years old) with nonmetastatic LGG enrolled on a prospective protocol and treated with proton therapy between 2007 and 2017. We assessed clinical outcomes and toxicity and analyzed patient, tumor, and treatment-related variables., Results: The median age was 10.2 years (range, 2-21). Fifty-eight percent of tumors were World Health Organization grade 1 and 30% were grade 2; 12% were diagnosed on imaging characteristics alone. The most common histology was pilocytic astrocytoma (47%). The most common tumor subsites were diencephalon/optic pathway (52%), caudal brainstem (16%), and cerebellum (13%). Forty-two percent received chemotherapy before radiation therapy. The median follow-up was 4.4 years. The 5-year actuarial rates of local control, progression-free survival, and overall survival were 85% (95% confidence interval [CI], 78%-90%), 84% (95% CI, 77%-89%), and 92% (95% CI, 85%-95%), respectively. On univariate analysis, brainstem/spinal cord tumor location (62% vs 90% elsewhere) and dose <54 GyRBE (67% vs 91% for 54 GyRBE) were associated with inferior local control (P < .01 for both). Twenty-two patients (12.6%) experienced acute nausea or vomiting requiring ondansetron; 2 patients (1.1%) required corticosteroids. Serious toxicities (4% of patients) included brainstem necrosis requiring corticosteroids (n = 2), symptomatic vasculopathy (n = 2), radiation retinopathy (n = 1), epilepsy (n = 1), and death from radiation-induced high-grade glioma (n = 1). Thirty-nine patients (22%) developed new-onset central hormone deficiency. Pseudoprogression was observed in 32.1%., Conclusions: Compared with modern photon series, proton therapy reduces the radiation dose to developing brain tissue, diminishing acute toxicities without compromising disease control., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumors involving the sella are commonly craniopharyngiomas, optic pathway gliomas, or pituitary adenomas. Functioning adenomas are expected, with prolactinomas topping the differential. The authors present the case of a silent corticotroph adenoma, which has not been described in the pediatric population, and they detail the use of proton therapy, which is also novel.

Purpose: To estimate the rate of and identify risk factors for vasculopathy after proton therapy in pediatric patients with central nervous system and skull base tumors., Methods and Materials: Between 2006 and 2015, 644 pediatric patients with central nervous system and skull base tumors were treated with proton therapy at a single institution. The 3 most common histologies were craniopharyngioma (n = 135), ependymoma (n = 135), and low-grade glioma (n = 131). The median age was 7.6 years (range, 0.7-21.8 years), and the median prescribed dose was 54 cobalt gray equivalent (CGE) (range, 25.2-75.6 CGE). For this analysis, vasculopathy included asymptomatic vessel narrowing identified on imaging, transient ischemic attacks, and cerebrovascular accidents. Serious vasculopathy was defined as events resulting in permanent neurologic complications or requiring revascularization surgery. Multivariate logistic regression (MVA) was used to assess predictors of toxicity. Variables examined included age, neurofibromatosis, extent of surgical resection, chemotherapy, postoperative stroke, total prescribed dose, and dose delivered to the optic nerves, chiasm, and hypothalamus., Results: With a median follow-up of 3.0 years (range, 0.1-9.6 years), the 3-year cumulative rates of any vasculopathy and serious vasculopathy were 6.4% and 2.6%, respectively. Seven children (1.2%) experienced a stroke with permanent neurologic deficits; 4 required revascularization surgery. On MVA, maximum dose to the optic chiasm ≥ 54 CGE was significantly associated with the development of any vasculopathy (13.1% vs 2.2%; P < .001); age < 5 years was also significant (8.4% vs 5.4%; P < .01). On MVA, maximum dose to the optic chiasm ≥ 54 CGE also predicted serious vasculopathy (3.8% vs 1.7%; P < .05)., Conclusions: Childhood cancer survivors are at risk of vasculopathy after cranial radiation therapy. Young children and those receiving ≥54 CGE to the chiasm are at an increased risk of this toxicity. These findings suggest appropriate follow-up and screening are important in this population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Although dosimetric comparisons demonstrate the advantage of proton therapy (PT) over conventional radiotherapy for nongerminomatous germ cell tumors (NGGCT), clinical outcome data for this rare tumor are lacking. We sought to evaluate outcomes for children with NGGCT treated with PT., Methods: Between 2007 and 2016, 14 children (median age 11, range, 5-19 years) with nonmetastatic NGGCT were treated with PT after induction chemotherapy. Most (8/14) were mixed germ cell. Five of 14 patients had complete resection of their primary tumor before radiation. Off study, eight patients received 36 Gy (RBE [relative biological effectiveness]) craniospinal irradiation (CSI). On study, two patients received 30.6 Gy (RBE) whole-ventricle irradiation and four received focal radiation alone. All patients received a total dose of 54 Gy (RBE) to the tumor/tumor bed., Results: At a median follow-up of 2.8 years, all patients were alive with no local recurrences. Three-year progression-free survival was 86%. Both metastatic recurrences occurred in patients treated with focal radiation alone; one with an immature teratoma developed an isolated spinal recurrence 5 months after treatment. Another with a mixed germ cell tumor developed a multifocal ventricular and shunt tract recurrence 7 months after treatment. Serious toxicity was minimal, including cataracts and hormone deficiency, and limited to children who received CSI., Conclusion: Early outcomes in children treated for NGGCT suggest the high conformality of PT does not compromise disease control and yields low toxicity. This pattern of failure data adds to growing evidence suggesting chemotherapy followed by focal radiotherapy alone is inadequate in controlling localized NGGCT., (© 2018 Wiley Periodicals, Inc.)

Background: Ewing sarcoma of the thoracic spine and chest wall is frequently treated with concurrent chemotherapy and radiation therapy (RT). Treatment-related acute esophagitis can lead to hospitalization and treatment delays. The aim of this study was to analyze the incidence, risk factors, and management of esophagitis in pediatric patients with Ewing sarcoma of the thoracic region., Methods: We conducted a single-institution retrospective review of patients treated over a 10-year period. Medical records were reviewed for patient and treatment characteristics associated with Common Terminology Criteria for Adverse Events grade 2 or higher esophagitis. RT plans were also reviewed and various esophageal dose metrics were analyzed., Results: Twelve of 37 patients (32%) developed acute esophagitis. Neutropenia was associated with an increased risk of esophagitis (60% vs. 14%; P < 0.01). RT significantly contributed to its incidence when maximum esophageal dose was >47 Gy (69% vs. 5%; P < 0.0001) and esophageal D5cm 3 was >15 Gy (67% vs. 9%; P < 0.001). All 12 patients with esophagitis were managed with oral opioid analgesics. Nine patients with persistent symptoms received subsequent fluconazole for empiric fungal treatment and each had a decreased need for opioid analgesics within 2-5 days., Conclusion: Approximately one-third of patients with Ewing sarcoma of the thoracic region will develop acute esophagitis. An esophageal D5cm 3 dose < 15 Gy and maximal esophageal dose < 47 Gy may keep the rate of acute esophagitis under 5%. However, the association with neutropenia and consistent response to antifungal therapy suggest chemotherapy-associated toxicity and an infectious component as part of the process., (© 2018 Wiley Periodicals, Inc.)

Background: Proton therapy can reduce the low and intermediate radiation dose to uninvolved brain tissue in children with intracranial ependymomas, which may improve functional outcomes and reduce second malignancies in survivors. Accordingly, ependymoma has become the most common pediatric tumor treated with proton therapy, yet data on efficacy and toxicity are limited., Material and Methods: Between June 2007 and February 2017, 179 children (≤21 years old) with nonmetastatic grade II/III intracranial ependymoma received proton therapy at our institution. Median age, 3.5 years (range, 0.7-21); 58% were male. Most (66%) tumors were in the posterior fossa and classified as WHO grade III (67%). 27% underwent multiple operations to maximize the extent of resection; ultimately 85% had a gross total or near total tumor resection before radiotherapy. 33% received preradiation chemotherapy. Median radiation dose in children ≤3 years old, 54 Gy(RBE). Most (>90%) children over 3 years old received 59.4 Gy(RBE). Patient and treatment variables were assessed for correlation with disease control., Results: Median follow-up, 3.2 years. 3-year local control, progression-free survival, and overall survival rates were 85%, 76%, and 90%, respectively. First site of progression was local, metastatic, or simultaneous in 14, 17 and 6 patients, respectively. On multivariate analysis, subtotal resection was associated with inferior local control (67% vs. 88%; p ≤ .01) and progression-free survival (59% vs. 79%; p < .05). Male sex was associated with inferior progression-free (67% vs. 87%; p< .05) and overall survival (84% vs. 99%; p < .01). The 3-year CTCAE grade 2 + brainstem toxicity rate was 5.5% (95% CI: 2.9-10.2), including 1 grade 5 toxicity., Conclusions: This series of proton therapy for pediatric intracranial ependymoma demonstrates disease control comparable to photon series without unexpected toxicity. Subtotal resection and male sex were associated with inferior disease control. Additional follow-up to quantify the expected reductions in late toxicity with proton therapy is ongoing.

Objectives: This single-institution report describes long-term disease control and late effects in pediatric patients with low-grade glioma (LGG) following radiotherapy (RT)., Materials and Methods: Twenty-nine pediatric patients with LGG were treated with photon-based RT from 1970 to 2004 (mean age at time of RT, 9.8 y; range, 0.6 to 19 y). One patient underwent gross total resection, 25 underwent subtotal resection or biopsy, and 3 were treated based on radiographic characteristics alone. Three patients underwent chemotherapy before RT. The median RT dose was 54 Gy (range, 40 to 55 Gy)., Results: The median follow-up was 17.8 years (range, 1.6 to 36.8 y) for all patients and 19.9 years (range, 1.6 to 36.8 y) for all living patients. The 5-, 10-, and 20-year local control and progression-free survival rates were equivalent at 82%, 74%, and 63%, respectively. The 5-, 10-, and 20-year cause-specific survival and overall survival rates were equivalent at 89%, 85%, and 58%, respectively. On univariate analysis, age below 4 years during treatment was associated with significantly inferior local control (P=0.0067), cause-specific survival (P=0.0021), and overall survival (P=0.0021). Of the 23 survivors analyzed for late toxicity, 15 (65%) developed grade 3+ toxicity. The most common Common Terminology Criteria for Adverse Events grade 3 toxicity (30% of survivors) was serious cognitive disability. Four patients (14%) died secondary to treatment complications, all occurring over a decade after completing RT., Conclusions: Over half of children diagnosed with LGG survive >20 years after RT; this report reveals the chronicity of toxicity beyond the typically reported follow-up. Our findings inform the therapeutic ratio of RT in this disease and may help guide late-effect screening recommendations.

Background: International, multidisciplinary care of children with central nervous system (CNS) tumors presents unique challenges. The aim of this study is to report patient outcomes of U.K. children referred for proton therapy to a North American facility., Methods: From 2008 to 2016, 166 U.K. children with approved CNS tumors were treated with proton therapy at a single academic medical center in the United States. Median age was 7 years (range, 1-19). Median follow-up was 2.6 years., Results: The 3-year actuarial overall survival (OS) and local control (LC) rates were 96% and 91%, respectively, for the overall group, 92% and 85% for the ependymoma subgroup (n = 57), 95% and 88% for the low-grade glioma subgroup (n = 54), and 100% and 100%, respectively, for the craniopharyngioma subgroup (n = 45). Cyst expansion was observed in 13 patients, including one case resulting in visual impairment. Serious side effects included new-onset seizures in three patients (1.8%), symptomatic vasculopathy in three patients (1.8%), and symptomatic brainstem necrosis in one patient (0.6%)., Conclusions: In this cohort of British children referred overseas for proton therapy, disease control does not appear compromised, toxicity is acceptable, and improvement in long-term function is anticipated in survivors owing to the reduced brain exposure afforded by proton therapy., (© 2017 Wiley Periodicals, Inc.)

Purpose: To report on the patterns of failure in children with rhabdomyosarcoma treated with proton therapy., Patients and Methods: Between February 2007 and November 2013, 66 children with a median age of 4.1 years (range, 0.6-15.3 years) diagnosed with nonmetastatic rhabdomyosarcoma were treated with proton therapy. Clinical target volume 1 was defined as the prechemotherapy tumor plus a 1-cm anatomically constrained margin. Clinical target volume 2 was defined as the postchemotherapy tumor (or tumor bed) plus a 0.5-cm anatomically constrained margin, further expanded to encompass potential pathways of spread, including soft tissue infiltrated with tumor at diagnosis., Results: Of the 66 children, 11 developed locally progressive disease at a median of 16 months (range, 14-32 months), for an actuarial 2-year local control rate of 88%. Among the children who progressed, median age and tumor size at diagnosis were 6.7 years (range, 0.6-16 years) and 6 cm (range, 2-8 cm), respectively. Of the recurrences, 64% and 36% were embryonal and alveolar, respectively. Disease progression was observed in 7 (64%) parameningeal, 2 (18%) head and neck (other), and 2 (18%) bladder/prostate subsites. At diagnosis, 8 of 11 patients who developed a recurrence were Intergroup Rhabdomyosarcoma Study stage 3, and all 11 were group III. Of the relapses, 100% (11 of 11) were confirmed as in-field within the composite 95% isodose line. One of the 11 patients (9%) developed a new simultaneous regional nodal recurrence outside of the previously treated radiation field., Conclusion: Early data suggest that the sharp dosimetric gradient associated with proton therapy is not associated with an increased risk of marginal failure. Routine use of a 0.5- to 1-cm clinical target volume 1/2 margin with highly conformal proton therapy does not compromise local control in children diagnosed with rhabdomyosarcoma with unfavorable risk features., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To analyze the effectiveness of a certified child life specialist (CCLS) in reducing the frequency of daily anesthesia at our institution, and to quantify the potential health care payer cost savings of CCLS utilization in the United States., Methods and Materials: From 2006 to 2014, 738 children (aged ≤21 years) were treated with radiation therapy at our institution. We retrospectively analyzed the frequency of daily anesthesia before and after hiring a CCLS in 2011 after excluding patients aged 0 to 2 and >12 years. In the analyzed cohort of 425 patients the median age was 7.6 years (range, 3-12.9 years). For the pre-CCLS period the overall median age was 7.5 years; for the post-CCLS period the median age was 7.7 years. An average 6-week course of pediatric anesthesia for radiation therapy costs $50,000 in charges to the payer. The average annual cost to employ one CCLS is approximately $50,000., Results: Before employing a CCLS, 69 of 121 children (57%) aged 3 to 12 years required daily anesthesia, including 33 of 53 children (62.3%) aged 5 to 8 years. After employing a CCLS, 124 of 304 children (40.8%) aged 3 to 12 years required daily anesthesia, including only 34 of 118 children (28.8%) aged 5 to 8 years (P<.0001). With a >16% absolute reduction in anesthesia use after employment of a CCLS, the health care payer cost savings was approaching $50,000 per 6 children aged 3 to 12 years treated annually with radiation therapy in our institution. This reduction resulted in a total of only 6 children aged 3 to 12 years required anesthesia to be treated per year at our center to achieve nearly break-even cost savings to the health care payer if the payer were to subsidize the employment expense of a CCLS. Overall, the CCLS intervention can provide an average annualized health care payer cost savings of "$[(anesthesia cost to payer during radiation therapy course/6) - (CCLS expense to payer/N)]" per child (N) treated with radiation therapy, where N equals the number of children aged 3 to 12 years treated in 1 year. This formula assumes that the payer subsidizes the cost for the employment of a CCLS, although our institution absorbed this expense for this data cohort. The predicted annualized health care system cost savings from reducing the frequency of anesthesia with radiation therapy when treating 100 children aged 3 to 12 years per year could exceed $775,000., Conclusions: These data suggest that a CCLS significantly reduces the frequency of daily anesthesia for children treated with radiation therapy. Health care system payers may achieve significant cost savings by financially supporting the employment of a CCLS in high-volume pediatric radiation therapy centers., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effectiveness of definitive or adjuvant external beam proton therapy on survival in patients with chordomas and chondrosarcomas of the spine., Methods and Materials: Between March 2007 and May 2013, 51 patients with a median age of 58 years (range, 22-83 years) with chordoma (n=34) or chondrosarcomas (n=17) of the sacrum (n=21), the cervical spine (n=20), and the thoracolumbar spine (n=10) were treated with external beam proton therapy to a median dose of 70.2 Gy(RBE) [range, 64.2-75.6 Gy(RBE)] at our institution. Distant metastases, overall survival, cause-specific survival, local control, and disease-free survival were calculated., Results: The mean follow-up time was 3.7 years (range, 0.3-7.7 years). Across all time points, 25 patients experienced disease recurrence: 18 local recurrences, 6 local and distant recurrences, and 1 distant metastasis. The 4-year rates of overall survival and cause-specific survival were 72%; disease-free survival was 57%, local control was 58%, and freedom from distant metastases was 86%. The median time to local progression was 1.7 years (range, 0.2-6.0 years), and the median time to distant progression was 1.6 years (range, 0.2-6.0 years). The risk factors for local recurrence were age ≤58 years (62% vs 26%; P=.04) and recurrence after prior surgery (29% vs 81%; P=.01). Secondary cancers developed in 2 patients: B-cell lymphoma 5.5 years after treatment and bladder cancer 2 years after treatment. We observed the following toxicities: sacral soft tissue necrosis requiring surgery (n=2), T1 vertebral fracture requiring fusion surgery (n=1), chronic urinary tract infections (n=1), surgery for necrotic bone cyst (n=1), and grade 2 bilateral radiation nephritis (n=1)., Conclusion: High-dose proton therapy controls more than half of spinal chordomas and chondrosarcomas and compares favorably with historic photon data. Local progression is the dominant mode of treatment failure and may be reduced by treating patients at the time of initial diagnosis. The impact of age is a novel finding of this study., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Object: Spinal chordomas can have high local recurrence rates after surgery with or without conventional dose radiation therapy (RT). Treatment outcomes and prognostic factors after high-dose proton-based RT with or without surgery were assessed., Methods: The authors conducted a retrospective review of 126 treated patients (127 lesions) categorized according to disease status (primary vs recurrent), resection (en bloc vs intralesional), margin status, and RT timing., Results: Seventy-one sacrococcygeal, 40 lumbar, and 16 thoracic chordomas were analyzed. Mean RT dose was 72.4 GyRBE (relative biological effectiveness). With median follow-up of 41 months, the 5-year overall survival (OS), local control (LC), locoregional control (LRC), and distant control (DC) for the entire cohort were 81%, 62%, 60%, and 77%, respectively. LC for primary chordoma was 68% versus 49% for recurrent lesions (p = 0.058). LC if treated with a component of preoperative RT was 72% versus 54% without this treatment (p = 0.113). Among primary tumors, LC and LRC were higher with preoperative RT, 85% (p = 0.019) and 79% (0.034), respectively, versus 56% and 56% if no preoperative RT was provided. Overall LC was significantly improved with en bloc versus intralesional resection (72% vs 55%, p = 0.016), as was LRC (70% vs 53%, p = 0.035). A trend was noted toward improved LC and LRC for R0/R1 margins and the absence of intralesional procedures., Conclusions: High-dose proton-based RT in the management of spinal chordomas can be effective treatment. In patients undergoing surgery, those with primary chordomas undergoing preoperative RT, en bloc resection, and postoperative RT boost have the highest rate of local tumor control; among 28 patients with primary chordomas who underwent preoperative RT and en bloc resection, no local recurrences were seen. Intralesional and incomplete resections are associated with higher local failure rates and are to be avoided.

Recent advances in pediatric cancer treatment have improved disease control and survival outcomes for childhood cancers survivors, including those treated for primary central nervous system and skull base malignancies. Future research in this population will focus on identifying risk factors for infertility, novel screening techniques and recommendations, and quality-of-life outcomes improvement. The purpose of this review is to define the infertility complications observed in pediatric cancer survivors who receive cranial irradiation for central nervous system and skull base malignancies., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Proton therapy offers superior low and intermediate radiation dose distribution compared with photon-based radiation for brain and skull base tumors; yet tissue within and adjacent to the target volume may receive a comparable radiation dose. We investigated the tolerance of the pediatric brainstem to proton therapy and identified prognostic variables., Material and Methods: All patients < 18 years old with tumors of the brain or skull base treated from 2007 to 2013 were reviewed; 313 who received > 50.4 CGE to the brainstem were included in this study. Brainstem toxicity was graded according to the NCI Common Terminology Criteria for Adverse Events v4.0., Results: The three most common histologies were ependymoma, craniopharyngioma, and low-grade glioma. Median patient age was 5.9 years (range 0.5-17.9 years) and median prescribed dose was 54 CGE (range 48.6-75.6 CGE). The two-year cumulative incidence of toxicity was 3.8% ± 1.1%. The two-year cumulative incidence of grade 3 + toxicity was 2.1% ± 0.9%. Univariate analysis identified age < 5 years, posterior fossa tumor location and specific dosimetric parameters as factors associated with an increased risk of toxicity., Conclusion: Utilization of current national brainstem dose guidelines is associated with a low risk of brainstem toxicity in pediatric patients. For young patients with posterior fossa tumors, particularly those who undergo aggressive surgery, our data suggest more conservative dosimetric guidelines should be considered.

Background: A single-institution review of long-term outcomes and factors affecting local control (LC) following radiotherapy for non-metastatic medulloblastoma., Material and Methods: From 1963 to 2008, 50 children (median age, 7.3 years; range 1.2-18.5) with stage M0 medulloblastoma were treated with radiotherapy; half underwent a gross total resection (no visible residual tumor) or near-total resection (< 1.5 cm(3) of gross disease remaining after resection). Median craniospinal dose was 28.8 Gy (range 21.8-38.4 Gy). Median total dose to the posterior fossa was 54.3 Gy (range 42.4-64.8 Gy). Eighteen patients (36%) received chemotherapy as part of multimodality management, including 11 who received concurrent chemotherapy., Results: Median follow-up was 15.7 years (range 0.3-44.4 years) for all patients and 26.6 years (range 7.3-44.4 years) for living patients. The 10-year overall survival, cancer-specific survival, and progression-free survival rates were 65%, 65%, and 69%. The 10-year LC rate was 84% and did not significantly change across eras. Four percent of patients experienced local progression five years after treatment. On univariate analysis, chemotherapy and overall duration of radiotherapy ≤ 45 days were associated with improved LC. Patients receiving chemotherapy had a 10-year 100% LC rate versus 76% in patients not receiving chemotherapy (p = 0.0454). When overall radiotherapy treatment lasted ≤ 45 days, patients experienced a superior 95% 10-year LC rate (vs. 73% in patients treated > 45 days; p = 0.0419). Three patients (6%) died from treatment complications, including radionecrosis/cerebellar degeneration, severe cerebral edema leading to herniation, and secondary malignancy., Conclusions: While we cannot draw definitive conclusions given the retrospective nature of our study, our long-term data suggest that reductions in craniospinal dose and boost target volume to reduce toxicity have not compromised disease control in the modern era. Our data also support analyses that implicate duration of radiotherapy, rather than interval between surgery and radiotherapy, as a factor in LC. Chemotherapy in multimodality management of medulloblastoma may have an underappreciated role in improving LC rates.

Background: The purpose of this study is to review late toxicity following craniospinal radiation for early-stage medulloblastoma., Material and Methods: Between 1963 and 2008, 53 children with stage M0 (n = 50) or M1 (n = 3) medulloblastoma were treated at our institution. The median age at diagnosis was 7.1 years (range 1.2-18.5). The median craniospinal irradiation (CSI) dose was 28.8 Gy (range 21.8-38.4). The median total dose, including boost, was 54 Gy (range 42.4-64.8 Gy). Since 1963, the CSI dose has been incrementally lowered and the high-risk boost volume reduced. Twenty-one patients (40%) received chemotherapy in their initial management, including 12 who received concurrent chemotherapy. Late sequelae were evaluated by analyzing medical records and conducting phone interviews with surviving patients and/or care-takers. Complications were graded using the NCI Common Terminology Criteria for Adverse Events, version 4.0., Results: The median follow-up for all patients was 15.4 years (range 0.4-44.4) and for living patients it was 24 years (range 5.6-44.4). The overall survival, cause-specific survival, and progression-free survival rates at 10 years were 67%, 67%, and 71%, respectively. Sixteen patients (41% of patients who survived five years or more) developed grade 3 + toxicity; 15 of these 16 patients received a CSI dose > 23.4 Gy. The most common grade 3 + toxicities for long-term survivors are hearing impairment requiring intervention (20.5%) and cognitive impairment (18%) prohibiting independent living. Four patients developed secondary (non-skin) malignancies, including three meningiomas, one rhabdomyosarcoma, and one glioblastoma multiforme. Three patients (5.6%) died from treatment complications, including radionecrosis, severe cerebral edema, and fatal secondary malignancy., Conclusion: Ongoing institutional and cooperative group efforts to minimize radiation exposure are justified given the high rate of serious toxicity observed in our long-term survivors. Follow-up through long-term multidisciplinary clinics is important and warranted for all patients exposed to radiotherapy in childhood.

Purpose: To compare the setup accuracy, comfort level, and setup time of two immobilization systems used in head-and-neck radiotherapy., Methods and Materials: Between February 2004 and January 2005, 21 patients undergoing radiotherapy for head-and-neck tumors were assigned to one of two immobilization devices: a standard thermoplastic head-and-shoulder mask fixed to a carbon fiber base (Type S) or a thermoplastic head mask fixed to the Accufix cantilever board equipped with the shoulder depression system. All patients underwent planning computed tomography (CT) followed by repeated control CT under simulation conditions during the course of therapy. The CT images were subsequently co-registered and setup accuracy was examined by recording displacement in the three cartesian planes at six anatomic landmarks and calculating the three-dimensional vector errors. In addition, the setup time and comfort of the two systems were compared., Results: A total of 64 CT data sets were analyzed. No difference was found in the cartesian total displacement errors or total vector displacement errors between the two populations at any landmark considered. A trend was noted toward a smaller mean systemic error for the upper landmarks favoring the Accufix system. No difference was noted in the setup time or comfort level between the two systems., Conclusion: No significant difference in the three-dimensional setup accuracy was identified between the two immobilization systems compared. The data from this study reassure us that our technique provides accurate patient immobilization, allowing us to limit our planning target volume to <4 mm when treating head-and-neck tumors.

We have used human brain-derived endothelial cells (HBECs) maintained under basal culture conditions in a Boyden chamber assay system as an in vitro model of migration of cells of systemic immune origin across the blood brain barrier (BBB) during the initiation of a CNS-directed inflammatory response. In this study we evaluated the molecular mechanisms that regulate passage of ex vivo peripheral blood-derived monocytes across this barrier and the effects of such migration on the properties of both the HBECs and the monocytes. Our results indicate that monocytes can migrate across HBECs in the absence of inflammatory conditions, at rates exceeding those of lymphocytes. Monocyte migration could be significantly inhibited by the addition of blocking antibodies to intercellular adhesion molecule (ICAM)-1, very late antigen (VLA)-4 integrin, and monocyte chemoattractant protein (CCL-2/MCP-1), or treatment with tissue inhibitor of metalloproteinase (TIMP-1). Following monocyte migration there was a significant increase in permeability of soluble molecules and an enhanced rate of T cell migration across HBECs. The enhanced permeability could be partially prevented with anti-TNF-alpha antibody. The migration process did not induce the upregulation of either co-stimulatory molecules or chemokine receptors on the monocytes. These studies emphasize the functional role of monocyte-endothelial interactions in permitting target access of a CNS-directed cell-mediated immune response.