Kinder und Jugendliche mit intrakraniellem Ependymom – Empfehlungen der HIT-MED-Studiengruppe der GPOH zur Erstlinientherapie

Zusammenfassung

In den letzten Jahren wurden biologische Subgruppen des Ependymoms (EPN) identifiziert und in die aktuelle WHO-Klassifikation eingeführt, allerdings haben diese derzeit noch keinen Einfluss auf die Therapiestratifizierung. Jedoch finden sich immer mehr Hinweise, dass das klinische Verhalten abhängig von der Tumorbiologie ist: PF-EPN-A mit einem Zugewinn des Chromosom 1q beispielsweise sind mit einem hohen Risiko für Rezidive assoziiert, während das Überleben bei ST-EPN-YAP1 bei>90% liegt. Die insgesamt noch nicht zufriedenstellende Prognose zeigt, dass die Therapiestrategien weiter verbessert werden müssen. Das Ausmaß der Tumorresektion ist der wichtigste klinische Prognosefaktor, weshalb die Evaluation einer erneuten OP bei einem postoperativen Resttumor höchste Priorität hat. Darüber hinaus wird die Wirksamkeit der Lokalbestrahlung als bewiesen angesehen und derzeit im Alter>1 Jahr empfohlen. Der Stellenwert der Chemotherapie ist weiterhin unklar. Ein Ziel der europäischen klinischen Studie SIOP Ependymoma II ist, die Wirksamkeit verschiedener Chemotherapien zu evaluieren, so dass deutsche Patienten im Rahmen dieser Studie behandelt werden sollten, um den Kenntnisstand voranzutreiben. Neue prognostische biologische Parameter werden im Rahmen des Begleitprojekts BIOMECA validiert. Die Erkenntnisse dieser Begleitstudie sollen auch genutzt werden, um zielgerichtete Therapien sog. Targeted Therapies zu entwickeln. Für Patienten, die nicht im Rahmen der interventionellen Strata der Studie behandelt werden können, stellt die HIT-MED Guidance (aktuelle Version 5.2) eine Handlungsempfehlung dar. Der vorliegende Artikel gibt einen Überblick über Empfehlungen zu Diagnostik und Therapie für Kinder- und Jugendliche mit intrakraniellem Ependymom, sowie zur Behandlung im Rahmen der SIOP Ependymoma II Studie.

Abstract

Biological subtypes of ependymoma (EPN) have been introduced by the recent WHO classification and appear to have great impact on the clinical course, but have not yet found their way into clinical risk stratification. Further, the overall unfavorable prognosis underlines the fact that current therapeutic strategies need further evaluation for improvement. To date, there is no international consensus regarding first-line treatment for children with intracranial EPN. Extent of resection is known to be the most important clinical risk factor, leading to the consensus that consequent evaluation for re-surgery of postoperative residual tumor needs to have highest priority. Furthermore, efficacy of local irradiation is unquestioned and recommended for patients aged>1 year. In contrast, efficacy of chemotherapy is still under discussion. The European trial SIOP Ependymoma II aims at evaluating efficacy of different chemotherapy elements, leading to the recommendation to include German patients. The BIOMECA study, as biological accompanying study, aims at identifying new prognostic parameters. These results might help to develop targeted therapies for unfavorable biological subtypes. For patient who are not qualified for inclusion into the interventional strata, the HIT-MED Guidance 5.2 provides specific recommendations. This article is meant as an overview of national guidelines regarding diagnostics and treatment as well as of treatment according to the SIOP Ependymoma II trial protocol.

Schlüsselwörter

Ependymom - Therapieempfehlung - Radiotherapie - Chemotherapie - Kinder

Key words

ependymoma - guideline - radiotherapy - chemotherapy - children

Publication History

Article published online:
12 May 2023

• Literatur

• 1 Andreiuolo F, Varlet P, Tauziède-Espariat A. et al. Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features. Brain pathology (Zurich, Switzerland) 2019; 29: 205-216
• 2 Avula S, Peet A, Morana G. et al. European Society for Paediatric Oncology (SIOPE) MRI guidelines for imaging patients with central nervous system tumours. Child’s nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2021; 37: 2497-2508
• 3 Baroni LV, Sundaresan L, Heled A. et al. Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro-oncology 2021; 23: 1360-1370
• 4 Benesch M, Mynarek M, Witt H. et al. Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series. Oncologist 2019; 24: e921-e929
• 5 Bennett J, Erker C, Lafay-Cousin L. et al. Canadian Pediatric Neuro-Oncology Standards of Practice. Front Oncol 2020; 10: 593192
• 6 Board PDQPTE. Childhood Ependymoma Treatment (PDQ^®): Health Professional Version. In, PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US); 2002
• 7 Bouffet E, Tabori U, Bartels U. Paediatric ependymomas: should we avoid radiotherapy?. Lancet Oncol 2007; 8: 665-666
• 8 Cacciotti C, Fleming A, Ramaswamy V. Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy. J Pathol 2020; 251: 249-261
• 9 Cage TA, Clark AJ, Aranda D. et al. A systematic review of treatment outcomes in pediatric patients with intracranial ependymomas. Journal of neurosurgery Pediatrics 2013; 11: 673-681
• 10 Cavalli FMG, Hübner JM, Sharma T. et al. Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta neuropathologica 2018; 136: 227-237
• 11 Chang CH, Housepian EM, Herbert C. An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 1969; 93: 1351-1359
• 12 Copeland DR, deMoor C, Moore BD. et al. Neurocognitive development of children after a cerebellar tumor in infancy: A longitudinal study. J Clin Oncol 1999; 17: 3476-3486
• 13 Dobrovoljac M, Hengartner H, Boltshauser E. et al. Delay in the diagnosis of paediatric brain tumours. Eur J Pediatr 2002; 161: 663-667
• 14 Dufour C, Beaugrand A, Pizer B. et al. Metastatic Medulloblastoma in Childhood: Chang’s Classification Revisited. International journal of surgical oncology 2012; 2012: 245385
• 15 Elsamadicy AA, Koo AB, David WB. et al. Comparison of epidemiology, treatments, and outcomes in pediatric versus adult ependymoma. Neurooncol Adv 2020; 2: vdaa019-vdaa019
• 16 Erdmann F, Grabow D, Kaatsch P et al. Jahresbericht 2019 des Deutschen Kinderkrebsregister DKKR. In https://www.kinderkrebsregister.de/dkkr/ergebnisse/jahresberichte/jahresbericht-2019.html
• 17 Faltermeier V, Hagel C, Petrasch K. et al. MB-69 Relevance of cytospin quality for detection of microscopic leptomeningeal dissemination in medulloblastoma patients. Neuro-oncology 2016; 18: iii112-iii113
• 18 Fukuoka K, Kanemura Y, Shofuda T. et al. Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors. Acta neuropathologica communications 2018; 6: 134
• 19 Garvin JH, Selch MT, Holmes E. et al. Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children’s Cancer Group protocol 9942: a report from the Children’s Oncology Group. Pediatric blood & cancer 2012; 59: 1183-1189
• 20 Gessi M, Giagnacovo M, Modena P. et al. Role of Immunohistochemistry in the Identification of Supratentorial C11ORF95-RELA Fused Ependymoma in Routine Neuropathology. Am J Surg Pathol 2019; 43: 56-63
• 21 GPOH. Ependymome im Kindes- und Jugendalter (S1-Leitlinie). (01.04.2018)
• 22 GPOH. Langzeit – Nachsorge von krebskranken Kindern, Jugendlichen und jungen Erwachsenen – Vermeiden, Erkennen und Behandeln von Spätfolgen (S1-Leitlinie). (30.04.2021 )
• 23 GPOH, GNP. ZNS-Tumoren im Kindes- und Jugendalter: Leitsymptome und Diagnostik (S1-Leitlinie). (26.09.2016)
• 24 Grill J, Deley M-CL, Gambarelli D. et al. Postoperative Chemotherapy Without Irradiation for Ependymoma in Children Under 5 Years of Age: A Multicenter Trial of the French Society of Pediatric Oncology. Journal of Clinical Oncology 2001; 19: 1288-1296
• 25 Grundy RG, Wilne SA, Weston CL. et al. Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol 2007; 8: 696-705
• 26 Grundy RG, Wilne SH, Robinson KJ. et al. Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. European journal of cancer (Oxford, England : 1990) 2010; 46: 120-133
• 27 Haroon-Mowahed Y, Cheen NgS, Barnett S. et al. Ultrasound in paediatric anaesthesia – A comprehensive review. Ultrasound 2021; 29: 112-122
• 28 Jünger ST, Andreiuolo F, Mynarek M. et al. CDKN2A deletion in supratentorial ependymoma with RELA alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort. Acta neuropathologica 2020; 140: 405-407
• 29 Kaatsch P, Rickert CH, Kühl J. et al. Population-based epidemiologic data on brain tumors in German children. Cancer 2001; 92: 3155-3164
• 30 Kerscher SR, Schweizer LL, Nägele T. et al. Transtemporal Ultrasound (US) Assessment of Third Ventricle Diameter (TVD): Comparison of US and MRI TVD in Pediatric Patients. Neuropediatrics 2020; 51: 185-191
• 31 Kilday JP, Mitra B, Domerg C. et al. Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children’s Cancer Leukaemia Group (CCLG), Societe Francaise d’Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res 2012; 18: 2001-2011
• 32 Klingebiel T, Jürgens H, Glauche I. et al. Register und Studien in der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) – Welchen Beitrag leisten sie zum Fortschritt?. Klin Padiatr 2020; 232: 124-135
• 33 Kresbach C, Neyazi S, Schüller U. Updates in the classification of ependymal neoplasms: The 2021 WHO Classification and beyond. Brain pathology (Zurich, Switzerland) 2022; 32: e13068
• 34 Kunz R, Burnand B, Schünemann HJ. [The GRADE System. An international approach to standardize the graduation of evidence and recommendations in guidelines]. Internist (Berl) 2008; 49: 673-680
• 35 Lindsay HB, Massimino M, Avula S. et al. Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. Lancet Oncol 2022; 23: e393-e401
• 36 Louis DN, Perry A, Wesseling P. et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-oncology 2021; 23: 1231-1251
• 37 Massimino M, Barretta F, Modena P. et al. Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up. Neuro-oncology 2021; 23: 848-857
• 38 Massimino M, Miceli R, Giangaspero F. et al. Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma. Neuro-oncology 2016; 18: 1451-1460
• 39 Mehta V, Chapman A, McNeely PD. et al. Latency between symptom onset and diagnosis of pediatric brain tumors: an Eastern Canadian geographic study. Neurosurgery 2002; 51: 365-372 discussion 372-363
• 40 Mendrzyk F, Korshunov A, Benner A. et al. Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 2006; 12: 2070-2079
• 41 Merchant TE, Bendel AE, Sabin ND. et al. Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma. J Clin Oncol 2019; 37: 974-983
• 42 Mulhern RK, Merchant TE, Gajjar A. et al. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5: 399-408
• 43 Ostrom QT, de Blank PM, Kruchko C. et al. Alex’s Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011. Neuro-oncology 2015; 16: x1-x36
• 44 Pagès M, Pajtler KW, Puget S. et al. Diagnostics of pediatric supratentorial RELA ependymomas: integration of information from histopathology, genetics, DNA methylation and imaging. Brain pathology (Zurich, Switzerland) 2019; 29: 325-335
• 45 Pajtler KW, Mack SC, Ramaswamy V. et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta neuropathologica 2017; 133: 5-12
• 46 Pajtler KW, Witt H, Sill M. et al. Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer cell 2015; 27: 728-743
• 47 Pejavar S, Polley MY, Rosenberg-Wohl S. et al. Pediatric intracranial ependymoma: the roles of surgery, radiation and chemotherapy. Journal of neuro-oncology 2012; 106: 367-375
• 48 Ramaswamy V, Hielscher T, Mack SC. et al. Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 2016; 34: 2468-2477
• 49 Sievers P, Henneken SC, Blume C. et al. Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors. Acta neuropathologica 2021; 142: 827-839
• 50 Timmermann B, Kortmann RD, Kühl J. et al. Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the German prospective trials HIT 88/89 and HIT 91. International journal of radiation oncology, biology, physics 2000; 46: 287-295
• 51 Timmermann B, Kortmann RD, Kühl J. et al. Role of radiotherapy in anaplastic ependymoma in children under age of 3 years: results of the prospective German brain tumor trials HIT-SKK 87 and 92. Radiother Oncol 2005; 77: 278-285
• 52 Upadhyaya SA, Robinson GW, Onar-Thomas A. et al. Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial. Neuro-oncology 2019; 21: 1319-1330
• 53 van Kalsbeek RJ, van der Pal HJH, Kremer LCM. et al. European PanCareFollowUp Recommendations for surveillance of late effects of childhood, adolescent, and young adult cancer. European journal of cancer (Oxford, England : 1990) 2021; 154: 316-328
• 54 Warmuth-Metz M, Bison B, Leykamm S. Neuroradiologic review in pediatric brain tumor studies. Klin Neuroradiol 2009; 19: 263-273
• 55 Weusthof K, Lüttich P, Regnery S. et al. Neurocognitive Outcomes in Pediatric Patients Following Brain Irradiation. Cancers (Basel) 2021; 13
• 56 Wilne S, Collier J, Kennedy C. et al. Presentation of childhood CNS tumours: a systematic review and meta-analysis. Lancet Oncol 2007; 8: 685-695
• 57 Wilne S, Koller K, Collier J. et al. The diagnosis of brain tumours in children: a guideline to assist healthcare professionals in the assessment of children who may have a brain tumour. Arch Dis Child 2010; 95: 534-539
• 58 Windeler J, Lauterberg J, Wieseler B. et al. Patientenregister für die Nutzenbewertung: Kein Ersatz für randomisierte Studien. Dtsch Arztebl 2017; 114 A 783–A786
• 59 Zapotocky M, Beera K, Adamski J. et al. Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost. Cancer 2019; 125: 1867-1876
• 60 Zheng T, Ghasemi DR, Okonechnikov K. et al. Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion-positive supratentorial ependymomas. Cancer Discov 2021;