Christian Carrie1, Virginie Kieffer2, Dominique Figarella-Branger3, Julien Masliah-Planchon4, Stéphanie Bolle5, Valérie Bernier6, Anne Laprie7, Stéphane Supiot8, Julie Leseur9, Jean-Louis Habrand10, Claire Alapetite11, Christine Kerr12, Christelle Dufour13, Line Claude14, Sophie Chapet15, Aymeri Huchet16, Pierre-Yves Bondiau17, Alexandre Escande18, Gilles Truc19, Tan Dat Nguyen20, Caroline Pasteuris21, Céline Vigneron22, Xavier Muracciole23, Franck Bourdeaut24, Romain Appay3, Bernard Dubray25, Carole Colin3, Céline Ferlay26, Sophie Dussart26, Sylvie Chabaud26, Laetitia Padovani23. 1. Department of Radiotherapy, Leon Berard Cancer Center, and University of Lyon, CNRS UMR 5220, INSERM U1044, INSA, Lyon, France. Electronic address: christian.carrie@lyon.unicancer.fr. 2. Neuropsychologue CSI (Saint-Maurice hospital)/Gustave Roussy, Département de cancérologie de l'enfant et de l'adolescent, Gustave Roussy, Villejuif, France. 3. Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathology, Marseille, France; Department of AnatomoPathology and Neuropathology, AP-HM, University Hospital Center la Timone, Marseille, France. 4. Department of Anatomopathology, Curie Institute, Paris, France. 5. Radiation Oncology Department, Gustave Roussy Cancer Campus, Villejuif, France. 6. Department of Radiotherapy, Alexis Vautrin Cancer Center, Vandoeuvre-les-Nancy, France. 7. Department of Radiotherapy, University Institute of Cancer Toulouse-Oncopôle, France. 8. Department of Radiation Oncology, Institut de Cancérologie de l'Ouest (ICO), Nantes-Saint-Herblain, France. 9. Department of Radiotherapy, Centre Eugène Marquis, Rennes, France. 10. Department of Radiotherapy, François Baclesse Cancer Center, Caen, France. 11. Department of Radiotherapy, Curie Institute Paris, France. 12. Department of Radiotherapy, Institut regional du Cancer, Val d'Aurelle, Montpellier, France. 13. Pediatric Department, Gustave Roussy, Villejuif, France. 14. Department of Radiotherapy, Leon Berard Cancer Center, and University of Lyon, CNRS UMR 5220, INSERM U1044, INSA, Lyon, France. 15. Department of Radiotherapy, University Hospital Center of Tours, Tours, France. 16. Department of Radiotherapy, University Hospital Center of Bordeaux, Bordeaux, France. 17. Department of Radiotherapy, Centre Antoine Lacassagne, Nice, France. 18. Department of Radiotherapy, Centre Oscar Lambret, Lille, France. 19. Department of Radiotherapy, Georges-François Leclerc Cancer Center, Dijon, France. 20. Department of Radiotherapy, Jean Godinot Institute, Reims, France. 21. Department of Radiotherapy, University Hospital Center of Grenoble, Grenoble, France. 22. Department of Radiotherapy, Centre Paul Strauss, Strasbourg, France. 23. Department of Radiotherapy, CHU La Timone, AP-HM, Marseille, France. 24. SIREDO Pediatric Cancer Center, Institut Curie, Paris-Sciences-Lettres, Paris, France. 25. Department of Radiotherapy, Henri Becquerel Cancer Center, Rouen, France. 26. Department of Clinical Research and Innovation, Leon Berard Cancer center, Lyon, France.
Abstract
PURPOSE: Medulloblastoma has recently been characterized as a heterogeneous disease with 4 distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4, with a new definition of risk stratification. We report progression-free survival, overall survival, and long-term cognitive effects in children with standard-risk medulloblastoma exclusively treated with hyperfractionated radiation therapy (HFRT), reduced boost volume, and online quality control, and we explore the prognostic value of biological characteristics in this chemotherapy-naïve population. METHODS AND MATERIALS: Patients with standard-risk medulloblastoma were enrolled in 2 successive prospective multicentric studies, MSFOP 98 and MSFOP 2007, and received exclusive HFRT (36 Gy, 1 Gy/fraction twice daily) to the craniospinal axis followed by a boost at 68 Gy restricted to the tumor bed (1.5 cm margin), with online quality assurance before treatment. Patients with MYC or MYCN amplification were not excluded at the time of the study. We report progression-free survival and overall survival in the global population, and according to molecular subgroups as per World Health Organization 2016 molecular classification, and we present cognitive evaluations based on the Wechsler scale. RESULTS: Data from 114 patients included in the MSFOP 98 trial from December 1998 to October 2001 (n = 48) and in the MSFOP 2007 from October 2008 to July 2013 (n = 66) were analyzed. With a median follow-up of 16.2 (range, 6.4-19.6) years for the MSFOP 98 cohort and 6.5 (1.6-9.6) years for the MSFOP 2007 cohort, 5-year overall survival and progression-free survival in the global population were 84% (74%-89%) and 74% (65%-81%), respectively. Molecular classification was determined for 91 patients (WNT [n = 19], SHH [n = 12], and non-WNT/non-SHH [n = 60]-including group 3 [n = 9], group 4 [n = 29], and not specified [n = 22]). Our results showed more favorable outcome for the WNT-activated subgroup and a worse prognosis for SHH-activated patients. Three patients had isolated extra-central nervous system relapse. The slope of neurocognitive decline in the global population was shallower than that observed in patients with a normofractionated regimen combined with chemotherapy. CONCLUSIONS: HFRT led to a 5-year survival rate similar to other treatments combined with chemotherapy, with a reduced treatment duration of only 6 weeks. We confirm the MSFOP 98 results and the prognostic value of molecular status in patients with medulloblastoma, even in the absence of chemotherapy. Intelligence quotient was more preserved in children with medulloblastoma who received exclusive HFRT and reduced local boost, and intelligence quotient decline was delayed compared with patients receiving standard regimen. HFRT may be appropriate for patients who do not consent to or are not eligible for prospective clinical trials; for patients from developing countries for whom aplasia or ileus may be difficult to manage in a context of high cost/effectiveness constraints; and for whom shortened duration of RT may be easier to implement.
PURPOSE:Medulloblastoma has recently been characterized as a heterogeneous disease with 4 distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4, with a new definition of risk stratification. We report progression-free survival, overall survival, and long-term cognitive effects in children with standard-risk medulloblastoma exclusively treated with hyperfractionated radiation therapy (HFRT), reduced boost volume, and online quality control, and we explore the prognostic value of biological characteristics in this chemotherapy-naïve population. METHODS AND MATERIALS: Patients with standard-risk medulloblastoma were enrolled in 2 successive prospective multicentric studies, MSFOP 98 and MSFOP 2007, and received exclusive HFRT (36 Gy, 1 Gy/fraction twice daily) to the craniospinal axis followed by a boost at 68 Gy restricted to the tumor bed (1.5 cm margin), with online quality assurance before treatment. Patients with MYC or MYCN amplification were not excluded at the time of the study. We report progression-free survival and overall survival in the global population, and according to molecular subgroups as per World Health Organization 2016 molecular classification, and we present cognitive evaluations based on the Wechsler scale. RESULTS: Data from 114 patients included in the MSFOP 98 trial from December 1998 to October 2001 (n = 48) and in the MSFOP 2007 from October 2008 to July 2013 (n = 66) were analyzed. With a median follow-up of 16.2 (range, 6.4-19.6) years for the MSFOP 98 cohort and 6.5 (1.6-9.6) years for the MSFOP 2007 cohort, 5-year overall survival and progression-free survival in the global population were 84% (74%-89%) and 74% (65%-81%), respectively. Molecular classification was determined for 91 patients (WNT [n = 19], SHH [n = 12], and non-WNT/non-SHH [n = 60]-including group 3 [n = 9], group 4 [n = 29], and not specified [n = 22]). Our results showed more favorable outcome for the WNT-activated subgroup and a worse prognosis for SHH-activated patients. Three patients had isolated extra-central nervous system relapse. The slope of neurocognitive decline in the global population was shallower than that observed in patients with a normofractionated regimen combined with chemotherapy. CONCLUSIONS: HFRT led to a 5-year survival rate similar to other treatments combined with chemotherapy, with a reduced treatment duration of only 6 weeks. We confirm the MSFOP 98 results and the prognostic value of molecular status in patients with medulloblastoma, even in the absence of chemotherapy. Intelligence quotient was more preserved in children with medulloblastoma who received exclusive HFRT and reduced local boost, and intelligence quotient decline was delayed compared with patients receiving standard regimen. HFRT may be appropriate for patients who do not consent to or are not eligible for prospective clinical trials; for patients from developing countries for whom aplasia or ileus may be difficult to manage in a context of high cost/effectiveness constraints; and for whom shortened duration of RT may be easier to implement.
Authors: Jeff M Michalski; Anna J Janss; L Gilbert Vezina; Kyle S Smith; Catherine A Billups; Peter C Burger; Leanne M Embry; Patricia L Cullen; Kristina K Hardy; Scott L Pomeroy; Johnnie K Bass; Stephanie M Perkins; Thomas E Merchant; Paul D Colte; Thomas J Fitzgerald; Timothy N Booth; Joel M Cherlow; Karin M Muraszko; Jennifer Hadley; Rahul Kumar; Yuanyuan Han; Nancy J Tarbell; Maryam Fouladi; Ian F Pollack; Roger J Packer; Yimei Li; Amar Gajjar; Paul A Northcott Journal: J Clin Oncol Date: 2021-06-10 Impact factor: 50.717