Treatment of children under 4 years of age with medulloblastoma and ependymoma in the HIT2000/HIT-REZ 2005 trials: Neuropsychological outcome 5 years after treatment

Autoři: Holger Ottensmeier aff001;  Paul G. Schlegel aff001;  Matthias Eyrich aff001;  Johannes E. Wolff aff003;  Björn-Ole Juhnke aff004;  Katja von Hoff aff004;  Stefanie Frahsek aff001;  Rene Schmidt aff005;  Andreas Faldum aff005;  Gudrun Fleischhack aff006;  Andre von Bueren aff007;  Carsten Friedrich aff008;  Anika Resch aff008;  Monika Warmuth-Metz aff009;  Jürgen Krauss aff010;  Rolf D. Kortmann aff011;  Udo Bode aff012;  Joachim Kühl aff001;  Stefan Rutkowski aff004
Působiště autorů: Department of Paediatric Haematology and Oncology, University Children's Hospital, University Medical Center, Wuerzburg, Germany aff001;  Comprehensive Cancer Center Mainfranken, University Medical Center, Wuerzburg, Germany aff002;  AbbvVie, Oncology Development, Chicago, Illinois, United States of America aff003;  Department of Paediatric Haematology and Oncology, University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany aff004;  Institute of Biostatistics and Clinical Research, University Muenster, Muenster, Germany aff005;  Pediatrics III Oncology, University Hospital of Essen, Essen, Germany aff006;  Department of Paediatrics and Adolescent Medicine Division of Paediatric Haematology and Oncology, University Hospital of Geneva, Geneva, Switzerland aff007;  Department of Haematology Oncology, University Children´s Hospital Rostock, Rostock, Germany aff008;  Department of Neuroradiology, HIT 2000 National Reference Center, University Medical Center Wuerzburg, Wuerzburg, Germany aff009;  Department of Paediatric Neurosurgery, University of Wuerzburg, University Medical Center Wuerzburg, Wuerzburg, Germany aff010;  Department of Radiotherapy, University of Leipzig, Leipzig, Germany aff011;  Department of Paediatric Oncology, University of Bonn, Bonn, Germany aff012
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article


Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping “Speed”, and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.

Klíčová slova:

Cancer chemotherapy – Cancer treatment – Cognition – Intelligence tests – Medulloblastoma – Neuropsychological testing – Neuropsychology – Surgical and invasive medical procedures


1. Rutkowski S, Gerber NU, von Hoff K, Gnekow A, Bode U, Graf N et al: Treatment of early childhood medulloblastoma by postoperative Chemotherapy and deferred radiotherapy. Neuro-Oncology 2009, 11(2):201–210. doi: 10.1215/15228517-2008-084 18818397

2. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N et al: Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. The New England journal of medicine 2005, 352(10):978–986. doi: 10.1056/NEJMoa042176 15758008

3. von Hoff K, Kieffer V, Habrand JL, Kalifa C, Dellatolas G, Grill J: Impairment of intellectual functions after surgery and posterior fossa irradiation in children with ependymoma is related to age and neurologic complications. BMC Cancer 2008, 8:15. doi: 10.1186/1471-2407-8-15 18208613

4. Palmer SL: Neurodevelopmental impact on children treated for medulloblastoma: a review and proposed conceptual model. Developmental disabilities research reviews 2008, 14(3):203–210. doi: 10.1002/ddrr.32 18924159

5. Mulhern RK, Palmer SL, Merchant TE, Wallace D, Kocak M, Brouwers et al: Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol 2005, 23(24):5511–5519. doi: 10.1200/JCO.2005.00.703 16110011

6. Prabhakaran V, Smith JAL, Desmond JE, Glover GH: Neural Substrates of Fluid Reasoning: An fMRI Study of Neocortical Activation during Performance of the Raven´s Progressive Matrices Test. Cognitive Psychology 1997, 33:43–63. doi: 10.1006/cogp.1997.0659 9212721

7. Ottensmeier H, Zimolong B, Wolff JE, Ehrich J, Galley N, Rutkowski S et al: Neuropsychological short assessment of disease- and treatment-related intelligence deficits in children with brain tumours. Eur J Paediatr Neurol 2015, 19(3):298–307. doi: 10.1016/j.ejpn.2014.12.019 25617910

8. Rutkowski S, Gerber NU, von Hoff K, Gnekow A, Bode U, Graf N et al: Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol 2009, 11(2):201–210. doi: 10.1215/15228517-2008-084 18818397

9. Conklin HM, Li C, Xiong X, Ogg RJ, Merchant TE: Predicting change in academic abilities after conformal radiation therapy for localized ependymoma. J Clin Oncol 2008, 26(24):3965–3970. doi: 10.1200/JCO.2007.15.9970 18711186

10. Palmer SL, Reddick WE, Glass JO, Ogg R, Patay Z, Wallace D et al: Region et al al white matter anisotropy and reading ability in patients treated for pediatric embryonal tumors. Brain Imaging Behav 2010, 4(2):132–140. doi: 10.1007/s11682-010-9092-1 20502994

11. Schreiber JE, Gurney JG, Palmer SL, Bass JK, Wang M, Chen S et al: Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. Neuro Oncol, 16(8):1129–1136. doi: 10.1093/neuonc/nou006 24497405

12. Palmer SL, Hassall T, Evankovich K, Mabbott DJ, Bonner M, Deluca C et al: Neurocognitive outcome 12 months following cerebellar mutism syndrome in pediatric patients with medulloblastoma. Neuro Oncol, 12(12):1311–1317. doi: 10.1093/neuonc/noq094 20713408

13. Korah MP, Esiashvili N, Mazewski CM, Hudgins RJ, Tighiouart M, Janss AJ et al: Incidence, risks, and sequelae of posterior fossa syndrome in pediatric medulloblastoma. Int J Radiat Oncol Biol Phys, 77(1):106–112. doi: 10.1016/j.ijrobp.2009.04.058 19695790

14. Mulhern RK, Palmer SL, Reddick W, E., Glass JO, Kun LE, Taylor J et al: Risk of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss Journal of Clinical Oncology 2001, 19(2):472–479.

15. Mulhern RK, Hancock J, Fairclough D, Kun L: Neuropsychological status of children treated for brain tumors: a critical review and integrative analysis. Med Pediatr Oncol 1992, 20(3):181–191. doi: 10.1002/mpo.2950200302 1574027

16. Nagel BJ, Delis DC, Palmer SL, Reeves C, Gajjar A, Mulhern RK: Early patterns of verbal memory impairment in children treated for medulloblastoma. Neuropsychology 2006, 20(1):105–112. doi: 10.1037/0894-4105.20.1.105 16460226

17. Kiehna EN, Mulhern RK, Li C, Xiong X, Merchant TE: Changes in attentional performance of children and young adults with localized primary brain tumors after conformal radiation therapy. J Clin Oncol 2006, 24(33):5283–5290. doi: 10.1200/JCO.2005.03.8547 17114662

18. Kieffer-Renaux V, Bulteau C, Grill J, Kalifa C, Viguier D, Jambaque I: Patterns of neuropsychological deficits in children with medulloblastoma according to craniospatial irradiation doses. Dev Med Child Neurol 2000, 42(11):741–745. doi: 10.1017/s0012162200001377 11104345

19. Riva D, Giorgi C, Nichelli F, Bulgheroni S, Massimino M, Cefalo G et al: Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology 2002, 59(1):48–53. doi: 10.1212/wnl.59.1.48 12105306

20. Pangelinan MM, Zhang G, VanMeter JW, Clark JE, Hatfield BD, Haufler AJ: Beyond age and gender: relationships between cortical and subcortical brain volume and cognitive-motor abilities in school-age children. Neuroimage 2011, 54(4):3093–3100. doi: 10.1016/j.neuroimage.2010.11.021 21078402

21. Hanzlik E, Woodrome SE, Abdel-Baki M, Geller TJ, Elbabaa SK: A systematic review of neuropsychological outcomes following posterior fossa tumor surgery in children. Child's nervous system: ChNS: official journal of the International Society for Pediatric Neurosurgery 2015, 31(10):1869–1875.

22. Robinson KE, Kuttesch JF, Champion JE, Andreotti CF, Hipp DW, Bettis A et al: A Quantitative Meta-Analysis of Neurocognitive Sequelae in Survivors of Pediatric. Pediatric Blood & Cancer 2010, 55:525–531.

23. Schneider WJ, McGrew KS: The Cattell-Horn-Carroll model of intelligence. In: Contemporary intellectual assessment: Theories, tests, and issues (3rd ed) edn. Edited by Flanagan DP. New York, NY: US: Guilford Press; 2012: 99–144

24. Ottensmeier H, Kuehl J: Pilot Trial HIT-SKK´87/HIT-SKK´92: A retrospective neuropsychological study in children < 3 years of age with medulloblastoma. Neuro Oncol 2000, 2 (Supplement 2):71–96.

25. McGrew KS: CHC theory and the human cognitive abilities project: Standing on the shoulders of the giants of psychometric intelligence research. Intelligence 2009, 37:1–10.

26. Melchers P, Preuss U: Assessment Battery for Children (K-ABC) dt. Version., 8 th ed edn. Frankfurt/Main: Pearson Assessment; 2009.

27. Fry AF, Hale S: Relationship among processing speed, working memory, and fluid intelligence. Biological Psychology 2000, 54:1–34. doi: 10.1016/s0301-0511(00)00051-x 11035218

28. Koustenis E, Hernaiz Driever P, de Sonneville L, Rueckriegel SM: Executive function deficits in pediatric cerebellar tumor survivors. Eur J Paediatr Neurol 2016, 20(1):25–37. doi: 10.1016/j.ejpn.2015.11.001 26631949

29. Wolff JE, Daumling E, Dirksen A, Dabrock A, Hartmann M, Jurgens H: [Munster Heidelberg Abilities Scale—a measuring instrument for global comparison of illness sequelae]. Klinische Padiatrie 1996, 208(5):294–298. doi: 10.1055/s-2008-1046486 8992097

30. Raven JC, Bulheller S, Häcker H: Coloured Progressive Matrices (3. neu normierte Auflage). Frankfurt: Swets Test Sevices; 2002.

31. Ullen F, Forsman L, Blom O, Karabanov A, Madison G: Intelligence and variability in a simple timing task share neural substrates in the prefrontal white matter. The Journal of neuroscience: the official journal of the Society for Neuroscience 2008, 28(16):4238–4243.

32. Beery KE: The Beery-Buktenica Developmental Test of Visual-Motor Integration VMI. Manual (5th ed.). Minneapolis: Pearson; 2006.

33. Luria AR: The Working Brain. In., edn. London; 1973.

34. Piaget J, Inhelder B: Mental imagery in the child. A study of the development of imaginal representations. London: Routledge & Kegal Paul; 1971.

35. Beery KE, Visual-motor integration. Monograph. Chicago: Follett Publishing Company; 1967.

36. Rosvold HE, Mirsky AF, Sarason I, Bransone ED, Beck LH: A Continuous performance test of brain damage. Journal of Consulting Psychology 1956, 20(5):343–350. doi: 10.1037/h0043220 13367264

37. Tapping: Computersoftware for the measurement of handedness. In. Wedemark (Germany): Meditech; 2008.

38. Ottensmeier H, Galley N, Rutkowski S, Kühl J: Kurzgefasste Intelligenzdiagnostik bei Hirntumoren. Kindheit & Entwicklung 2006, 15:100–106.

39. Grill J, Le Deley MC, Gambarelli D, Raquin MA, Couanet D, Pierre-Kahn A et al: Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology. J Clin Oncol 2001, 19(5):1288–1296. doi: 10.1200/JCO.2001.19.5.1288 11230470

40. Kuhl J: Modern treatment strategies in medulloblastoma. Child's nervous system: ChNS: official journal of the International Society for Pediatric Neurosurgery 1998, 14(1–2):2–5.

41. Collett D: Modelling survival data in medical research, 1st edn. London; New York: Chapman & Hall; 1994.

42. Muller K, Mynarek M, Zwiener I, Siegler N, Zimmermann M, Christiansen H et al: Postponed is not canceled: role of craniospinal radiation therapy in the management of recurrent infant medulloblastoma—an experience from the HIT-REZ 1997 & 2005 studies. Int J Radiat Oncol Biol Phys 2014, 88(5):1019–1024. doi: 10.1016/j.ijrobp.2014.01.013 24661654

43. Liu AK, Marcus KJ, Fischl B, Grant PE, Poussaint TY, Rivkin MJ et al: Changes in cerebral cortex of children treated for medulloblastoma. Int J Radiat Oncol Biol Phys 2007, 68(4):992–998. doi: 10.1016/j.ijrobp.2007.01.034 17379433

44. von Bueren AO, von Hoff K, Pietsch T, Gerber NU, Warmuth-Metz M, Deinlein F et al: Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology. Neuro Oncol 2011, 13(6):669–679. doi: 10.1093/neuonc/nor025 21636711

45. Dhall G: Medulloblastoma. Journal of child neurology 2009, 24(11):1418–1430. doi: 10.1177/0883073809341668 19841429

46. Saury JM, Emanuelson I: Cognitive consequences of the treatment of medulloblastoma among children. Pediatric neurology 2011, 44(1):21–30. doi: 10.1016/j.pediatrneurol.2010.07.004 21147383

47. Ris MD, Walsh K, Wallace D, Armstrong FD, Holmes E, Gajjar A et al: Intellectual and academic outcome following two chemotherapy regimens and radiotherapy for average-risk medulloblastoma: COG A9961. Pediatr Blood Cancer 2013, 60(8):1350–1357. doi: 10.1002/pbc.24496 23444345

48. Anderson FS, Kunin-Batson AS: Neurocognitive late effects of chemotherapy in children: the past 10 years of research on brain structure and function. Pediatr Blood Cancer 2009, 52(2):159–164. doi: 10.1002/pbc.21700 18680151

49. Limond JA, Bull KS, Calaminus G, Kennedy CR, Spoudeas HA, Brain Tumour Quality of Survival Group ISoPO et al: Quality of survival assessment in European childhood brain tumour trials, for children aged 5 years and over. Eur J Paediatr Neurol 2015, 19(2):202–210. doi: 10.1016/j.ejpn.2014.12.003 25617909

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