TY - JOUR A1 - Dietzsch, Stefan A1 - Braesigk, Annett A1 - Seidel, Clemens A1 - Remmele, Julia A1 - Kitzing, Ralf A1 - Schlender, Tina A1 - Mynarek, Martin A1 - Geismar, Dirk A1 - Jablonska, Karolina A1 - Schwarz, Rudolf A1 - Pazos, Montserrat A1 - Weber, Damien C. A1 - Frick, Silke A1 - Gurtner, Kristin A1 - Matuschek, Christiane A1 - Harrabi, Semi Ben A1 - Glück, Albrecht A1 - Lewitzki, Victor A1 - Dieckmann, Karin A1 - Benesch, Martin A1 - Gerber, Nicolas U. A1 - Obrecht, Denise A1 - Rutkowski, Stefan A1 - Timmermann, Beate A1 - Kortmann, Rolf-Dieter T1 - Types of deviation and review criteria in pretreatment central quality control of tumor bed boost in medulloblastoma—an analysis of the German Radiotherapy Quality Control Panel in the SIOP PNET5 MB trial JF - Strahlentherapie und Onkologie N2 - Purpose In Germany, Austria, and Switzerland, pretreatment radiotherapy quality control (RT-QC) for tumor bed boost (TB) in non-metastatic medulloblastoma (MB) was not mandatory but was recommended for patients enrolled in the SIOP PNET5 MB trial between 2014 and 2018. This individual case review (ICR) analysis aimed to evaluate types of deviations in the initial plan proposals and develop uniform review criteria for TB boost. Patients and methods A total of 78 patients were registered in this trial, of whom a subgroup of 65 patients were available for evaluation of the TB treatment plans. Dose uniformity was evaluated according to the definitions of the protocol. Additional RT-QC criteria for standardized review of target contours were elaborated and data evaluated accordingly. Results Of 65 initial TB plan proposals, 27 (41.5%) revealed deviations of target volume delineation. Deviations according to the dose uniformity criteria were present in 14 (21.5%) TB plans. In 25 (38.5%) cases a modification of the RT plan was recommended. Rejection of the TB plans was rather related to unacceptable target volume delineation than to insufficient dose uniformity. Conclusion In this analysis of pretreatment RT-QC, protocol deviations were present in a high proportion of initial TB plan proposals. These findings emphasize the importance of pretreatment RT-QC in clinical trials for MB. Based on these data, a proposal for RT-QC criteria for tumor bed boost in non-metastatic MB was developed. KW - brain tumor KW - pediatric KW - focal radiotherapy KW - quality assurance KW - individual case review Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307812 SN - 0179-7158 SN - 1439-099X VL - 198 IS - 3 ER - TY - JOUR A1 - Wiegering, Verena A1 - Riedmeier, Maria A1 - Thompson, Lester D. R. A1 - Virgone, Calogero A1 - Redlich, Antje A1 - Kuhlen, Michaela A1 - Gultekin, Melis A1 - Yalcin, Bilgehan A1 - Decarolis, Boris A1 - Härtel, Christoph A1 - Schlegel, Paul-Gerhardt A1 - Fassnacht, Martin A1 - Timmermann, Beate T1 - Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature JF - Clinical and Translational Radiation Oncology N2 - Background and purpose Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy. KW - pediatric adrenocortical cancer KW - pediatric adrenocortical carcinoma KW - pediatric adrenocortical tumor KW - radiotherapy KW - therapy KW - treatment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300472 VL - 35 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 - TY - JOUR A1 - Kandels, Daniela A1 - Pietsch, Torsten A1 - Bison, Brigitte A1 - Warmuth‐Metz, Monika A1 - Thomale, Ulrich‐Wilhelm A1 - Kortmann, Rolf‐Dieter A1 - Timmermann, Beate A1 - Hernáiz Driever, Pablo A1 - Witt, Olaf A1 - Schmidt, René A1 - Gnekow, Astrid K. T1 - Loss of efficacy of subsequent nonsurgical therapy after primary treatment failure in pediatric low‐grade glioma patients—Report from the German SIOP‐LGG 2004 cohort JF - International Journal of Cancer N2 - First‐line treatment of pediatric low‐grade glioma using surgery, radio‐ or chemotherapy fails in a relevant proportion of patients. We analyzed efficacy of subsequent surgical and nonsurgical therapies of the German cohort of the SIOP‐LGG 2004 study (2004‐2012, 1558 registered patients; median age at diagnosis 7.6 years, median observation time 9.2 years, overall survival 98%/96% at 5/10 years, 15% neurofibromatosis type 1 [NF1]). During follow‐up, 1078/1558 patients remained observed without (n = 217), with 1 (n = 707), 2 (n = 124) or 3 to 6 (n = 30) tumor volume reductions; 480/1558 had 1 (n = 332), 2 (n = 80), 3 or more (n = 68) nonsurgical treatment‐lines, accompanied by up to 4 tumor‐reductive surgeries in 215/480; 265/480 patients never underwent any neurosurgical tumor volume reduction (163/265 optic pathway glioma). Patients with progressing tumors after first‐line adjuvant treatment were at increased risk of suffering further progressions. Risk factors were young age (<1 year) at start of treatment, tumor dissemination or progression within 18 months after start of chemotherapy. Progression‐free survival rates declined with subsequent treatment‐lines, yet remaining higher for patients with NF1. In non‐NF1‐associated tumors, vinblastine monotherapy vs platinum‐based chemotherapy was noticeably less effective when used as second‐line treatment. Yet, for the entire cohort, results did not favor a certain sequence of specific treatment options. Rather, all can be aligned as a portfolio of choices which need careful balancing of risks and benefits. Future molecular data may predict long‐term tumor biology. KW - chemotherapy KW - pediatric low‐grade glioma KW - progression KW - radiotherapy KW - surgery Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216130 VL - 147 IS - 12 SP - 3471 EP - 3489 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 - 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 - Bartelheim, Kerstin A1 - Nemes, Karolina A1 - Seeringer, Angela A1 - Kerl, Kornelius A1 - Buechner, Jochen A1 - Boos, Joachim A1 - Graf, Norbert A1 - Dürken, Matthias A1 - Gerss, Joachim A1 - Hasselblatt, Martin A1 - Kortmann, Rolf-Dieter A1 - Teichert von Luettichau, Irene A1 - Nagel, Inga A1 - Nygaard, Randi A1 - Oyen, Florian A1 - Quiroga, Eduardo A1 - Schlegel, Paul-Gerhardt A1 - Schmid, Irene A1 - Schneppenheim, Reinhard A1 - Siebert, Reiner A1 - Solano-Paez, Palma A1 - Timmermann, Beate A1 - Warmuth-Metz, Monika A1 - Frühwald, Michael Christoph T1 - Improved 6-year overall survival in AT/RT - results of the registry study Rhabdoid 2007 JF - Cancer Medicine N2 - Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU‐RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high‐dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ‐line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3 years, radiotherapy and achievement of a complete remission. 6‐year overall and event‐free survival rates were 46% (±0.10) and 45% (±0.09), respectively. Serious adverse events and one treatment‐related death due to insufficiency of a ventriculo peritoneal shunt (VP‐shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU‐RHAB provides the best available basis for phase I/II clinical trials. KW - AT/RT KW - EU‐RHAB Registry KW - pediatric brain tumor KW - Rhabdoid 2007 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164799 VL - 5 IS - 8 ER -