Chemotherapy for children with medulloblastoma.

Abstract

BACKGROUND: Post-surgical radiotherapy (RT) in combination with chemotherapy is considered as standard of care for medulloblastoma in children. Chemotherapy has been introduced to improve survival and to reduce RT-induced adverse effects. Reduction of RT-induced adverse effects was achieved by deleting (craniospinal) RT in very young children and by diminishing the dose and field to the craniospinal axis and reducing the boost volume to the tumour bed in older children. OBJECTIVES: Primary objectives: 1. to determine the event-free survival/disease-free survival (EFS/DFS) and overall survival (OS) in children with medulloblastoma receiving chemotherapy as a part of their primary treatment, as compared with children not receiving chemotherapy as part of their primary treatment; 2. to determine EFS/DFS and OS in children with medulloblastoma receiving standard-dose RT without chemotherapy, as compared with children receiving reduced-dose RT with chemotherapy as their primary treatment.Secondary objectives: to determine possible adverse effects of chemotherapy and RT, including long-term adverse effects and effects on quality of life. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 7), MEDLINE/PubMed (1966 to August 2013) and EMBASE/Ovid (1980 to August 2013). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (August 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the above treatments in children (aged 0 to 21 years) with medulloblastoma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and risk of bias assessment. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Where possible, we pooled results. MAIN RESULTS: The search identified seven RCTs, including 1080 children, evaluating treatment including chemotherapy and treatment not including chemotherapy. The meta-analysis of EFS/DFS not including disease progression during therapy as an event in the definition showed a difference in favour of treatment including chemotherapy (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.54 to 0.91; P value = 0.007; 2 studies; 465 children). However, not including disease progression as an event might not be optimal and the finding was not confirmed in the meta-analysis of EFS/DFS including disease progression during therapy as an event in the definition (HR 1.02; 95% CI 0.70 to 1.47; P value = 0.93; 2 studies; 300 children). Two individual studies using unclear or other definitions of EFS/DFS also showed no clear evidence of difference between treatment arms (one study with unclear definition of DFS: HR 1.67; 95% CI 0.59 to 4.71; P value = 0.34; 48 children; one study with other definition of EFS: HR 0.84; 95% CI 0.58 to 1.21; P value = 0.34; 233 children). In addition, it should be noted that in one of the studies not including disease progression as an event, the difference in DFS only reached statistical significance while the study was running, but due to late relapses in the chemotherapy arm, this significance was no longer evident with longer follow-up. There was no clear evidence of difference in OS between treatment arms (HR 1.06; 95% CI 0.67 to 1.67; P value = 0.80; 4 studies; 332 children). Out of eight reported adverse effects, of which seven were reported in one study, two (severe infections and fever/neutropenia) showed a difference in favour of treatment not including chemotherapy (severe infections: risk ratio (RR) 5.64; 95% CI 1.28 to 24.91; P value = 0.02; fever/neutropenia: RR not calculable; Fisher's exact P value = 0.01). There was no clear evidence of a difference between treatment arms for other adverse effects (acute alopecia: RR 1.00; 95% CI 0.92 to 1.08; P value = 1.00; reduction in intelligence quotient: RR 0.78; 95% CI 0.46 to 1.30; P value = 0.34; secondary malignancies: Fisher's exact P value = 0.5; haematological toxicity: RR 0.54; 95% CI 0.20 to 1.45; P value = 0.22; hepatotoxicity: Fisher's exact P value = 1.00; treatment-related mortality: RR 2.37; 95% CI 0.43 to 12.98; P value = 0.32; 3 studies). Quality of life was not evaluated. In individual studies, the results in subgroups (i.e. younger/older children and high-risk/non-high-risk children) were not univocal.The search found one RCT comparing standard-dose RT with reduced-dose RT plus chemotherapy. There was no clear evidence of a difference in EFS/DFS between groups (HR 1.54; 95% CI 0.81 to 2.94; P value = 0.19; 76 children). The RCT did not evaluate other outcomes and subgroups.The presence of bias could not be ruled out in any of the studies. AUTHORS' CONCLUSIONS: