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

BackgroundThe 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.MethodsWithin 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.FindingsNo 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.InterpretationThe 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’.

Targeted therapy for infants with diencephalic syndrome: A case report and review of management strategies

“…A recent international phase III trial of low‐grade glioma patients treated with chemotherapy confirmed that infants <1 year presenting with DS were at greatest risk for death, especially if there is progression following an initial carboplatin‐containing regimen . Alternate therapies are particularly needed for these higher‐risk patients.…”

Response in a child with a BRAF V600E mutated desmoplastic infantile astrocytoma upon retreatment with vemurafenib

“…Surprisingly, fast responses were observed, even in the retreatment situation, associated with clinical benefit (vision, endocrinology). Infant patients with an LGG and diencephalic syndrome have a worse outcome after standard first‐line chemotherapy treatment . This underlines the importance of BRAF V600E inhibition as an alternative treatment option in BRAF V600E mutated cases in the course or even upfront of this chronic disease.…”

“…The patient was successfully treated with first‐line vincristine and carboplatin according to the SIOP‐LGG‐2004 registry recommendation for 63 weeks and showed an initial response at week 24, followed by sustained disease stabilization. In parallel, the diencephalic syndrome resolved with a BMI of 16.2 kg/m 2 (48th percentile) at the end of treatment.…”

“…11 LGG has a high 5-year overall survival (OS) of 89% and progressionfree survival (PFS) of 44% with standard of care chemotherapy, however, infants with diencephalic syndrome have a particularly poor prognosis (5-year OS < 70% and PFS < 20%). 12 DIA has a rather good prognosis, but aggressive behavior with malignant transformation has been described. 13 Mortality is mainly associated with hypothalamic localization.…”

Favorable prognosis in pediatric brainstem low‐grade glioma: Report from the German SIOP‐LGG 2004 cohort

“…Overall survival (OS) of children and adolescents suffering from low‐grade glioma (LGG) exceeds 90% at 5 to 10 years . Still, the prognostic risk‐factors determining natural biology are not fully understood .…”