A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma – A final report

Astrid K. Gnekow, David A. Walker, Daniela Kandels, Susan Picton, Giorgio Perilongo, Jacques Grill, Tore Stokland, Per Eric Sandstrom, Monika Warmuth-Metz, Torsten Pietsch, Felice Giangaspero, René Schmidt, Andreas Faldum, Denise Kilmartin, Angela De Paoli, Gian Luca De Salvo, Astrid K. Gnekow, Irene Slavc, Giorgio Perilongo, Sue PictonDavid Walker, Tore Stokland, Per Erik Sandstrom, Niels Clausen, Mikko Arola, Olafur Gisli Jonsson, Ofelia Cruz, Aurora Navajas, Anna Teijeiro, Jacques Grill, Chantal Kalifa, Marie Anne Raquin, Joris Verlooy, Volkmar Hans, Torsten Pietsch, Wolfram Scheurlen, Johannes Hainfellner, Felice Giangaspero, James Ironside, Keith Robson, Kari Skullerud, David Scheie, NN, Marie Madeleine Ruchoux, Anne Jouvet, Dominique Figarella-Branger, Arielle Lellouch-Toubiana, Monika Warmuth-Metz, Daniela Prayer, Milena Calderone, Tim Jaspan, Soren Jacob Bakke, Eli Vazquez, Dominique Couanet, Rolf D. Kortmann, Karin Diekmann, Giovanni Scarzello, Roger Taylor, Knut Lote, Jordi Giralt, Christian Carrie, Jean Louis Habrand, Niels Soerensen, Thomas Czech, Paul Chumas, Bengt Gustavson, Michel Zerah, Bettina Wabbels, Maria Luisa Pinello, Alistair Fielder, Ian Simmons, Terje Christoffersen, Gabriele Calaminus, Knut Brockmann, Ronald Straeter, Friedrich Ebinger, Pablo Hernaiz-Driever, Herwig Lackner, Colin Kennedy, Adam Glaser, Bo Stromberg, Jose Ma Indiano, Chantal Rodary, Eric Bouffet, Didier Frappaz, Andreas Faldum, Angela Emser, Gian Luca De Salvo, Suzanne Stephens, David Machin, Marie Cécile Le Deley, Thore Egeland, Carolyn Freemann, Martin Schrappe, Richard Sposto

Research output: Contribution to journalArticle

Abstract

Background The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection. Methods Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology–Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m2, days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m2 × 10 wkly) and carboplatin (550 mg/m2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02–7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site. Findings No differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively. Interpretation The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of ‘duration of therapy’ and ‘age at stopping therapy’.

Original languageEnglish
Pages (from-to)206-225
Number of pages20
JournalEuropean Journal of Cancer
Volume81
DOIs
Publication statusPublished - Aug 1 2017

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Keywords

  • Chemotherapy
  • Childhood
  • Low grade glioma
  • Randomised trial

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gnekow, A. K., Walker, D. A., Kandels, D., Picton, S., Perilongo, G., Grill, J., Stokland, T., Sandstrom, P. E., Warmuth-Metz, M., Pietsch, T., Giangaspero, F., Schmidt, R., Faldum, A., Kilmartin, D., De Paoli, A., De Salvo, G. L., Gnekow, A. K., Slavc, I., Perilongo, G., ... Sposto, R. (2017). A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma – A final report. European Journal of Cancer, 81, 206-225. https://doi.org/10.1016/j.ejca.2017.04.019