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

Gnekow, Astrid K.; Walker, David A.; Kandels, Daniela; Picton, Susan; Perilongo, Giorgio; Grill, Jacques; Stokland, Tore; Sandstrom, Per Eric; Warmuth-Metz, Monika; Pietsch, Torsten; Giangaspero, Felice; Schmidt, Ren�; Faldum, Andreas; Kilmartin, Denise; De Paoli, Angela; De Salvo, Gian Luca

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’.

Citation

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. (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, https://doi.org/10.1016/j.ejca.2017.04.019

• Journal Article Type: Article
• Acceptance Date: Apr 18, 2017
• Online Publication Date: Jun 22, 2017
• Publication Date: Aug 31, 2017
• Deposit Date: Jul 31, 2017
• Publicly Available Date: Jul 31, 2017
• Journal: European Journal of Cancer
• Print ISSN: 0959-8049
• Electronic ISSN: 1879-0852
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 81
• DOI: https://doi.org/10.1016/j.ejca.2017.04.019
• Keywords: Low grade glioma; Childhood; Chemotherapy; Randomised trial
• Public URL: https://nottingham-repository.worktribe.com/output/880511
• Publisher URL: https://doi.org/10.1016/j.ejca.2017.04.019
• Contract Date: Jul 31, 2017