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1.
Acta Oncol ; : 1-6, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32762400

RESUMO

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 cm3. 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 cm3 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 cm3 results in an approximately 5% risk of visual acuity decline for children with suprasellar or optic pathway tumors. A dose to 0.1 cm3 of 56 GyRBE appears to be safe for children with tumors elsewhere in the brain.

2.
Pediatr Blood Cancer ; : e28622, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32743915

RESUMO

BACKGROUND: Management of pediatric patients with ependymoma includes posttreatment surveillance imaging to identify asymptomatic recurrences. However, it is unclear whether early detection translates into improved survival. The objective was to determine whether detection of ependymoma relapses on surveillance imaging translates into a survival benefit. PROCEDURE: Patients with ependymoma aged <21 years at diagnosis treated in the Nemours' Children's Health System between January 2003 and October 2016 underwent chart review. Relapsed patients' charts were assessed for details of initial therapy, surveillance imaging regimen, details of relapse including detection and therapy, and outcome. Median follow up of the entire cohort was 6.5 years from diagnosis and 3.5 years from relapse. RESULTS: Ninety of 198 (45%) patients experienced relapse with 61 (68%) detected by surveillance imaging and 29 (32%) detected based on symptoms. Five-year OS in the surveillance group was 67% (confidence interval [CI] 55-82%, SE 0.1) versus 51% (CI 35-73%, SE 0.19) in the symptoms group (P = .073). From relapse, the 3-year OS in the surveillance group was 62% (CI 50-78%, SE 0.11) versus 55% (CI 39-76%, SE 0.17) in the symptoms group (P = .063) and the 3-year SPFS was 45% (CI 33-61%, SE 0.16) in the surveillance group versus 32% (CI 19-55%, SE 0.27) in the symptoms group (P = .028). CONCLUSION: Surveillance imaging may identify recurrences in patients when they are more amenable to salvage therapy, resulting in superior 3-year SPFS, but given limited salvage options for children with recurrent ependymoma, the survival advantage of frequent surveillance imaging in asymptomatic patients remains ambiguous.

3.
Int J Radiat Oncol Biol Phys ; 107(5): 974-981, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437922

RESUMO

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.

4.
J Appl Clin Med Phys ; 21(6): 100-107, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32268008

RESUMO

PURPOSE: To evaluate the dosimetric differences between photon intensity-modulated radiation therapy (IMRT) plans, 3D conformal proton therapy (3DCPT), and intensity-modulated proton therapy (IMPT) plans and to investigate the dosimetric impact of different beam spot size and beam apertures in IMPT for pediatric Ewing sarcoma of the chest wall. METHODS AND MATERIALS: Six proton pediatric patients with Ewing sarcoma in the upper, middle, and lower thoracic spine regions as well as upper lumbar spine region were treated with 3DCPT and retrospectively planned with photon IMRT and IMPT nozzles of different beam spot sizes with/without beam apertures. The plan dose distributions were compared both on target conformity and homogeneity, and on organs-at-risk (OARs) sparing using QUANTEC metrics of the lung, heart, liver, and kidney. The total integral doses of healthy tissue of all plans were also evaluated. RESULTS: Target conformity and homogeneity indices are generally better for the IMPT plans with beam aperture. Doses to the lung, heart, and liver for all patients are substantially lower with the 3DPT and IMPT plans than those of IMRT plans. In the IMPT plans with large spot without beam aperture, some OAR doses are higher than those of 3DCPT plans. The integral dose of each photon IMRT plan ranged from 2 to 4.3 times of proton plans. CONCLUSION: Compared to IMRT, proton therapy delivers significant lower dose to almost all OARs and much lower healthy tissue integral dose. Compared to 3DCPT, IMPT with small beam spot size or using beam aperture has better dose conformity to the target.

6.
J Neurooncol ; 147(2): 387-395, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32086697

RESUMO

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. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03224767. Accessed December 3, 2019.

7.
Am J Clin Oncol ; 43(3): 149-159, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028342

RESUMO

AIM/OBJECTIVES/BACKGROUND: The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for proton beam radiation therapy. Proton radiotherapy is the application of a high-energy proton beam to a patient in a clinical setting with therapeutic intent. Proton radiotherapy may permit improved therapeutic ratios with lower doses to sensitive normal structures and greater dose to target tumor tissues. METHODS: A literature search was performed to identify published articles regarding clinical outcomes, reviews, quality assurance methodologies, and guidelines and standards for proton radiation therapy. Selected articles are referenced in the text. The following recommendations are based on firsthand experiences of multiple clinical authorities who employ proton therapy and have been peer reviewed by experts at different practicing institutions. RESULTS: This practice parameter is developed to serve as a tool in the appropriate application of this evolving technology in the care of cancer patients or other patients with conditions where radiation therapy is indicated. It addresses clinical implementation of proton radiation therapy, including personnel qualifications, quality assurance standards, indications, and suggested documentation. CONCLUSIONS: This practice parameter is a tool to guide technical use of proton therapy and does not assess the relative clinical indication of proton radiotherapy when compared with other forms of radiotherapy, but to focus on the best practices required to deliver proton therapy safely and effectively, when clinically indicated. Costs of proton treatments are high, and the economic costs of proton radiotherapy may also need to be considered.


Assuntos
Neoplasias/radioterapia , Terapia com Prótons/métodos , Terapia com Prótons/normas , Humanos
8.
Int J Radiat Oncol Biol Phys ; 107(2): 325-333, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32044412

RESUMO

PURPOSE: To determine patterns of failure, clinical outcomes, and prognostic factors among pediatric patients treated with radiation therapy for parameningeal alveolar rhabdomyosarcoma. METHODS AND MATERIALS: We evaluated clinical and treatment planning records of patients aged ≤21 years with parameningeal alveolar rhabdomyosarcoma treated with definitive or adjuvant radiation therapy at our institution. The Kaplan-Meier product limit method assessed disease control and survival; the log-rank test was used to evaluate prognostic impact. RESULTS: We identified 24 patients with a median age of 3.5 years (range, 1-20) treated between 2009 and 2016. The median follow-up was 2.4 years for all (range, 0.3-5.6) and 3.2 years for living patients (range, 0.7-5.6). Most patients had group III (96%), node-negative (67%), positive FOX fusion status (63%) disease, and intracranial extension (54%). The paranasal sinus was the most common subsite (29%). All patients were treated with concurrent chemotherapy and proton radiation therapy with a median dose of 50.4 Gy relative biological effectiveness (range, 41.4-59.4) at a median 13 weeks after induction chemotherapy (range, 3-25). The 3-year local control, regional control, disease-free survival, and overall survival rates were 66%, 94%, 40%, and 58%, respectively. Median time to any failure was 0.5 years (range, 0.2-2.1). N1 disease and intracranial extension (ICE) portended inferior overall survival (P = .002 and .02, respectively). Female sex portended better local control (P = .05). All 7 patients with distant metastases as the first site of recurrence had central nervous system metastases. Age <4 years, absence of ICE, N0 disease, and primary tumor <5 cm were associated with a statistically significant improvement in freedom from distant metastases. CONCLUSIONS: Although regional nodal failures were rare, in-field local recurrences and leptomeiningeal progression in those with ICE suggest the need for modification of local and central nervous system therapies.

9.
Int J Radiat Oncol Biol Phys ; 106(5): 968-976, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987977

RESUMO

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 cm3 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.


Assuntos
Neoplasias Pélvicas/radioterapia , Terapia com Prótons , Rabdomiossarcoma/radioterapia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Terapia com Prótons/efeitos adversos , Resultado do Tratamento , Adulto Jovem
10.
Pract Radiat Oncol ; 10(1): 53-58, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31629089

RESUMO

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.

11.
Br J Radiol ; 93(1107): 20190673, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31600082

RESUMO

OBJECTIVE: The Pediatric Proton/Photon Consortium Registry (PPCR) is a comprehensive data registry composed of pediatric patients treated with radiation. It was established to expedite outcomes-based research. The attributes which allow the PPCR to be a successful collaboration are reviewed. METHODS AND MATERIALS: Current eligibility criteria are radiotherapy patients < 22 years treated at one of the 15 US participating institutions. Detailed health and treatment data are collected about the disease presentation and treatment exposures, and annually thereafter, in REDCap (Research Electronic Data Capture). DICOM (Digital Imaging and Communications in Medicine) imaging and radiation plans are collected through MIM/MIMcloud. An optional patient-reported quality-of-life (PedsQL) study is administered at 10 sites. RESULTS: Accrual started October 2012 with 2,775 participants enrolled as of 25 July 2019. Most patients, 62.0%, were treated for central nervous system (CNS) tumors, the most common of which are medulloblastoma (n = 349), ependymoma (n = 309), and glial/astrocytoma tumors (n = 279). The most common non-CNS diagnoses are rhabdomyosarcoma (n = 284), Ewing's sarcoma (n = 153), and neuroblastoma (n = 130). While the majority of participants are US residents, 18.7% come from 36 other countries. Over 685 patients participate in the PedsQL study. CONCLUSIONS: The PPCR is a valuable research platform capable of answering countless research questions that will ultimately improve patient care. Centers outside of the USA are invited to participate directly or may engage with the PPCR to align data collection strategies to facilitate large-scale international research. ADVANCES IN KNOWLEDGE: For investigators looking to carry out research in a large pediatric oncology cohort or interested in registry work, this paper provides an updated overview of the PPCR.


Assuntos
Coleta de Dados/normas , Neoplasias/radioterapia , Fótons/uso terapêutico , Terapia com Prótons/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Adolescente , Astrocitoma/radioterapia , Neoplasias do Sistema Nervoso Central/radioterapia , Neoplasias Cerebelares/radioterapia , Criança , Pré-Escolar , Computação em Nuvem , Ependimoma/radioterapia , Feminino , Glioma/radioterapia , Humanos , Lactente , Cooperação Internacional , Masculino , Meduloblastoma/radioterapia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Autorrelato , Adulto Jovem
12.
Acta Neuropathol ; 139(2): 259-271, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31802236

RESUMO

Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.

13.
Radiother Oncol ; 142: 140-146, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472997

RESUMO

BACKGROUND AND PURPOSE: Reducing radiation exposure to the temporal lobes could be beneficial to preserve cognitive function in paediatric brain tumour patients. The distribution of doses to brain substructures associated with cognition (BSCs) both within and outside of the temporal lobe have not been reported. The aim of this study was therefore to investigate temporal lobe sparing photon vs. proton therapy for paediatric suprasellar tumours. MATERIAL AND METHODS: Data from ten anonymized craniopharyngioma patients were used in this study. Temporal lobe sparing volumetric modulated arc therapy (VMAT) and pencil beam scanning (PBS) proton therapy plans were optimized to maintain consistent target metrics as in the delivered double scattering proton therapy (DSPT) plans. Thirty BSCs were delineated, including temporal lobe substructures (i.e. amygdala, hippocampus, entorhinal cortex). The dose/volume fractions to each BSC were analysed, and intelligence quotient (IQ) as well as memory scores were estimated to compare the different modalities. RESULTS: The exposed volumes of the temporal lobes and their substructures were consistently reduced with PBS compared to DSPT and VMAT, e.g. the left hippocampus V10Gy from 100% (VMAT) or 41% (DSPT) to 5% with PBS (p = 0.002). Some of the ventricular substructures were better spared with VMAT compared to both proton modalities. The reduced doses to the temporal lobes achieved with PBS translated into improved predicted memory outcomes, but not for the estimated IQ. CONCLUSION: The irradiated volumes of temporal lobe BSCs were consistently the lowest with PBS, whereas the model-based estimates of cognitive outcomes were less consistent.

14.
Pediatr Blood Cancer ; 67(2): e28080, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31736243

RESUMO

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.


Assuntos
Neoplasias Ósseas/mortalidade , Neoplasias dos Nervos Cranianos/mortalidade , Recidiva Local de Neoplasia/mortalidade , Terapia com Prótons/mortalidade , Sarcoma de Ewing/mortalidade , Neoplasias da Base do Crânio/mortalidade , Adolescente , Adulto , Neoplasias Ósseas/patologia , Neoplasias Ósseas/radioterapia , Criança , Pré-Escolar , Neoplasias dos Nervos Cranianos/patologia , Neoplasias dos Nervos Cranianos/radioterapia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Prognóstico , Estudos Prospectivos , Dosagem Radioterapêutica , Sarcoma de Ewing/patologia , Sarcoma de Ewing/radioterapia , Neoplasias da Base do Crânio/patologia , Neoplasias da Base do Crânio/radioterapia , Taxa de Sobrevida , Adulto Jovem
16.
Acta Oncol ; 58(10): 1404-1409, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31530120

RESUMO

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.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Orbitárias/terapia , Terapia com Prótons/métodos , Rabdomiossarcoma Embrionário/terapia , Carga Tumoral/efeitos da radiação , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Lactente , Masculino , Terapia Neoadjuvante/métodos , Neoplasias Orbitárias/mortalidade , Intervalo Livre de Progressão , Estudos Prospectivos , Terapia com Prótons/efeitos adversos , Planejamento da Radioterapia Assistida por Computador , Rabdomiossarcoma Embrionário/mortalidade , Carga Tumoral/efeitos dos fármacos
17.
Pediatr Blood Cancer ; 66(12): e27990, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31524334

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/mortalidade , Quimioterapia de Indução/mortalidade , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/mortalidade , Terapia com Prótons/mortalidade , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Prognóstico , Estudos Prospectivos , Dosagem Radioterapêutica , Taxa de Sobrevida , Adulto Jovem
18.
J Clin Oncol ; 37(31): 2866-2874, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513481

RESUMO

PURPOSE: The primary aim of this clinical trial was to prioritize bevacizumab or temsirolimus for additional investigation in rhabdomyosarcoma (RMS) when administered in combination with cytotoxic chemotherapy to patients with RMS in first relapse with unfavorable prognosis. PATIENTS AND METHODS: Patients were randomly assigned to receive bevacizumab on day 1 or temsirolimus on days 1, 8, and 15 of each 21-day treatment cycle, together with vinorelbine on days 1 and 8, and cyclophosphamide on day 1 for a maximum of 12 cycles. Local tumor control with surgery and/or radiation therapy was permitted after 6 weeks of treatment. The primary end point was event-free survival (EFS). Radiographic response was assessed at 6 weeks. The study had a phase II selection that was design to detect a 15% difference between the two regimens (α = .2; 1-ß = 0.8; two sided test). RESULTS: Eighty-seven of 100 planned patients were enrolled when the trial was closed after the second interim analysis after 46 events occurred in 68 patients with sufficient follow-up. The O'Brien Fleming boundary at this analysis corresponded to a two-sided P value of .058 with an observed two-sided P value of .003 favoring temsirolimus. The 6-month EFS for the bevacizumab arm was 54.6% (95% CI, 39.8% to 69.3%) and 69.1% (95% CI, 55.1% to 83%) for the temsirolimus arm. Objective response rates were 28% (95% CI, 13.7% to 41.3%) and 47% (95% CI, 31.5% to 63.2%) for the bevacizumab and temsirolimus arms, respectively (P = .12) and, 28% of patients on bevacizumab and 11% on temsirolimus had progressive disease at 6 weeks. CONCLUSION: Patients who received temsirolimus had a superior EFS compared with bevacizumab. Temsirolimus has been selected for additional investigation in newly diagnosed patients with intermediate-risk RMS.

19.
Acta Oncol ; 58(10): 1416-1422, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364899

RESUMO

Background: Children with brain tumors undergoing radiotherapy are at particular risk of radiation-induced morbidity and are therefore routinely considered for proton therapy (PT) to reduce the dose to healthy tissues. The aim of this study was to apply pediatric constraints and normal tissue complication probability (NTCP) models when evaluating the differences between PT and contemporary photon-based radiotherapy, volumetric modulated arc therapy (VMAT). Methods: Forty patients (aged 1-17 years) referred from Norwegian institutions to cranial PT abroad during 2014-2016 were selected for VMAT re-planning using the original CT sets and target volumes. The VMAT and delivered PT plans were compared by dose/volume metrics and NTCP models related to growth hormone deficiency, auditory toxicity, visual impairment, xerostomia, neurocognitive outcome and secondary brain and parotid gland cancers. Results: The supratentorial brain, temporal lobes, hippocampi, hypothalamus, pituitary glands, cochleas, salivary glands, optic nerves and chiasm received lower mean doses from PT. Reductions in population median NTCP were significant for auditory toxicity (VMAT: 3.8%; PT: 0.3%), neurocognitive outcome (VMAT: 3.0 IQ points decline at 5 years post RT; PT: 2.5 IQ points), xerostomia (VMAT: 2.0%; PT: 0.6%), excess absolute risk of secondary cancer of the brain (VMAT: 9.2%; PT: 6.7%) and salivary glands (VMAT: 2.8%; PT:0.5%). Across all patients, 23/38 PT plans had better or comparable estimated risks for all endpoints (within ±10% of the risk relative to VMAT), whereas for 1/38 patients all estimates were better or comparable with VMAT. Conclusions: PT reduced the volumes of normal tissues exposed to radiation, particularly low-to-intermediate dose levels, and this was reflected in lower NTCP. Of the included endpoints, substantial reductions in population medians were seen from the delivered PT plans for auditory complications, xerostomia, and risk of secondary cancers of the brain and salivary glands.


Assuntos
Neoplasias Encefálicas/radioterapia , Modelos Biológicos , Órgãos em Risco/efeitos da radiação , Terapia com Prótons/efeitos adversos , Lesões por Radiação/epidemiologia , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta à Radiação , Feminino , Humanos , Lactente , Masculino , Noruega/epidemiologia , Fótons/efeitos adversos , Fótons/uso terapêutico , Probabilidade , Terapia com Prótons/métodos , Lesões por Radiação/etiologia , Lesões por Radiação/prevenção & controle , Radiometria , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/métodos , Medição de Risco/métodos , Carga Tumoral/efeitos da radiação
20.
Acta Oncol ; 58(10): 1451-1456, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31303090

RESUMO

Background: Proton arc therapy may improve physical dose conformity and reduce concerns of elevated linear energy transfer (LET) and relative biological effectiveness (RBE) at the end of the proton range, while offering more degrees of freedom for normal tissue sparing. To explore the potential of proton arc therapy, we studied the effect of increasing the number of beams on physical and biologically equivalent dose conformity in the setting of pediatric brain tumors. Material and methods: A cylindrical phantom (Ø = 150 mm) with central cylindrical targets (Ø = 25 and 30 mm) was planned with increasing number of equiangular coplanar proton beams (from 3 to 36). For four anonymized pediatric brain tumor patients, two 'surrogate' proton arc plans (18 equiangular coplanar or sagittal beams) and a reference plan with 3 non-coplanar beams were constructed. Biologically equivalent doses were calculated using two RBE scenarios: RBE1.1; and RBELET, the physical dose weighted by the LET. For both RBE scenarios, dose gradients were assessed, and doses to cognitive brain structures were reported. Results: Increasing the number of beams resulted in an improved dose gradient and reduced volume exposed to intermediate LET levels, at the expense of increased low-dose and low-LET volumes. Most of the differences between the two RBE scenarios were seen around the prescription dose level, where the isodose volumes increased with the RBELET plans, e.g. up to 63% in the 3-beam plan for the smallest phantom target. Overall, the temporal lobes were better spared with the sagittal proton arc surrogate plans, e.g. a mean dose of 3.9 Gy compared to 6 Gy in the reference 3-beam plan (median value, RBE1.1). Conclusion: Proton arc therapy has the potential to improve dose gradients to better spare cognitive brain structures. However, this is at the expense of increased low-dose/low-LET volumes, with possible implications for secondary cancer risks.


Assuntos
Neoplasias Encefálicas/radioterapia , Tratamentos com Preservação do Órgão/métodos , Terapia com Prótons/métodos , Lesões por Radiação/prevenção & controle , Radioterapia de Intensidade Modulada/métodos , Encéfalo/efeitos da radiação , Criança , Cognição/efeitos da radiação , Relação Dose-Resposta à Radiação , Humanos , Transferência Linear de Energia , Tratamentos com Preservação do Órgão/efeitos adversos , Órgãos em Risco/efeitos da radiação , Imagens de Fantasmas , Terapia com Prótons/efeitos adversos , Lesões por Radiação/etiologia , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada/efeitos adversos
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