Local and Systemic Therapy of Recurrent Medulloblastomas in Children and Adolescents: Results of the P-HIT-REZ 2005 Study

Christine Gaab¹, Jonas E Adolph¹, Stephan Tippelt¹, Ruth Mikasch¹, Denise Obrecht², Martin Mynarek^{2

3}, Stefan Rutkowski², Stefan M Pfister^{4

5

6}, Till Milde^{4

6

7}, Olaf Witt^{4

6

7}, Brigitte Bison⁸, Monika Warmuth-Metz⁹, Rolf-Dieter Kortmann¹⁰, Stefan Dietzsch^{10

11}, Torsten Pietsch¹², Beate Timmermann¹¹, Ronald Sträter¹³, Udo Bode¹⁴, Andreas Faldum¹⁵, Robert Kwiecien¹⁵, Gudrun Fleischhack¹

Affiliations

¹ Department of Pediatrics III, Center for Translational Neuro- and Behavioral Sciences (CTNBS), University Hospital of Essen, Hufelandstrasse 55, 45147 Essen, Germany.
² Department of Pediatric Hematology and Oncology, Center for Obstetrics and Pediatrics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
³ Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴ Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany.
⁵ Division of Pediatric Neuro-Oncology, German Cancer Consortium/DKTK and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁶ Department of Pediatric Oncology and Hematology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
⁷ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), 69120 Heidelberg, Germany.
⁸ Department of Neuroradiology, University Hospital Augsburg, 86156 Augsburg, Germany.
⁹ Institute of Diagnostic and Interventional Neuroradiology, University of Würzburg, 97080 Würzburg, Germany.
¹⁰ Department of Radio-Oncology, University of Leipzig, 04103 Leipzig, Germany.
¹¹ Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), German Cancer Consortium (DKTK), 45147 Essen, Germany.
¹² Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, 53127 Bonn, Germany.
¹³ Department of Pediatric Hematology and Oncology, University Hospital Münster, 48129 Münster, Germany.
¹⁴ Department of Pediatric Hematology and Oncology, University Hospital Bonn, 53127 Bonn, Germany.
¹⁵ Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-Universität Münster, Schmeddingstraße 56, 48149 Münster, Germany.

PMID: 35158738
PMCID: PMC8833340
DOI: 10.3390/cancers14030471

Local and Systemic Therapy of Recurrent Medulloblastomas in Children and Adolescents: Results of the P-HIT-REZ 2005 Study

Christine Gaab et al. Cancers (Basel). 2022.

. 2022 Jan 18;14(3):471.

doi: 10.3390/cancers14030471.

Authors

Affiliations

¹ Department of Pediatrics III, Center for Translational Neuro- and Behavioral Sciences (CTNBS), University Hospital of Essen, Hufelandstrasse 55, 45147 Essen, Germany.
² Department of Pediatric Hematology and Oncology, Center for Obstetrics and Pediatrics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
³ Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴ Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany.
⁵ Division of Pediatric Neuro-Oncology, German Cancer Consortium/DKTK and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁶ Department of Pediatric Oncology and Hematology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
⁷ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), 69120 Heidelberg, Germany.
⁸ Department of Neuroradiology, University Hospital Augsburg, 86156 Augsburg, Germany.
⁹ Institute of Diagnostic and Interventional Neuroradiology, University of Würzburg, 97080 Würzburg, Germany.
¹⁰ Department of Radio-Oncology, University of Leipzig, 04103 Leipzig, Germany.
¹¹ Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), German Cancer Consortium (DKTK), 45147 Essen, Germany.
¹² Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, 53127 Bonn, Germany.
¹³ Department of Pediatric Hematology and Oncology, University Hospital Münster, 48129 Münster, Germany.
¹⁴ Department of Pediatric Hematology and Oncology, University Hospital Bonn, 53127 Bonn, Germany.
¹⁵ Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-Universität Münster, Schmeddingstraße 56, 48149 Münster, Germany.

PMID: 35158738
PMCID: PMC8833340
DOI: 10.3390/cancers14030471

Abstract

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.

Keywords: chemotherapy; children; intraventricular therapy; medulloblastoma; radiotherapy; re-irradiation; recurrent; refractory; surgery.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

**Figure 1**
Treatment algorithm in relapsed/refractory medulloblastoma in the P-HIT-REZ 2005 Study (CHT: chemotherapy; ivCHT: intravenous chemotherapy; oCHT: oral chemotherapy; Doc: documentation; ivc: intraventricular; HDCHT: high-dose chemotherapy; APBSCT: autologous peripheral stem cell transplantation; CSA: craniospinal axis; PF: posterior fossa).

**Figure 2**
Therapy flowchart of the P-HIT-REZ 2005 Study. CHT: chemotherapy; HDCHT: high-dose chemotherapy; Doc: documentation; APBSC(T): autologous blood stem cell (transplantation); TT, thiotepa; TMZ: temozolomide; CP: carboplatin; VP16: etoposide; ivc: intraventricular; CR: complete remission; PR: partial response; SD: stable disease; PD: progressive disease.

**Figure 3**
Eligible and evaluable patients in the P-HIT-REZ 2005 Study. (MB: medulloblastomas; CNS-PNET: central nervous system primitive neuroectodermal tumors; PIN: pineoblastomas; HGG: high grade glioma).

**Figure 4**
Survival curves for PFS_1stRD and OS_1stRD after diagnosis of first recurrence of medulloblastoma.

**Figure 5**
Time to recurrence from initial diagnosis of <18 months correlates with a significantly worse PFS_1stRD (p < 0.001) and OS_1stRD (p < 0.001).

**Figure 6**
Application of high-dose chemotherapy after CR/PR at MRI after 4 cycles of initial systemic chemotherapy did not improve either PFS_TS (p = 0.51) or OS_TS (p = 0.25).

**Figure 7**
Surgery at first recurrence significantly improves both PFS_1stRD (p = 0.015) and OS_1stRD (p = 0.025).

**Figure 8**
In radiotherapy-naïve patients, radiotherapy significantly improves both PFS_1stRD (p = 0.004) and OS_1stRD (p = 0.005) compared to patients with either re-irradiation or no radiotherapy at first recurrence. Re-irradiation showed no significant increase in PFS_1stRD (p = 0.078) and OS_1stRD (p = 0.54) compared to patients without radiotherapy. Improvements in survival between first-irradiated patients and re-irradiated patients did not reach significance for PFS_1stRD (p = 0.21) and OS_1stRD (p = 0.13).

See this image and copyright information in PMC

References

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Grants and funding

DKS 2006.01, DKS 2008.07, DKS 2012.03, DKS 2015.02, DKS 2017.12, DKS 2020.02/German Children Cancer Foundation

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Local and Systemic Therapy of Recurrent Medulloblastomas in Children and Adolescents: Results of the P-HIT-REZ 2005 Study

Affiliations

Local and Systemic Therapy of Recurrent Medulloblastomas in Children and Adolescents: Results of the P-HIT-REZ 2005 Study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding