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Prognostic Relevance of Clinical and Biological Risk Factors in Childhood Medulloblastoma: Results of Patients Treated in the Prospective Multicenter Trial HIT'91

Authors' Affiliations: ¹ University Children's Hospital of Wuerzburg; Departments of ² Neuroradiology and ³ Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, Germany; ⁴ Department of Pediatric Oncology, University of Zurich, Zurich, Switzerland; ⁵ Department of Neuropathology, University of Bonn; ⁶ University Children's Hospital of Bonn, Bonn, Germany; ⁷ Institute of Medical Biostatistics, Epidemiology and Informatics, University of Mainz, Mainz, Germany; ⁸ University Children's Hospital of Magdeburg, Magdeburg, Germany; ⁹ University Children's Hospital of Graz, Graz, Austria; and ¹⁰ Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

Requests for reprints: Stefan Rutkowski, Children's University Hospital, Josef-Schneider-Strasse 2, D-97080 Wuerzburg, Germany. Phone: 49-931-201-27728; Fax: 49-931-201-27722; E-mail: Rutkowski_S{at}klinik.uni-wuerzburg.de.

Purpose: To identify better risk stratification systems in childhood medulloblastoma based on clinical factors and analysis of routinely processed formalin-fixed tumor material.

Experimental Design: Formalin-fixed paraffin-embedded tumor samples from well-documented patients treated within the prospective randomized multicenter trial HIT'91 were analyzed for DNA amplification of c-myc and N-myc (n = 133) and mRNA expression of c-myc and trkC (n = 104; compared with human cerebellum) using validated methods of quantitative PCR and reverse transcription-PCR. Results were related to clinical data and outcome.

Results: TrkC and c-myc mRNA expression were identified as independent prognostic factors by multivariate analysis. Three risk groups were identified. (a) Favorable risk group: all 8 patients (2 metastatic) with high trkC (>1x human cerebellum) and low c-myc mRNA expression (1x human cerebellum) remained relapse-free [7-year event-free survival (EFS), 100%]. (b) Poor risk group: 10 of 15 patients with metastatic disease and high c-myc and low trkC mRNA expression relapsed (7-year EFS, 33%). (c) Intermediate risk group: the 7-year EFS of the remaining 78 patients was 65%. Among 47 M₀ stage patients, all 10 patients with high trkC mRNA expression remained relapse-free compared with 15 events in 37 patients with low trkC mRNA expression levels (7-year EFS, 100% versus 62%; P = 0.056).

Conclusions: Whereas the collection of fresh-frozen tumor samples remains a major challenge in large clinical trials, routinely processed paraffin-embedded tissue samples can be used to quantitate the prognostic biological markers trkC and c-myc. On prospective validation of cutoff levels, this may lead to improved stratification of treatment for children with medulloblastoma.

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