Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial

Stefan Dietzsch; Felix Placzek; Klaus Pietschmann; André O. von Bueren; Christiane Matuschek; Albrecht Glück; Matthias Guckenberger; Volker Budach; Jutta Welzel; Christoph Pöttgen; Heinz Schmidberger; Frank Heinzelmann; Frank Paulsen; Montserrat Pazos Escudero; Rudolf Schwarz; Dagmar Hornung; Carmen Martini; Anca Ligia Grosu; Georg Stueben; Karolina Jablonska; Juergen Dunst; Heidi Stranzl-Lawatsch; Karin Dieckmann; Beate Timmermann; Torsten Pietsch; Monika Warmuth-Metz; Brigitte Bison; Robert Kwiecien; Martin Benesch; Nicolas U. Gerber; Michael A. Grotzer; Stefan M. Pfister; Steven C. Clifford; Katja von Hoff; Sabine Klagges; Stefan Rutkowski; Rolf Dieter Kortmann; Martin Mynarek

doi:10.1016/j.adro.2020.09.018

Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial

Stefan Dietzsch, Felix Placzek, Klaus Pietschmann, André O. von Bueren, Christiane Matuschek, Albrecht Glück, Matthias Guckenberger, Volker Budach, Jutta Welzel, Christoph Pöttgen, Heinz Schmidberger, Frank Heinzelmann, Frank Paulsen, Montserrat Pazos Escudero, Rudolf Schwarz, Dagmar Hornung, Carmen Martini, Anca Ligia Grosu, Georg Stueben, Karolina JablonskaJuergen Dunst, Heidi Stranzl-Lawatsch, Karin Dieckmann, Beate Timmermann, Torsten Pietsch, Monika Warmuth-Metz, Brigitte Bison, Robert Kwiecien, Martin Benesch, Nicolas U. Gerber, Michael A. Grotzer, Stefan M. Pfister, Steven C. Clifford, Katja von Hoff, Sabine Klagges, Stefan Rutkowski, Rolf Dieter Kortmann^*, Martin Mynarek

^*Corresponding author for this work

Department of Radiotherapy

22 Citations (Scopus)

Abstract

Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany. Methods and Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients. Results: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% (P =.62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%; P =.052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; P =.014) and time interval between surgery and irradiation (hazard ratio, 2.2; P =.018) were confirmed as independent risk factors. Conclusions: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.

Original language	English
Journal	Advances in Radiation Oncology
Volume	5
Issue number	6
Pages (from-to)	1158-1169
Number of pages	12
DOIs	https://doi.org/10.1016/j.adro.2020.09.018
Publication status	Published - 01.11.2020

Funding

Disclosures: Dr Dietzsch reports grants from the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) during the conduct of the study. Dr Budach reports personal fees from Merck Co, Germany, personal fees from Varian Co, personal fees from Accuray Co, personal fees from Bristol-Myers Co, personal fees from Seattle Genetics Co, personal fees from Novocure Co, and personal fees from Sennewald Co outside the submitted work. Dr Bison reports personal fees from Deutsche Kinderkrebsstiftung (German Childhood Foundation) during the conduct of the study and personal fees from Deutsche Kinderkrebsstiftung (German Childhood Foundation) outside the submitted work. Dr Mynarek reports grants from the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) during the conduct of the study. The authors thank all attending physicians of the participating centers for their meticulous documentation and the “Deutsche Kinderkrebsstiftung“ (German Childhood Cancer Foundation) and “Steirische Kinderkrebshilfe” (Styrian Childhood Cancer Foundation) for the support of the HIT network.

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SDG 3 Good Health and Well-being

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10.1016/j.adro.2020.09.018

Cite this

Dietzsch, S., Placzek, F., Pietschmann, K., von Bueren, A. O., Matuschek, C., Glück, A., Guckenberger, M., Budach, V., Welzel, J., Pöttgen, C., Schmidberger, H., Heinzelmann, F., Paulsen, F., Escudero, M. P., Schwarz, R., Hornung, D., Martini, C., Grosu, A. L., Stueben, G., ... Mynarek, M. (2020). Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial. Advances in Radiation Oncology, 5(6), 1158-1169. https://doi.org/10.1016/j.adro.2020.09.018

@article{e6fb13d10e74412b97890c649d9199e2,

title = "Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial",

abstract = "Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany. Methods and Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1\%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients. Results: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5\% ± 3.1\% versus 78.7\% ± 3.1\% (P =.62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4\% ± 2.2\% vs 64.6\% ± 9.1\%; P =.052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; P =.014) and time interval between surgery and irradiation (hazard ratio, 2.2; P =.018) were confirmed as independent risk factors. Conclusions: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.",

author = "Stefan Dietzsch and Felix Placzek and Klaus Pietschmann and \{von Bueren\}, \{Andr{\'e} O.\} and Christiane Matuschek and Albrecht Gl{\"u}ck and Matthias Guckenberger and Volker Budach and Jutta Welzel and Christoph P{\"o}ttgen and Heinz Schmidberger and Frank Heinzelmann and Frank Paulsen and Escudero, \{Montserrat Pazos\} and Rudolf Schwarz and Dagmar Hornung and Carmen Martini and Grosu, \{Anca Ligia\} and Georg Stueben and Karolina Jablonska and Juergen Dunst and Heidi Stranzl-Lawatsch and Karin Dieckmann and Beate Timmermann and Torsten Pietsch and Monika Warmuth-Metz and Brigitte Bison and Robert Kwiecien and Martin Benesch and Gerber, \{Nicolas U.\} and Grotzer, \{Michael A.\} and Pfister, \{Stefan M.\} and Clifford, \{Steven C.\} and \{von Hoff\}, Katja and Sabine Klagges and Stefan Rutkowski and Kortmann, \{Rolf Dieter\} and Martin Mynarek",

note = "Funding Information: Disclosures: Dr Dietzsch reports grants from the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) during the conduct of the study. Dr Budach reports personal fees from Merck Co, Germany, personal fees from Varian Co, personal fees from Accuray Co, personal fees from Bristol-Myers Co, personal fees from Seattle Genetics Co, personal fees from Novocure Co, and personal fees from Sennewald Co outside the submitted work. Dr Bison reports personal fees from Deutsche Kinderkrebsstiftung (German Childhood Foundation) during the conduct of the study and personal fees from Deutsche Kinderkrebsstiftung (German Childhood Foundation) outside the submitted work. Dr Mynarek reports grants from the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) during the conduct of the study. Funding Information: The authors thank all attending physicians of the participating centers for their meticulous documentation and the “Deutsche Kinderkrebsstiftung“ (German Childhood Cancer Foundation) and “Steirische Kinderkrebshilfe” (Styrian Childhood Cancer Foundation) for the support of the HIT network. Publisher Copyright: {\textcopyright} 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = nov,

day = "1",

doi = "10.1016/j.adro.2020.09.018",

language = "English",

volume = "5",

pages = "1158--1169",

journal = "Advances in Radiation Oncology",

number = "6",

}

Dietzsch, S, Placzek, F, Pietschmann, K, von Bueren, AO, Matuschek, C, Glück, A, Guckenberger, M, Budach, V, Welzel, J, Pöttgen, C, Schmidberger, H, Heinzelmann, F, Paulsen, F, Escudero, MP, Schwarz, R, Hornung, D, Martini, C, Grosu, AL, Stueben, G, Jablonska, K, Dunst, J, Stranzl-Lawatsch, H, Dieckmann, K, Timmermann, B, Pietsch, T, Warmuth-Metz, M, Bison, B, Kwiecien, R, Benesch, M, Gerber, NU, Grotzer, MA, Pfister, SM, Clifford, SC, von Hoff, K, Klagges, S, Rutkowski, S, Kortmann, RD & Mynarek, M 2020, 'Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial', Advances in Radiation Oncology, vol. 5, no. 6, pp. 1158-1169. https://doi.org/10.1016/j.adro.2020.09.018

Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial. / Dietzsch, Stefan; Placzek, Felix; Pietschmann, Klaus et al.
In: Advances in Radiation Oncology, Vol. 5, No. 6, 01.11.2020, p. 1158-1169.

Research output: Journal Articles › Journal articles › Research › peer-review

TY - JOUR

T1 - Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial

AU - Dietzsch, Stefan

AU - Placzek, Felix

AU - Pietschmann, Klaus

AU - von Bueren, André O.

AU - Matuschek, Christiane

AU - Glück, Albrecht

AU - Guckenberger, Matthias

AU - Budach, Volker

AU - Welzel, Jutta

AU - Pöttgen, Christoph

AU - Schmidberger, Heinz

AU - Heinzelmann, Frank

AU - Paulsen, Frank

AU - Escudero, Montserrat Pazos

AU - Schwarz, Rudolf

AU - Hornung, Dagmar

AU - Martini, Carmen

AU - Grosu, Anca Ligia

AU - Stueben, Georg

AU - Jablonska, Karolina

AU - Dunst, Juergen

AU - Stranzl-Lawatsch, Heidi

AU - Dieckmann, Karin

AU - Timmermann, Beate

AU - Pietsch, Torsten

AU - Warmuth-Metz, Monika

AU - Bison, Brigitte

AU - Kwiecien, Robert

AU - Benesch, Martin

AU - Gerber, Nicolas U.

AU - Grotzer, Michael A.

AU - Pfister, Stefan M.

AU - Clifford, Steven C.

AU - von Hoff, Katja

AU - Klagges, Sabine

AU - Rutkowski, Stefan

AU - Kortmann, Rolf Dieter

AU - Mynarek, Martin

N1 - Funding Information: Disclosures: Dr Dietzsch reports grants from the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) during the conduct of the study. Dr Budach reports personal fees from Merck Co, Germany, personal fees from Varian Co, personal fees from Accuray Co, personal fees from Bristol-Myers Co, personal fees from Seattle Genetics Co, personal fees from Novocure Co, and personal fees from Sennewald Co outside the submitted work. Dr Bison reports personal fees from Deutsche Kinderkrebsstiftung (German Childhood Foundation) during the conduct of the study and personal fees from Deutsche Kinderkrebsstiftung (German Childhood Foundation) outside the submitted work. Dr Mynarek reports grants from the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) during the conduct of the study. Funding Information: The authors thank all attending physicians of the participating centers for their meticulous documentation and the “Deutsche Kinderkrebsstiftung“ (German Childhood Cancer Foundation) and “Steirische Kinderkrebshilfe” (Styrian Childhood Cancer Foundation) for the support of the HIT network. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany. Methods and Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients. Results: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% (P =.62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%; P =.052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; P =.014) and time interval between surgery and irradiation (hazard ratio, 2.2; P =.018) were confirmed as independent risk factors. Conclusions: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.

AB - Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany. Methods and Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients. Results: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% (P =.62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%; P =.052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; P =.014) and time interval between surgery and irradiation (hazard ratio, 2.2; P =.018) were confirmed as independent risk factors. Conclusions: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.

UR - https://www.scopus.com/pages/publications/85095445352

U2 - 10.1016/j.adro.2020.09.018

DO - 10.1016/j.adro.2020.09.018

M3 - Journal articles

AN - SCOPUS:85095445352

VL - 5

SP - 1158

EP - 1169

JO - Advances in Radiation Oncology

JF - Advances in Radiation Oncology

IS - 6

ER -

Dietzsch S, Placzek F, Pietschmann K, von Bueren AO, Matuschek C, Glück A et al. Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial. Advances in Radiation Oncology. 2020 Nov 1;5(6):1158-1169. doi: 10.1016/j.adro.2020.09.018

Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial

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