Register und Studien in der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) – Welchen Beitrag leisten sie zum Fortschritt?

Zusammenfassung

Krebserkrankungen bei Kindern und Jugendlichen unter 18 Jahren sind selten; im Jahr 2017 wurden ca. 2220 Neuerkrankungen in Deutschland an das Deutsche Kinderkrebsregister gemeldet. Ziel der GPOH war es immer, möglichst alle betroffenen Patienten standardisiert, am besten in prospektiven, kontrollierten Studien, zu behandeln. Diese Vorgabe hat auch der Gemeinsame Bundesausschuss in der Kinderonkologierichtlinie festgeschrieben. In einer Umfrage unter den Studienleitern der GPOH wurde ermittelt, wie sich nach der geänderten Arzneimittelgesetzgebung, die Zahl der klinischen Studien verändert hat. Im Jahr 2002 waren 33 Therapieoptimierungs-studien (TOS) der GPOH geöffnet. Insgesamt ist ein Rückgang der TOS von 33 im Jahre 2002 auf 2 im Jahre 2017 zu verzeichnen. Die Zahl der Arzneimittelstudien hat sich bis zum Jahr 2017 auf 16 erhöht (knapp 1100 erfasste Patienten). Zeitgleich hat sich die Zahl der klinischen Register auf 28 erhöht mit insgesamt mehr als 1800 dort erfassten Patienten. Diese Beobachtung zeigt, dass die klinischen Register eine neue Bedeutung in der pädiatrischen Onkologie bekommen haben. An 3 Beispielen wird dargelegt, welche Beiträge Register im Verhältnis zu Studien zur Behandlung der Patienten und zum wissenschaftlichen Fortschritt leisten können. Zusammengefasst verdeutlichen die bisherigen Erfahrungen aus den diskutierten Beispielen, dass Studien und Register wechselseitig eine sinnvolle und notwendige Ergänzung der Studiengruppenstruktur in der Kinderonkologie darstellen.

Abstract

Cancer in children and adolescents under the age of 18 is rare; in 2017, approximately 2220 new cases in Germany were reported to the German Childhood Cancer Registry. The aim of the GPOH has always been to treat as many affected patients as possible in a standardized way, preferably in prospective, controlled studies. The Joint Federal Committee has also laid down this requirement in the paediatric oncology guideline. In a survey among the study chairs of the GPOH, it was determined how the number of clinical trials has changed following the amended drug legislation. In 2002, 33 therapy optimization studies (TOS) of the GPOH were open. Overall, TOS decreased from 33 in 2002 to 2 in 2017. The number of drug trials has increased to 16 by 2017 (almost 1100 patients registered). At the time, the number of clinical registries has increased to 28 with a total of more than 1800 registered patents. This observation shows that the clinical registers have taken on a new significance in paediatric oncology. Three examples are used to examine what contributions registries can make in relation to studies on the treatment of patients and to scientific progress. In summary, the experience gained so far from the examples discussed illustrates that studies and registries mutually represent a meaningful and necessary addition to the study group structure in paediatric oncology.

Schlüsselwörter

Klinische Studien - Register - Arzneimittelgesetz - pädiatrische Hämatologie und Onkologie

Key words

Clinical studies - registries - drug law - paediatric haematology and oncology

• Literatur

• 1 Agrawal M, Garg RJ, Kantarjian H. et al. Chronic myeloid leukemia in the tyrosine kinase inhibitor era: what is the “best” therapy? Review. Curr Oncol Rep 2010; 12: 302-313
• 2 Attarbaschi A, Beishuizen A, Mann G. et al. Children and adolescents with follicular lymphoma have an excellent prognosis with either limited chemotherapy or with a “watch and wait” strategy after complete resection. Ann Hematol 2013; 92: 1537-1541
• 3 Attarbaschi A, Carraro E, Abla O. et al. Non-Hodgkin's lymphoma and pre-existing conditions: spectrum, clinical characteristics and outcome in 213 children and adolescents. Haematologica 2016; 101: 1581-1591
• 4 Baccarani M, Deininger MW, Rosti G. et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Blood 2013; 122: 872-884
• 5 Balbach ST, Makarova O, Bonn BR. et al. Proposal of a genetic classifier for risk group stratification in pediatric T-cell lymphoblastic lymphoma reveals differences from adult T-cell lymphoblastic leukemia. Leukemia 2016; 30: 970-973
• 6 Berthold F, Ernst A, Hero B. et al. Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation. Br J Cancer 2018; 119: 282-290
• 7 Bienemann K, Burkhardt B, Modlich S. et al. Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol 2011; 155: 468-476
• 8 Bison B, Warmuth-Metz M, Schneckenburger M. et al. Contrast Enhancement of Low Grade Gliomas (LGG) during Follow-Up. Neuroradiol J 2011; 24: 415-418
• 9 Bonn BR, Rohde M, Zimmermann M. et al. Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 2013; 121: 3153-3160
• 10 Bray F, Max Parkin D. Evaluation of data quality in the cancer registry: Principles and methods. Part I: Comparability, validity and timeliness. European journal of cancer 2009; 45: 747-755
• 11 Burkhardt B, Mueller S, Khanam T. et al. Current status and future directions of T-lymphoblastic lymphoma in children and adolescents. Br J Haematol 2016; 173: 545-559
• 12 Calaminus G, Wessalowski R, Harms D. et al. Juvenile granulosa cell tumors of the ovary in children and adolescents: results from 33 patients registered in a prospective cooperative study. Gynecol Oncol 1997; 65: 447-452
• 13 Damm-Welk C, Mussolin L, Zimmermann M. et al. Early Assessment of Minimal Residual Disease Identifies Patients at Very High Relapse Risk in NPM-ALK-positive Anaplastic Large Cell Lymphoma. Blood 2014; 123: 334-337
• 14 de Bruijn CMA, Millot F, Suttorp M. et al. Discontinuation of imatinib in children with chronic myeloid leukaemia in sustained deep molecular remission: results of the STOP IMAPED study. Br J Haematol 2019; 185: 718-724
• 15 Gnekow AK, Falkenstein F, von Hornstein S. et al. 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: 1265-1284
• 16 Gnekow AK, Kortmann RD, Pietsch T. et al. Low grade chiasmatic-hypothalamic glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy – report from the multicenter treatment study for children and adolescents with a low grade glioma – HIT-LGG 1996 – of the Society of Pediatric Oncology and Hematology (GPOH). Klin Padiatr 2004; 216: 331-342
• 17 Gnekow AK, Kaatsch P, Kortmann R. et al. HIT-LGG: effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood –an interim report. Klin Padiatr 2000; 212: 177-184
• 18 Gnekow AK, Walker DA, Kandels D. et al. A European randomized controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatmentprogramme for childhood ( < /=16 years) low grade glioma – A final report. European J Cancer 2017; 81: 206-225
• 19 Gnekow AK, Kandels D, van Tilburg C. et al. SIOP-E-BTG and GPOH Guidelines. Klin Padiatr 2019; 231: 107-135
• 20 Gore L, Kearns PR, de Martino ML. et al. Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial. J Clin Oncol 2018; 36: 1330-1338
• 21 Hernáiz Driever P, von Hornstein S, Pietsch T. et al. Natural history and management of low-grade glioma in NF-1 children. J Neurooncol 2010; 100: 199-207
• 22 Hijiya N, Schultz KR, Metzler M. et al. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach (Review). Blood 2016; 127: 392-399
• 23 Hijiya N, Suttorp M. How I Treat Chronic Myeloid Leukemia in Children and Adolescents. Blood 2019; 133: 2374-2384
• 24 Hijiya N, Maschan A, Rizzari C. et al. Efficacy and Safety of Nilotinib in Pediatric Patients with Philadelphia Chromosome-Positive (PH+) Chronic Myeloid Leukemia (CML): Results from A PHASE 2 Trial. Pediatr Blood Cancer 2017; 64 (e26772) 22
• 25 Hochhaus A. Optimizing tolerability of TKI therapy in CML. Blood 2014; 123: 1284-1285
• 26 Hupp M, Falkenstein F, Bison B. et al. Infarction following chiasmatic low grade glioma resection. Childs Nerv Syst 2012; 28: 391-398
• 27 Khare R, Utidjian L, Ruth BJ. et al. A longitudinal analysis of data quality in a large pediatric data research network. J Am Med Inform Assoc 2017; 24: 1072-1079
• 28 Knörr F, Damm-Welk C, Ruf S. et al. Blood cytokine concentrations of pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma patients. Haematologica 2018; 103: 477-485
• 29 Kontny U, Oschlies I, Woessmann W. et al. Non-anaplastic peripheral T-cell lymphoma in children and adolescents – a retrospective analysis of the NHL-BFM study group. Br J Haematol 2015; 168: 835-844
• 30 Körholz D, Schneider D, von Kries R. et al. How to Overcome Scientific Standstill for Very Rare Diseases: Clinical Trials or Clinical Registries?. Klin Padiatr 2015; 227: 303-304
• 31 Kretzmer H, Bernhart SH, Wang W. et al. ICGC MMML-Seq project; BLUEPRINT project, Küppers R, Ammerpohl O, Lichter P, Siebert R, Hoffmann S, Radlwimmer B. DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. Nat Genet 2015; 47: 1316-1325
• 32 Kunz R, Ollenschläger G, Raspe H. et al. Lehrbuch Evidenzbasierte Medizin in Klinik und Praxis. Deutscher Ärzte Verlag; 2007
• 33 Mahon FX, Réa D, Guilhot J. et al. Intergroupe Français des Leucémies Myéloïdes Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010; 11: 1029-1035
• 34 Makarova O, Oschlies I, Müller S. et al. Excellent outcome with limited treatment in paediatric patients with marginal zone lymphoma. Br J Haematol 2018; 182: 735-739
• 35 Meira-Machado L, de Uña-Alvarez J, Cadarso-Suárez C. et al. Multi-state models for the analysis of time-to-event data. Stat Methods Med Res 2009; 18: 195-222
• 36 Mirow C, Pietsch T, Berkefeld S. et al. Children <1 year show an inferior outcome when treated according to the traditional LGG treatment strategy: a report from the German multicenter trial HIT-LGG 1996 for children with low grade glioma (LGG). Pediatr Blood Cancer 2014; 61: 457-463
• 37 Möricke A, Zimmermann M, Reiter A. et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010; 24: 265-284
• 38 Müller K, Gnekow A, Falkenstein F. et al. 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: 647-655
• 39 Mussolin L, Pillon M, Zimmermann M. et al. Course of anti-ALK antibody titres during chemotherapy in children with anaplastic large cell lymphoma. Br J Haematol 2018; 182: 733-735
• 40 Peters O, Gnekow AK, Rating D. et al. Impact of location on outcome in children with low-grade oligodendroglioma. Pediatr Blood Cancer 2004; 43: 250-256
• 41 Pui CH, Yang JJ, Hunger SP. et al. Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. J Clin Oncol 2015; 33: 2938-2948
• 42 Rohde M, Richter J, Schlesner M. et al. on behalf of the German ICGC MMML-Seq-Project and the NHL-BFM Study Group Recurrent RHOA mutations in pediatric Burkitt lymphoma treated according to the NHL-BFM protocols. Genes Chromosomes Cancer 2014; 53: 911-916
• 43 Rohde M, Bonn BR, Zimmermann M. et al. MMML-MYC-SYS Project; ICGC MMML-Seq Project, Loeffler M, Siebert R, Reiter A, Burkhardt B Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols. Haematologica 2017; 102: 1091-1098
• 44 Rössig C, Juergens H, Schrappe M. et al. Effective Childhood Cancer Treatment: The Impact of Large Scale Clinical Trials in Germany and Austria. Pediatr Blood Cancer 2013; 60: 1574-1581
• 45 Ronceray L, Abla O, Barzilai-Birenboim S. et al. European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) and the International Berlin-Frankfurt-Münster (i-BFM) Study Group. Children and adolescents with marginal zone lymphoma have an excellent prognosis with limited chemotherapy or a watch-and-wait strategy after complete resection. Pediatr Blood Cancer. 2018 65. e2693
• 46 Schneider DT, Calaminus G, Wessalowski R. et al. Therapy of advanced ovarian juvenile granulosa cell tumors. Klin Padiatr 2002; 214: 173-178
• 47 Schneider D, Puscz D, Hippert D. et al. Ovarian Juvenile Granulosa Cell Tumors: Report of the German MAKEI and STEP Registries. Ped Blood Cancer 2018; 65: S57
• 48 Singh VK, Werner S, Hackstein H. et al. Analysis of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-reactive CD8⁺ T cell responses in children with NPM-ALK⁺ anaplastic large cell lymphoma. Clin Exp Immunol 2016; 186: 96-105
• 49 Suttorp M. Chronische myeloische Leukämie. “In” Niemeyer C, Eggert A Pädiatrische Hämatologie und Onkologie. Springer; Heidelberg: 2018. 2. Auflage, 303-308
• 50 Suttorp M, Claviez A, Bader P. et al. Allogeneic stem cell transplantation for treatment of chronic myeloid leukemia in pediatric and adolescent patients: Results of the prospective trial CML-paed I. Klin Padiatr 2009; 221: 351-357
• 51 Suttorp M, Schulze P, Glauche I. et al. Response to Front-Line Imatinib Treatment in Children and Adolescents with Chronic Myeloid Leukemia – Results from a Phase III Trial. Leukemia 2018; 32: 1657-1669
• 52 Szczepanowski M, Masqué-Soler N, Schlesner M. et al. ICGC MMML-Seq Consortium, Klapper W Immunohistochemical detection of inhibitor of DNA binding 3 mutational variants in mature aggressive B-cell lymphoma. Haematologica 2016; 101: e259-e261
• 53 Thorer H, Zimmermann M, Makarova O. et al. Primary CNS lymphoma in children and adolescents: Low relapse rate after treatment according to NHL-BFM protocols for systemic lymphoma. Haematologica 2014; 99: e238-e241
• 54 von Hornstein S, Kortmann RD, Pietsch T. et al. Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. Pediatr Blood Cancer 2011; 56: 1046-1054
• 55 WHO Classification of tumours of haematopoietic and lymphoid tissues. Editors Swerdlow et al. Revised. 4^th edition International Agency for Research; Lyon: 2017
• 56 Woessmann W. How to treat children and adolscents with relapsed non-Hodgkin lymphoma?. Hematol Oncol 2013; 31 (Suppl 1) 64-68
• 57 Woessmann W, Zimmermann M, Lenhard M. et al. Relapsed or refractory anaplastic large-cell lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a BFM-group study. J Clin Oncol 2011; 29: 3065-3071
• 58 https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2017/krebs_in_deutschland_2017.pdf; jsessionid=EBFD44CAF93D8F01710F35A0C82721C3.1_cid390?–blob=publicationFile
• 59 http://www.kinderkrebsregister.de/typo3temp/secure_downloads/22605/0/bd894cced68c7950a69875dc2588a29281fd6fbc/jb2017_s.pdf
• 60 https://www.g-ba.de/downloads/62-492-1511/KiOn-RL_2017-11-01_iK-2018-01-01.pdf