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1
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Miyagishima KJ, Qiao F, Stasheff SF, Nadal-Nicolás FM. Visual Deficits and Diagnostic and Therapeutic Strategies for Neurofibromatosis Type 1: Bridging Science and Patient-Centered Care. Vision (Basel) 2024; 8:31. [PMID: 38804352 PMCID: PMC11130890 DOI: 10.3390/vision8020031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/03/2024] [Accepted: 05/04/2024] [Indexed: 05/29/2024] Open
Abstract
Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical manifestations. Mutations in neurofibromin, the protein encoded by the Nf1 tumor suppressor gene, result in dysregulation of the RAS/MAPK pathway leading to uncontrolled cell growth and migration. Neurofibromin is highly expressed in several cell lineages including melanocytes, glial cells, neurons, and Schwann cells. Individuals with NF1 possess a genetic predisposition to central nervous system neoplasms, particularly gliomas affecting the visual pathway, known as optic pathway gliomas (OPGs). While OPGs are typically asymptomatic and benign, they can induce visual impairment in some patients. This review provides insight into the spectrum and visual outcomes of NF1, current diagnostic techniques and therapeutic interventions, and explores the influence of NF1-OPGS on visual abnormalities. We focus on recent advancements in preclinical animal models to elucidate the underlying mechanisms of NF1 pathology and therapies targeting NF1-OPGs. Overall, our review highlights the involvement of retinal ganglion cell dysfunction and degeneration in NF1 disease, and the need for further research to transform scientific laboratory discoveries to improved patient outcomes.
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Affiliation(s)
- Kiyoharu J. Miyagishima
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; (K.J.M.); (F.Q.); (S.F.S.)
| | - Fengyu Qiao
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; (K.J.M.); (F.Q.); (S.F.S.)
| | - Steven F. Stasheff
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; (K.J.M.); (F.Q.); (S.F.S.)
- Center for Neuroscience and Behavioral Medicine, Gilbert Neurofibromatosis Institute, Children’s National Health System, Washington, DC 20010, USA
- Neurology Department, George Washington University School of Medicine, Washington, DC 20037, USA
| | - Francisco M. Nadal-Nicolás
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; (K.J.M.); (F.Q.); (S.F.S.)
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Elbeltagy M, Abbassy M. Neurofibromatosis type1, type 2, tuberous sclerosis and Von Hippel-Lindau disease. Childs Nerv Syst 2023; 39:2791-2806. [PMID: 37819506 DOI: 10.1007/s00381-023-06160-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 09/16/2023] [Indexed: 10/13/2023]
Abstract
Neurocutaneous syndromes (also known as phakomatoses) are heterogenous group of disorders that involve derivatives of the neuroectoderm. Each disease has diagnostic and pathognomonic criteria, once identified, thorough clinical examination to the patient and the family members should be done. Magnetic resonance imaging (MRI) is used to study the pathognomonic findings withing the CNS (Evans et al. in Am J Med Genet A 152A:327-332, 2010). This chapter includes the 4 most common syndromes faced by neurosurgeons and neurologists; neurofibromatosis types 1 and 2, tuberous sclerosis and Von Hippel-Lindau disease. Each syndrome has specific genetic anomaly that involves a tumor suppressor gene and the loss of inhibition of specific pathways. The result is a spectrum of cutaneous manifestations and neoplasms.
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Affiliation(s)
- M Elbeltagy
- Department of Neurosurgery, Cairo University, 1 University Street, Giza Governorate, 12613, Egypt.
- Department of Neurosurgery, Children's Cancer Hospital Egypt, Sekat Hadid Al Mahger, Zeinhom, El Sayeda Zeinab, Cairo Governorate, 4260102, Egypt.
| | - M Abbassy
- Department of Neurosurgery, Children's Cancer Hospital Egypt, Sekat Hadid Al Mahger, Zeinhom, El Sayeda Zeinab, Cairo Governorate, 4260102, Egypt
- Department of Neurosurgery, Alexandria University, 22 El-Gaish Rd, Al Azaritah WA Ash Shatebi, Bab Sharqi, Alexandria Governorate, 5424041, Egypt
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3
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Cipri S, Del Baldo G, Fabozzi F, Boccuto L, Carai A, Mastronuzzi A. Unlocking the power of precision medicine for pediatric low-grade gliomas: molecular characterization for targeted therapies with enhanced safety and efficacy. Front Oncol 2023; 13:1204829. [PMID: 37397394 PMCID: PMC10311254 DOI: 10.3389/fonc.2023.1204829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/01/2023] [Indexed: 07/04/2023] Open
Abstract
In the past decade significant advancements have been made in the discovery of targetable lesions in pediatric low-grade gliomas (pLGGs). These tumors account for 30-50% of all pediatric brain tumors with generally a favorable prognosis. The latest 2021 WHO classification of pLGGs places a strong emphasis on molecular characterization for significant implications on prognosis, diagnosis, management, and the potential target treatment. With the technological advances and new applications in molecular diagnostics, the molecular characterization of pLGGs has revealed that tumors that appear similar under a microscope can have different genetic and molecular characteristics. Therefore, the new classification system divides pLGGs into several distinct subtypes based on these characteristics, enabling a more accurate strategy for diagnosis and personalized therapy based on the specific genetic and molecular abnormalities present in each tumor. This approach holds great promise for improving outcomes for patients with pLGGs, highlighting the importance of the recent breakthroughs in the discovery of targetable lesions.
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Affiliation(s)
- Selene Cipri
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Giada Del Baldo
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesco Fabozzi
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Luigi Boccuto
- Healthcare Genetics Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC, United States
| | - Andrea Carai
- Department of Neurosciences, Neurosurgery Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Angela Mastronuzzi
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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Kalelioglu T, Rama B, Cho BB, Lopes BM, Patel SH. Pediatric-type diffuse low-grade glioma with MYB/MYBL1 alteration: report of 2 cases. Neuroradiol J 2023; 36:232-235. [PMID: 36074655 PMCID: PMC10034699 DOI: 10.1177/19714009221126015] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) has shown how molecular features can impact the classification of brain tumors. The continued combination of molecular features with histopathology has led to distinguish tumors with similar histopathologic features but distinct clinical prognosis. The 2021 revised 5. edition of the WHO classification further includes molecular features for CNS tumor categorization including MYB/MYBL1 altered diffuse astrocytoma which is a newly recognized type of low-grade pediatric-type brain tumor. We discuss imaging features of two pediatric-type low-grade gliomas with MYB/MYBL1-mutation that encountered at our institution.
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Affiliation(s)
| | - Bharath Rama
- University of Virginia, Charlottesville, VA, USA
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Bianchi F, Cocilovo FM, Ruggiero A, Tamburrini G. Optic Pathway Gliomas: The Trends of Basic Research to Reduce the Impact of the Disease on Visual Function. Adv Tech Stand Neurosurg 2023; 48:123-137. [PMID: 37770684 DOI: 10.1007/978-3-031-36785-4_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023]
Abstract
Pediatric optic pathway gliomas (OPG) are low-grade brain tumors characterized by slow progression and invalidating visual loss. Common therapeutic strategies include surgery, radiotherapy, chemotherapy, and combinations of these modalities, but despite the different treatment strategies, no actual treatment exists to prevent or revert visual impairment. Nowadays, several reports of the literature show promising results regarding NGF eye drop instillation and improvement of visual outcome. Such results seem to be related with the NGF-linked prevention in caspase activation, which reduces retinal ganglion cell loss.Reducing retinal ganglion cell loss results clinically in visual field improvement as well as visual electric potential and optical coherence tomography gain. Nonetheless, visual acuity fails to show significant changes.Visual impairment represents nowadays one of the major issues in dealing with OPGs. Secondary to the interesting results offered by NGF eye drop administration, further studies are warranted to better comprehend potential treatment strategies.
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Affiliation(s)
| | | | - Antonio Ruggiero
- Fondazione Policlinico Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Milan, Italy
| | - Gianpiero Tamburrini
- Fondazione Policlinico Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Milan, Italy
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6
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Jumah F, Abou-Al-Shaar H, Mallela AN, Wiley CA, Lunsford LD. Gamma Knife Radiosurgery in the Management of Hypothalamic Glioma: A Case Report with Long-Term Follow-Up. Pediatr Neurosurg 2022; 57:118-126. [PMID: 34969032 DOI: 10.1159/000521732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 12/27/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Optic pathway/hypothalamic gliomas are rare pediatric brain tumors. The management paradigm for these challenging tumors includes chemotherapy, radiotherapy, or surgical resection, but the optimal management strategy remains elusive. Gamma knife radiosurgery (GKRS) has emerged as a promising treatment for such lesions as documented by a small number of cases in the literature. CASE PRESENTATION We present a rare case of hypothalamic glioma in a 13-year-old girl who was referred to our service due to growth of an incidentally diagnosed hypothalamic lesion following head injury at the age of 8 years. The lesion demonstrated hypointensity on T1- and hyperintensity on T2-weighted imaging without contrast enhancement. Given the growth of the lesion on serial imaging, a stereotactic biopsy was performed demonstrating low-grade glioma. The patient underwent GKRS treatment with a marginal dose of 15 Gy at 50% isodose line for a tumor volume of 2.2 mL. Annual radiological surveillance over the next 17 years demonstrated a gradual shrinkage of the lesion until it completely disappeared. The patient is currently a healthy 31-year-old female without any visual, endocrine, or neurocognitive deficits. CONCLUSION The outcome obtained after extended follow-up in our patient highlights the safety and efficacy of GKRS in the management of hypothalamic gliomas in pediatrics, which in turn can avoid potentially serious complications of surgery in this vulnerable patient population, especially in this sensitive location.
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Affiliation(s)
- Fareed Jumah
- Department of Neurosurgery, Rutgers-Robert Wood Johnson Medical School & University Hospital, Rutgers-New Jersey Medical School, New Brunswick, New Jersey, USA,
| | - Hussam Abou-Al-Shaar
- Department of Neurological Surgery, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Arka N Mallela
- Department of Neurological Surgery, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Clayton A Wiley
- Division of Neuropathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - L Dade Lunsford
- Department of Neurological Surgery, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Sager O, Dincoglan F, Demiral S, Uysal B, Gamsiz H, Colak O, Ozcan F, Gundem E, Elcim Y, Dirican B, Beyzadeoglu M. Concise review of stereotactic irradiation for pediatric glial neoplasms: Current concepts and future directions. World J Methodol 2021; 11:61-74. [PMID: 34026579 PMCID: PMC8127424 DOI: 10.5662/wjm.v11.i3.61] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/07/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Brain tumors, which are among the most common solid tumors in childhood, remain a leading cause of cancer-related mortality in pediatric population. Gliomas, which may be broadly categorized as low grade glioma and high grade glioma, account for the majority of brain tumors in children. Expectant management, surgery, radiation therapy (RT), chemotherapy, targeted therapy or combinations of these modalities may be used for management of pediatric gliomas. Several patient, tumor and treatment-related characteristics including age, lesion size, grade, location, phenotypic and genotypic features, symptomatology, predicted outcomes and toxicity profile of available therapeutic options should be considered in decision making for optimal treatment. Management of pediatric gliomas poses a formidable challenge to the physicians due to concerns about treatment induced toxicity. Adverse effects of therapy may include neurological deficits, hemiparesis, dysphagia, ataxia, spasticity, endocrine sequelae, neurocognitive and communication impairment, deterioration in quality of life, adverse socioeconomic consequences, and secondary cancers. Nevertheless, improved understanding of molecular pathology and technological advancements may pave the way for progress in management of pediatric glial neoplasms. Multidisciplinary management with close collaboration of disciplines including pediatric oncology, surgery, and radiation oncology is warranted to achieve optimal therapeutic outcomes. In the context of RT, stereotactic irradiation is a viable treatment modality for several central nervous system disorders and brain tumors. Considering the importance of minimizing adverse effects of irradiation, radiosurgery has attracted great attention for clinical applications in both adults and children. Radiosurgical applications offer great potential for improving the toxicity profile of radiation delivery by focused and precise targeting of well-defined tumors under stereotactic immobilization and image guidance. Herein, we provide a concise review of stereotactic irradiation for pediatric glial neoplasms in light of the literature.
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Affiliation(s)
- Omer Sager
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Ferrat Dincoglan
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Selcuk Demiral
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Bora Uysal
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Hakan Gamsiz
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Onurhan Colak
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Fatih Ozcan
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Esin Gundem
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Yelda Elcim
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Bahar Dirican
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Murat Beyzadeoglu
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
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8
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Trunin YY, Golanov AV, Konovalov AN, Pronin IN, Zagirov RI, Ryzhova MV, Kadyrov SU, Igoshina EN. [Stereotactic irradiation in the complex treatment of patients with intracranial pilocytic astrocytoma]. ZHURNAL VOPROSY NEĬROKHIRURGII IMENI N. N. BURDENKO 2021; 85:34-46. [PMID: 33864667 DOI: 10.17116/neiro20218502134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Complex management of patients with intracranial pilocytic astrocytoma (PA) consists of surgical treatment, drug therapy (mainly in young children) and radiotherapy. For many years, radiotherapy (RT) has been a standard for residual tumors, recurrence or continued growth of PA. Currently, stereotactic radiosurgery and radiotherapy are preferred for PA, because these procedures are characterized by high conformity and selectivity, precise irradiation of tumor with minimal damage to surrounding intact tissues. Stereotaxic approach is very important since PAs are localized near functionally significant and radiosensitive brain structures in most cases. There is significant experience of single-center studies devoted to radiotherapy of patients with PA at the Department of Neuroradiosurgery of the Burdenko Neurosurgery Center. In this research, the authors analyzed the results of stereotactic irradiation of 430 patients with PA for the period from 2005 to 2018.
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Affiliation(s)
| | - A V Golanov
- Burdenko Neurosurgical Center, Moscow, Russia
| | | | - I N Pronin
- Burdenko Neurosurgical Center, Moscow, Russia
| | - R I Zagirov
- Burdenko Neurosurgical Center, Moscow, Russia
| | - M V Ryzhova
- Burdenko Neurosurgical Center, Moscow, Russia
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9
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Nellan A, Wright E, Campbell K, Davies KD, Donson AM, Amani V, Judd A, Hemenway MS, Raybin J, Foreman NK, Rush S, Dorris K. Retrospective analysis of combination carboplatin and vinblastine for pediatric low-grade glioma. J Neurooncol 2020; 148:569-575. [PMID: 32506370 DOI: 10.1007/s11060-020-03549-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/29/2020] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Low-grade glioma (LGG) represent the most common pediatric central nervous system tumor. When total surgical resection is not feasible, chemotherapy is first-line therapy in children. Multiple pediatric LGG chemotherapy regimens have been investigated with variable 2-year event free survival (EFS) rates of 39-69%. To date, treatment of pediatric LGG with a carboplatin and vinblastine (C/VBL) chemotherapy regimen has only been evaluated in a phase 1 dose-finding study. METHODS A retrospective review of pediatric patients with LGG who were treated with C/VBL at Children's Hospital of Colorado or Akron Children's Hospital from 2011 to 2017 was conducted. Data collected included patient demographics, tumor location, disease response, neurofibromatosis 1 (NF1) status, therapy duration and toxicities. Response to therapy was determined by objective findings on imaging and treating physicians' evaluation. RESULTS Forty-six patients were identified for analysis, all of whom were chemotherapy-naive. Only five patients treated in this cohort had NF1. BRAF fusion was identified in 65% (22/34) of tested tumors. Best therapy response was partial response in nine patients and stable disease in twenty-five patients. Twelve patients had progressive disease. One-year, 3-year, and 5-year EFS probabilities for all patients were 69.6%, 39.4%, and 34.5%, respectively. Nine patients had admissions for febrile neutropenia and seven patients experienced one delay in chemotherapy due to neutropenia. Only two patients had to discontinue this chemotherapy regimen because of treatment-related toxicities [carboplatin allergy (n = 1) and vinblastine neuropathy (n = 1)]. CONCLUSION C/VBL achieves similar EFS rates to other single-agent and combination cytotoxic chemotherapy regimens for pediatric LGG with manageable toxicities.
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Affiliation(s)
- Anandani Nellan
- Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. .,Center for Cancer and Blood Disorders, Morgan Adams Foundation Pediatric Brain Tumor Research Program, University of Colorado School of Medicine, 13123 East 16th Avenue, Box B115, Aurora, CO, 80045, USA.
| | - Erin Wright
- Division of Hematology Oncology, Akron Children's Hospital, One Perkins Square, Akron, OH, 44308, USA
| | - Kristen Campbell
- Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kurtis D Davies
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew M Donson
- Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Vladimir Amani
- Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Alexis Judd
- Division of Hematology Oncology, Akron Children's Hospital, One Perkins Square, Akron, OH, 44308, USA
| | - Molly S Hemenway
- Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jennifer Raybin
- Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Nicholas K Foreman
- Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Sarah Rush
- Division of Hematology Oncology, Akron Children's Hospital, One Perkins Square, Akron, OH, 44308, USA
| | - Kathleen Dorris
- Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Ryall S, Tabori U, Hawkins C. Pediatric low-grade glioma in the era of molecular diagnostics. Acta Neuropathol Commun 2020; 8:30. [PMID: 32164789 PMCID: PMC7066826 DOI: 10.1186/s40478-020-00902-z] [Citation(s) in RCA: 211] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 02/21/2020] [Indexed: 12/17/2022] Open
Abstract
Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior – in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS–mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.
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Abstract
PURPOSE OF REVIEW Optic pathway gliomas are low-grade neoplasms that affect the precortical visual pathway of children and adolescents. They can affect the optic nerve, optic chiasm, optic tracts and radiations and can either be sporadic or associated with neurofibromatosis type one. Gliomas isolated to the optic nerve (ONG) represent a subgroup of optic pathway gliomas, and their treatment remains controversial. New developments in ONG treatment have emerged in recent years, and it is necessary for clinicians to have a current understanding of available therapies. RECENT FINDINGS The current review of the literature covers the background of and recent developments in ONG treatment, with a focus on standard chemotherapy, new molecularly targeted therapies, radiation therapy and surgical resection and debulking. SUMMARY Although standard chemotherapy remains the mainstay of ONG treatment, newer molecularly targeted therapies such as mitogen-activated protein kinase kinase inhibitors and bevacizumab represent a promising new treatment modality, and clinical studies are ongoing.
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12
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Ajithkumar T, Taylor R, Kortmann RD. Radiotherapy in the Management of Paediatric Low-Grade Gliomas. Clin Oncol (R Coll Radiol) 2018; 31:151-161. [PMID: 30528521 DOI: 10.1016/j.clon.2018.11.032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 11/04/2018] [Indexed: 12/18/2022]
Abstract
Paediatric low-grade (World Health Organization grade I-II) gliomas (LGGs) represent a spectrum of primary central nervous system tumours. Local tumour control is the cornerstone in the general management of childhood gliomas. Surgery is the primary treatment of choice in the majority. Non-surgical treatments are recommended for progressive or symptomatic inoperable disease. Although chemotherapy is increasingly used as first non-surgical treatment, radiotherapy remains standard as salvage treatment or as primary treatment in selected cases in which surrounding normal tissue can be optimally preserved. The role of targeted therapies is currently under investigation in clinical trials. Modern high-precision radiotherapy techniques, including proton therapy, have the potential to improve long-term toxicities. There is therefore an urgent need for prospective studies to compare the efficacy and safety of modern radiotherapy with systemic treatment in children with LGGs. New information on molecular genetic patterns in LGGs may also have an impact on the selection and sequencing of radiotherapy.
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Affiliation(s)
- T Ajithkumar
- Department of Oncology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
| | - R Taylor
- Department of Oncology, Swansea University and South West Wales Cancer Centre, Singleton Hospital, Swansea, UK
| | - R D Kortmann
- Department of Radiation Oncology, University of Leipzig, Leipzig, Germany
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13
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Cherlow JM, Shaw DWW, Margraf LR, Bowers DC, Huang J, Fouladi M, Onar-Thomas A, Zhou T, Pollack IF, Gajjar A, Kessel SK, Cullen PL, McMullen K, Wellons JC, Merchant TE. Conformal Radiation Therapy for Pediatric Patients with Low-Grade Glioma: Results from the Children's Oncology Group Phase 2 Study ACNS0221. Int J Radiat Oncol Biol Phys 2018; 103:861-868. [PMID: 30419305 DOI: 10.1016/j.ijrobp.2018.11.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/29/2018] [Accepted: 11/02/2018] [Indexed: 12/11/2022]
Abstract
PURPOSE To determine the rate of marginal relapse, progression-free survival (PFS), and overall survival (OS) in patients with pediatric low-grade glioma (PLGG) treated with conformal radiation therapy (CRT) with a clinical target volume (CTV) margin of 5 mm in the Children's Oncology Group trial ACNS0221. METHODS AND MATERIALS Patients aged 3 to 21 years with unresectable progressive, recurrent, or residual PLGG were eligible for this study. Patients younger than 10 years were required to have received at least 1 chemotherapy course. Patients with neurofibromatosis type I were not eligible. All patients underwent magnetic resonance imaging-based planning and received 54 Gy CRT in 30 fractions with a 5-mm CTV margin. RESULTS Of 85 eligible patients (median age, 13.6 years) treated between March 2006 and December 2010, 14 were younger than 10 years and 36 received prior chemotherapy. Sixty-six had pilocytic astrocytoma, 15 had other histologic subtypes, and 4 had unbiopsied chiasmatic lesions. Events included 23 relapses (19 central, 4 distant, and no marginal) and 7 deaths. At a median follow-up of 5.15 years, 5-year PFS was 71% ± 6% and OS was 93% ± 4%. Male sex (P = .068) and large tumor size (P = .050) trended toward significance for association with decreased PFS. Age, histology, tumor location, time between diagnosis and study entry, and MIB-1 status were not associated with PFS. OS was negatively associated with male sex (P = .064), non-pilocytic astrocytoma histology (P = .010), and large tumor size (P = .0089). CONCLUSIONS For patients with PLGG, CRT with a CTV margin of 5 mm yields an acceptable PFS and does not lead to a high rate of marginal relapse.
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Affiliation(s)
- Joel M Cherlow
- Department of Radiation Oncology, MemorialCare Long Beach Medical Center Long Beach, California
| | - Dennis W W Shaw
- Department of Diagnostic Imaging, Seattle Children's Hospital, Seattle, Washington
| | - Linda R Margraf
- Department of Pathology, Cook Children's Medical Center, Ft. Worth, Texas
| | - Daniel C Bowers
- Department of Pediatrics, UT Southwestern Medical School, Dallas, Texas
| | - Jie Huang
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Maryam Fouladi
- Department of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Arzu Onar-Thomas
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Tianni Zhou
- Department of Mathematics, California State University, Long Beach, California
| | - Ian F Pollack
- Department of Neurosurgery, Children's Hospital of Pittsburgh of UMPC, Pittsburgh, Pennsylvania
| | - Amar Gajjar
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Sandy K Kessel
- Imaging and Radiation Oncology Core Rhode Island, Lincoln, Rhode Island
| | - Patricia L Cullen
- Rueckert-Hartman College for Health Professions, Regis University, Denver, Colorado
| | - Kevin McMullen
- Department of Radiation Oncology, Columbus Regional Health, Columbus, Indiana
| | - John C Wellons
- Department of Neurosurgery, Vanderbilt University/Ingram Cancer Center, Nashville, Tennessee
| | - Thomas E Merchant
- Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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14
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Hessissen L, Parkes J, Amayiri N, Mushtaq N, Sirachainan N, Anacak Y, Mitra D, Figaji A, Schouten-van Meeteren A, Sullivan M, Burger H, Davidson A, Bouffet E, Bailey S. SIOP PODC Adapted treatment guidelines for low grade gliomas in low and middle income settings. Pediatr Blood Cancer 2017; 64 Suppl 5. [PMID: 29297618 DOI: 10.1002/pbc.26737] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 06/22/2017] [Indexed: 12/15/2022]
Abstract
Effective treatment of children with low grade glioma (LGG) requires a functioning multi-disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition, the treating centre should have the capacity to manage a variety of LGG and treatment-associated complications. These requirements have made it difficult for many centers in low and middle-income countries (LMIC) to offer effective treatment and follow up. This article provides management recommendations for children with LGG according to the level of facilities available.
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Affiliation(s)
- Laila Hessissen
- Department of Hematology and Pediatric Oncology, Hospital University Ibn Sina, Rabat, Morocco
| | - Jeannette Parkes
- Department of Radiation Oncology, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
| | - Nisreen Amayiri
- Department of Hematology and Oncology, King Hussein Cancer Centre, Amman, Jordan
| | - Naureen Mushtaq
- Department of Pediatric Haematology and Oncology, Aga Khan University Hopsital, Karachi, Pakistan
| | - Nongnuch Sirachainan
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Yavuz Anacak
- Department of Radiation Oncology, Ege University School of Medicine & Hospital, Izmir, Turkey
| | - Dipayan Mitra
- Department of Radiology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Anthony Figaji
- Department of Neurosurgery, Red Cross War Memorial Children's Hospital and University of Cape Town, Cape Town, South Africa
| | | | - Michael Sullivan
- Department of Paediatric Haematology and Oncology, Royal Hospital for Sick Children, Melbourne, Victoria, Australia
| | - Hester Burger
- Department Medical Physics, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
| | - Alan Davidson
- Haematology Oncology Service, Red Cross War Memorial Children's Hospital, Department of Paediatrics and Child Health, University of Cape Town, South Africa
| | - Eric Bouffet
- Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Simon Bailey
- Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
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15
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Jalali R, Gupta T, Goda JS, Goswami S, Shah N, Dutta D, Krishna U, Deodhar J, Menon P, Kannan S, Sarin R. Efficacy of Stereotactic Conformal Radiotherapy vs Conventional Radiotherapy on Benign and Low-Grade Brain Tumors: A Randomized Clinical Trial. JAMA Oncol 2017; 3:1368-1376. [PMID: 28570730 DOI: 10.1001/jamaoncol.2017.0997] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Importance Evidence for application of stereotactic and other conformal radiotherapy techniques in treating brain tumors is largely based on data derived from dosimetric, retrospective, or small prospective studies. Therefore, we conducted a randomized clinical trial of stereotactic conformal radiotherapy (SCRT) compared with conventional radiotherapy (ConvRT) evaluating clinically meaningful end points. Objective To compare neurocognitive and endocrine functional outcomes and survival at 5 years in young patients with residual and/or progressive benign or low-grade brain tumors treated with SCRT and ConvRT techniques. Design, Setting, and Participants This phase 3 randomized clinical trial enrolled 200 young patients (ages 3-25 years) with residual or progressive benign or low-grade brain tumors at a single center between April 2001 to March 2012. Patients were randomly allocated (1:1) to either SCRT (n = 104) or ConvRT (n = 96) arms. Interventions Patients were randomly assigned to either high-precision SCRT or ConvRT to a dose of 54 Gy in 30 fractions over 6 weeks. Main Outcomes and Measures Detailed neuropsychological and neuroendocrine assessments were performed at preradiotherapy baseline, at 6 months, and annually thereafter until 5 years on longitudinal follow-up. Change in these functional parameters was compared between the 2 arms as the primary end point and overall survival (OS) as the secondary end point. Results In total, 200 young patients (median [interquartile range] age, 13 [9-17] years; 133 males and 67 females) were enrolled. Mean full-scale or global intelligence quotient (IQ) and performance IQ scores over a period of 5 years were significantly superior in patients treated with SCRT compared with those treated with ConvRT (difference in slope = 1.48; P = .04 vs difference in slope = 1.64; P = .046, respectively). Cumulative incidence of developing new neuroendocrine dysfunction at 5 years was significantly lower in patients treated with SCRT compared with ConvRT (31% vs 51%; P = .01) while developing a new neuroendocrine axis dysfunction in patients with preexisting dysfunction in at least 1 axis at baseline was also significantly lower in the SCRT arm compared with the ConvRT arm (29% vs 52%; P = .02). Five-year OS in SCRT and ConvRT arms was 86% and 91%, respectively (P = .54). Conclusions and Relevance In young patients with residual and/or progressive benign or low-grade brain tumors requiring radiotherapy for long-term tumor control, SCRT compared with ConvRT achieves superior neurocognitive and neuroendocrine functional outcomes over 5 years without compromising survival. Trial Registration clinicaltrials.gov Identifier: NCT00517959.
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Affiliation(s)
- Rakesh Jalali
- Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, India
| | - Tejpal Gupta
- Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, India
| | - Jayant S Goda
- Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, India
| | - Savita Goswami
- Departments of Clinical Psychology and Psychiatry, Tata Memorial Centre, Mumbai, India
| | - Nalini Shah
- Department of Endocrinology, King Edward Memorial Hospital, Mumbai, India
| | - Debnarayan Dutta
- Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, India
| | - Uday Krishna
- Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, India
| | - Jayita Deodhar
- Departments of Clinical Psychology and Psychiatry, Tata Memorial Centre, Mumbai, India
| | - Padmavati Menon
- Department of Endocrinology, King Edward Memorial Hospital, Mumbai, India
| | - Sadhna Kannan
- Department of Biostatistics, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Mumbai, India
| | - Rajiv Sarin
- Neuro-Oncology Disease Management Group, Tata Memorial Centre, Mumbai, India
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16
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Kumar RS, Rotondo RL, Bradley JA, Vern-Gross T, Huh S, Indelicato DJ. Mid-treatment magnetic resonance imaging in pediatric intracranial low-grade gliomas treated with proton beam therapy. Acta Oncol 2017; 56:1243-1247. [PMID: 28339304 DOI: 10.1080/0284186x.2017.1306105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
| | - Ronny L. Rotondo
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Julie A. Bradley
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL, USA
| | | | - Soon Huh
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Daniel J. Indelicato
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL, USA
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17
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Krishnatry R, Zhukova N, Guerreiro Stucklin AS, Pole JD, Mistry M, Fried I, Ramaswamy V, Bartels U, Huang A, Laperriere N, Dirks P, Nathan PC, Greenberg M, Malkin D, Hawkins C, Bandopadhayay P, Kieran MW, Manley PE, Bouffet E, Tabori U. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study. Cancer 2016; 122:1261-9. [PMID: 26970559 DOI: 10.1002/cncr.29907] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 12/01/2015] [Accepted: 12/23/2015] [Indexed: 01/05/2023]
Abstract
BACKGROUND The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown. METHODS This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. RESULTS At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. CONCLUSIONS The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients.
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Affiliation(s)
- Rahul Krishnatry
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Labatt Brain Tumor Research Centre, University of Toronto, Toronto, Canada.,Radiation Medicine Program, Princess Margaret Hospital, University of Toronto, Toronto, Canada
| | - Nataliya Zhukova
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Labatt Brain Tumor Research Centre, University of Toronto, Toronto, Canada.,Program in Genetics and Genome Biology, University of Toronto, Toronto, Canada.,Pediatric Oncology Group of Ontario, Toronto, Canada
| | | | - Jason D Pole
- Pediatric Oncology Group of Ontario, Toronto, Canada
| | - Matthew Mistry
- Labatt Brain Tumor Research Centre, University of Toronto, Toronto, Canada.,Program in Genetics and Genome Biology, University of Toronto, Toronto, Canada.,Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Iris Fried
- Hadassah Medical Centre, Jerusalem, Israel
| | - Vijay Ramaswamy
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Ute Bartels
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Annie Huang
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Labatt Brain Tumor Research Centre, University of Toronto, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Normand Laperriere
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Radiation Medicine Program, Princess Margaret Hospital, University of Toronto, Toronto, Canada
| | - Peter Dirks
- Labatt Brain Tumor Research Centre, University of Toronto, Toronto, Canada.,Division of Neurosurgery, University of Toronto, Toronto, Canada
| | - Paul C Nathan
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Mark Greenberg
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Pediatric Oncology Group of Ontario, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - David Malkin
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Program in Genetics and Genome Biology, University of Toronto, Toronto, Canada.,Pediatric Oncology Group of Ontario, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Cynthia Hawkins
- Labatt Brain Tumor Research Centre, University of Toronto, Toronto, Canada.,Division of Pathology, University of Toronto, Toronto, Canada
| | - Pratiti Bandopadhayay
- Division of Pediatric Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute/Boston Children's Hospital, Boston, Massachusetts.,Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Mark W Kieran
- Division of Pediatric Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute/Boston Children's Hospital, Boston, Massachusetts
| | - Peter E Manley
- Division of Pediatric Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute/Boston Children's Hospital, Boston, Massachusetts
| | - Eric Bouffet
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Uri Tabori
- Division of Hematology/Oncology, University of Toronto, Toronto, Canada.,Labatt Brain Tumor Research Centre, University of Toronto, Toronto, Canada.,Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
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18
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Abstract
BACKGROUND Low-grade gliomas have good overall survival rates in pediatric patients compared to adults. There are some case series that reported the effectiveness and safety of Gamma Knife radiosurgery, yet they are limited in number of patients. We aimed to review the relevant literature for pediatric low-grade glial tumors treated with stereotactic radiosurgery, specifically Gamma Knife radiosurgery, and to present an exemplary case. CASE DESCRIPTION A 6-year-old boy was admitted to clinic due to head trauma. He was alert, cooperative, and had no obvious motor or sensorial deficit. A head CT scan depicted a hypodense zone at the right caudate nucleus. The brain magnetic resonance imaging (MRI) depicted a mass lesion at the same location. A stereotactic biopsy was performed. Histopathological diagnosis was low-grade astrocytoma (grade II, World Health Organization (WHO) classification, 2007). Gamma Knife radiosurgery was applied to the tumor bed. Tumor volume was 21.85 cm(3). Fourteen gray was given to 50% isodose segment of the lesion (maximal dose of 28 Gy). The tumor has disappeared totally in 4 months, and the patient was tumor-free 21 months after the initial treatment. DISCUSSION AND CONCLUSION The presented literature review represents mostly single-center experiences with different patient and treatment characteristics. Accordingly, a mean/median margin dose of 11.3-15 Gy with Gamma Knife radiosurgery (GKRS) is successful in treatment of pediatric and adult low-grade glial tumor patients. However, prospective studies with a large cohort of pediatric patients should be conducted to make a more comprehensive conclusion for effectiveness and safety of GKRS in pediatric low-grade glial tumors.
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19
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Greenberger BA, Pulsifer MB, Ebb DH, MacDonald SM, Jones RM, Butler WE, Huang MS, Marcus KJ, Oberg JA, Tarbell NJ, Yock TI. Clinical Outcomes and Late Endocrine, Neurocognitive, and Visual Profiles of Proton Radiation for Pediatric Low-Grade Gliomas. Int J Radiat Oncol Biol Phys 2014; 89:1060-1068. [DOI: 10.1016/j.ijrobp.2014.04.053] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 03/27/2014] [Accepted: 04/29/2014] [Indexed: 12/18/2022]
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20
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Bergthold G, Bandopadhayay P, Bi WL, Ramkissoon L, Stiles C, Segal RA, Beroukhim R, Ligon KL, Grill J, Kieran MW. Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta Rev Cancer 2014; 1845:294-307. [PMID: 24589977 DOI: 10.1016/j.bbcan.2014.02.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 02/20/2014] [Indexed: 12/17/2022]
Abstract
Low-grade gliomas represent the most frequent brain tumors arising during childhood. They are characterized by a broad and heterogeneous group of tumors that are currently classified by the WHO according to their morphological appearance. Here we review the clinical features of these tumors, current therapeutic strategies and the recent discovery of genomic alterations characteristic to these tumors. We further explore how these recent biological findings stand to transform the treatment for these tumors and impact the diagnostic criteria for pediatric low-grade gliomas.
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Affiliation(s)
| | - Pratiti Bandopadhayay
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Boston Children's Hospital, Boston, MA, USA
| | - Wenya Linda Bi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Lori Ramkissoon
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Charles Stiles
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Rosalind A Segal
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA
| | - Rameen Beroukhim
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Keith L Ligon
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jacques Grill
- Departement de Cancerologie de l'enfant et de l'adolescent, Gustave Roussy and Unité Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Université Paris-Sud, Villejuif, France
| | - Mark W Kieran
- Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
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21
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Radiotherapy in pediatric pilocytic astrocytomas. A subgroup analysis within the prospective multicenter study HIT-LGG 1996 by the German Society of Pediatric Oncology and Hematology (GPOH). Strahlenther Onkol 2013; 189:647-55. [PMID: 23831852 DOI: 10.1007/s00066-013-0357-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Accepted: 03/25/2013] [Indexed: 12/19/2022]
Abstract
PURPOSE We evaluated clinical outcomes in the subset of patients who underwent radiotherapy (RT) due to progressive pilocytic astrocytoma within the Multicenter Treatment Study for Children and Adolescents with a Low Grade Glioma HIT-LGG 1996. PATIENTS AND METHODS Eligibility criteria were fulfilled by 117 patients. Most tumors (65 %) were located in the supratentorial midline, followed by the posterior fossa (26.5 %) and the cerebral hemispheres (8.5 %). Median age at the start of RT was 9.2 years (range 0.7-17.4 years). In 75 cases, external fractionated radiotherapy (EFRT) was administered either as first-line nonsurgical treatment (n = 58) or after progression following primary chemotherapy (n = 17). The median normalized total dose was 54 Gy. Stereotactic brachytherapy (SBT) was used in 42 selected cases. RESULTS During a median follow-up period of 8.4 years, 4 patients (3.4 %) died and 33 (27.4 %) experienced disease progression. The 10-year overall (OS) and progression-free survival (PFS) rates were 97 and 70 %, respectively. No impact of the RT technique applied (EFRT versus SBT) on progression was observed. The 5-year PFS was 76 ± 5 % after EFRT and 65 ± 8 % after SBT. Disease progression after EFRT was not influenced by gender, neurofibromatosis type 1 (NF1) status, tumor location (hemispheres versus supratentorial midline versus posterior fossa), age or prior chemotherapy. Normalized total EFRT doses of more than 50.4 Gy did not improve PFS rates. CONCLUSION EFRT plays an integral role in the treatment of pediatric pilocytic astrocytoma and is characterized by excellent tumor control. A reduction of the normalized total dose from 54 to 50.4 Gy appears to be feasible without jeopardizing tumor control. SBT is an effective treatment alternative.
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22
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Magrini S, Feletti A, Marton E, Longatti P. Gliomas of the pineal region. J Neurooncol 2013; 115:103-11. [PMID: 23820809 DOI: 10.1007/s11060-013-1200-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 06/27/2013] [Indexed: 10/26/2022]
Abstract
Although several series of pineal region tumors are available, the issue of pineal gliomas has been scarcely faced in the literature. Gliomas are usually included in largest series of pineal neoplasms. Therefore, whether pineal gliomas share the biological behavior of either hemispheric gliomas or other midline lesions is not yet defined. The aim of this retrospective study is to analyze long-term morbidity and mortality of these lesions. In English published literature gliomas account for about 14-22 % of all pineal region tumors. Most of these tumors are pilocytic astrocytomas, while glioblastoma multiforme is rare. We retrospectively analyzed all pineal region tumors operated on in our department in the last 28 years, and identified eight pineal astrocytomas, accounting for 14.03 % of all pineal tumors. The series includes four pilocytic astrocytomas, two grade II diffuse astrocytomas, and two anaplastic astrocytomas. A comprehensive review of the available literature data shows that the mean survival time of WHO grade II gliomas is shorter when tumor grows in the pineal region than for hemispheric locations, although the limited amount of available data prevents a rigorous statistical analysis. This difference might be due to the peculiar infiltrating behavior of pineal tumors, which often can't be satisfactorily resected from vital structures.
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Affiliation(s)
- Salima Magrini
- Department of Neurosurgery, Treviso Regional Hospital, University of Padova, Piazzale Ospedale 1, 31100, Treviso, Italy
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23
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Paulino AC, Mazloom A, Terashima K, Su J, Adesina AM, Okcu MF, Teh BS, Chintagumpala M. Intensity-modulated radiotherapy (IMRT) in pediatric low-grade glioma. Cancer 2013; 119:2654-9. [PMID: 23633429 DOI: 10.1002/cncr.28118] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Accepted: 03/11/2013] [Indexed: 11/11/2022]
Abstract
BACKGROUND The objective of this study was to evaluate local control and patterns of failure in pediatric patients with low-grade glioma (LGG) who received treatment with intensity-modulated radiation therapy (IMRT). METHODS In total, 39 children received IMRT after incomplete resection or disease progression. Three methods of target delineation were used. The first was to delineate the gross tumor volume (GTV) and add a 1-cm margin to create the clinical target volume (CTV) (Method 1; n = 19). The second was to add a 0.5-cm margin around the GTV to create the CTV (Method 2; n = 6). The prescribed dose to the GTV was the same as dose to the CTV for both Methods 1 and 2 (median, 50.4 grays [Gy]). The final method was dose painting, in which a GTV was delineated with a second target volume (2TV) created by adding 1 cm to the GTV (Method 3; n = 14). Different doses were prescribed to the GTV (median, 50.4 Gy) and the 2TV (median, 41.4 Gy). RESULTS The 8-year progression-free and overall survival rates were 78.2% and 93.7%, respectively. Seven failures occurred, all of which were local in the high-dose (≥95%) region of the IMRT field. On multivariate analysis, age ≤5 years at time of IMRT had a detrimental impact on progression-free survival. CONCLUSIONS IMRT provided local control rates comparable to those provided by 2-dimensional and 3-dimensional radiotherapy. Margins ≥1 cm added to the GTV may not be necessary, because excellent local control was achieved by adding a 0.5-cm margin (Method 2) and by dose painting (Method 3).
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Affiliation(s)
- Arnold C Paulino
- Department of Radiation Oncology, The Methodist Hospital and Weil-Cornell Medical College, Houston, Texas, USA.
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24
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Gnekow AK, Falkenstein F, von Hornstein S, Zwiener I, Berkefeld S, Bison B, Warmuth-Metz M, Driever PH, Soerensen N, Kortmann RD, Pietsch T, Faldum A. Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol 2012; 14:1265-84. [PMID: 22942186 DOI: 10.1093/neuonc/nos202] [Citation(s) in RCA: 180] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The Hirntumorstudien (HIT)-LGG-1996 protocol offered a comprehensive treatment strategy for pediatric patients with low-grade glioma (LGG), ie, observation, surgery, adjuvant radiotherapy, and chemotherapy to defer the start of irradiation in young children. In this current study, we sought to determine clinical factors for progression and survival. Between October 1, 1996 and March 31, 2004, 1031 patients were prospectively recruited into an observation arm (n = 668) and a nonsurgical arm stratifying 12 months of vincristine-carboplatin chemotherapy (n = 216) and conventional radiotherapy/brachytherapy (n = 147) in an age-dependent manner. Median patient age was 6.9 years; 28 patients had diencephalic syndrome, 44 had dissemination, and 108 had neurofibromatosis type 1(NF-1). Main tumor location was the supratentorial midline (40.4%), and the main histology was pilocytic astrocytoma (67.9%). Following a median observation of 9.3 years, 10-year overall survival (OS) was 0.94 and 10-year event-free survival (EFS) was 0.47. Ten-year progression-free survival was 0.62 following radiotherapy and 0.44 following chemotherapy. Sixty-one of 216 chemotherapy patients received radiotherapy 0.3-8.7 years after initial diagnosis. By multivariate analysis, diencephalic syndrome and incomplete resection were found to be unfavorable factors for OS and EFS, age ≥11 years for OS, and supratentorial midline location for EFS. Dissemination, age <1 year, and nonpilocytic histology were unfavorable factors for progression following radiotherapy (138 patients); and diencephalic syndrome, dissemination, and age ≥11 years were unfavorable factors following chemotherapy (210 patients). NF-1 patients and boys experienced prolonged tumor stabilization with chemotherapy. A nationwide multimodal treatment strategy is feasible for pediatric LGG. Extended follow-up yielded results comparable to single-institution series for the treatment groups. Three-quarters of surviving chemotherapy patients have not yet received radiation therapy. Infants with or without diencephalic syndrome and dissemination bear the highest risk for death and progression following diagnosis or treatment.
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Affiliation(s)
- Astrid K Gnekow
- Hospital for Children and Adolescents, Klinikum Augsburg, Germany.
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25
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Bernier-Chastagner V, Supiot S, Carrie C, Helfre S. [Stereotactic radiotherapy in pediatric indications]. Cancer Radiother 2012; 16 Suppl:S111-5. [PMID: 22658965 DOI: 10.1016/j.canrad.2011.09.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 08/11/2011] [Accepted: 09/01/2011] [Indexed: 11/26/2022]
Abstract
Stereotactic radiotherapy is a very high precision procedure, which has been limited to radiosurgery for a long time. Technological improvements allowed the development of radiotherapy in stereotactic conditions, leading to a lot of innovations. Previously indicated for cerebral pathologies, this procedure is now developed for extracerebral locations. In paediatrics, stereotactic radiotherapy is still limited, delivered precociously, due to the possibility of long-term late effects that needs to be addressed. This review reports the different useful conditions, technical evolutions, and the current validated paediatric indications, with differences from adults, and future directions.
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Affiliation(s)
- V Bernier-Chastagner
- Département de radiothérapie, centre Alexis-Vautrin, avenue de Bourgogne, Vandœuvre-lès-Nancy cedex, France.
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Stereotactic iodine-125 brachytherapy for treatment of inoperable focal brainstem gliomas of WHO grades I and II: feasibility and long-term outcome. J Neurooncol 2012; 109:273-83. [PMID: 22580799 DOI: 10.1007/s11060-012-0889-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 04/23/2012] [Indexed: 11/27/2022]
Abstract
Microsurgical resection is the most frequently suggested treatment option for accessible focal brainstem gliomas (F-BSG) of World Health Organization (WHO) grades I and II. Because of their location in the highly eloquent brain, however, resection is associated with permanent postoperative morbidity, ranging from 12 to 33 %. Only a few reports have suggested stereotactic brachytherapy (SBT) with implantation of iodine-125 seeds as a local treatment alternative. Between 1993 and 2010, 47 patients were treated with SBT (iodine-125 seeds; cumulative surface dose 50-65 Gy) for inoperable F-BSG, WHO grades I and II, in one of the largest reported patient series. We evaluated procedure-related complications, clinical outcome, and progression-free and overall survival (PFS, OS). Median follow-up was 81.6 months. Procedure-related mortality was zero. Within 30 days of seed implantation six patients (12.8 %) had transient neurological deficits. Two patients (4.3 %) deteriorated permanently. Space-occupying cysts occurred in six patients (12.8 %) after a median of 28.5 months, and required surgical intervention. Nine patients (19.1 %) presented with tumor relapse after a median of 56.6 months (range 7.9-118.0 months). For the remaining 38 patients complete response was observed for 23.4 %, partial response for 29.8 %, and stable disease for 27.7 %. Actuarial PFS was 97.7 ± 2.2, 92.8 ± 4.0, 81.2 ± 6.5, and 62.0 ± 10.4 % after 1, 2, 5, and 10 years, respectively. Corresponding OS was 100 ± 0.0 % (1 and 2 years), 97.4 ± 2.6 % (5 years), and 87.6 ± 7.0 % (10 years). SBT is a comparatively safe, minimally invasive, and highly effective local treatment option for patients with inoperable F-BSG WHO grades I and II; it merits further evaluation in prospective randomized trials.
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Sobol G, Musioł K, Kalina M, Kalina-Faska B, Mizia-Malarz A, Ficek K, Mandera M, Woś H, Małecka-Tendera E. The evaluation of function and the ultrasonographic picture of thyroid in children treated for medulloblastoma. Childs Nerv Syst 2012; 28:399-404. [PMID: 22080382 DOI: 10.1007/s00381-011-1625-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 10/18/2011] [Indexed: 10/15/2022]
Abstract
PURPOSE Medulloblastoma (MB) is one of the most frequent and sensitive to radiation aggressive brain tumor in children. Abnormalities of the thyroid function are common complications of head and neck irradiation for childhood cancer. The aim of this study was to assess thyroid function in children treated for medulloblastoma according to the treatment protocol phase. PATIENTS AND METHODS Twenty-three children with MB were enrolled to this study. All patients underwent chemotherapy and radiotherapy to the whole craniospinal axis and boost with the conformal therapy restricted to the tumor bed to a total dose of 54 Gy. Thyroid function was evaluated based on thyroid-stimulating hormone (TSH), free thyroxine (fT4) levels controlled before MB treatment, directly after irradiation and at the end of the treatment protocol. Ultrasonography has been used to detect parenchymal abnormalities. RESULTS All patients presented normal thyroid hormone range before chemotherapy. Hypothyroidism was found in 12 patients in the course of treatment, in 2 patients hormone deficits diagnosed directly after irradiation, in 10 patients such condition was observed at the end of the whole therapy. All of these patients needed thyroid hormone substitution. None of them presented clinical symptoms of hypothyroidism. Ultrasound-detected abnormalities have been found in 20 patients. CONCLUSIONS It is crucial to monitor the functions of the thyroid gland in children treated for medulloblastoma because of the high risk of hypothyroidism resulting from the treatment. The change in the echogenicity of the thyroid gland may be an early marker for a dysfunction of this organ in children treated for medulloblastoma.
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Affiliation(s)
- G Sobol
- Department of Pediatric Oncology, Haematology and Chemotherapy, Medical University of Silesia, Upper Silesia Children's Care Health Centre, Katowice, Poland.
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Newton HB, Rudà R, Soffietti R. Ependymomas, neuronal and mixed neuronal-glial tumors, dysembroblastic neuroepithelial tumors, pleomorphic xanthoastrocytomas, and pilocytic astrocytomas. HANDBOOK OF CLINICAL NEUROLOGY 2012; 105:551-567. [PMID: 22230518 DOI: 10.1016/b978-0-444-53502-3.00008-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Affiliation(s)
- Herbert B Newton
- Department of Neurology, The Ohio State University Medical Center, Columbus, OH, USA.
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Diagnosis and management of optic nerve glioma. J Clin Neurosci 2011; 18:1585-91. [DOI: 10.1016/j.jocn.2011.09.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 09/10/2011] [Indexed: 11/30/2022]
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Ruge MI, Simon T, Suchorska B, Lehrke R, Hamisch C, Koerber F, Maarouf M, Treuer H, Berthold F, Sturm V, Voges J. Stereotactic brachytherapy with iodine-125 seeds for the treatment of inoperable low-grade gliomas in children: long-term outcome. J Clin Oncol 2011; 29:4151-9. [PMID: 21969508 DOI: 10.1200/jco.2011.37.3381] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Resection is generally considered the gold standard for treatment of low-grade (WHO grades I and II) gliomas (LGGs) in childhood. However, approximately 30% to 50% of these tumors are inoperable because of their localization in highly eloquent brain areas. A few reports have suggested stereotactic brachytherapy (SBT) with implantation of iodine-125 ((125)I) seeds as a safe and effective local treatment alternative. This single-center study provides a summary of the long-term outcome after SBT in one of the largest reported patient series. PATIENTS AND METHODS All pediatric patients treated with SBT ((125)I seeds; cumulative therapeutic dose 50-65 Gy within 9 months) by our group for LGG with follow-up of more than 6 months were included. Clinical and radiologic outcome, time to progression, and overall survival were evaluated. Prognostic factors (age, sex, Karnofsky performance score, tumor volume, and histology) for survival and disease progression were investigated. RESULTS In all, 147 of 160 pediatric patients treated with SBT (from 1982 through 2009) were analyzed in detail. Procedure-related mortality was zero, and the 30-day morbidity was transient and low (5.4%). Survival rates at 5 and 10 years were 93%, and 82%, respectively, with no significant difference between WHO grades I and II tumors (median follow-up, 67.1 ± 57.7 months). Twenty-one (14.8%) of 147 patients presented with tumor relapse. The remaining 126 patients revealed complete response in 24.6%, partial response in 31.0%, and stable disease in 29.6%. Neurologic status improved (57.8%) or remained stable (23.0%). None of the evaluated factors had significant impact on the study's end points except tumor volume more than 15 mL, which caused significantly higher rates of tumor recurrence (P < .05). CONCLUSION We demonstrate that SBT represents a safe, minimally invasive, and highly effective local treatment option for pediatric patients with inoperable LGG WHO grades I and II.
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Packer RJ. Radiation Therapy for Pediatric Low-Grade Gliomas: Survival and Sequelae. Curr Neurol Neurosci Rep 2010; 10:10-3. [DOI: 10.1007/s11910-009-0084-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Brain Tumors. Neurosurgery 2010. [DOI: 10.1007/978-3-540-79565-0_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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[Stereotactical radiotherapy in pediatrics indications]. Cancer Radiother 2009; 13:543-9. [PMID: 19762263 DOI: 10.1016/j.canrad.2009.06.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2009] [Revised: 06/04/2009] [Accepted: 06/05/2009] [Indexed: 12/25/2022]
Abstract
Stereotactical radiotherapy is a very high precision procedure, limited to radiosurgery since a long time. Technologic progress permitted to develop radiotherapy in stereotactical conditions, leading to a lot of innovations. Previously indicated for cerebral pathologies, this procedure is now developed for extracerebral locations. In pediatrics, stereotactical radiotherapy is still limited, delivered precociously, due to the possibility of long-term late effects that needs to be to addressed. This review reports the different useful conditions, technical evolutions, and the current validated pediatric indications, with differences from adults, and future directions. Current state of pediatric stereotactical radiotherapy used in France is presented.
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Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 2009; 27:3691-7. [PMID: 19581535 DOI: 10.1200/jco.2008.21.2738] [Citation(s) in RCA: 281] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE We conducted a prospective trial to evaluate late effects in pediatric patients with low-grade glioma (LGG) treated with conformal radiation therapy (CRT). PATIENTS AND METHODS Between August 1997 and August 2006, 78 pediatric patients with LGG (mean age, 9.7 years; standard deviation, +/-4.4 years) received 54 Gy of CRT with a 10-mm clinical target volume margin. Tumor locations were diencephalon (n = 58), cerebral hemisphere (n = 3), and cerebellum (n = 17). Baseline and serial evaluations were performed to identify deficits in cognition, endocrine function, and hearing. Deficits were correlated with clinical factors and radiation dose within specific normal tissue volumes. RESULTS Cognitive effects of CRT through 5 years after CRT correlated with patient age, neurofibromatosis type 1 status, tumor location and volume, extent of resection, and radiation dose. The effect of age exceeded that of radiation dose; patients younger than 5 years experienced the greatest decline in cognition. Before CRT, growth hormone (GH) secretion abnormality was diagnosed in 24% of tested patients, and 12% had precocious puberty. The 10-year cumulative incidence of GH replacement was 48.9%; of thyroid hormone replacement, 64.0%; of glucocorticoid replacement, 19.2%; and of gonadotropin-releasing hormone analog therapy, 34.2%. The mean +/- standard errors of the cumulative incidence of hearing loss at 10 years did not exceed 5.7% +/- 3.3% at any frequency. CONCLUSION To our knowledge, this is the largest series of prospectively followed children with LGG to undergo irradiation. Adverse effects are limited and predictable for most patients; however, this study provides additional evidence that CRT should be delayed for young patients and identifies the potential benefits of reducing radiation dose to normal brain.
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Affiliation(s)
- Thomas E Merchant
- Department of Radiological Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105-3678, USA.
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Merchant TE, Kun LE, Wu S, Xiong X, Sanford RA, Boop FA. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 2009; 27:3598-604. [PMID: 19581536 DOI: 10.1200/jco.2008.20.9494] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The use of radiotherapy in pediatric low-grade glioma (LGG) is controversial, especially for young patients. We conducted a phase II trial of conformal radiation therapy (CRT) to estimate disease control by using a 10-mm clinical target volume (CTV) margin. MATERIALS AND METHODS Between August 1997 and August 2006, 78 pediatric patients with LGG and a median age of 8.9 years (range, 2.2 to 19.8 years) received 54 Gy CRT by using a 10-mm CTV and by targeting with systematic magnetic resonance imaging (MRI) registration. Tumor locations were diencephalon (n = 58), cerebral hemisphere (n = 3), and cerebellum (n = 17). Sixty-seven patients had documented or presumed WHO grade 1 tumors, 25 patients had prior chemotherapy, and 13 patients had neurofibromatosis type 1. RESULTS During a median follow-up of 89 months, 13 patients experienced disease progression. One patient experienced marginal treatment failure, eight experienced local failures, and four experienced metastatic failure. The mean and standard error 5- and 10-year event-free (87.4% +/- 4.4% and 74.3% +/- 15.4%, respectively) and overall (98.5% +/- 1.6% and 95.9% +/- 5.8%, respectively) survival rates were determined. The mean and standard error cumulative incidences of local failure at 5 and 10 years were 8.7% +/- 3.5% and 16.4% +/- 5.4%, respectively. The mean and standard error cumulative incidence of vasculopathy was 4.79% +/- 2.73% at 6 years, and it was higher for those younger than 5 years of age (P = .0105) at the time of CRT. CONCLUSION This large, prospective series of irradiated children with LGG demonstrates that CRT with a 10-mm CTV does not compromise disease control. The results suggest that CRT should be delayed in young patients to reduce the risk of vasculopathy.
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Affiliation(s)
- Thomas E Merchant
- Dept of Radiological Sciences, Mail Stop 220, St Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105-3678, USA.
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Abstract
Modern neuroimaging provides excellent characterization of anterior visual pathway gliomas, often obviating the need for biopsy of the tumor. Management remains controversial, but if there is progression, chemotherapy is preferred for young patients. Stereotactically guided conformal radiotherapy and proton beam radiotherapy allow smaller, more precise doses of radiation to be administered and can be considered in older children with progressive disease. A mouse model of NF-1 with optic pathway gliomas has the potential to provide important insights into the development of gliomas as well as serving as a model for their effective treatment.
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Affiliation(s)
- Susan M Pepin
- Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
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Abstract
PURPOSE OF REVIEW Advances have been made in the treatment of primary optic nerve tumours. With a focus on the last few years' publications, recommendations for clinical management are being developed. RECENT FINDINGS In low-grade optic nerve glioma, two divergent developments are observed: an increasing reluctance in treating such tumours because of reports about treatment toxicity (secondary tumours, moyamoya syndrome) and a steady and marked improvement both in radiotherapy and chemotherapy. Many reports on beneficial effects of radiotherapy on optic nerve meningioma have been published. Radiotherapy does not only preserve but in many cases even improves or restores visual function and has, therefore, become the therapy of choice in this tumour. SUMMARY Establishing a treatment plan in cases of optic nerve glioma is difficult and must be made on an individual basis. Although both chemotherapy and radiotherapy can stabilize and sometimes improve vision in progressive tumours, chemotherapy is the preferred modality in children younger than 9 years and in patients with neurofibromatosis 1. In functionally progressive optic nerve meningioma with useful visual function, multifractioned stereotactic conformal radiotherapy is the treatment of choice.
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Wilhelm H. How to Handle Benign Optic Glioma of Childhood: A Short Overview. Neuroophthalmology 2009. [DOI: 10.1080/01658100902930529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Wentworth S, Pinn M, Bourland JD, deGuzman AF, Ekstrand K, Ellis TL, Glazier SS, McMullen KP, Munley M, Stieber VW, Tatter SB, Shaw EG. Clinical Experience With Radiation Therapy in the Management of Neurofibromatosis-Associated Central Nervous System Tumors. Int J Radiat Oncol Biol Phys 2009; 73:208-13. [DOI: 10.1016/j.ijrobp.2008.03.073] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2008] [Revised: 03/25/2008] [Accepted: 03/27/2008] [Indexed: 10/21/2022]
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Lo SS, Fakiris AJ, Abdulrahman R, Henderson MA, Chang EL, Suh JH, Timmerman RD. Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy in pediatric brain tumors. Expert Rev Neurother 2008; 8:121-32. [PMID: 18088205 DOI: 10.1586/14737175.8.1.121] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Brain tumors are the most common solid tumor in childhood. Surgery and/or fractionated radiotherapy are conventional treatment modalities. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) are advanced radiation therapy techniques that have been frequently used in adults with brain tumors but they are less frequently used in pediatric patients. SRS and FSRT can potentially add to the armamentarium against brain tumors in children. This article will review the role of SRS and FSRT in the management of pediatric brain tumors.
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Affiliation(s)
- Simon S Lo
- Department of Radiation Medicine, Arthur G James Cancer Hospital, Ohio State University Medical Center, 300 West 10th Avenue, Ste 088A, Columbus, OH 43210, USA.
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Massimi L, Tufo T, Di Rocco C. Management of optic-hypothalamic gliomas in children: still a challenging problem. Expert Rev Anticancer Ther 2008; 7:1591-610. [PMID: 18020927 DOI: 10.1586/14737140.7.11.1591] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Optic pathway-hypothalamic gliomas (OPHGs) are rare, often unresectable tumors that mostly occur in childhood. Their biological behavior is unpredictable, although they tend to follow an aggressive clinical course in infants and a benign course in children with neurofibromatosis type 1. Optimal management is still controversial. Nonprogressing OPHGs are usually followed by surveillance alone. Surgery is advocated for progressing tumors to decompress the optic pathways, obtain a quick relief from intracranial hypertension and allow histologic examination (when needed). The current trend is in favor of conservative surgical behavior, except for resectable tumors. Chemotherapy is increasingly used in the management of OPHGs, especially in infants, to delay radiotherapy. Carboplatin and vincristine are the most frequently used drugs, although several chemotherapeutic agents in different combinations are currently employed with good results. Radiotherapy is utilized in children over 5 years of age as an adjuvant or as an alternative to surgery. The prognosis of OPHGs is quite good, with regard to the overall survival rate (70-100% at 5 years), but less favorable in terms of late morbidity.
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Affiliation(s)
- Luca Massimi
- Catholic University Medical School, Pediatric Neurosurgery, Institute of Neurosurgery, Largo A Gemelli 8, 00168, Rome, Italy.
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Hargrave DR, Zacharoulis S. Pediatric CNS tumors: current treatment and future directions. Expert Rev Neurother 2007; 7:1029-42. [PMID: 17678498 DOI: 10.1586/14737175.7.8.1029] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Pediatric CNS tumors are the most common solid tumor of childhood and are the leading cause of cancer-related death in this age group. Improving prognosis is not the only challenge facing physicians managing these young patients as it is vital to consider the quality of survival. Current management strategies rely on surgery, radiotherapy and conventional cytotoxic chemotherapy, and although ongoing clinical trials continue to refine these treatments, newer approaches are required. This article will discuss current treatment standards for the most common pediatric CNS tumors: astrocytomas (low- and high-grade glioma), ependymoma and primitive neuroectodermal tumors (medulloblastoma), as well as future biological-based novel therapies.
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Affiliation(s)
- Darren R Hargrave
- Drug Development, Pediatric Oncology Unit, Royal Marsden Hospital, Sutton, Surrey, UK.
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Hafez RFA. Stereotaxic gamma knife surgery in treatment of critically located pilocytic astrocytoma: preliminary result. World J Surg Oncol 2007; 5:39. [PMID: 17394660 PMCID: PMC1852107 DOI: 10.1186/1477-7819-5-39] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2006] [Accepted: 03/29/2007] [Indexed: 11/30/2022] Open
Abstract
Background Low-grade gliomas are uncommon primary brain tumors, located more often in the posterior fossa, optic pathway, and brain stem and less commonly in the cerebral hemispheres. Case presentations Two patients with diagnosed recurrent cystic pilocytic astrocytoma critically located within the brain (thalamic and brain stem) were treated with gamma knife surgery. Gamma knife surgery (GKS) did improve the patient's clinical condition very much which remained stable later on. Progressive reduction on the magnetic resonance imaging (MRI) studies of the solid part of the tumor and almost disappearance of the cystic component was achieved within the follow-up period of 36 months in the first case with the (thalamic located lesion) and 22 months in the second case with the (brain stem located lesion). Conclusion Gamma knife surgery represents an alternate tool in the treatment of recurrent and/or small postoperative residual pilocytic astrocytoma especially if they are critically located
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Affiliation(s)
- Raef F A Hafez
- International Medical Center, Gamma Knife Center, Cairo- Egypt.
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Abstract
Strategies for the treatment of childhood cancer have changed considerably during the last 50 years and have led to dramatic improvements in long-term survival. Despite these accomplishments, CNS tumors remain the leading cause of death in pediatric oncology. Astrocytic tumors form the most common histologic group among childhood brain tumors. They are a heterogeneous group that from a practical therapeutic point of view can be subdivided into low-grade astrocytomas (LGA), optic pathway gliomas (OPG), high-grade astrocytomas (HGA), and brainstem gliomas (BSG). This article focuses on the practical application of treatments that lead to long-term survival, improved quality of life, and reduced long-term complications. Improvement in therapy has led to better outcomes for patients with LGA and OPG. Careful follow-up without any treatment is indicated for a small percentage of patients diagnosed with LGA with an indolent course including children with neurofibromatosis type 1 (NF1). Surgery is the main recommended treatment for children with resectable LGA. Radiation therapy is generally recommended for children with progressive LGA, or after failure of chemotherapy, accomplishing tumor control at 10 years in over 60% of patients. Cytotoxic chemotherapy is usually reserved for children who have had treatment failure with surgery and radiation therapy. It is also offered for children who are too young to be treated with radiation or to defer or avoid radiotherapy. Carboplatin and vincristine achieve 5% complete and 28% partial responses but the use of vincristine is criticized due to poor penetration of the CNS. A regimen of tioguanine, procarbazine, mitolactol, lomustine, and vincristine is frequently administered as an alternative to carboplatin and vincristine in LGA. The introduction of temozolomide has allowed better responses, including a 24% complete response rate compared with 0-5% complete response rates with the previous regimens. OPG are usually histologically LGA, and are treated with similar chemotherapy regimens. OPG is the most common type of brain tumor associated with NF1. Tumor growth in some of these patients is slow with no treatment recommended for an extended period of time. The prognosis for children with the remaining types of astrocytomas remains poor. Surgical resection is typically the first step in the treatment of HGA followed in older children by radiation therapy. The data regarding chemotherapy are mixed. Combination chemotherapy before or after radiation, including cisplatin, carmustine, cyclophosphamide, and vincristine or carboplatin, ifosfamide, cyclophosphamide, and etoposide has provided disappointing results. Clinical trials with temozolomide and agents directed against single targets have not shown substantially better results, but it is hoped that currently conducted studies will provide better outcomes. Diffuse intrinsic BSG are among the most difficult-to-treat brain tumors. Surgical treatment is not recommended for diffuse intrinsic BSG and standard radiation therapy is typically given in children aged >3 years. None of the numerous chemotherapy regimens, including temozolomide, has provided a significant response rate or an improvement in survival. It is expected that newer agents affecting multiple targets such as AEE-788 and antineoplastons, and combinations of single-targeted agents with chemotherapy will provide better results. Careful evaluation of histology, location of the tumor, patient age, and consideration of treatment-related morbidity play an important part in selecting between clinical observation, surgery, radiation, chemotherapy, or investigational agents. The goals of treatment for astrocytic tumors should extend well beyond objective responses and increased survival. Improvement of quality of life is an equally important objective of treatment. Radiation therapy and chemotherapy result in serious late toxicities.
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Taylor RE. Current developments in radiotherapy for paediatric brain tumours. Eur J Paediatr Neurol 2006; 10:167-75. [PMID: 16954052 DOI: 10.1016/j.ejpn.2006.07.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Accepted: 07/30/2006] [Indexed: 11/23/2022]
Abstract
This review summarises current developments in radiation oncology and how they impact on the management of children with brain tumours. Improved understanding of radiobiology has led to attempts to improve the therapeutic ratio with hyperfractionated radiotherapy. Recent advances in planning and delivery of radiotherapy, including three-dimensional conformal radiotherapy, intensity modulated radiotherapy, and proton therapy allow a more precise localisation of the maximum dose region with maximum sparing of normal brain. Increasingly interactions between drugs and radiotherapy are exploited, but it is important to evaluate toxicity of combined modality therapy. The introduction of models to predict the impact of radiotherapy dose-volume parameters on long-term neuropsychological function will hopefully lead to further benefit with respect to sparing of normal tissue morbidity.
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Affiliation(s)
- Roger E Taylor
- Clinical Oncology, South West Wales Cancer Institute, Singleton Hospital, Swansea, West Glamorgan, SA2 8QA, UK.
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Siegel MJ, Finlay JL, Zacharoulis S. State of the art chemotherapeutic management of pediatric brain tumors. Expert Rev Neurother 2006; 6:765-79. [PMID: 16734524 DOI: 10.1586/14737175.6.5.765] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
CNS tumors are the most common solid tumor of childhood. This article will review current treatments for pediatric brain tumors; low-grade gliomas, high-grade gliomas, medulloblastomas and ependymomas. It will also highlight the treatments that are used for brain tumors in very young children and in children with recurrent brain tumors. The management of recurrent pediatric brain tumors unresponsive to standard therapy will be discussed. The agents used in this setting are mainly biological modifiers, which attempt to provide molecularly targeted therapy. Future directions of therapy for pediatric brain tumors are described. Future treatment paradigms will need to consider examining the use of multiple biological modifiers. Similarly, these agents will need to be examined in combination with cytotoxic chemotherapy. Finally, the future direction of pediatric neuro-oncology and the focus of the field as it battles pediatric brain tumors is discussed.
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Affiliation(s)
- Melissa J Siegel
- Childrens Hospital Los Angeles, The Neural Tumos Program, Childrens Center for Cancer and Blood Diseases, Los Angeles, California, USA.
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Higgins PD, Gerbi BJ, Macedon M, Dusenbery KE. Fractionated stereotactic radiotherapy for pediatric patients with retinoblastoma. J Appl Clin Med Phys 2006; 7:9-17. [PMID: 17533322 PMCID: PMC5722448 DOI: 10.1120/jacmp.v7i2.2161] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2005] [Revised: 01/26/2006] [Accepted: 12/31/1969] [Indexed: 12/04/2022] Open
Abstract
In this report, we discuss the application of a modified Gill‐Thomas‐Cosman (GTC) relocatable head frame to enable fractionated stereotactic radiotherapy (SRT) of infants under anesthesia. This system has been used to treat two infants, ages 12 and 18 months, for bilateral retinoblastoma on a Varian 6/100 linear accelerator. The GTC head frame was used to reproducibly position and treat the orbits of these children to between 2520 cGy and 3960 cGy in 180‐cGy fractions. A standard head and neck tray, with accompanying thermoplastic mask, was adapted to mount to the head frame to enable these treatments. We found the maximum average deviation in the repeat fixations, as compared with the initial fitting data, to be ±2mm. The overall average difference and standard deviation in measurement was 0.47±0.63mm for the first case and 0.19±0.94mm for the second case, with a combined average of 0.35±0.79mm overall from a total of 381 point measurements. The stereotactic treatment plan (Radionics®) incorporated a single isocenter for each orbit and 3 or 4 arcs per isocenter. An intercomparison has been made between this technique and a standard lateral field technique, designed using the stereotactic radiosurgery (SRS) planning system. Dose‐volume histograms and corresponding normal tissue complication probabilities (NTCP) based on pediatric bone growth inhibition have been calculated for each method for the orbital bone areas. We found that the NTCP is reduced from 95% or more in the standard treatment method to 16% or less with SRT. Use of the modified head frame provides excellent setup reproducibility, facilitates access to patients for anesthesia, and reduces the chances of a poor cosmetic result in these growing children. PACS number: 87.53.Ly
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Affiliation(s)
- Patrick D Higgins
- Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
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Abstract
The long-term survival of children with brain tumor has improved considerably in the last three decades, owing to advances in neuroimaging, neurosurgical, and radiation therapy modalities, coupled with the application of conventional chemotherapy. MRI, MR spectroscopy and diffusion-weighted MRI have contributed to more accurate diagnosis, prognostication and better treatment planning. Neurosurgical treatment has been advanced by the use of functional MRI, and intraoperative image-guided stereotactic techniques and electrophysiologic monitoring. The use of 3-D conformal and intensity-modulated radiation therapy, stereotactic radiosurgery, and radiosensitizing agents has made radiation therapy safer and more effective. Conventional chemotherapy, administered either alone or combined with radiation therapy has improved survival and quality of life of children with brain tumors. These improved outcomes have also occurred, due, in part, to their treatment on collaborative national and international studies. Recent promising diagnostic and therapeutic strategies have resulted from advances in understanding molecular brain tumor biology. Important new approaches include the refinement of drug-delivery strategies, the evaluation of biologic markers to stratify patients for optimal treatment and to exploit these molecular differences using "targeted" therapeutic strategies. These approaches include blocking tumor cell drug resistance mechanisms, immunotherapy, inhibition of molecular signal transduction pathways important in tumorigenesis, anti-angiogenic therapy, and gene therapy. The thrust of such approaches for children with brain tumors is especially directed at reducing the toxicity of therapy and improving quality-of-life, as well as increasing disease-free survival.
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Affiliation(s)
- Patricia L Robertson
- Department of Pediatrics and Neurology, Division of Pediatric Neurology, University of Michigan Health System, 1500 E. Medical Center Dr., L3215 Women's Hospital, Ann Arbor, 48109-0203, USA.
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