Review Questions

The review has 2 objectives: (1A) to determine if event-free survival/disease-free survival (EFS/DFS) and overall survival (OS) in children with medulloblastoma receiving chemotherapy as part of their primary treatment is longer compared with children not receiving chemotherapy as part of their primary treatment, (1B) to determine EFS/DFS and OS in children with medulloblastoma receiving standard-dose radiotherapy (RT) without chemotherapy as compared with those end points in children receiving reduced-dose RT with chemotherapy as their primary treatment, and (2) to determine possible adverse effects of chemotherapy and RT, including long-term effects and effects on quality of life.

Type of Review

1. This is a Cochrane Review1 consisting of 7 randomized controlled trials (RCTs)2-8 that examined the first question (1A, 1B), that of comparing the addition of chemotherapy to full-dose RT without chemotherapy. The meta-analysis of EFS/DFS was performed using the 7 RCTs.

2. This is a Cochrane Review9 that further examined the second question (2), and because only 1 RCT9 was found addressing standard-dose RT without chemotherapy versus reduced-dose RT with chemotherapy, a meta-analysis was not applicable.

The total number of identified RCTs was 8.

Relevance for Nursing

For decades, the standard therapy for children with medulloblastoma has been neurosurgery with a maximum of debulking, followed by craniospinal RT. However, craniospinal irradiation causes significant long-term adverse effects. As a consequence, chemotherapy has been introduced in older children to improve survival and diminish the long-term effects caused by RT, whereas in very young children, chemotherapy's goal is mainly to omit or delay RT, while preserving or even improving survival rates.

The study was solely concerned with the effects of 2 treatments on the cancer, not the effects of choices of treatment on the child patient.

Characteristics of the Evidence

1. The review identified 7 RCTs,2-8 including 1080 children, evaluating treatment including chemotherapy and treatment not including chemotherapy. The primary outcomes that this review considered were EFS/DFS and OS. Secondary outcomes included adverse effects of grade 3 or higher and quality of life.

2. The review identified 1 RCT,8 consisting of 76 children, comparing standard-dose RT without chemotherapy, with a regimen of reduced-dose RT, with the addition of chemotherapy.

Summary of Key Evidence

1. The search identified 7 RCTs,1-8 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 favor of treatment including chemotherapy (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.54-0.91; P = .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, 0.70-1.47; P = .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 (1 study with unclear definition of DFS: HR, 1.67; 95% CI, 0.59-4.71; P = .34; 48 children2; 1 study with other definition of EFS: HR, 0.84; 95% CI, 0.58-1.21; P = .34; 23 children). In addition, it should be noted that in 1 of the studies not including disease progression as an event, the difference in DFS reached statistical significance only while the study was running, but because of 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, 0.67-1.67; P = .80; 4 studies, 332 children). Of 8 reported adverse effects, of which 7 were reported in 1 study, 2 (severe infections and fever/neutropenia) showed a difference in favor of treatment not including chemotherapy (severe infections: risk ratio [RR], 5.64; 95% CI, 1.28-24.91; P = .02; fever/neutropenia: RR not calculable; Fisher exact P = .01). There was no clear evidence of a difference between treatment arms for other adverse effects (acute alopecia: RR, 1.00; 95% CI, 0.92-1.08; P = 1.00; reduction in intelligence quotient: RR, 0.78; 95% CI, 0.46-1.30; P = .34; secondary malignancies: Fisher exact P = .5; hematological toxicity: RR, 0.54; 95% CI, 0.20-1.45; P = .22; hepatotoxicity: Fisher exact P = 1.00; treatment-related mortality: RR, 2.37; 95% CI, 0.43-12.98; P = .32; 3 studies). Quality of life was not evaluated. In individual studies, the results in subgroups (ie, younger/older children and high-risk/non-high-risk children) were not univocal.

2. The search found 1 RCT9 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, 0.81-2.94; P = .19; 76 children). The RCT did not evaluate other outcomes and subgroups. Only 1 study8 compared children receiving standard-dose RT without chemotherapy with children receiving reduced-dose RT with chemotherapy. In children receiving chemotherapy, the start of RT was delayed as compared with children receiving only RT. In this study, 76 children were eligible for evaluation (40 in the standard-dose RT arm and 36 in the reduced-dose RT arm). The exact ages of the children were unclear, but to be eligible for inclusion, they had to be aged between 0 and 16 years of age. According to the study protocol, in the reduced-dose arm, the RT dose to the cranio-spinal axis was reduced to 25 Gy instead of 35 Gy, whereas the tumor-bearing area received 55 Gy in both study arms. In children younger than 2 years, reduced RT doses were recommended. In the combined treatment arm, chemotherapy was administered before RT. The chemotherapy regimen consisted of vincristine, procarbazine, methotrexate, and prednisolone.

The presence of bias could not be ruled out in any of the studies.

Best Practice Recommendations

1. Based on the available evidence, the authors were unable to determine whether treatment with or without chemotherapy in children with medulloblastoma is preferable.

2. Based on the evidence identified in this systematic review, no definitive conclusions can be made regarding reduced-dose RT with chemotherapy and standard-dose RT without chemotherapy in children with medulloblastoma. "No evidence of effect," as identified in this review, is not the same as "evidence of no effect." The only eligible study was 25 years old.

Research Recommendations

More high-quality research is needed, focusing on all important outcomes, not only on EFS/DFS. However, in the current treatment era, it is considered unethical to use standard-dose RT as the long-term consequences are devastating. It is thus very unlikely that these studies will be performed. Without evidence from high-quality RCTs, we have to acknowledge that the true efficacy of these treatments in children with medulloblastoma remains unclear.

The full review report, including references, can be accessed at http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006678.pub2/pdf.

References