TY  - JOUR
A1  - Sabel, Magnus
A1  - Fleischhack, Gudrun
A1  - Tippelt, Stephan
A1  - Gustafsson, Göran
A1  - Doz, François
A1  - Kortmann, Rolf
A1  - Massimino, Maura
A1  - Navajas, Aurora
A1  - von Hoff, Katja
A1  - Rutkowski, Stefan
A1  - Warmuth-Metz, Monika
A1  - Clifford, Steven C.
A1  - Pietsch, Torsten
A1  - Pizer, Barry
A1  - Linnering, Birgitta
T1  - Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study
JF  - Journal of Neurooncology
N2  - The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 +/- 2 % and 78 +/- 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. > 5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 +/- 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour.
KW  - High-dose chemotherapy
KW  - Childhood medulloblastoma
KW  - Adolescents
KW  - Primitive neuroectodermal
KW  - Tumors
KW  - Recurrent medulloblastoma
KW  - Childrens-cancer
KW  - Phase-II
KW  - Trial
KW  - Therapy
KW  - Reirradiation
KW  - Medulloblastoma
KW  - Relapse
KW  - Survival
KW  - Treatment
KW  - Clinical trial
KW  - Chemotherapy
KW  - Radiotherapy
KW  - Paediatric
KW  - Secondary tumours
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187498
VL  - 129
IS  - 3
ER  - 
TY  - JOUR
A1  - Nemes, Karolina
A1  - Johann, Pascal D.
A1  - Steinbügl, Mona
A1  - Gruhle, Miriam
A1  - Bens, Susanne
A1  - Kachanov, Denis
A1  - Teleshova, Margarita
A1  - Hauser, Peter
A1  - Simon, Thorsten
A1  - Tippelt, Stephan
A1  - Eberl, Wolfgang
A1  - Chada, Martin
A1  - Lopez, Vicente Santa-Maria
A1  - Grigull, Lorenz
A1  - Hernáiz-Driever, Pablo
A1  - Eyrich, Matthias
A1  - Pears, Jane
A1  - Milde, Till
A1  - Reinhard, Harald
A1  - Leipold, Alfred
A1  - van de Wetering, Marianne
A1  - Gil-da-Costa, Maria João
A1  - Ebetsberger-Dachs, Georg
A1  - Kerl, Kornelius
A1  - Lemmer, Andreas
A1  - Boztug, Heidrun
A1  - Furtwängler, Rhoikos
A1  - Kordes, Uwe
A1  - Vokuhl, Christian
A1  - Hasselblatt, Martin
A1  - Bison, Brigitte
A1  - Kröncke, Thomas
A1  - Melchior, Patrick
A1  - Timmermann, Beate
A1  - Gerss, Joachim
A1  - Siebert, Reiner
A1  - Frühwald, Michael C.
T1  - Infants and newborns with atypical teratoid rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors (eMRT) in the EU-RHAB registry: a unique and challenging population
JF  - Cancers
N2  - Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.
KW  - atypical teratoid rhabdoid tumors
KW  - extracranial malignant rhabdoid tumor
KW  - RTPS1
KW  - RTPS2
KW  - germline mutation
KW  - EU-RHAB registry
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270730
SN  - 2072-6694
VL  - 14
IS  - 9
ER  - 
TY  - JOUR
A1  - Gaab, Christine
A1  - Adolph, Jonas E.
A1  - Tippelt, Stephan
A1  - Mikasch, Ruth
A1  - Obrecht, Denise
A1  - Mynarek, Martin
A1  - Rutkowski, Stefan
A1  - Pfister, Stefan M.
A1  - Milde, Till
A1  - Witt, Olaf
A1  - Bison, Brigitte
A1  - Warmuth-Metz, Monika
A1  - Kortmann, Rolf-Dieter
A1  - Dietzsch, Stefan
A1  - Pietsch, Torsten
A1  - Timmermann, Beate
A1  - Sträter, Ronald
A1  - Bode, Udo
A1  - Faldum, Andreas
A1  - Kwiecien, Robert
A1  - Fleischhack, Gudrun
T1  - Local and systemic therapy of recurrent medulloblastomas in children and adolescents: results of the P-HIT-REZ 2005 Study
JF  - Cancers
N2  - Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients' survival.
KW  - medulloblastoma
KW  - refractory
KW  - recurrent
KW  - children
KW  - chemotherapy
KW  - surgery
KW  - radiotherapy
KW  - re-irradiation
KW  - intraventricular therapy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254809
SN  - 2072-6694
VL  - 14
IS  - 3
ER  - 
TY  - JOUR
A1  - Peters, Sarah
A1  - Frisch, Sabine
A1  - Stock, Annika
A1  - Merta, Julien
A1  - Bäumer, Christian
A1  - Blase, Christoph
A1  - Schuermann, Eicke
A1  - Tippelt, Stephan
A1  - Bison, Brigitte
A1  - Frühwald, Michael
A1  - Rutkowski, Stefan
A1  - Fleischhack, Gudrun
A1  - Timmermann, Beate
T1  - Proton beam therapy for pediatric tumors of the central nervous system — experiences of clinical outcome and feasibility from the KiProReg study
JF  - Cancers
N2  - As radiotherapy is an important part of the treatment in a variety of pediatric tumors of the central nervous system (CNS), proton beam therapy (PBT) plays an evolving role due to its potential benefits attributable to the unique dose distribution, with the possibility to deliver high doses to the target volume while sparing surrounding tissue. Children receiving PBT for an intracranial tumor between August 2013 and October 2017 were enrolled in the prospective registry study KiProReg. Patient’s clinical data including treatment, outcome, and follow-up were analyzed using descriptive statistics, Kaplan–Meier, and Cox regression analysis. Adverse events were scored according to the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 before, during, and after PBT. Written reports of follow-up imaging were screened for newly emerged evidence of imaging changes, according to a list of predefined keywords for the first 14 months after PBT. Two hundred and ninety-four patients were enrolled in this study. The 3-year overall survival of the whole cohort was 82.7%, 3-year progression-free survival was 67.3%, and 3-year local control was 79.5%. Seventeen patients developed grade 3 adverse events of the CNS during long-term follow-up (new adverse event n = 7; deterioration n = 10). Two patients developed vision loss (CTCAE 4°). This analysis demonstrates good general outcomes after PBT.
KW  - proton beam therapy
KW  - childhood cancer
KW  - brain cancer
KW  - adverse events
KW  - imaging changes
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297489
SN  - 2072-6694
VL  - 14
IS  - 23
ER  -