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

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 stra...

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Hauptverfasser: Gnekow, AK, Walker, DA, Kandels, D, Picton, S, Giorgio Perilongo, Grill, J, Stokland, T, Sandstrom, PE, Warmuth-Metz, M, Pietsch, T, Giangaspero, F, Schmidt, R, Faldum, A, Kilmartin, D, De Paoli, A, De Salvo, GL, Slavc, I, Perilongo, G, Walker, D, Clausen, N, Arola, M, Jonsson, OG, Cruz, O, Navajas, A, Teijeiro, A, Kalifa, C, Raquin, M-A, Verlooy, J, Hans, V, Scheurlen, W, Hainfellner, J, Ironside, J, Robson, K, Skullerud, K, Scheie, D, NN, Ruchoux, M-M, Jouvet, A, Figarella-Branger, D, Lellouch-Toubiana, A, Prayer, D, Calderone, M, Jaspan, T, Bakke, SJ, Vazquez, E, Couanet, D, Kortmann, RD, Diekmann, K, Scarzello, G, Taylor, R, Lote, K, Giralt, J, Carrie, C, Habrand, JL, Soerensen, N, Czech, T, Chumas, P, Gustavson, B, Zerah, M, Wabbels, B, Pinello, ML, Fielder, A, Simmons, I, Christoffersen, T, Calaminus, G, Brockmann, K, Straeter, R, Ebinger, F, Hernaiz-Driever, P, Lackner, H, Kennedy, C, Glaser, A, Stromberg, B, Indiano, JM, Rodary, C, Bouffet, E, Frappaz, D, Emser, A, Stephens, S, Machin, D, Le Deley, M-C, Egeland, T, Freemann, C, Schrappe, M, Sposto, R
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Zusammenfassung: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
DOI:10.1016/j.ejca.2017.04.019