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. 2024 Nov 4;26(11):2113-2124.
doi: 10.1093/neuonc/noae092.

Risk factors for domain-specific neurocognitive outcome in pediatric survivors of a brain tumor in the posterior fossa-Results of the HIT 2000 trial

Martin Mynarek  1   2 , Anne Rossius  1 , Anika Guiard  3 , Holger Ottensmeier  4 , Katja von Hoff  1   5 , Denise Obrecht-Sturm  1 , Lisa Bußenius  1 , Carsten Friedrich  6 , Andre O von Bueren  7   8 , Nicolas U Gerber  9 , Thomas Traunwieser  1   10 , Rolf-Dieter Kortmann  11 , Monika Warmuth-Metz  12 , Brigitte Bison  13 , Ulrich-W Thomale  14 , Juergen Krauss  15 , Torsten Pietsch  16 , Steven C Clifford  17 , Stefan M Pfister  18   19   20 , Dominik Sturm  18   19   20 , Felix Sahm  18   21   22 , Tanja Tischler  1   10 , Stefan Rutkowski  1
Affiliations

Risk factors for domain-specific neurocognitive outcome in pediatric survivors of a brain tumor in the posterior fossa-Results of the HIT 2000 trial

Martin Mynarek et al. Neuro Oncol. .

Abstract

Background: Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization, and biology in pediatric survivors of a posterior fossa tumor.

Methods: Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic tool based on Cattell-Horn-Carroll's model for intelligence were analyzed.

Results: Cognitive performance 5.14 years (mean; range = 1.52-13.02) after diagnosis was significantly below normal for all subtests. Processing speed and psychomotor abilities were most affected. Influencing factors were domain-specific: CSI-dose had a strong impact on most subtests. pCMS was associated with psychomotor abilities (β = -0.25 to -0.16) and processing speed (β = -0.32). Postoperative hydrocephalus correlated with crystallized intelligence (β = -0.20) and short-term memory (β = -0.15), age with crystallized intelligence (β = 0.15) and psychomotor abilities (β = -0.16 and β = -0.17). Scores for fluid intelligence (β = -0.23), short-term memory (β = -0.17) and visual processing (β = -0.25) declined, and scores for selective attention improved (β = 0.29) with time after diagnosis.

Conclusions: The dose of CSI was strongly associated with neurocognitive outcomes. Low psychomotor abilities and processing speed both in patients treated with and without CSI suggest a strong contribution of the tumor and its surgery on these functions. Future research therefore should analyze strategies to both reduce CSI dose and toxicity caused by other treatment modalities.

Keywords: ependymoma; infant; medulloblastoma; neuropsychological late effects; quality of survival.

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Conflict of interest statement

S.R. received consulting fees for membership in advisory boards (Bayer, Novartis, BMS, and Roche), data safety monitoring boards (Celgene) and consulting (German Childhood Cancer Foundation and myChildsCancer). He received travel costs from the German Society for Pediatric Oncology (GPOH) and the German Childhood Cancer Foundation. S.M.P. received an IMI-2 Grant “ITCC-P4” with research funding from the EU, Eli-Lilly, Roche, Pfizer, Bayer, PharmaMar, Astra Zeneca, Johnson & Johnson, Sanofi, Servier and Amgen. Moreover, S.M.P. received payment honoraria for presentations from NeoGenomics, is involved in a patent on DNA methylation-based tumor classification, and received drugs for preclinical studies from Pfizer, Karyopharm and Astra Zeneca. A.v.B. received travel support from Servier and consulting fees (Advisory board for Novartis, Alexion Pharmaceuticals, and Bayern). B.B. declared additional travel support from the German Childhood Cancer Foundation. The other authors did not declare a conflict of interest.

Figures

Figure 1.
Figure 1.
Consort Diagram for Recruitment into the Neuropsychology Follow-up Study from the HIT2000 Clinical Trial Strata for Children Older Than 4 Years at Diagnosis. (R): Randomized Allocation, (S): Stratified Allocation. *For 16 HIT-AB4 Observational Patients, CSI-Dose Was Not Reported; None of These Were Included Into the Neuropsychology Follow-up Study
Figure 2.
Figure 2.
Distribution of the Cognitive Outcome of the Patient Cohort for Each Subtest According to CSI-Dose (No CSI [Focal RT to Tumor Bed] vs. Moderate-Dose CSI [<30 Gy] vs. high-dose CSI [≥30 Gy]). Z-Values Were Used as a Unit of Standardization with a Mean of 0 and a Norm Range of 2 SD. Outliers Are Marked as Points Outside the Boxes. ANOVA Results (P-values Bonferroni-Corrected) Are Described Below the Variable Names and Post Hoc Significant Differences (P-Values Bonferroni-Corrected) Are Marked by a Horizontal Bracket. Please Note That the Subtests CPT-k (Selective Attention and Processing Speed) and Purdue Pegboard (Psychomotor Abilities) Had to be Completed Within a Time Limit.
Figure 3.
Figure 3.
Distribution of the Cognitive Outcome for Each Subtest According to: (A) Preoperative Hydrocephalus According to MRI; (B) Postoperative Hydrocephalus; (C) Postoperative Cerebellar Mutism Syndrome (pCMS); z-Values Were Used as a Unit of Standardization With a Mean of 0 and a Norm Range of 2 SD. Outliers Are Marked as Points Outside the Boxes. Significant Differences (t-Tests, P-Values Bonferroni-Corrected) Are Marked by a Horizontal Bracket.
Figure 4.
Figure 4.
Results of Multivariate Linear Regression Analysis. Multivariate Regression Analysis of Potentially Influencing Factors (Y-Axis) With Backward Selection Was Computed For Each of the Subtests (X-Axis). Factors Selected During Variable Selection Are Displayed as Circles, with the Size and Color of the Dot Representing the Standardized Coefficient β. Within the Circles, the Regression Coefficient (β) Is Specified.
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