B-Ole Juhnke1, Marco Gessi2, Nicolas U Gerber3, Carsten Friedrich4, Martin Mynarek1, André O von Bueren5, Christine Haberler6, Ulrich Schüller7, Rolf-Dieter Kortmann8, Beate Timmermann9, Brigitte Bison10,11, Monika Warmuth-Metz11, Robert Kwiecien12, Stefan M Pfister13,14,15, Claudia Spix16, Torsten Pietsch17, Marcel Kool13,14,18, Stefan Rutkowski1, Katja von Hoff19. 1. HIT-MED Study Centre, Clinic for Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. 2. Neuropathology Unit, Division of Pathology, Fondazione Policlinico Universitario "A Gemelli" IRCCS, Catholic University Rome, Rome, Italy. 3. Department of Oncology, University Children's Hospital Zürich, Zürich, Switzerland. 4. Department of Paediatrics and Paediatric Haematology/Oncology, University Children's Hospital, Klinikum Oldenburg AöR, Oldenburg, Germany. 5. Department of Paediatrics, Obstetrics and Gynaecology, Division of Paediatric Haematology and Oncology, University Hospital of Geneva, Geneva, Switzerland. 6. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria. 7. Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf and Research Institute Children's Cancer Center Hamburg, Hamburg, Germany. 8. HIT Radiotherapy Reference Centre, Clinic for Radiotherapy, Leipzig University Medicine, Leipzig, Germany. 9. Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Centre (WTZ) and German Cancer Consortium (DKTK), Essen, Germany. 10. Institute for Diagnostic and Interventional Neuroradiology, University Hospital Augsburg, Augsburg, Germany. 11. HIT Neuroradiology Reference Centre, Institute for Diagnostic and Interventional Neuroradiology, University Hospital Würzburg, Würzburg, Germany. 12. Institute of Biostatistics and Clinical Research, Faculty of Medicine, University of Münster, Münster, Germany. 13. Hopp Children's Cancer Center (KITZ), Heidelberg, Germany. 14. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. 15. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany. 16. Division of Childhood Cancer Epidemiology, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 17. DGNN Brain Tumour Reference Centre, Institute of Neuropathology, University Hospital Bonn, Bonn, Germany. 18. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. 19. Department of Paediatric Oncology and Haematology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Abstract
BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive tumors occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry. PATIENTS AND METHODS: Age-stratified treatment included carboplatin/etoposide induction, tandem high-dose chemotherapy ("CARBO/ETO + HDCT"), and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n = 19), the HIT2000-interim-registry (2012-2014; n = 12), and earlier HIT trials (n = 4) were selected for analysis. RESULTS: Age-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumor location, 5-year progression-free survival (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO + HDCT (n = 17), compared to 0% and 8% with other treatments (n = 13, P[OS] = .011). All 4 patients with brainstem tumor died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR [PFS]: 0.07 [95%CI: 0.01-0.38], P = .003), localized disease (M0): (HR [OS] M0, no residual tumor: 0.30 [95%CI: 0.009-1.09], P = .068; M0, residual tumor: 0.18 [95%CI: 0.04-0.76], P = .020), and CARBO/ETO + HDCT treatment (HR [OS]: 0.16 [95%CI: 0.05-054], P = .003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2). CONCLUSIONS: Our data indicate improved survival with intensified chemotherapy (CARBO/ETO + HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting.
BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive tumors occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry. PATIENTS AND METHODS: Age-stratified treatment included carboplatin/etoposide induction, tandem high-dose chemotherapy ("CARBO/ETO + HDCT"), and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n = 19), the HIT2000-interim-registry (2012-2014; n = 12), and earlier HIT trials (n = 4) were selected for analysis. RESULTS: Age-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumor location, 5-year progression-free survival (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO + HDCT (n = 17), compared to 0% and 8% with other treatments (n = 13, P[OS] = .011). All 4 patients with brainstem tumor died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR [PFS]: 0.07 [95%CI: 0.01-0.38], P = .003), localized disease (M0): (HR [OS] M0, no residual tumor: 0.30 [95%CI: 0.009-1.09], P = .068; M0, residual tumor: 0.18 [95%CI: 0.04-0.76], P = .020), and CARBO/ETO + HDCT treatment (HR [OS]: 0.16 [95%CI: 0.05-054], P = .003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2). CONCLUSIONS: Our data indicate improved survival with intensified chemotherapy (CARBO/ETO + HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting.
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