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

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'.

Keywords: Chemotherapy; Childhood; Low grade glioma; Randomised trial.

Fig. 1

Flow diagram of the study.

Fig. 2

CONSORT diagram.

Fig. 3

a: Kaplan–Meier estimates and p-value of log-rank test for overall survival stratified according to randomisation arm (VC, VCE). b: Kaplan–Meier estimates and p-value of log-rank test for overall survival stratified according to age group (strata at randomisation: <1 year, ≥1 and <8 years, ≥8 years) by randomisation arm (VC, VCE). c: Kaplan–Meier estimates and p-value of log-rank test for overall survival measured from response assessment in week 24 stratified according to response status at week 24: (1) Complete response (CR), partial response (PR) or objective response (OR), (2) stable disease (SD), (3) progressive disease (PD). d: Kaplan–Meier estimates and p-value of log-rank test for overall survival stratified according to indication to start treatment (diencephalic syndrome (DS), other).

Fig. 4

Full legend can be found on the next page. a: Kaplan–Meier estimates and p-value of log-rank test for progression-free survival stratified according to randomisation arm (VC, VCE). b: Kaplan–Meier estimates and p-value of log-rank test for progression-free survival stratified according to localisation strata at randomisation: (i) Pure chiasmatic/Dodge II, (ii) chiasmatic-hypothalamic/Dodge III plus other midline structures, (iii) tumours outside the supratentorial midline. SM: Supratentorial midline. c: Kaplan–Meier estimates and p-value of log-rank test for progression-free survival stratified according to age group (strata at randomisation: <1 year, ≥1 and <8 years, ≥8 years) by randomisation arm (VC, VCE). d: For all patients without event by the time of response assessment at week 24: Kaplan–Meier estimates and p-value of log-rank test for progression-free survival measured from response assessment in week 24 stratified according to response status at week 24: (i) Complete response (CR), partial response (PR) or objective response (OR), (ii) stable disease (SD). e: Kaplan–Meier estimates and p-value of log-rank test for progression-free survival stratified according to indication to start treatment (diencephalic syndrome (DS), other).