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

• Published in: European journal of cancer (1990) Vol. 81; pp. 206 - 225
• Main Authors: Gnekow, Astrid K., Walker, David A., Kandels, Daniela, Picton, Susan, Giorgio Perilongo, Grill, Jacques, Stokland, Tore, Sandstrom, Per Eric, Warmuth-Metz, Monika, Pietsch, Torsten, Giangaspero, Felice, Schmidt, René, Faldum, Andreas, Kilmartin, Denise, De Paoli, Angela, De Salvo, Gian Luca, Slavc, Irene, Perilongo, Giorgio, Picton, Sue, Walker, David, Sandstrom, Per Erik, Clausen, Niels, Arola, Mikko, Jonsson, Olafur Gisli, Cruz, Ofelia, Navajas, Aurora, Teijeiro, Anna, Kalifa, Chantal, Raquin, Marie-Anne, Verlooy, Joris, Hans, Volkmar, Scheurlen, Wolfram, Hainfellner, Johannes, Ironside, James, Robson, Keith, Skullerud, Kari, Scheie, David, NN, Ruchoux, Marie-Madeleine, Jouvet, Anne, Figarella-Branger, Dominique, Lellouch-Toubiana, Arielle, Prayer, Daniela, Calderone, Milena, Jaspan, Tim, Bakke, Soren Jacob, Vazquez, Eli, Couanet, Dominique, Kortmann, Rolf D., Diekmann, Karin, Scarzello, Giovanni, Taylor, Roger, Lote, Knut, Giralt, Jordi, Carrie, Christian, Habrand, Jean Louis, Soerensen, Niels, Czech, Thomas, Chumas, Paul, Gustavson, Bengt, Zerah, Michel, Wabbels, Bettina, Pinello, Maria Luisa, Fielder, Alistair, Simmons, Ian, Christoffersen, Terje, Calaminus, Gabriele, Brockmann, Knut, Straeter, Ronald, Ebinger, Friedrich, Hernaiz-Driever, Pablo, Lackner, Herwig, Kennedy, Colin, Glaser, Adam, Stromberg, Bo, Indiano, Jose Ma, Rodary, Chantal, Bouffet, Eric, Frappaz, Didier, Emser, Angela, Stephens, Suzanne, Machin, David, Le Deley, Marie-Cécile, Egeland, Thore, Freemann, Carolyn, Schrappe, Martin, Sposto, Richard
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2017; Elsevier Science Ltd
• Subjects: Age; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biopsy; Brain Neoplasms - drug therapy; Carboplatin; Carboplatin - administration & dosage; Chemotherapy; Child; Child, Preschool; Childhood; Children; Clinical Trial; Clinical trials; Etoposide; Etoposide - administration & dosage; Female; Glioma; Glioma - drug therapy; Humans; Induction Chemotherapy - methods; Infant; Infants; Low grade glioma; Male; Patients; Pediatrics; Randomised trial; Randomization; Risk analysis; Risk factors; Studies; Survival; Survival Analysis; Toxicity; Tumors; Vincristine; Vincristine - administration & dosage; Visual discrimination; Chemotherapy; Low grade glioma; Randomised trial; Childhood
• ISSN: 0959-8049; 1879-0852; 1879-0852
• DOI: 10.1016/j.ejca.2017.04.019

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. 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. 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. 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’. •A randomised trial in the commonest brain tumour type in children – low grade glioma.•Tumour response assessment at 6 months identifies those at greatest risk of subsequent progression and death.•Intensifying induction treatment with etoposide does not improve progression-free survival.•International consortium successfully recruits from 11 European countries in a childhood brain tumour.•Carboplatin hypersensitivity is reduced by coadministration of etoposide.