Outcomes following proton therapy for pediatric esthesioneuroblastoma.

BACKGROUND: Pediatric esthesioneuroblastoma (EN) can infiltrate skull base anatomy, presenting challenges due to high radiation doses and pediatric tissue sensitivity. This study reports outcomes of pediatric EN treated with proton radiotherapy (PT). PROCEDURE: Using an IRB-approved prospective outcomes registry, we evaluated patient, tumor, and treatment-related variables impacting disease control and toxicity in pediatric nonmetastatic EN treated with modern multimodality therapy, including PT. RESULTS: Fifteen consecutive patients (median age 16) comprising Kadish stage B (n = 2), C (n = 9), and D (n = 4) tumors were assessed, including six with intracranial involvement, four with cranial nerve deficits, and four with cervical lymphadenopathy. Before radiation, two had subtotal and 13 had gross total resections (endoscopic or craniofacial). Two underwent neck dissection. Eleven received chemotherapy before radiation (n = 5), concurrent with radiation (n = 4), or both (n = 2). Median total radiation dose (primary site) was 66 Gy/CGE for gross disease and 54 Gy/CGE (cobalt Gray equivalent) for microscopic disease. Median follow-up was 4.8 years. No patients were lost to follow-up. Five-year disease-free and overall survival rates were 86% (no local or regional recurrences). Two patients developed vertebral metastases and died. Two required a temporary feeding tube for oral mucositis/dysphagia. Late toxicities included symptomatic retinopathy, major reconstructive surgery, cataracts, chronic otitis media, chronic keratoconjunctivitis, hypothyroidism, and in-field basal cell skin cancer. CONCLUSIONS: A multimodality approach for pediatric EN results in excellent local control. Despite the moderate-dose PT, serious radiation toxicity was observed; further dose and target volume reductions may benefit select patients. Longer follow-up and comparative data from modern photon series are necessary to fully characterize any relative PT advantage.

Proton therapy and limited surgery for paediatric and adolescent patients with craniopharyngioma (RT2CR): a single-arm, phase 2 study.

BACKGROUND: Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated with radiotherapy. Because there are known physical differences between the two methods of radiotherapy, we aimed to estimate progression-free survival and overall survival distributions for paediatric and adolescent patients with craniopharyngioma treated with limited surgery and proton therapy, while monitoring for excessive CNS toxicity. METHODS: In this single-arm, phase 2 study, patients with craniopharyngioma at St Jude Children's Research Hospital (Memphis TN, USA) and University of Florida Health Proton Therapy Institute (Jacksonville, FL, USA) were recruited. Patients were eligible if they were aged 0-21 years at the time of enrolment and had not been treated with previous radiotherapeutic or intracystic therapies. Eligible patients were treated using passively scattered proton beams, 54 Gy (relative biological effect), and a 0·5 cm clinical target volume margin. Surgical treatment was individualised before proton therapy and included no surgery, single procedures with catheter and Ommaya reservoir placement through a burr hole or craniotomy, endoscopic resection, trans-sphenoidal resection, craniotomy, or multiple procedure types. After completing treatment, patients were evaluated clinically and by neuroimaging for tumour progression and evidence of necrosis, vasculopathy, permanent neurological deficits, vision loss, and endocrinopathy. Neurocognitive tests were administered at baseline and once a year for 5 years. Outcomes were compared with a historical cohort treated with surgery and photon therapy. The coprimary endpoints were progression-free survival and overall survival. Progression was defined as an increase in tumour dimensions on successive imaging evaluations more than 2 years after treatment. Survival and safety were also assessed in all patients who received photon therapy and limited surgery. This study is registered with ClinicalTrials.gov, NCT01419067. FINDINGS: Between Aug 22, 2011, and Jan 19, 2016, 94 patients were enrolled and treated with surgery and proton therapy, of whom 49 (52%) were female, 45 (48%) were male, 62 (66%) were White, 16 (17%) were Black, two (2%) were Asian, and 14 (15%) were other races, and median age was 9·39 years (IQR 6·39-13·38) at the time of radiotherapy. As of data cutoff (Feb 2, 2022), median follow-up was 7·52 years (IQR 6·28-8·53) for patients who did not have progression and 7·62 years (IQR 6·48-8·54) for the full cohort of 94 patients. 3-year progression-free survival was 96·8% (95% CI 90·4-99·0; p=0·89), with progression occurring in three of 94 patients. No deaths occurred at 3 years, such that overall survival was 100%. At 5 years, necrosis had occurred in two (2%) of 94 patients, severe vasculopathy in four (4%), and permanent neurological conditions in three (3%); decline in vision from normal to abnormal occurred in four (7%) of 54 patients with normal vision at baseline. The most common grade 3-4 adverse events were headache (six [6%] of 94 patients), seizure (five [5%]), and vascular disorders (six [6%]). No deaths occurred as of data cutoff. INTERPRETATION: Proton therapy did not improve survival outcomes in paediatric and adolescent patients with craniopharyngioma compared with a historical cohort, and severe complication rates were similar. However, cognitive outcomes with proton therapy were improved over photon therapy. Children and adolescents treated for craniopharyngioma using limited surgery and post-operative proton therapy have a high rate of tumour control and low rate of severe complications. The outcomes achieved with this treatment represent a new benchmark to which other regimens can be compared. FUNDING: American Lebanese Syrian Associated Charities, American Cancer Society, the US National Cancer Institute, and Research to Prevent Blindness.

Long-term outcomes of fractionated proton beam therapy for benign or radiographic intracranial meningioma.

PURPOSE: Benign intracranial meningioma is one of the most common primary brain neoplasms. Proton therapy has been increasingly utilized for nonoperative management of this neoplasm, yet few long-term outcomes studies exist. METHODS: The medical records of a total of 59 patients with 64 lesions were reviewed under a prospective outcomes tracking protocol for histologically proven or radiographically benign meningioma. The patients were treated with proton therapy at the University of Florida Proton Therapy Institute between 2007 and 2019 and given a median dose of 50.4 GyRBE at 1.8 GyRBE (relative biological effectiveness) (range 48.6-61.2 GyRBE) in once-daily treatments. RESULTS: With a median clinical and imaging follow-up of 6.3 and 4.7 years, the rates of 5-year actuarial local progression and cumulative incidence of grade 3 or greater toxicity were 6% (95% confidence interval [CI] 1%-14%), and 2% (95% CI < 1%-15%), respectively. Two patients experienced local progression after 5 years. The 5-year actuarial overall survival rate was 87% (95% CI 74-94%). CONCLUSION: Fractionated PBT up to 50.4 GyRBE is a safe and highly effective therapy for treating benign intracranial meningioma.

Radiotherapy for Atypical Teratoid/Rhabdoid Tumor (ATRT) on the Pediatric Proton/Photon Consortium Registry (PPCR).

PURPOSE: Atypical teratoid/rhabdoid tumors (ATRT) of the central nervous system (CNS) are rare tumors with a poor prognosis and variable use of either focal or craniospinal (CSI) radiotherapy (RT). Outcomes on the prospective Pediatric Proton/Photon Consortium Registry (PPCR) were evaluated according to RT delivered. METHODS: Pediatric patients receiving RT were prospectively enrolled on PPCR to collect initial patient, disease, and treatment factors as well as provide follow-up for patient outcomes. All ATRT patients with evaluable data were included. Kaplan-Meier analyses with log-rank p-values and cox proportional hazards regression were performed. RESULTS: The PPCR ATRT cohort includes 68 evaluable ATRT patients (median age 2.6 years, range 0.71-15.40) from 2012 to 2021. Median follow-up was 40.8 months (range 3.4-107.7). Treatment included surgery (65% initial gross total resection or GTR), chemotherapy (60% with myeloablative therapy including stem cell rescue) and RT. For patients with M0 stage (n = 60), 50 (83%) had focal RT and 10 (17%) had CSI. Among patients with M + stage (n = 8), 3 had focal RT and 5 had CSI. Four-year overall survival (OS, n = 68) was 56% with no differences observed between M0 and M + stage patients (p = 0.848). Local Control (LC) at 4 years did not show a difference for lower primary dose (50-53.9 Gy) compared to ≥ 54 Gy (73.3% vs 74.7%, p = 0.83). For patients with M0 disease, four-year OS for focal RT was 54.6% and for CSI was 60% (Hazard Ratio 1.04, p = 0.95. Four-year event free survival (EFS) among M0 patients for focal RT was 45.6% and for CSI was 60% (Hazard Ratio 0.71, p = 0.519). For all patients, the 4-year OS comparing focal RT with CSI was 54.4% vs 60% respectively (p = 0.944), and the 4-year EFS for focal RT or CSI was 42.8% vs 51.4% respectively (p = 0.610). CONCLUSION: The PPCR ATRT cohort found no differences in outcomes according to receipt of either higher primary dose or larger RT field (CSI). However, most patients were M0 and received focal RT. A lower primary dose (50.4 Gy), regardless of patient age, is appealing for further study as part of multi-modality therapy.

Facial deformation following treatment for pediatric head and neck rhabdomyosarcoma; the difference between treatment modalities. Results of a trans-Atlantic, multicenter cross-sectional cohort study.

BACKGROUND: The four different local therapy strategies used for head and neck rhabdomyosarcoma (HNRMS) include proton therapy (PT), photon therapy (RT), surgery with radiotherapy (Paris-method), and surgery with brachytherapy (AMORE). Local control and survival is comparable; however, the impact of these different treatments on facial deformation is still poorly understood. This study aims to quantify facial deformation and investigates the differences in facial deformation between treatment modalities. METHODS: Across four European and North American institutions, HNRMS survivors treated between 1990 and 2017, more than 2 years post treatment, had a 3D photograph taken. Using dense surface modeling, we computed facial signatures for each survivor to show facial deformation relative to 35 age-sex-ethnicity-matched controls. Additionally, we computed individual facial asymmetry. FINDINGS: A total of 173 HNRMS survivors were included, survivors showed significantly reduced facial growth (p < .001) compared to healthy controls. Partitioned by tumor site, there was reduced facial growth in survivors with nonparameningeal primaries (p = .002), and parameningeal primaries (p ≤.001), but not for orbital primaries (p = .080) All patients were significantly more asymmetric than healthy controls, independent of treatment modality (p ≤ .001). There was significantly more facial deformation in orbital patients when comparing RT to AMORE (p = .046). In survivors with a parameningeal tumor, there was significantly less facial deformation in PT when compared to RT (p = .009) and Paris-method (p = .007). INTERPRETATION: When selecting optimal treatment, musculoskeletal facial outcomes are an expected difference between treatment options. These anticipated differences are currently based on clinicians' bias, expertise, and experience. These data supplement clinician judgment with an objective analysis highlighting the impact of patient age and tumor site between existing treatment options.

Spinal ectopic recurrence of craniopharyngioma in a pediatric patient.

Craniopharyngiomas are rare, benign lesions that can be treated with surgery, radiation therapy, or a combination of these modalities. They have a propensity for local recurrence, but there have also been rare cases reported of ectopic recurrence. Here, we present the case of a 15-year-old girl with a recurrence of craniopharyngioma in the spine, which is the second-ever reported case of recurrence outside of the brain in a pediatric patient, and review the 19 reported cases of ectopic recurrence in pediatric patients due to cerebrospinal fluid dissemination.

Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.

Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.

Physical function, body mass index, and fitness outcomes in children, adolescents, and emerging adults with craniopharyngioma from proton therapy through five years of follow-up.

PURPOSE: Children diagnosed with craniopharyngioma are vulnerable to adverse health outcomes. Characterization of body mass index (BMI), physical function, and cardiopulmonary fitness in those treated with proton radiotherapy (PRT) will serve to design interventions to improve outcomes. METHODS: Ninety-four children with craniopharyngioma completed physical function testing prior to PRT and annually for 5 years. For each outcome, age- and sex-specific z-scores were calculated using normative values. Participants with z-scores > 1.5 or < - 1.5 were classified as impaired. Those with z-scores > 2.0 or < - 2.0 were classified as significantly impaired. Descriptive statistics were used to describe study outcomes and change in prevalence of impairments from 2 to 5 years after treatment. RESULTS: Nearly half of participants [45.2%, 95% confidence interval (CI) 39.4, 51.0] had mean BMI z-scores > 1.5 at baseline, with prevalence increasing to 66.7% (95% CI 61.5, 71.9) at 5 years. More than half of participants (54.2%, 95% CI 48.4, 60.0) had knee extension strength z-scores < - 1.5 at baseline, with prevalence increasing to 81.3% (95% CI 77.7, 84.9) at 5 years. BMI and knee extension strength had the largest proportion of participants impaired at both 2 and 5 years (53.2% and 62.3%, respectively). Resting heart rate had the highest proportion of participants not impaired at 2 years but became impaired at 5 years (26.6%). CONCLUSIONS: Children with craniopharyngioma have BMI and fitness abnormalities at diagnosis and continue 5 years after treatment. This cohort may benefit from interventions designed to improve BMI, strength, and resting indicators of cardiopulmonary fitness.

Disease Control after Radiotherapy for Adult Craniopharyngioma: Clinical Outcomes from a Large Single-Institution Series.

PURPOSE: To report disease control and treatment-related side effects among adult patients with craniopharyngioma treated with radiotherapy. METHODS: We performed a single-institution review of adult patients (> 21 years old) with craniopharyngioma treated with radiotherapy either definitively or postoperatively for gross residual disease. We report disease control, survival, and radiotherapy-related side effects. RESULTS: A total of 49 adult patients with craniopharyngioma were included, 27 of whom were treated at initial presentation and 22 for recurrent disease following initial surgery and observation. Overall, 77% received radiotherapy postoperatively (either after primary surgery or surgery for recurrence). With a median clinical and radiographic follow-up of 4.2 (range, 0.4-21.6) years and 3.0 (range, 0-21.5) years, the 5- and 10-year local control rates were 100 and 94%, respectively. The 5- and 10-year overall survival rates were 80 and 66%, respectively. Eleven percent of patients experienced grade 2 vision deterioration and 18% suffered grade 2 endocrinopathies following radiotherapy. CONCLUSIONS: Radiotherapy provides excellent disease control with acceptable toxicity among adult patients with craniopharyngioma. These data support the use of fractionated radiotherapy in adult patients with recurrent or gross residual disease after surgery. For inoperable patients or those with moderate or high surgical risk to neurologic and/or vascular structures, we advocate for limited surgical resection and postoperative radiotherapy to balance optimal tumor control with tumor- and treatment-related morbidity.

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

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

Simultaneous Diagnosis of Craniopharyngioma in 2 Brothers.

Craniopharyngioma is a rare suprasellar tumor. Approximately one-third of cases occur in pediatric patients. Depending on the size and extent of the lesion, the main treatment options include complete surgical removal of the tumor or limited surgery followed by radiotherapy. Craniopharyngiomas are not thought to be hereditary. Herein the authors present a case report of 2 brothers, ages 9 and 10, diagnosed with craniopharyngioma within weeks of each other and managed with different approaches. One sibling underwent gross total resection followed by observation while the other underwent biopsy followed by postoperative proton therapy.

Proton therapy for adult medulloblastoma: Acute toxicity and disease control outcomes.

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.

Osteosarcoma.

Osteosarcoma is a rare tumor that requires complex multidisciplinary management. This paper reviews the general management and standard radiotherapy guidelines for osteosarcoma in both North America and Europe in a joined effort between the Children's Oncology Group and International Society of Pediatric Oncology. Standard treatment involves multiagent induction chemotherapy followed by surgical resection for local tumor control and consolidation local control to metastatic sites. Radiotherapy is reserved for cases with a marginal or incomplete resection or for definitive treatment in the case of unresectable disease. We present supporting data for the role of chemotherapy, surgery, and radiation therapy.

Ewing sarcoma.

Ewing sarcoma is a rare tumor that requires complex multidisciplinary management. This report describes the general management and standard radiotherapy guidelines in both North America (Children's Oncology Group) and Europe (International Society of Pediatric Oncology). Standard treatment involves multiagent induction chemotherapy followed by local treatment with surgery, definitive radiation, or a combination of surgery and radiation followed by additional chemotherapy and consolidation local treatment to metastatic sites. The data supporting the role of chemotherapy, surgery, and radiation and specific radiation therapy guidelines are presented.

Pulmonary dose tolerance in hemithorax radiotherapy for Ewing sarcoma of the chest wall: Are we overestimating the risk of radiation pneumonitis?

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.

Outcomes following limited-volume proton therapy for multifocal spinal myxopapillary ependymoma.

PURPOSE: Spinal myxopapillary ependymoma (MPE) often presents with a multifocal distribution, complicating attempts at resection. There remains no standard approach to irradiating these patients. We report disease control and toxicity in pediatric patients with multifocal spinal MPE treated with limited-volume proton therapy. MATERIALS/METHODS: Twelve patients (≤21 years old) with multifocal spinal MPE were treated between 2009 and 2018 with limited-volume brain-sparing proton therapy. Median age was 13.5 years (range, 7-21). Radiotherapy was given as adjuvant therapy after primary surgery in five patients (42%) and for recurrence in seven (58%). No patient received prior radiation. Eleven patients (92%) had evidence of gross disease at radiotherapy. Eleven patients received 54 GyRBE; one received 50.4 GyRBE. Treatment toxicity was graded per the CTCAEv4.0. We estimated disease control and survival using the Kaplan-Meier product-limit method. RESULTS: The median follow-up was 3.6 years (range, 1.8-10.6). The five-year actuarial rates of local control, progression-free survival, and overall survival were 100%, 92%, and 100%, respectively. One patient experienced an out-of-field recurrence in the spine superior to the irradiated region. No patients developed in-field recurrences. Following surgery and irradiation, one patient developed grade three spinal kyphosis and one patient developed grade 2 unilateral L5 neuropathy. CONCLUSION: 54 GyRBE to a limited volume appears effective for disseminated spinal MPE in both the primary and salvage settings, sparing children the toxicity of full craniospinal irradiation. Compared with historical reports, this approach using proton therapy improves the therapeutic ratio, resulting in minimal side effects and high rates of disease control.

Second tumor risk in children treated with proton therapy.

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.

Incorporation of the LETd-weighted biological dose in the evaluation of breast intensity-modulated proton therapy plans.

PURPOSE: To evaluate the LETd-weighted biological dose to OARs in proton therapy for breast cancer and to study the relationship of the LETd-weighted biological dose relative to the standard dose (RBE = 1.1) and thereby to provide estimations of the biological dose uncertainties with the standard dose calculations (RBE = 1.1) commonly used in clinical practice. METHOD: This study included 20 patients who received IMPT treatment to the whole breast/chest wall and regional lymph nodes. The LETd distributions were calculated along with the physical dose using an open-source Monte Carlo simulation package, MCsquare. Using the McMahon linear model, the LETd-weighted biological dose was computed from the physical dose and LETd. OAR doses were compared between the Dose (RBE = 1.1) and the LETd-weighted biological dose, on brachial plexus, rib, heart, esophagus, and Ipsilateral lung. RESULTS: On average, the LETd-weighted biological dose compared to the Dose (RBE = 1.1) was higher by 8% for the brachial plexus D0.1 cc, 13% for the ribs D0.5 cc, 24% for mean heart dose, and 10% for the esophagus D0.1 cc, respectively. The LETd-weighted doses to the Ipsilateral lung V5, V10, and V20 were comparable to the Dose (RBE = 1.1). No statistically significant difference in biological dose enhancement to OARs was observed between the intact breast group and the CW group, with the exception of the ribs: the CW group experienced slightly greater biological dose enhancement (13% vs. 12%, p = 0.04) to the ribs than the intact breast group. CONCLUSION: Enhanced biological dose was observed compared to standard dose with assumed RBE of 1.1 for the heart, ribs, esophagus, and brachial plexus in breast/CW and regional nodal IMPT plans. Variable RBE models should be considered in the evaluation of the IMPT breast plans, especially for OARs located near the end of range of a proton beam. Clinical outcome studies are needed to validate model predictions for clinical toxicities.

Variation in relative biological effectiveness for cognitive structures in proton therapy of pediatric brain tumors.

BACKGROUND: Clinically, a constant value of 1.1 is used for the relative biological effectiveness (RBE) of protons, whereas in vitro the RBE has been shown to vary depending on physical dose, tissue type, and linear energy transfer (LET). As the LET increases at the distal end of the proton beam, concerns exist for an elevated RBE in normal tissues. The aim of this study was therefore to investigate the heterogeneity of RBE to brain structures associated with cognition (BSCs) in pediatric suprasellar tumors. MATERIAL AND METHODS: Intensity-modulated proton therapy (IMPT) plans for 10 pediatric craniopharyngioma patients were re-calculated using 11 phenomenological and two plan-based variable RBE models. Based on LET, tissue dependence and number of data points used to fit the models, the three RBE models considered the most relevant for the studied endpoint were selected. Thirty BSCs were investigated in terms of RBE and dose/volume parameters. RESULTS: For a representative patient, the median (range) dose-weighted mean RBE (RBEd) across all BSCs from the plan-based models was among the lowest (1.09 (1.02-1.52) vs. the phenomenological models at 1.21 (0.78-2.24)). Omitting tissue dependency resulted in RBEd at 1.21 (1.04-2.24). Across all patients, the narrower RBE model selection gave median RBEd values from 1.22 to 1.30. CONCLUSION: For all BSCs, there was a systematic model-dependent variation in RBEd, mirroring the uncertainty in biological effects of protons. According to a refined selection of in vitro models, the RBE variation across BSCs was in effect underestimated when using a fixed RBE of 1.1.

The Role of Radiation Therapy for Symptomatic Desmoid Tumors.

OPINION STATEMENT: Desmoid tumors have a variable clinical course that ranges from indolence or spontaneous regression to an aggressive pattern marked by local invasion. Up to half may remain stable or regress; watchful waiting is the preferred approach in the initial management of desmoid tumors. Symptomatic or progressive tumors or those that may affect adjacent critical structures require surgery, radiotherapy, or systemic therapy. Although radiotherapy effectively controls desmoid tumors in most cases, concerns regarding late toxicity exist. Definitive radiotherapy for macroscopic disease is indicated when a non-morbid complete surgical resection cannot be accomplished and provides similar control rates to surgery plus radiotherapy but avoids toxicity from combined-modality treatment (surgery and radiotherapy). Adjuvant radiotherapy can be considered for microscopically involved margins, particularly for recurrent cases or when a future recurrence may be challenging to treat. Large size, extremity site, and younger age are poor prognostic factors after radiotherapy. In the extremity, radiotherapy may have superior outcomes to surgery. Younger patients, especially children, are challenging to manage as they are at particular risk for late toxicity due to the number of potential years at risk. For patients under 20 years old, for whom a non-morbid complete resection is not possible, we recommend systemic therapy as the first line of treatment. Although the long-term efficacy of systemic therapy is unproven, this strategy allows additional time for growth and development prior to radiotherapy. In younger patients and those with axial desmoid tumors adjacent to critical organs, consideration should be given to using proton therapy as the dosimetric advantages may mitigate some of the toxicity associated with conventional radiotherapy.