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
Based on the evidence identified in this systematic review, a benefit of chemotherapy cannot be excluded, but at this moment we are unable to draw a definitive conclusion regarding treatment with or without chemotherapy. Treatment results must be viewed in the context of the complete therapy (e.g. the effect of surgery and craniospinal RT), and the different chemotherapy protocols used. This systematic review only allowed a conclusion on the concept of treatment, not on the best strategy regarding specific chemotherapeutic agents and radiation dose. Several factors complicated the interpretation of results including the long time span between studies with important changes in treatment in the meantime. 'No evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. The fact that no significant differences between treatment arms were identified could, besides the earlier mentioned reasons, also be the result of low power or too short a follow‐up period. Even though RCTs are the highest level of evidence, it should be recognised that data from non‐randomised studies are available, for example on the use of chemotherapy only in very young children with promising results for children without metastatic disease. We found only one RCT addressing standard‐dose RT without chemotherapy versus reduced‐dose RT with chemotherapy, so no definitive conclusions can be made. More high‐quality research is needed.
Plain language summary
Chemotherapy for children with medulloblastoma
Background
Medulloblastoma is one of the most common malignant brain tumours in children. Chemotherapy is used to improve survival and diminish potential radiotherapy‐induced side effects. The reduction of radiotherapy‐induced side effects is achieved in very young children by not treating them with radiotherapy and in older children by diminishing the craniospinal radiotherapy (radiotherapy applied to the brain and spinal cord) dose and by reducing the boost volume to the tumour bed only instead of the whole posterior fossa (part of the brain). A well‐informed decision on the use of chemotherapy in the treatment of medulloblastoma in children should be based on high‐quality evidence on both the effectiveness against the tumour and side effects.
Study characteristics
We searched databases for randomised trials (studies where participants are allocated to one of two or more treatment groups in a random manner) evaluating the effectiveness of treatment including chemotherapy versus treatment not including chemotherapy (seven available studies) and on randomised studies evaluating the effectiveness of standard‐dose radiotherapy without chemotherapy versus reduced‐dose radiotherapy plus chemotherapy (one available study) in children (aged 0 to 21 years). The evidence is current to August 2013.
Key results and quality of the evidence
Based on the evidence identified in this systematic review a benefit of chemotherapy cannot be excluded, but at this moment we are unable to draw a definitive conclusion to favour treatment with or without chemotherapy. Even though randomised studies are the highest level of evidence, it should be recognised that data from non‐randomised studies were available, for example on the use of chemotherapy only in very young children. The results are promising for children without metastatic disease. For treatment with standard‐dose radiotherapy without chemotherapy as compared with reduced‐dose radiotherapy with chemotherapy, we also cannot make definitive recommendations. More high‐quality research is needed.
Background
Medulloblastoma represents one of the most common malignant brain tumours in childhood, occurring mostly in children younger than 10 years of age. Survival of children with medulloblastoma is correlated with the age at diagnosis, the presence of metastatic disease, the treatment given and the presence of extensive residual disease following neurosurgery. Five‐year event‐free survival (EFS) varies from around 30% to more than 80% (Kortmann 2000; Zeltzer 1999). More recently, the histological subtypes and molecular characteristics of the tumour were added as prognostic markers. While nodular/desmoplastic tumours appear to have a favourable prognosis (Rutkowski 2010), children with large cell/anaplastic medulloblastoma have a poor prognosis (Brown 2000; Ellison 2005; Gajjar 2006; Giangaspero 1999; Grotzer 2001; Northcott 2011). Molecular characteristics with a favourable prognosis are nuclear expression of beta‐catenin (Ellison 2005; Gajjar 2006), and TrkC expression (Grotzer 2000; Rutkowski 2007); a worse prognosis is related to MYC/MYCN amplification (Pfister 2009). Four main subgroups of medulloblastoma exist; Wnt (very good prognosis), Shh (intermediate prognosis), Group 3 (poor prognosis) and Group 4 (intermediate prognosis) (Taylor 2012).
For decades, the standard therapy for children with medulloblastoma has been neurosurgery with a maximum of debulking, followed by craniospinal radiotherapy (CSRT). However, craniospinal irradiation causes significant long‐term adverse effects. Children aged less than 36 months who received whole‐brain radiotherapy (cranial radiotherapy (CRT)) as part of their treatment of a cerebellar tumour showed more neurocognitive and psychosocial deficits than non‐irradiated infants (Copeland 1999). Palmer et al. found that the decline in intelligence quotient (IQ) values was the result of an inability to acquire new skills and information at a rate comparable to their healthy peers, and not to a loss of previously acquired information and skills (Palmer 2001). On the endocrinological level, deficiencies following CSRT have been known for a very long time (Livesey 1990; Shalet 1977). In accordance, Spoudeas et al. showed that growth hormone is especially sensitive to radiation injury (Spoudeas 2003), and Gurney et al. demonstrated hypothyroidism in 30% of irradiated participants and a growth hormone deficiency in 39.2% of irradiated participants (Gurney 2003).
As a consequence, chemotherapy has been introduced in older children to improve survival and diminish the long‐term effects caused by radiotherapy (RT), while in very young children, its goal is mainly to omit or delay RT, while preserving or even improving survival rates (Evans 1990; Geyer 2005; Grill 2005; Merchant 2008; Oyharcabal‐Bourden 2005; Packer 2006; Tait 1990; Rutkowski 2005). In recent years, high‐dose chemotherapy followed by stem cell rescue has been increasingly used for children with a poor prognosis (Gajjar 2006; Gandola 2009; Grill 2005; Pérez‐Martinez 2004).
Several randomised controlled trials (RCT) have been conducted to analyse the effects of chemotherapy, and to detect possible subgroups of children that might benefit most from chemotherapy. However, until now, no systematic review had been carried out.
Objectives
Primary objectives: 1. to determine the EFS/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.
Methods
Criteria for considering studies for this review
Types of studies
Primary objective 1
RCTs comparing the EFS/DFS or OS (or both) in children with medulloblastoma receiving chemotherapy as part of their primary treatment compared with children not receiving chemotherapy as part of their primary treatment.
As mentioned in the protocol of this review, we would only have included controlled clinical trials (CCTs) if we had identified no RCTs.
Primary objective 2
RCTs comparing the EFS/DFS or OS (or both) in children with medulloblastoma receiving standard‐dose RT without chemotherapy compared with children receiving reduced‐dose RT with chemotherapy as their primary treatment.
As mentioned in the protocol of this review, we would only have included CCTs if we had identified no RCTs.
Types of participants
Children (aged 0 to 21 years) with a primary diagnosis of medulloblastoma.
Types of interventions
Primary objective 1
Neurosurgery or RT (or both) with or without chemotherapy.
Primary objective 2
Neurosurgery and standard‐dose RT (30 Gray (Gy) or greater on the craniospinal axis (CSA) and 50 Gy or greater on the posterior fossa) without chemotherapy or reduced‐dose RT (less than 30 Gy on the CSA and 50 Gy or greater on the posterior fossa) with chemotherapy.
Types of outcome measures
Primary outcomes
EFS/DFS, defined as the time to recurrence or progression of primary disease or death from any cause.
OS, defined as the time to death from any cause.
Secondary outcomes
Adverse effects, defined as toxicities grade 3 or higher (as classified by, for example, the Common Toxicity Criteria of the World Health Organization (WHO)) and including long‐term adverse effects, such as neurocognitive impairment and endocrinological deficiencies (as defined by the authors of the original study).
Quality of life.
Search methods for identification of studies
We searched the following electronic databases:
the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 7);
MEDLINE/PubMed (from 1966 to 6 August 2013);
EMBASE/Ovid (from 1980 to 6 August 2013).
The search strategies for the different electronic databases are shown in Appendix 1; Appendix 2; and Appendix 3.
We handsearched the reference lists of relevant articles and review articles for information about trials, published or unpublished, not registered in CENTRAL, MEDLINE or EMBASE. We also scanned the conference proceedings of the International Society for Paediatric Oncology (SIOP), American Society for Pediatric Hematology and Oncology (ASPHO) and the International Symposium of Paediatric Neuro‐Oncology (ISPNO) from 2001 to 2008, if available electronically and otherwise by handsearching. We searched for ongoing trials by scanning the International Standard Randomised Controlled Trial Number (ISRCTN) register and the National Institutes of Health Register (www.controlled‐trials.com; both screened 15 August 2013). We applied no language restrictions.
Data collection and analysis
Study identification
Two review authors independently identified studies meeting the inclusion criteria on grounds of the title or abstract (or both) and if necessary obtained the full‐text reports for closer inspection. We reported details of reasons for exclusion of any study considered for the review clearly in the Characteristics of excluded studies table. We resolved discrepancies by consensus and required no third‐party arbitration. We reported full details of included studies in the Characteristics of included studies table.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias in included studies according to the following criteria: concealment of treatment allocation; blinding of care provider, blinding of participants, blinding of outcome assessor (for each outcome separately); intention‐to‐treat (ITT) analyses (for each outcome separately) and completeness of follow‐up (for each outcome separately). We have used the definitions as described in the module of the Cochrane Childhood Cancer Group at the time of writing the protocol for this systematic review (see Table 1). We resolved discrepancies between review authors by consensus and required no third‐party arbitration.
1. Criteria for the assessment of risk of bias in included studies.
| Risk of bias item | Type of bias | Implementation |
| Allocation concealment | Selection bias | Adequate: use of randomisation method that did not allow investigator and participant to know or influence the allocation of treatment before eligible participants entered the study Inadequate: use of alternate medical record numbers or unsealed envelopes as randomisation method, or there was information in the study indicating that investigators or participants could have influenced the allocation of treatment, or both Unclear: randomisation stated but no information on method used was available |
| Blinding of care providers | Performance bias | Adequate information about blinding must have been provided |
| Blinding of participants | Performance bias | Adequate information about blinding must have been provided |
| Blinding of outcome assessors | Detection bias | Adequate information about blinding must have been provided |
| Intention‐to‐treat analysis | Attrition bias | Yes: all participants were analysed in the treatment group to which they were randomised, regardless of whether or not they received the allocated intervention No: some participants (< 5%, 5‐10%, 11‐20%, > 20%) were not analysed in the treatment group to which they were randomised because they did not receive study intervention, they withdrew from the study or because of protocol violation Unclear: inability to determine if participants were analysed according to the intention‐to‐treat principle |
| Completeness of follow‐up | Attrition bias | Percentage of participants excluded or lost to follow‐up (< 5%, 5‐10%, 11‐20%, > 20%) should be stated |
Data extraction
Two review authors independently performed data extraction using standardised forms. We extracted data on:
characteristics of participants (e.g. age, sex, tumour staging, histological subtype and molecular markers);
characteristics of interventions (e.g. extent of surgical resection, posterior fossa and CSRT dose, type and dosage of chemotherapy, duration of chemotherapy, route of delivery of chemotherapy);
characteristics of outcome measures (see Types of outcome measures);
duration of follow‐up.
In cases of disagreement between review authors, we re‐examined the abstracts and articles and discussed findings until we achieved consensus. We required no third‐party arbitration.
Data analysis
We entered data into Review Manager 5 (RevMan 2012), and analysed data according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). For dichotomous variables, we calculated risk ratio (RR) and 95% confidence intervals (CI). For the assessment of survival, we used the generic inverse variance function of Review Manager 5 to combine logs of the hazard ratios (HRs) (RevMan 2012) and reported 95% CI. We used Parmar's method if HRs had not been explicitly presented in the study (Parmar 1998). We extracted data by allocation intervention, irrespective of compliance with the allocated intervention, in order to allow an ITT analysis. If it was not possible to perform an ITT analysis, we stated this. We assessed heterogeneity both by visual inspection of the forest plots and by a formal statistical test for heterogeneity (i.e. the I2 statistic). If there was evidence of substantial heterogeneity (I2 greater than 50%) (Higgins 2008), we reported this. We used a random‐effects model for the estimation of treatment effects throughout the review. . We pooled data if we identified two or more studies, otherwise we summarised the results descriptively. For outcomes where only one study was available, we were unable to calculate an RR if one of the treatment arms experienced no events and we used the Fischer's exact test instead (calculated using GraphPad software; www.graphpad.com/quickcalcs/contingency1.cfm). Where possible, we separated data for younger/older children and high‐risk/non‐high‐risk children (i.e. subgroups). For all outcomes for which pooling was possible, we performed sensitivity analyses for all quality criteria separately. We excluded the low‐quality studies and the studies for which the quality was unclear and compared the results of the good‐quality studies with the results of all available studies. We considered the quality of studies included in the analyses in the interpretation of the results of the review. We planned to construct a funnel plot to ascertain graphically the existence of publication bias. However, generally, tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta‐analysis, because when there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2008). Since only a maximum of four trials could be included in the different meta‐analyses, we did not construct funnel plots.
Results
Description of studies
After performing the searches of the electronic databases of CENTRAL (277 studies; some studies were included twice due to updates of the search), MEDLINE (1936 studies; some studies were included twice due to updates of the search) and EMBASE (1258 studies; some studies were included twice due to updates of the search) we excluded 3459 articles based on the title or abstract (or both) since they were not RCTs, did not compare children treated with chemotherapy with children treated without chemotherapy, did not include children at all or did not include children with medulloblastoma. We excluded a further four articles after assessing the full‐text article for reasons described in the Characteristics of excluded studies table. Therefore, we included eight articles that fulfilled all the criteria for considering studies for this review. Two of these eight articles described the same study (Taylor 2003/4); in one article, children eligible for both our objectives were included (Bailey 1995 CT vs no CT; Bailey 1995 RTvslowRT/CT).
We found no further studies by scanning the reference lists of relevant studies and reviews and the conference proceedings of SIOP, ASPHO and ISPNO. In addition, we identified no ongoing studies by scanning the ongoing trials databases.
Therefore, the total number of identified RCTs was eight. Seven studies compared children with medulloblastoma receiving chemotherapy as a part of their treatment with children not receiving chemotherapy as part of their treatment. One study compared children with medulloblastoma receiving standard‐dose RT without chemotherapy with children receiving reduced‐dose RT with chemotherapy. Figure 1 shows the PRISMA flow diagram.
1.
Flow diagram of study selection
Characteristics of included studies are summarised below (for further details see the Characteristics of included studies table).
Description of studies comparing treatment including and treatment not including chemotherapy
In the seven RCTs that compared treatment including versus treatment not including chemotherapy the total number of included children was 1080; 499 children in the experimental arm (receiving chemotherapy) and 502 children in the standard arm; for 79 children (from Bailey 1995 CT vs no CT), it was unclear to which treatment arm they were randomised. Ages of the children were not mentioned in two studies, and ranged from zero to 20 years in the other RCTs. Chemotherapy was administered during and after RT in three studies, before RT in two studies (thus delaying the start of RT) and after RT in two studies. Chemotherapy regimens contained vincristine in all seven RCTs, but in combination with many different other chemotherapeutics: etoposide in two studies; procarbazine in two studies; predniso(lo)ne in three studies; CCNU in two studies and cisplatin, methotrexate, nitrogen mustard, carboplatin, cyclophosphamide and intrathecal methotrexate and hydrocortisone respectively in one study. CRT doses varied from 25 to 45 Gy; some studies reduced this dose in children younger than either two or three years of age (see Characteristics of included studies table for more information on RT doses in individual studies). Prescribed dose to the fossa posterior was 50 Gy or greater in all studies; however, some studies reduced this dose in children younger than either two or three years. Only two studies mentioned the actual received RT doses.
Description of studies comparing treatment with standard‐dose radiotherapy and treatment with reduced‐dose radiotherapy and chemotherapy
Only one study compared children receiving standard‐dose RT without chemotherapy with children receiving reduced‐dose RT with chemotherapy (Bailey 1995 RTvslowRT/CT). In children receiving chemotherapy, the start of RT was delayed as compared with children only receiving 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 zero and 16 years of age. According to protocol of the study, in the reduced‐dose arm, the RT dose to the CSA was reduced to 25 Gy instead of 35 Gy, while the tumour‐bearing area received 55 Gy in both arms. In children under two years of age, reduced RT doses were recommended (see Characteristics of included studies table for more information). In the combined treatment arm, chemotherapy was administered before RT. The chemotherapy regimen consisted of vincristine, procarbazine, methotrexate and prednisolone.
Risk of bias in included studies
See Table 2 for the exact scores per included study.
2. Risk of bias in included studies.
| Study | Comparison | Allocation concealment | Blinding of care providers | Blinding of participants | Blinding of outcome assessors | Intention‐to‐treat analysis | Completeness of follow‐up |
| Abd El‐Aal 2005 | Chemotherapy vs. no chemotherapy | Unclear | No | No | DFS and adverse effects: unclear | OS, DFS and adverse effects: unclear | OS, DFS and adverse effects: unclear |
| Bailey 1995 CT vs no CT | Chemotherapy vs. no chemotherapy | Adequate | No | No | EFS: unclear | EFS: yes | EFS: unclear |
| Evans 1990 | Chemotherapy vs. no chemotherapy | Unclear | No | No | EFS and adverse effects: unclear | EFS and adverse effects: unclear | EFS and adverse effects: unclear |
| Krischer 1991 | Chemotherapy vs. no chemotherapy | Unclear | No | No | EFS and adverse effects: unclear | OS, EFS and adverse effects: unclear | OS, EFS and adverse effects: unclear |
| Tait 1990 | Chemotherapy vs. no chemotherapy | Unclear | No | No | DFS and adverse effects: unclear | DFS and adverse effects: yes | DFS and adverse effects: no |
| Taylor 2003/4 | Chemotherapy vs. no chemotherapy | Adequate | No | No | EFS and adverse effects: unclear | OS, EFS and adverse effects: unclear | OS, EFS and adverse effects: unclear |
| Van Eys 1981 | Chemotherapy vs. no chemotherapy | Unclear | No | No | Not applicable for OS | OS: unclear | OS: unclear |
| Bailey 1995 RTvslowRT/CT | Standard‐dose radiotherapy without chemotherapy vs. reduced‐dose radiotherapy and chemotherapy | Adequate | No | No | EFS: unclear | EFS: yes | EFS: unclear |
DFS: disease‐free survival; EFS: event‐free survival; OS: overall survival.
Risk of bias in studies comparing treatment including and treatment not including chemotherapy
The search identified seven studies.
Two studies applied a concealed treatment allocation (Bailey 1995 CT vs no CT; Taylor 2003/4), whereas in five studies this was unclear (Abd El‐Aal 2005; Evans 1990; Krischer 1991; Tait 1990; Van Eys 1981).
None of the seven studies blinded care providers and participants to treatment. However, it should be noted that due to the nature of the interventions blinding of care providers and participants was impossible.
For blinding of the outcome assessors, we scored each outcome separately, with the exception of OS, since for that outcome blinding was not relevant. Six studies evaluated EFS/DFS (Abd El‐Aal 2005; Bailey 1995 CT vs no CT; Evans 1990; Krischer 1991; Tait 1990; Taylor 2003/4): in all studies, it was unclear if the outcome assessor was blinded to treatment. Five studies evaluated adverse effects: in all studies, it was unclear if the outcome assessor was blinded to treatment (Abd El‐Aal 2005; Evans 1990; Krischer 1991; Tait 1990; Taylor 2003/4).
We scored the presence of an ITT analysis for each outcome separately. Six studies reported EFS/DFS. Two of the six studies used an ITT analysis (Bailey 1995 CT vs no CT; Tait 1990), whereas this was unclear in four studies (Abd El‐Aal 2005; Evans 1990; Krischer 1991; Tait 1990). Four studies reported OS. It was unclear if an ITT analysis was used in all four studies (Abd El‐Aal 2005; Krischer 1991; Taylor 2003/4; Van Eys 1981). Five studies reported adverse effects. One of the five studies used an ITT analysis (Tait 1990), whereas this was unclear in four studies (Abd El‐Aal 2005; Evans 1990; Krischer 1991; Taylor 2003/4).
We scored participants lost to follow‐up for each outcome separately. Six studies evaluated EFS/DFS. Some participants were lost to follow‐up in one of the six studies (Tait 1990), whereas in five studies this was unclear (Abd El‐Aal 2005; Bailey 1995 CT vs no CT; Evans 1990; Krischer 1991; Taylor 2003/4). For OS, the number of participants lost to follow‐up was unclear in all four studies (Abd El‐Aal 2005; Krischer 1991; Taylor 2003/4; Van Eys 1981). Five studies reported adverse effects. Some participants were lost to follow‐up in one study (Tait 1990), whereas in four studies this was unclear (Abd El‐Aal 2005; Evans 1990; Krischer 1991; Taylor 2003/4).
In conclusion, selection bias (based on concealment of treatment allocation) could not be ruled out in five of the seven included studies. Performance bias (based on blinding of the care provider and participant) could not be ruled out in any of the included studies. Detection bias (based on blinding of the outcome assessor) could not be ruled in any of the studies evaluating EFS/DFS and adverse effects. Attrition bias (based on the use of an ITT analysis and completeness of follow‐up) could not be ruled out in any of the studies evaluating EFS/DFS, OS and adverse effects.
Risk of bias in studies comparing treatment with standard‐dose radiotherapy and treatment with reduced‐dose radiotherapy and chemotherapy
The search identified one study.
This study applied a concealed treatment allocation. The care provider and participants were not blinded to treatment, but it should be noted that due to the nature of the interventions, blinding of care providers and participants was impossible. For EFS/DFS, it was unclear whether the outcome assessor was blinded to treatment. For EFS/DFS, this study used an ITT analysis. For EFS/DFS, the number of participants lost to follow‐up was unclear.
In conclusion, in this study, selection bias (based on concealment of treatment allocation) could be ruled out, whereas performance bias (based on blinding of the care provider and participant), detection bias (based on blinding of the outcome assessor) and attrition bias (based on the use of an ITT analysis and completeness of follow‐up) could not be ruled out.
Effects of interventions
Not all articles allowed data extraction for all outcomes; see Characteristics of included studies table for a more detailed description of the extractable outcomes of each study.
In the Bailey 1995 CT vs no CT/Bailey 1995 RTvslowRT/CT study, children were randomised to one of four treatment arms: 1. standard‐dose RT only, 2. reduced‐dose RT only, 3. chemotherapy plus standard‐dose RT or 4. chemotherapy plus reduced‐dose RT. In children receiving chemotherapy, the start of RT was delayed. For the analyses of treatment including and treatment not including chemotherapy, children receiving RT only (either standard or reduced dose) (treatment arms 1 and 2) were compared with children receiving both chemotherapy and RT (either the standard or reduced dose) (treatment arms 3 and 4). For the analyses of treatment with standard‐dose RT and treatment with reduced‐dose RT and chemotherapy, children from treatment arm 1 were compared with children from treatment arm 4. Children from only treatment arm 2 (reduced‐dose RT only) were not included in the analyses, since comparing reduced‐dose RT without the addition of chemotherapy was not an objective of our review.
Studies comparing treatment including and treatment not including chemotherapy
Event‐free survival or disease‐free survival
We were able to extract data on EFS/DFS from six trials (see Analysis 1.1; Figure 2).
1.1. Analysis.
Comparison 1 Treatment including chemotherapy versus treatment not including chemotherapy, Outcome 1 Event‐free survival/disease‐free survival (EFS/DFS).
2.
Forest plot of comparison: 1 Chemotherapy versus no chemotherapy, outcome: 1.1 Event‐free survival/disease‐free survival (EFS/DFS).
The trials of Bailey 1995 CT vs no CT and Krischer 1991, including 300 children, used comparable outcome definitions (i.e. time to recurrence or progression of primary disease or death from any cause; for further details see Characteristics of included studies table) and, therefore, we could pool their results. The meta‐analysis showed no significant difference between treatment including and treatment not including chemotherapy (HR 1.02; 95% CI 0.70 to 1.47; P value = 0.93). There was no heterogeneity (I2 = 0%).
The trials of Tait 1990 and Taylor 2003/4, including 465 children, used comparable outcome definitions (i.e. time to recurrence or death from any cause; for further details see Characteristics of included studies table) and, therefore, we pooled their results. The meta‐analysis showed a significant difference in favour of children treated with chemotherapy (HR 0.70; 95% CI 0.54 to 0.91; P value = 0.007). There was no heterogeneity (I2 = 0%).
In the study of Abd El‐Aal 2005, including 48 children, no definition for DFS was provided and the definition of EFS used by Evans 1990, including 233 children, was not comparable to the other definitions, therefore, we could not pool the results. However, in both studies there was no significant difference between treatment including and treatment not including chemotherapy (Abd El‐Aal 2005: HR 1.67; 95% CI 0.59 to 4.71; P value = 0.34; Evans 1990: HR 0.84; 95% CI 0.58 to 1.21; P value = 0.34). For Evans 1990, an ITT analysis was not possible, since 42 children were not randomised (21 in each treatment arm) and 12 children switched between treatment arms after randomisation (six in each treatment arm).
Overall survival
We were able to extract data on OS from four trials including 332 children (Abd El‐Aal 2005; Krischer 1991; Taylor 2003/4; Van Eys 1981). The meta‐analysis showed no significant difference between treatment including and treatment not including chemotherapy (HR 1.06; 95% CI 0.67 to 1.67; P value = 0.80; see Analysis 1.2; Figure 3). There was no substantial heterogeneity detected (I2 = 13%).
1.2. Analysis.
Comparison 1 Treatment including chemotherapy versus treatment not including chemotherapy, Outcome 2 Overall survival.
3.
Forest plot of comparison: 1 Chemotherapy versus no chemotherapy, outcome: 1.2 Overall survival.
Adverse effects grade 3 or higher
Six studies evaluated eight different adverse effects grade 3 or higher (see Analysis 1.3; Figure 4). Of these, only two were long‐term adverse effects (reduction in IQ and secondary malignant disease). The others were all short‐term adverse effects. Treatment‐related mortality was reported in three studies but the other adverse effects were evaluated in only one study. Therefore, we could only perform a meta‐analysis for treatment‐related mortality.
1.3. Analysis.
Comparison 1 Treatment including chemotherapy versus treatment not including chemotherapy, Outcome 3 Adverse effects.
4.
Forest plot of comparison: 1 Chemotherapy versus no chemotherapy, outcome: 1.3 Adverse effects.
Alopecia grade 3
We were able to extract data on acute alopecia grade 3 from one trial including 48 children (Abd El‐Aal 2005). There was no significant difference between treatment arms as all children had alopecia grade 3 (RR 1.00; 95% CI 0.92 to 1.08; P value = 1.00). Hair re‐growth occurred in all children six weeks after ending RT and chemotherapy.
Reduction in intelligence quotient
We were able to extract data on reduction in IQ from one trial including 48 children (Abd El‐Aal 2005). There were 13 cases (reduction of 12% to 21% in comparison with normal siblings) among 27 children randomised to treatment including chemotherapy and 13 cases (reduction of 8% to 20% in comparison with normal siblings) among 21 children randomised to treatment not including chemotherapy. There was no significant difference between treatment arms (RR 0.78; 95% CI 0.46 to 1.30; P value = 0.34).
Secondary malignant disease
We were able to extract data on secondary malignant disease from one trial including 286 children (Tait 1990). The length of follow‐up was not mentioned; the maximal follow‐up was 13 years. There were no cases among 141 children randomised to treatment including chemotherapy and two cases among 145 children randomised to treatment not including chemotherapy. One child developed a meningioma within the area of the posterior fossa boost nine years after treatment; one child developed a low‐grade sarcoma in the occipital region 10 years after treatment. Since one treatment arm experienced no events, we were unable to calculate an RR, but there was no significant difference between treatment arms using the Fisher's exact test (P value = 0.50).
Severe infections
We were able to extract data on severe infections from one trial including 233 children (Evans 1990). There were 11 cases among 115 children randomised to treatment including chemotherapy and two cases among 118 children randomised to treatment not including chemotherapy. There was a significant difference in the occurrence of severe infections in favour of children randomised to treatment not including chemotherapy (RR 5.64; 95% CI 1.28 to 24.91; P value = 0.02). An ITT analysis was not possible, since 42 children were not randomised (21 in each treatment arm) and 12 children switched between treatment arms after randomisation (six in each arm).
Haematological toxicity grade 3 or 4
We were able to extract data on haematological toxicity grade 3 or 4 (white blood cells or platelet count, or both) from one trial including 71 patients (Krischer 1991). There were five cases (all grade 4) among 36 children randomised to treatment including chemotherapy and nine cases (eight cases were grade 3; one case was grade 4) among 35 children randomised to treatment not including chemotherapy. In children who received chemotherapy, it was started 4 weeks after the completion of RT. There was no significant difference between treatment groups (RR 0.54; 95% CI 0.20 to 1.45; P value = 0.22).
Hepatotoxicity grade 3
We were able to extract data on hepatotoxicity grade 3 from one trial including 71 patients (Krischer 1991). There was one case among 36 children randomised to treatment including chemotherapy and no cases among 35 children randomised to treatment not including chemotherapy. Since one treatment arm experienced no events, we were unable to calculate an RR, but there was no significant difference between treatment groups using the Fisher's exact test (P value = 1.00).
Fever and neutropenia
We were able to extract data on fever and neutropenia from one trial including 71 patients (Krischer 1991). There were seven cases among 36 children randomised to treatment including chemotherapy and no cases among 35 children randomised to treatment not including chemotherapy. Since one treatment arm experienced no events, we were unable to calculate an RR, but there was a significant difference in favour of treatment not including chemotherapy using the Fisher's exact test (P value = 0.01).
Treatment‐related mortality
We were able to extract data on treatment‐related mortality from three trials including 284 children (Krischer 1991; Taylor 2003/4; Van Eys 1981). There were four cases among 142 children randomised to treatment including chemotherapy and one case among 142 children randomised to treatment not including chemotherapy. Children in the chemotherapy arm died from pneumococcal sepsis and pericarditis (one child), septicaemia and toxic dilation of the gastrointestinal tract (one child), sepsis (one child) and life‐threatening myelosuppression (one child, but the exact cause of death was not ascertained). One child in the treatment not including chemotherapy arm died from disseminated intravascular coagulopathy and meningitis. The meta‐analysis showed no significant difference between treatment groups (RR 2.37; 95% CI 0.43 to 12.98; P value = 0.32). There was no heterogeneity (I2 = 0%).
Quality of life
None of the studies evaluated quality of life.
Sensitivity analyses
The results of the sensitivity analyses were consistent among the trials and did not differ from the overall analyses.
Subgroup analyses
Three studies presented adequate survival data on younger/older children (Taylor 2003/4), or high‐risk/non‐high‐risk children (Evans 1990; Tait 1990). Since definitions used for high‐risk/non‐high‐risk children were not comparable between the studies, we could not pool results. Thus, we have summarised the results descriptively (i.e. as presented in the individual articles).
Younger versus older children
One study reported EFS/DFS and OS for three age groups: aged three to seven, eight to 11 and 12 to 16 years. There was no significant effect of age on outcome in relation to EFS/DFS (P value = 0.44) or OS (P value = 0.54) (Taylor 2003/4).
High‐risk versus non‐high‐risk children
In one study, for the 113 children with early‐stage disease (T1 and T2), chemotherapy had no effect on EFS/DFS (Tait 1990). However, with advanced disease (T3 and T4), the 91 children who received chemotherapy had significantly better EFS/DFS than the 72 children who did not receive chemotherapy (P value = 0.002).
In one study, there was no benefit in EFS/DFS from chemotherapy in 67 children who had tumour stage T1‐2/M0 and in 124 children with tumour stage T3‐4/M0 (P value = 0.27; Evans 1990). There were too few children with low T‐stage and advanced M‐stage disease (T3 or 4, M1 to 3; 12 children) for analysis, but the group with advanced T‐stage and M‐stage disease (T3 or T4, M1 to M3) showed a striking effect of chemotherapy (46% with chemotherapy versus 0% with no chemotherapy; P value = 0.006). It should be noted that these data were not from an ITT analysis.
Studies comparing treatment with standard‐dose radiotherapy and treatment with reduced‐dose radiotherapy and chemotherapy
Event‐free survival or disease‐free survival
One study, including 76 children, reported data on EFS/DFS (Bailey 1995 RTvslowRT/CT). There was no significant difference between treatment with standard‐dose RT and treatment with reduced‐dose RT and chemotherapy (HR 1.54; 95% CI 0.81 to 2.94; P value = 0.19) (see Analysis 2.1; Figure 5).
2.1. Analysis.
Comparison 2 Treatment including reduced‐dose radiotherapy (RT) and chemotherapy versus treatment including standard‐dose RT, Outcome 1 Event‐free survival/disease‐free survival (EFS/DFS).
5.
Forest plot of comparison: 2 Treatment including reduced‐dose radiotherapy (RT) and chemotherapy versus treatment including standard‐dose RT, outcome: 2.1 Event‐free survival/disease‐free survival (EFS/DFS).
Other outcomes
We found no studies comparing the effects of treatment with standard‐dose RT and treatment with reduced‐dose RT and chemotherapy on OS, adverse effects or quality of life.
Subgroup analyses
We found no data on younger/older children and high‐risk/non‐high‐risk children; thus, we could not perform subgroup analyses.
Discussion
This systematic review evaluated the current state of evidence on the effectiveness of treatment including chemotherapy compared with treatment not including chemotherapy in children with medulloblastoma. Furthermore, we evaluated the current state of evidence on the effectiveness of treatment with standard‐dose RT compared with treatment with reduced‐dose RT and chemotherapy in children with medulloblastoma. We only included RCTs since it is widely recognised that an RCT is the only study design that can produce unbiased evidence on the use of different treatment options, provided that the design and execution are adequate.
Treatment including chemotherapy compared with treatment not including chemotherapy
We identified seven RCTs, published between 1981 and 2005 (Abd El‐Aal 2005; Bailey 1995 CT vs no CT; Evans 1990; Krischer 1991; Tait 1990; Taylor 2003/4; Van Eys 1981). Unfortunately, different definitions of study end points, numerous chemotherapy regimens and doses (none of which would be considered standard of care today), changes inherent to three decades of technological and histo/biological knowledge and the fact that, in most studies, results for different risk groups were not reported separately were major obstacles in comparing the results of the different studies.
The studies used three different definitions of EFS and DFS, and one study provided no definition of DFS. This made pooling of the results of all studies impossible. The definitions of other outcome measures (OS and adverse events) were comparable between studies. Furthermore, none of the studies used exactly the same chemotherapy schedule. Eleven different drugs were administered in seven different regimens and the actual received doses of chemotherapy were not mentioned in most of the studies. For evaluation of the effect of chemotherapy, this is important information. The lack of efficacy of a certain chemotherapy regimen might be due to dose reduction due to toxicity. In that respect, it is important to realise that the inclusion period encompassed 30 years. In this time, supportive care has improved substantially and the expectation might thus be that in later time periods, stricter adherence to the chemotherapy protocols was possible. Furthermore, over three decades, both diagnosis and treatment have evolved substantially: improved imaging techniques (not all included studies used magnetic resonance imaging as imaging modality) and different staging criteria. In addition, neurosurgical and RT procedures have changed substantially.
Only one study provided information on histological subtypes of medulloblastoma, that is, nodular/desmoplastic versus classical variants, and no study mentioned large cell/anaplastic variants. Evaluating the effect of chemotherapy by considering all these subtypes as one group may result in under‐ or overestimating the effectiveness of chemotherapy. No study provided information on molecular characteristics of the medulloblastomas. New molecular subgroups have emerged that show clear differences in prognosis of children with medulloblastoma (Taylor 2012). The included studies did not examine these molecular characteristics. This is likely to have influenced the overall results of the included studies, as did the fact that, in most studies, different risk groups were not analysed separately.
With regard to EFS/DFS, pooling of the trials of Bailey 1995 CT vs no CT and Krischer 1991 including 300 children showed no significant advantage of the addition of chemotherapy; in these studies, EFS/DFS were defined as time to recurrence or progression of primary disease or death from any cause. This result was confirmed in two individual studies that we could not pool (Abd El‐Aal 2005; Evans 1990). In contrast, the meta‐analysis of the studies of Tait 1990 and Taylor 2003/4 including 465 children showed a significant difference in favour of treatment with chemotherapy; in these studies, EFS/DFS were defined as time to recurrence of primary disease or death from any cause and not including disease progression as an event might not be optimal. It should be noted that in the study of Tait 1990, the difference in DFS 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.
The discordance between the two meta‐analyses is difficult to explain. Whether the results in favour of chemotherapy in the second meta‐analysis can be explained by the fact that the studies of Tait 1990 and Taylor 2003/4 did not include progression of disease in their definition of EFS/DFS cannot be ruled out. The Primitive Neuroectodermal Tumour Study (PNET)‐3 study of Taylor 2003/4 advised that people progressing under chemotherapy would go for immediate RT, but no actual data were given on the exact number of participants that progressed. It would be interesting to take into account the number of participants that progressed, and determine whether addition of chemotherapy would still give a significant EFS/DFS advantage.
Regarding OS, we pooled the results of four studies including 332 children. There was no significant difference in OS between treatment with and without chemotherapy.
Adverse effects (grade 3 or higher) were scarcely reported. Most adverse events were only mentioned in one RCT, or data were only provided for the chemotherapy arm and not for the RT only arm. Thus, as the risk of underreporting was real, caution must be taken in interpreting these results. Of eight different adverse effects grade 3 or higher, two (severe infections and fever/neutropenia) showed a significant difference in favour of the treatment not including chemotherapy. For the six other adverse effects (i.e. acute alopecia, reduction in IQ, secondary malignant disease, haematological toxicity, hepatotoxicity (all evaluated in one study); and treatment‐related mortality (based on a meta‐analysis of three studies including 284 children)), there was no significant difference between the treatment arms. However, in a small subgroup (26%) of participants included in the PNET‐3 study (i.e. the same protocol as in the Taylor 2003/4 study), which was included in this review, permanent cranial alopecia was more prevalent in children receiving chemotherapy and RT compared with people receiving only RT (Rogers 2011). The number of cases of secondary malignant disease in the study of Tait 1990 (two cases of secondary malignant disease on 286 children treated) seems low in comparison to the Children's Oncology Group (COG) study, which reported 14 cases of secondary malignant disease at eight years of follow‐up on 379 children treated (Packer 2010). Even taking into account the lower survival in the study of Tait 1990, and thus the lower number of children at risk for developing a secondary malignant disease, the discrepancy remains. In the study of Tait 1990, 66% of children were lost to follow‐up by nine years. This might explain these results.
The health status of a subgroup of children (i.e. part of the surviving UK participants) included in the study of Taylor 2003/4, together with some participants who did receive the same treatment in a non‐randomised manner, was reported separately (Bull 2007). In these participants, the addition of chemotherapy to CSRT was associated with a significant decrease in health status (assessed at a mean of 7.2 years after diagnosis). Unfortunately, quality of life was not evaluated in any of the included articles in this review.
In the individual studies, different subgroups were evaluated. One study provided survival data on children in different age groups (three to seven, eight to 11 and 12 to 16 years of age); there was no significant effect of age in relation to EFS/DFS and OS (Taylor 2003/4). However, no comparison was made for children younger or older than three years of age, which is a broadly used cut‐off point in determining risk group in children. Two trials examined EFS/DFS for the subgroups high‐risk versus non‐high‐risk, but, as the definition of the risk groups was different in the two studies, we could not pool the results (Evans 1990; Tait 1990). The individual study results showed no significant difference in EFS/DFS between the treatment arms in some subgroups, while in other subgroups (all children with advanced disease, but differently defined) children receiving chemotherapy responded significantly better. The criteria for defining standard‐risk disease versus high‐risk disease have changed since 1990, but re‐assigning people of those studies into risk groups that are commonly used today was not possible because of lack of information. As a result, no definitive conclusions were made regarding the effect of chemotherapy in the different subgroups as they would be classified in contemporary protocols.
'No evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. A benefit of chemotherapy cannot be excluded. The reason that some studies did not identify a significant difference between study arms could, besides reasons mentioned earlier, also be due to the number of participants included in these studies being too small to detect a difference between the treatment arms (i.e. low power). Furthermore, the length of follow‐up could have been too short to detect a significant difference between the treatment arms. For example, for secondary malignant disease, the maximal follow‐up was 13 years, but it is possible that in participants with a shorter follow‐up, a secondary malignant disease has not yet developed, but will develop when follow‐up increases.
The risk of bias in the included studies was difficult to assess due to a lack of reporting. As a result, we could not rule out the presence of selection bias, performance bias, detection bias and attrition bias. However, at the moment this is the best available evidence of RCTs comparing the effectiveness of treatment including chemotherapy compared with treatment not including chemotherapy in children with medulloblastoma. With regard to performance bias, it should be noted that due to the nature of the interventions, blinding of care providers and participants was virtually impossible. In this review, we only performed ITT analyses, since they provide the most realistic and unbiased answer to the question of clinical effectiveness (Lachin 2000; Lee 1991). However, for Evans 1990, an ITT analysis was not possible, and therefore, we performed an as‐treated analysis.
The results of this systematic review must be viewed in the context of the complete therapy (e.g. the effect of surgery and CSRT, and the different chemotherapy protocols used (such as different agents or different doses, or both)). We have pooled the results of all eligible studies, but, as stated before, the above mentioned items differed between the studies. As a result, in this systematic review, we can only provide conclusions on the concept of treatment including chemotherapy versus treatment not including chemotherapy. We cannot make conclusions with regard to specific treatment options (such as type of surgery, RT fields and doses, different chemotherapeutic agents and doses).
Treatment with standard‐dose radiotherapy compared with treatment with reduced‐dose radiotherapy and chemotherapy
We identified one RCT, published in 1995, including 76 children (Bailey 1995 RTvslowRT/CT). The treatment protocol used in the study would not be considered standard of care today. Only EFS/DFS was evaluated and there was no significant difference between treatment arms. Unfortunately, there was no information on effects on OS, adverse effects and quality of life or for different subgroup analyses.
It should be noted that results of only a small proportion of the eligible participants have been presented (see Characteristics of included studies table), and, as a result, there was a high risk of attrition bias. The same obstacles in interpreting the results as in the previous studies were encountered: the actual received doses of chemotherapy were not mentioned and the study did not provide information on histological subtypes of medulloblastoma or on molecular characteristics.
In this study, we ruled out selection bias, whereas we could not rule out performance bias, detection bias and attrition bias. However, at the moment this is the best‐available evidence of RCTs comparing the effectiveness of treatment with standard‐dose RT with treatment with reduced‐dose RT and chemotherapy in children with medulloblastoma. With regard to performance bias, it should be noted that due to the nature of the interventions, blinding of care providers and participants was virtually impossible.
In addition, even though RCTs are the highest level of evidence, it should be recognised that data from non‐randomised studies are available, for example on the use of chemotherapy only in very young children. The results are promising for children without metastatic disease (Grill 2005; Rutkowski 2005), which is important since without craniospinal irradiation fewer long‐term adverse effects will occur. Furthermore, it should be noted that in this systematic review, we did not evaluate the effect of reductions in radiation fields (at the tumour bed) and RT dose other than the definitions we used in this review for standard and reduced dose (as described in the Methods section). These issues are also important in further optimising the treatment of children with medulloblastoma and should be kept in mind.
Authors' conclusions
Implications for practice.
Treatment including chemotherapy compared with treatment not including chemotherapy
Only the meta‐analysis of event‐free survival/disease‐free survival (EFS/DFS), not including disease progression during therapy in the definition, showed a significant difference in favour of treatment including chemotherapy. This finding was not confirmed in either the meta‐analysis of EFS/DFS including disease progression during therapy in the definition or individual randomised controlled trials (RCTs) using unclear or other definitions of EFS/DFS (which showed no significant difference between treatment arms). The discordance between these results is difficult to explain. Not including disease progression as an event might not be optimal. We identified no significant difference in overall survival (OS) between treatment arms. Data on adverse effects were scarce. Out of eight reported adverse effects, of which seven were reported in one study only, severe infections and fever/neutropenia showed a significant difference in favour of treatment not including chemotherapy. For the other adverse effects, there was no significant difference between treatment arms. No information on quality of life was provided. In addition, we can make no definitive conclusions regarding the effect of treatment including and not including chemotherapy in different subgroups. However, two studies show that children with advanced disease might have an improved EFS/DFS when receiving chemotherapy, but we could not pool the results and also, some definitions of advanced disease as used in the included studies differed from the currently used definitions. The results of this systematic review must be viewed in the context of the complete therapy (e.g. the effect of surgery and craniospinal radiotherapy, and the different chemotherapy protocols used). Thus, this systematic review only allows a conclusion on the concept of treatment including chemotherapy versus treatment not including chemotherapy; we can make no conclusions regarding the best treatment strategy.
Several factors complicated the interpretation of results: different definitions of study end points, numerous chemotherapy regimens and doses, a long time span between the first and the last studies with important changes in supportive care and progress in imaging and treatment techniques in the meantime, no information on histological subtypes and molecular characteristics of the tumour, no uniform definition of standard‐risk versus high‐risk children and the fact that in most studies different risk groups were not analysed separately. In addition, the fact that we identified no significant differences between treatment arms could be, for example, the result of low power or too short a follow‐up period. Based on the currently available evidence, we are unable to determine whether treatment with or without chemotherapy in children with medulloblastoma is preferable.
Treatment with standard‐dose radiotherapy compared with treatment with reduced‐dose radiotherapy and chemotherapy
Since we identified only one RCT comparing standard‐dose radiotherapy with reduced‐dose radiotherapy and chemotherapy, no definitive conclusions can be made about these treatments. In this small study group of 76 children, there was no significant difference in EFS/DFS, but this finding should be confirmed in other RCTs. The study did not report on OS, adverse effects and quality of life.
Implications for research.
In order to state with a high level of certainty if and for which children the addition of chemotherapy (with or without reduced‐dose radiotherapy) to the previous standard therapy of radiation only will improve treatment results in children with medulloblastoma, we need high‐quality RCTs in which uniform stratification criteria for standard‐risk and high‐risk children are used, as well as uniform outcome definitions (including EFS/DFS, OS, adverse effects and quality of life). However, in the current treatment era, it is considered unethical to use RCTs of the former higher 'standard‐dose' radiotherapy in one arm, as the long‐term consequences are devastating. Thus, it is very unlikely that such high‐quality RCTs will be developed in the future. It is widely recognised that an RCT is the only study design that can provide unbiased evidence on interventions, provided that the design and execution are adequate. Without evidence from high‐quality RCTs, we have to acknowledge that the true efficacy of these treatments in children with medulloblastoma remains unclear.
Acknowledgements
The review authors wish to thank Leontien Kremer, the Co‐ordinating Editor of the Childhood Cancer Group, for her support in preparing the protocol of the review. We would like to thank Edith Leclercq, the Trials Search Co‐ordinator of the Childhood Cancer Group, for helping to develop the search strategy, for running the search strategy in the different databases and for providing us with the titles and abstracts of the searches. We thank Stichting Kinderen Kankervrij (KIKA), Netherlands for the financial support that made it possible to perform this systematic review. Dr. M. Massimino, Dr. R. Geyer and an undisclosed person kindly agreed to peer review our manuscript, for which we are grateful. The editorial base of the Cochrane Childhood Cancer Group is funded by KIKA. For survival analyses, the hazard ratio and associated statistics were calculated using an Excel spreadsheet developed by Matthew Sydes and Jayne Tierney of the MRC Clinical Trials Unit, London, UK.
Appendices
Appendix 1. CENTRAL search strategy
(1) For medulloblastoma, we used the following subject headings and text words for searching title, abstract or keywords in clinical trials:
medulloblastoma OR medulloblastomas OR circumscribed arachnoidal cerebellar sarcoma OR desmoplastic medulloblastoma OR desmoplastic medulloblastomas OR childhood medulloblastoma OR childhood medulloblastomas OR medullomyoblastoma OR medullomyoblastomas OR melanocytic medulloblastoma OR melanocytic medulloblastomas OR medulloblast* OR medullomyoblast* OR large cell medulloblastoma OR large cell medulloblastomas OR brain neoplasm OR brain neoplasms OR intracranial neoplasm OR intracranial neoplasms OR cerebellar neoplasm OR cerebellar neoplasms OR brain tumor OR brain tumors OR cerebellar tumors OR cerebellar tumor OR primitive neuroepithelial tumor OR primitive neuroepithelial tumors OR primitive neuroectodermal tumor OR primitive neuroectodermal tumors OR primitive neuroepithelial neoplasm OR primitive neuroepithelial neoplasms OR primitive neuroectodermal neoplasms OR primitive neuroectodermal neoplasm OR PNET OR PNETs OR cerebral primitive neuroectodermal tumor OR ependymoblastoma OR ependymoblastomas OR ependymoblast* OR medulloepithelioma OR medulloepitheliomas OR medulloepitheliom* OR spongioblastoma OR spongioblastomas OR spongioblast* OR germ cell neoplasm OR embryonal neoplasm OR large cell anaplastic medulloblastoma OR large cell anaplastic medulloblastomas OR nodular desmoplastic medulloblastoma OR nodular desmoplastic medulloblastomas
(2) For survival, we used the following subject headings and text words for searching title, abstract or keywords in clinical trials:
survival OR survival rate OR survival rates OR cumulative survival rate OR cumulative survival rates OR survivorship OR mean survival time OR mean survival times OR survival time OR surviv* OR median survival time OR median survival times OR overall survival OR survival analysis OR survival analyses OR disease‐free survival OR disease free survival OR event‐free survival OR event‐free survivals OR event free survival OR progression‐free survival OR progression free survival OR progression‐free survivals OR event‐free OR event free OR progression free OR progression‐free OR time to progression OR treatment outcome OR treatment effectiveness OR treatment efficacy OR neoplasm recurrence OR neoplasm recurrences OR disease‐free survivals OR disease free survivals OR event free survivals OR progression free survivals OR treatment failure
(3) For chemotherapy, we used the following subject headings and text words for searching title, abstract or keywords in clinical trials:
chemotherapy OR chemotherapies OR chemotherap* OR antineoplastic protocol OR antineoplastic protocols OR cancer treatment protocols OR cancer treatment protocol OR antineoplastic combined chemotherapy protocols OR antineoplastic drug combinations OR antineoplastic drug combination OR anticancer drug combinations OR anticancer drug combination OR combined antineoplastic agents OR antineoplastic combined chemotherapy regimens OR antineoplastic chemotherapy protocols OR antineoplastic chemotherapy protocol OR cancer chemotherapy protocols OR cancer chemotherapy protocol
(4) For children, we used the following subject headings and text words for searching title, abstract or keywords in clinical trials:
infant OR infan* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy
Finally, searches were combined as (1) AND (2) AND (3) AND (4).
Appendix 2. MEDLINE/PubMed search strategy
(1) For medulloblastoma, we used the following MeSH headings and text words:
medulloblastoma OR medulloblastomas OR circumscribed arachnoidal cerebellar sarcoma OR desmoplastic medulloblastoma OR desmoplastic medulloblastomas OR childhood medulloblastoma OR childhood medulloblastomas OR medullomyoblastoma OR medullomyoblastomas OR melanocytic medulloblastoma OR melanocytic medulloblastomas OR medulloblast* OR medullomyoblast* OR large cell medulloblastoma OR large cell medulloblastomas OR brain neoplasm OR brain neoplasms OR intracranial neoplasm OR intracranial neoplasms OR cerebellar neoplasm OR cerebellar neoplasms OR brain tumor OR brain tumors OR cerebellar tumors OR cerebellar tumor OR primitive neuroepithelial tumor OR primitive neuroepithelial tumors OR primitive neuroectodermal tumor OR primitive neuroectodermal tumors OR primitive neuroepithelial neoplasm OR primitive neuroepithelial neoplasms OR primitive neuroectodermal neoplasms OR primitive neuroectodermal neoplasm OR PNET OR PNETs OR cerebral primitive neuroectodermal tumor OR ependymoblastoma OR ependymoblastomas OR ependymoblast* OR medulloepithelioma OR medulloepitheliomas OR medulloepitheliom* OR spongioblastoma OR spongioblastomas OR spongioblast* OR germ cell neoplasm OR embryonal neoplasm OR large cell anaplastic medulloblastoma OR large cell anaplastic medulloblastomas OR nodular desmoplastic medulloblastoma OR nodular desmoplastic medulloblastomas
(2) For survival, we used the following MeSH headings and text words:
survival OR survival rate OR rate, survival OR rates, survival OR survival rates OR cumulative survival rate OR cumulative survival rates OR rate, cumulative survival OR rates, cumulative survival OR survival rate, cumulative OR survival rates, cumulative OR survivorship OR mean survival time OR mean survival times OR survival time, mean OR survival times, mean OR time, mean survival OR times, mean survival OR survival time OR surviv* OR median survival time OR median survival times OR survival time, median OR survival times, median OR time, median survival OR times, median survival OR overall survival OR analysis, survival OR analyses, survival OR survival analysis OR survival analyses OR disease‐free survival OR disease free survival OR survival, disease‐free OR disease‐free survivals OR survival, disease free OR survivals, disease‐free OR event‐free survival OR event‐free survivals OR event free survival OR survival, event‐free OR survivals, event‐free OR progression‐free survival OR progression free survival OR progression‐free survivals OR survival, progression‐free OR survivals, progression‐free OR event‐free OR event free OR progression free OR progression‐free OR time to progression OR treatment outcome OR treatment effectiveness OR treatment efficacy OR neoplasm recurrence OR neoplasm recurrences
(3) For chemotherapy, we used the following MeSH headings and text words:
chemotherapy OR chemotherapies OR chemotherap* OR antineoplastic protocol OR antineoplastic protocols OR protocol, antineoplastic OR protocols, antineoplastic OR cancer treatment protocols OR cancer treatment protocol OR protocol, cancer treatment OR protocols, cancer treatment OR treatment protocol, cancer OR treatment protocols, cancer OR antineoplastic combined chemotherapy protocols OR antineoplastic agents, combined OR agent, combined antineoplastic OR agents, combined antineoplastic OR antineoplastic agent, combined OR combined antineoplastic agent OR antineoplastic drug combinations OR antineoplastic drug combination OR combinations, antineoplastic drug OR drug combination, antineoplastic OR anticancer drug combinations OR anticancer drug combination OR drug combination, anticancer OR drug combinations, anticancer OR Combined antineoplastic agents OR antineoplastic combined chemotherapy regimens OR drug combinations, antineoplastic OR antineoplastic chemotherapy protocols OR antineoplastic chemotherapy protocol OR chemotherapy protocol, antineoplastic OR protocol, antineoplastic chemotherapy OR protocols, antineoplastic chemotherapy OR cancer chemotherapy protocols OR cancer chemotherapy protocol OR chemotherapy protocol, cancer OR chemotherapy protocols, cancer OR protocol, cancer chemotherapy OR protocols, cancer chemotherapy OR chemotherapy protocols, antineoplastic
(4) For children, we used the following MeSH headings and text words:
infant OR infan* OR newborn OR newborn* OR new‐born* OR baby OR baby* OR babies OR neonat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy OR schools, nursery OR infant, newborn
(5) For identifying RCTs and CCTs, we used the highly sensitive search strategy as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005).
Finally, searches were combined as (1) AND (2) AND (3) AND (4) AND (5).
[RCT: randomised controlled trial; CCT: controlled clinical trial].
Appendix 3. EMBASE/Ovid search strategy
(1) For medulloblastoma, we used the following Emtree terms and text words:
1. (medulloblastoma or medulloblastomas or circumscribed arachnoidal cerebellar sarcoma or desmoplastic medulloblastoma or desmoplastic medulloblastomas or childhood medulloblastoma or childhood medulloblastomas or medullomyoblastoma or medullomyoblastomas or melanocytic medulloblastoma or melanocytic medulloblastomas or medulloblast$ or medullomyoblast$ or large cell medulloblastoma or large cell medulloblastomas or brain neoplasm or brain neoplasms or intracranial neoplasm or intracranial neoplasms or cerebellar neoplasm or cerebellar neoplasms or brain tumor or brain tumors or cerebellar tumors or cerebellar tumor or primitive neuroepithelial tumor or primitive neuroepithelial tumors or primitive neuroectodermal tumor or primitive neuroectodermal tumors or primitive neuroepithelial neoplasm or primitive neuroepithelial neoplasms or primitive neuroectodermal neoplasms or primitive neuroectodermal neoplasm or PNET or PNETs or cerebral primitive neuroectodermal tumor or ependymoblastoma or ependymoblastomas or ependymoblast$ or medulloepithelioma or medulloepitheliomas or medulloepitheliom$ or spongioblastoma or spongioblastomas or spongioblast$ or germ cell neoplasm or embryonal neoplasm).mp.
2. (large cell anaplastic medulloblastoma or large cell anaplastic medulloblastomas or nodular desmoplastic medulloblastoma or nodular desmoplastic medulloblastomas).mp.
3. 1 or 2
4. medulloblastoma/ or circumscribed arachnoidal cerebellar sarcoma/
5. desmoplastic medulloblastoma/
6. cerebellum tumor/ or intracranial tumor/
7. Neuroepithelioma/
8. Neuroectoderm Tumor/
9. EPENDYMOBLASTOMA/
10. spongioblastoma/ or medullomyoblastoma/
11. or/4‐10
12. 3 or 11
(2) For survival, we used the following Emtree terms and text words:
1. (survival or survival rate or survival rates).mp.
2. (cumulative survival rate or cumulative survival rates).mp.
3. survivorship.mp.
4. (mean survival time or mean survival times).mp.
5. (survival time or surviv$).mp.
6. (median survival time or median survival times).mp.
7. overall survival.mp.
8. (survival analysis or survival analyses).mp.
9. (disease‐free survival or disease free survival).mp.
10. (disease‐free survivals or disease free survivals).mp.
11. (event‐free survival or event‐free survivals or event free survival or event free survivals).mp.
12. (progression‐free survival or progression free survival or progression‐free survivals or progression free survivals).mp.
13. (survival period or survival probability).mp.
14. (event‐free or event free or progression free or progression‐free).mp.
15. (time to progression or treatment outcome or treatment effectiveness or treatment efficacy).mp.
16. (neoplasm recurrence or neoplasm recurrences).mp.
17.(cancer recurrence or cancer recurrences or cancer recidive or cancer remission).mp.
18. (therapy outcome or therapeutic efficacy).mp.
19. or/1‐18
20. SURVIVAL RATE/ or SURVIVAL/ or SURVIVAL TIME/
21. Treatment Outcome/
22. Cancer survival/ or Cancer Recurrence/
23. or/20‐22
24. 19 or 23
(3) For chemotherapy, we used the following Emtree terms and text words:
1. (chemotherapy or chemotherapies or chemotherap$ or antineoplastic protocol or antineoplastic protocols or cancer treatment protocols or cancer treatment protocol or antineoplastic combined chemotherapy protocols or antineoplastic drug combinations or antineoplastic drug combination or anticancer drug combinations or anticancer drug combination or combined antineoplastic agents or antineoplastic combined chemotherapy regimens or antineoplastic chemotherapy protocols or antineoplastic chemotherapy protocol or cancer chemotherapy protocols or cancer chemotherapy protocol).mp.
2. (anticancer chemotherapy or antineoplastic chemotherapy or cancer multichemotherapy or cancer polychemotherapy).mp.
3. chemotherapy/ or combination chemotherapy/
4. cancer combination chemotherapy/
5. cancer chemotherapy/ or antineoplastic agent/
6. clinical protocol/
7. or/1‐6
(4) For children, we used the following Emtree terms and text words:
1. infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/
2. adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/
3. primary school/ or high school/ or kindergarten/ or nursery school/ or school/
4. or/1‐3
5. (infant$ or (newborn$ or new born$) or (baby or baby$ or babies) or neonate$).mp.
6. (child$ or (school child$ or schoolchild$) or (school age$ or schoolage$) or (pre school$ or preschool$)).mp.
7. (kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp.
8. (minors$ or (under ag$ or underage$) or juvenil$ or youth$).mp.
9. (puber$ or pubescen$ or prepubescen$ or prepubert$).mp.
10. (pediatric$ or paediatric$ or peadiatric$).mp.
11. (school or schools or (high school$ or highschool$) or primary school$ or nursery school$ or elementary school or secondary school$ or kindergar$).mp.
12. or/5‐11
13. 4 or 12
(5) For RCTs and CCTs, we used the following Emtree terms and text words:
1. Clinical Trial/
2. Controlled Study/
3. Randomized Controlled Trial/
4. Double Blind Procedure/
5. Single Blind Procedure/
6. Comparative Study/
7. RANDOMIZATION/
8. Prospective Study/
9. PLACEBO/
10. Phase 2 Clinical Trial/
11. phase 3 clinical study.mp.
12. phase 4 clinical study.mp.
13. Phase 3 Clinical Trial/
14. Phase 4 Clinical Trial/
15. or/1‐14
16. allocat$.mp.
17. blind$.mp.
18. control$.mp.
19. placebo$.mp.
20. prospectiv$.mp.
21. random$.mp.
22. ((singl$ or doubl$ or trebl$ or tripl$) and (blind$ or mask$)).mp.
23. (versus or vs).mp.
24. (randomized controlled trial$ or randomised controlled trial$).mp.
25. controlled clinical trial$.mp.
26. clinical trial$.mp.
27. or/16‐26
28 Human/
29. Nonhuman/
30. ANIMAL/
31. Animal Experiment/
32. or/29‐31
33. 32 not 28
34. (15 or 27) not 33
Finally, searches were combined as (1) AND (2) AND (3) AND (4) AND (5).
[mp: title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name; RCT: randomised controlled trial; CCT: controlled clinical trial].
Data and analyses
Comparison 1. Treatment including chemotherapy versus treatment not including chemotherapy.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Event‐free survival/disease‐free survival (EFS/DFS) | 6 | Hazard Ratio (Random, 95% CI) | Subtotals only | |
| 1.1 EFS including progression | 2 | Hazard Ratio (Random, 95% CI) | 1.02 [0.70, 1.47] | |
| 1.2 EFS/DFS not including progression | 2 | Hazard Ratio (Random, 95% CI) | 0.70 [0.54, 0.91] | |
| 1.3 Definition of DFS not provided | 1 | Hazard Ratio (Random, 95% CI) | 1.67 [0.59, 4.71] | |
| 1.4 EFS in participants without sepsis | 1 | Hazard Ratio (Random, 95% CI) | 0.84 [0.58, 1.21] | |
| 2 Overall survival | 4 | Hazard Ratio (Random, 95% CI) | 1.06 [0.67, 1.67] | |
| 3 Adverse effects | 5 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 Alopecia grade 3 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.92, 1.08] |
| 3.2 Reduction in intelligence quotient (IQ) | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.46, 1.30] |
| 3.3 Severe infections | 1 | 233 | Risk Ratio (M‐H, Random, 95% CI) | 5.64 [1.28, 24.91] |
| 3.4 Haematological toxicity grade 3 or 4 | 1 | 71 | Risk Ratio (M‐H, Random, 95% CI) | 0.54 [0.20, 1.45] |
| 3.5 Treatment‐related mortality | 3 | 284 | Risk Ratio (M‐H, Random, 95% CI) | 2.37 [0.43, 12.98] |
Comparison 2. Treatment including reduced‐dose radiotherapy (RT) and chemotherapy versus treatment including standard‐dose RT.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Event‐free survival/disease‐free survival (EFS/DFS) | 1 | Hazard Ratio (Random, 95% CI) | 1.54 [0.81, 2.94] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Abd El‐Aal 2005.
| Methods | Method of randomisation not clear | |
| Participants | 48 children with high‐risk medulloblastoma (defined as ≥ 1 of: positive cerebrospinal fluid, T3 and T4 lesions, < 4 years of age and ependymal or glial differentiation) 10 stage M1 children (6 in experimental arm (i.e. RT and chemotherapy); 4 in standard arm (i.e. RT)); no further information on stage was provided, but absence of metastases was an eligibility criterion Primary disease nm 30 classic medulloblastoma (18 in experimental arm; 12 in standard arm) and 18 desmoplastic medulloblastoma (9 in experimental arm; 9 in standard arm) Molecular markers nm Mean age in both the experimental and standard arm 7 years 32 boys (17 in experimental arm; 15 in standard arm) and 16 girls (10 in experimental arm; 6 in standard arm) Prior chemotherapy nm |
|
| Interventions |
Design: surgery followed by RT ± chemotherapy. If applicable, chemotherapy was given during and after RT. Randomisation: 27 children received chemotherapy; 21 children did not Surgery: 23 incisional biopsies (15 in experimental arm; 8 in standard arm), 23 total tumour excisions (11 in experimental arm; 12 in standard arm) and 2 stereotactic biopsies (1 in each treatment arm) Imaging: all participants underwent postoperative craniospinal MRI (interval between surgery and MRI nm) RT (according to protocol; actual received doses nm): target volume (Gy): dose/dose per fraction: craniospinal: 36/nm, posterior fossa: 56/nm, spinal: 36/1.5. RT was given by cobalt machine Chemotherapy (according to protocol; actual received doses nm): vincristine during spinal RT (weekly 1.4 mg/m2) and after RT 4 cycles (given every 21 days) of etoposide (100 mg/m2 on days 1‐3, route of delivery nm) and cisplatinum (75 mg/m2 on day 1, route of delivery nm) |
|
| Outcomes | OS (definition nm) DFS (definition nm) Adverse effects (according to the WHO grading criteria) |
|
| Notes | Length of follow‐up nm (it was stated that some children were followed for 3 years) Number of children who stopped chemotherapy or RT prematurely or who did not receive the full doses nm |
|
Bailey 1995 CT vs no CT.
| Methods | Randomisation was performed centrally using a minimising approach | |
| Participants | 229 children with low‐risk medulloblastoma. Participants defined as being at low risk for tumour recurrence if the tumour was totally (no visible residual tumour) or subtotally (a thin film of tumour left in the tumour bed) resected, the brain stem was not involved by the tumour and there was no evidence of metastatic disease within the CNS. Presence of tumour cells in the craniospinal fluid was not taken into account in assigning risk status T stage nm; 115 stage M0, 17 either stage M2 or M3, 97 stage nm Primary disease nm Histological subtype nm Molecular markers nm Exact age nm, but to be eligible for inclusion participants had to be aged 0‐16 years Sex nm No prior chemotherapy Data for children in each treatment arm were not provided |
|
| Interventions |
Design: surgery followed by RT ± chemotherapy. If applicable, chemotherapy given before RT. Randomisation: at least 74 children (total number nm) received chemotherapy; at least 76 children (total number nm) did not. Some of the low‐risk children (153 children) underwent a second randomisation regarding the RT dose on the CSA Surgery: attempts were made to remove as much of the tumour as possible (no data for children in the different treatment arms provided) Imaging: postoperative imaging (CT scans or myelography) not mandatory; they could be performed at the discretion of the centre and whenever tumour recurrence was suspected (no further data provided) RT (according to protocol; actual received doses nm for the 229 eligible children): target volume (Gy): dose/dose per fraction: craniospinal: 35 or 25/1.66 (depending on treatment arm children were assigned to while performing the second randomisation); tumour‐bearing area: 55/2 In children < 2 years of age (number nm) reduced doses were recommended (see Notes): CSA: 30‐35/1.4 tumour dose: 40‐45/1.4. The boost encompassed the whole posterior fossa with inclusion of the surgical scar. If children were randomised to RT only group, RT started as soon as possible after surgery and at least within 28 days; if children were randomised to the chemotherapy arm, RT commenced within 1 week of the third methotrexate infusion. RT was to be delivered by megavoltage equipment Chemotherapy (according to protocol; actual received doses nm for the 229 eligible children): vincristine (1.5 mg/m2 (maximum 2 g) intravenously on days 1, 8, 15, 22, 29 and 36), procarbazine (100 mg/m2 orally on days 1‐14), methotrexate (2 g/m2 intravenously with 6‐hour infusion on days 15, 22 and 29) and prednisolone (100 mg/m2 on days 15, 22 and 29; route of delivery nm). Chemotherapy was given in a 6‐week module before RT |
|
| Outcomes | EFS (an event was defined to have taken place if the participant either developed any type of recurrence including newly diagnosed metastases or progression of any residual tumour or died without any evidence of recurrence) | |
| Notes | Length of follow‐up nm (maximal follow‐up was 78 months) This study also included 135 high‐risk children (definition: if the tumour was incompletely resected, i.e. the surgeon reported the presence of macroscopic residual disease at the end of the procedure, if there was evidence of invasive brain stem involvement or if metastatic disease was present within the CNS), but since these children all received chemotherapy after the end of RT, they were not eligible for inclusion in this review Number of children who stopped chemotherapy or RT prematurely or who did not receive the full doses: nm for the 229 eligible participants. In this article, it was stated that in children < 2 years of age it was recommended to give reduced RT doses; however, the provided doses for CSRT were in some cases higher/equal to the doses given to older children. No explanation for this inconsistency was available |
|
Bailey 1995 RTvslowRT/CT.
| Methods | Randomisation was performed centrally using a minimising approach | |
| Participants | 153/229 children with low‐risk medulloblastoma included in the study of Bailey 1995 CT vs no CT underwent a second randomisation regarding the RT dose on the CSA; 76/153 children were eligible for the evaluation of standard‐dose RT on the CSA without chemotherapy versus reduced‐dose RT on the CSA and chemotherapy. Participant characteristics were not stated for only these 76 children. For details on all 229 children see Bailey 1995 CT vs no CT above | |
| Interventions |
Design: surgery followed by standard‐dose RT on the CSA without chemotherapy versus reduced‐dose RT on the CSA and chemotherapy (RT doses on the posterior fossa were similar in both treatment groups). If applicable, chemotherapy was given before RT. Randomisation: 40 children received standard‐dose RT without chemotherapy; 36 children received reduced‐dose RT and chemotherapy Surgery: attempts were made to remove as much of the tumour as possible (no data for children in the different treatment arms provided) Imaging: postoperative imaging (CT scans or myelography) was not mandatory; they could be performed at the discretion of the centre and whenever tumour recurrence was suspected (no further data provided) Standard‐dose RT (according to protocol; actual received doses nm for the 40 eligible children): target volume (Gy): dose/dose per fraction: CSA: 35/1.66, tumour‐bearing area: 55/2. RT started as soon as possible after surgery and at least within 28 days. The boost encompassed the whole posterior fossa with inclusion of the surgical scar Reduced‐dose RT (according to protocol; actual received doses nm for the 36 eligible children): CSA: 25/1.66, tumour‐bearing area: 55/2. In children < 2 years of age (number nm), reduced doses were recommended (see notes): CSA: 30‐35/1.4, tumour: 40‐45/1.4. RT commenced within 1 week of the third methotrexate infusion. The boost encompassed the whole posterior fossa with inclusion of the surgical scar Chemotherapy: vincristine (1.5 mg/m2 (maximum 2 g) intravenously on days 1, 8, 15, 22, 29 and 36), procarbazine (100 mg/m2 orally on days 1‐14), methotrexate (2 g/m2 intravenously with a 6‐hour infusion on days 15, 22 and 29) and prednisolone (100 mg/m2 on days 15, 22 and 29; route of delivery nm). Chemotherapy was given in a 6‐week module before RT RT was to be delivered by megavoltage equipment. No HART |
|
| Outcomes | EFS (an event was defined to have taken place if the participant either developed any type of recurrence including newly diagnosed metastases or progression of any residual tumour or died without any evidence of recurrence) | |
| Notes | Length of follow‐up nm (maximal follow‐up was 78 months) Number of children who stopped chemotherapy or RT prematurely or who did not receive the full doses: nm for the 76 eligible children In this article, it was stated that in children < 2 years of age it was recommended to give reduced RT doses; however, the provided doses for CSRT were in some cases higher/equal to the doses given to older children. No explanation for this inconsistency was available |
|
Evans 1990.
| Methods | Method of randomisation not clear (stratified by stage of medulloblastoma) | |
| Participants | 233 children with medulloblastoma 11 stage T1, 68 stage T2, 130 stage T3 and 24 stage T4; 191 stage M0 (see notes), 19 stage M1, 15 stage M2, 8 stage M3; children with stage M4 were not eligible for this study Primary disease Histological subtype nm Molecular markers nm Age range < 2 years to ≥ 16 years 154 boys and 79 girls No prior chemotherapy; corticosteroids were allowed 191 children were randomised, whereas 42 children were not; data for children in each treatment arm nm |
|
| Interventions |
Design: surgery followed by RT ± chemotherapy. If applicable, chemotherapy was given during and after RT. Randomisation: 115 children received chemotherapy, including 6 children who switched from the other arm and 21 non‐randomised children; 118 children received no chemotherapy, including 6 children who switched from the other arm and 21 non‐randomised children Surgery: as extensive a resection as was compatible with subsequent good neurological function. There were 93 total resections, 105 subtotal resections (defined as 50‐99%) and 33 partial resections (defined as < 50%); for the other 2 children it was not known; data for children in each treatment arm nm Imaging: a postoperative CT scan was not required RT: according to protocol: target volume (Gy): dose/dose per fraction: craniospinal: 35‐40/1.6‐2.0 (≤ 3 years: reduction of 5 Gy), posterior fossa: 50‐55/1.6‐2.0 (≤ 3 years: reduction of 5 Gy), localised spinal metastases: 50/nm. Of 220 children for whom posterior fossa data were reviewed, 74% received the protocol dose, 14% less and 12% more; 62% received the protocol dose to the brain, 15% less than 35 Gy and 23% more than 40 Gy; 66% received the protocol dose to the spine, 26% less than 35 Gy and 8% more than 40 Gy Chemotherapy (according to protocol; actual received doses nm: see notes): vincristine (1.5 mg/m2 intravenously on day 1 of each week of RT and on day 1 of first 3 weeks of each chemotherapy cycle), CCNU (100 mg/m2 orally on day 1 of each chemotherapy cycle) and prednisone (40 mg/m2/day orally for 14 days on day 1 of each chemotherapy cycle). There were 8 cycles (every 6 weeks) starting 4 weeks following the completion of RT (= 3 months since start of RT) |
|
| Outcomes | EFS (defined as alive without sepsis or disease recurrence or progression) Adverse effects (nm on which criteria they were based) |
|
| Notes | Length of follow‐up nm (maximal follow‐up was 10 years) Number of children who stopped chemotherapy prematurely or who did not receive the full doses: nm, but 60% of reviewed children received ≥ 75% of the recommended dose in every therapy course received ITT analyses were not possible, since 42 children were not randomised (21 in each treatment arm) and 12 children switched between treatment arms after randomisation (6 in each treatment arm) Data presented in this table were for all 233 children; no separate data for the randomised children only were presented All staging was done based on surgeon's impression. As stated by the authors: it is likely that the M0 group included children with stage M0 to M3 since cytology data were reported in only 56% of the M0 children and an initial myelogram was performed in only 11% of M0 children. However, the surgical check sheet classified the children as M0 |
|
Krischer 1991.
| Methods | Method of randomisation not clear (balanced by treatment institution and participant age at diagnosis (≤ 4 years and ≥ 5 years)) | |
| Participants | 71 children with medulloblastoma 29 stage T1 or T2 (15 in experimental arm (i.e. RT and chemotherapy); 14 in standard arm (i.e. RT)), 33 stage T3 (15 in experimental arm; 18 in standard arm) and 9 stage unknown (6 in experimental arm; 3 in standard arm); all children did not have metastases outside the CNS (number of children with stage M0‐3 nm) Primary disease Histological subtype nm Molecular markers nm Age range ≤ 4 years (13 in experimental arm; 12 in standard arm) to 20 years (23 in both arms) 48 males (25 in experimental arm; 23 in standard arm) and 23 females (11 in experimental arm; 12 in standard arm) No prior chemotherapy (with the exception of corticosteroids) |
|
| Interventions |
Design: surgery followed by RT ± chemotherapy. If applicable, chemotherapy was given after RT. Randomisation: 36 children received chemotherapy; 35 children did not Surgery: 51 subtotal excisions (28 in experimental arm; 23 in standard arm) and 20 total removals (8 in experimental arm; 12 in standard arm) Imaging: no postoperative imaging RT (according to protocol; actual received doses nm): target volume (Gy): dose/dose per fraction: cranial 35 Gy or 25 Gy (< 3 years) (later modified to 40 Gy and 35.2 Gy (< 3 years))/1.6‐1.7, posterior fossa: 54‐54.4 Gy or 48 Gy (< 3 years)/1.6‐1.7, spinal: 30 Gy or 25 Gy (< 3 years)/1.6‐1.7 Chemotherapy (according to protocol; actual received doses nm): nitrogen mustard (3 mg/m2 intravenously on days 1 and 8), vincristine (1.4 mg/m2 intravenously on days 1 and 8), procarbazine (50 mg on day 1, 100 mg on day 2 and 100 mg/m2 on days 3‐10; route of administration nm) and prednisone (40 mg/m2 orally on days 1‐10) (i.e. MOPP). Chemotherapy started 4 weeks after the completion of RT and was repeated every 4 weeks for 12 courses |
|
| Outcomes | OS (definition nm) EFS (defined as the time from start of treatment until disease progression or death, progression being an increase in measurable lesions or the development of recurrent or new lesions, as measured by CT scans of the brain or spinal imaging (or both) or the development of metastatic disease outside the CNS) Adverse effects (definition unclear, but at least some based on WHO criteria) |
|
| Notes | Length of follow‐up nm (maximal follow‐up was 9 years) Number of children who stopped chemotherapy or RT prematurely or who did not receive the full doses nm |
|
Tait 1990.
| Methods | Method of randomisation not clear (stratified according to age group, sex and extent of surgery) | |
| Participants | 286 children with medulloblastoma 113 stage T1 or T2, 163 stage T3 or T4 (91 in experimental arm, i.e. chemotherapy and RT; 72 in standard arm, i.e. RT) and 10 T‐stage nm; for all children the M‐stage was nm Primary disease Histological subtype nm Molecular markers nm Aged < 2 to 15 years 208 boys and 78 girls No previous therapy Data for children in each treatment arm were not provided unless otherwise stated |
|
| Interventions |
Design: surgery followed by RT ± chemotherapy. If applicable, chemotherapy was given during and after RT. Randomisation: 141 children received chemotherapy; 145 children did not Surgery: as radical as possible without undue risk to life and function. 128 total resections, 111 subtotal resections and 39 partial resections; for the other 8 children it was nm; data for children in each treatment arm were not provided Imaging: postoperative imaging nm RT (according to protocol; actual received doses nm: see notes): commencing as soon as possible following postoperative recovery, at least within 1 month of surgery. target volume (Gy): dose/dose per fraction: cranial: 35‐45 in 7‐8 weeks (< 2 years: 30‐35 Gy in 6‐7 weeks), posterior fossa: 50‐55 in 7‐8 weeks (< 2 years: 40‐45 Gy), spinal: 30‐35 in 5‐6 weeks (< 2 years: 30 Gy in 6 weeks). Treatment was daily, 5 days per week. Megavoltage or cobalt‐60 equipment was used Chemotherapy (according to protocol; actual received doses nm: see notes): vincristine during RT (weekly injection 1 mg/m2) and 8 courses of maintenance therapy commencing 1 month after completing irradiation consisting of CCNU (100 mg/m2 orally on day 1) and vincristine (1.5 mg/m2 intravenously on days 1, 8 and 15). Chemotherapy courses were cycled every 6 weeks for 1 year |
|
| Outcomes | DFS (defined as from time of operation to disease recurrence or death from other causes) Adverse effects (definition nm) |
|
| Notes | Length of follow‐up nm (maximal follow‐up was 13 years) Number of children who stopped chemotherapy or RT prematurely or who did not receive the full doses nm For information on actual received chemotherapy and RT doses and for more information on adverse effects this article refers to a conference abstract, but the abstract book shows only an empty page (Bloom 1981) |
|
Taylor 2003/4.
| Methods | The randomisation procedure involved the responsible clinician telephoning the data centre where the children's details were entered in a computer program and using the minimisation technique (stratified by age (3‐7, 8‐11 and 12‐16 years), extent of tumour resection (total or less than total) and treatment centre) | |
| Participants | 179 children with medulloblastoma T stage nm; stage M0 or M1 (number of children in each treatment arm nm); the exact number of children with M1 was unclear since too few children had undergone lumbar craniospinal fluid sampling to categorise the stage as M0 or M1 Primary disease nm Histological subtype nm Molecular markers nm Median age in experimental arm (i.e. RT and chemotherapy) 7.74 years (range 3.1 to 15 years); median age in standard arm (i.e. RT) 7.67 years (range 2.9 to 16.8 years) 111 boys (57 in experimental arm; 54 in standard arm) and 68 girls (33 in experimental arm; 35 in standard arm) Previous therapy nm |
|
| Interventions |
Design: surgery followed by RT ± chemotherapy. If applicable, chemotherapy was given before RT. Randomisation: 90 children received chemotherapy; 89 children did not Surgery: maximal safe tumour resection was recommended. 99 total resections (50 in experimental arm; 49 in standard arm), 79 less than total resections (40 in experimental arm; 39 in standard arm) and for 1 child (in standard arm) the extent of the resection was unknown (as assessed by the neurosurgeon) Imaging: postoperative imaging by cranial MRI or CT scan within 48‐72 hours after surgery was mandatory; nm if all children indeed underwent cranial MRI or CT scan RT: starting within 4 weeks of surgery (in children randomised to no chemotherapy) or as soon as possible after count recovery (i.e. neutrophils > 1 x 109/L, platelets > 100 x 109/L) after the final cycle of chemotherapy. According to protocol, target volume (Gy): dose/dose per fraction: craniospinal 35/1.67, posterior fossa: 55/1.67. Treatment was daily, 5 days per week. RT was recommended to be completed within 50 days. Mean/median/range of actually received craniospinal dose in intervention group: 34.72 Gy, 35.03 Gy, 25.2‐40.28 Gy (in 19 children, RT was not completed within 50 days); in control group: 34.57 Gy, 35.07 Gy, 15.03‐40 Gy (in 23 children, RT was not completed within 50 days) Chemotherapy (according to protocol; actual received doses nm): alternating cycles of vincristine (1.5 mg/m2 on days 1, 7 and 14), etoposide (100 mg/m2 on days 1, 2 and 3) and carboplatin (500 mg/m2 on days 1 and 2) and vincristine (1.5 mg/m2 on days 1, 7 and 14; day 1 only for cycle 4), etoposide (100 mg/m2 on days 1, 2 and 3) and cyclophosphamide (1.5 mg/m2 on day 1), 4 cycles (all intravenously) at 3‐week intervals. Chemotherapy was intended to begin within 28 days of surgery. Median time to complete chemotherapy was 78 days (shortest duration was 66 days) |
|
| Outcomes | OS (defined as the time from the date of diagnosis to the date of death) EFS (defined as the time from the date of diagnosis to the date of the first event; an event was defined as recurrence or death) Adverse effects (nm on which criteria they were based) |
|
| Notes | Median follow‐up was 5.4 years (range 0.2 to 10 years) 3/179 children had a review diagnosis of ganglioneuroblastoma, which is a tumour with a PNET component. These children were not retrospectively withdrawn from the analyses Number of children who stopped chemotherapy prematurely or who did not receive the full doses: 4 children. Number of children who stopped RT prematurely or who did not receive the full doses: 3 children received a CSRT dose of < 30 Gy, 3 children received a PF dose of < 50 Gy, no RT details available for 6 children We tried to contact these authors regarding more information on the definition of EFS; however, we did not receive a reply |
|
Van Eys 1981.
| Methods | Method of randomisation not clear (stratified by diagnosis (medulloblastoma versus ependymoma: see notes) and by the presence or absence of a ventriculoperitoneal or atrial shunt) | |
| Participants | 34 children with medulloblastoma Stage nm Primary disease Histological subtype nm Molecular markers nm Age nm Sex nm No prior treatment (with the exception of glucocorticoids) |
|
| Interventions |
Design: surgery followed by RT ± chemotherapy. If applicable, chemotherapy was given after RT. Randomisation: 16 children received chemotherapy; 18 children did not Surgery: as much tumour tissue as possible was resected Imaging: postoperative imaging nm RT (according to protocol; actual received doses nm) started as soon as the surgical wound has healed, usually within 10 days. Target volume (Gy): dose/dose per fraction: cranial: 40/nm or 35/nm (< 3 years), posterior fossa: 50/nm or 45/nm (< 3 years), spinal: 30/nm or 25/nm (< 3 years). RT was done with megavoltage equipment Chemotherapy (according to protocol; actual received doses nm): vincristine (2 mg/m2 intravenously; with a maximum dose of 2 mg), methotrexate (15 mg/m2 intrathecally; no maximum dose) and hydrocortisone (15 mg/m2 intrathecally; no maximum dose). Initially chemotherapy was started on the first week after RT, with all 3 drugs given weekly for 4 doses and then every 4 weeks thereafter for 12 doses (total course 52 weeks). Doses were delayed for toxicity but not decreased. However, serious toxicity with myelosuppression was observed in this schedule. Therefore, it was altered to give vincristine as above, for 4 doses starting the first week after RT, followed by vincristine and methotrexate plus hydrocortisone weekly for 4 doses. Then the treatment was given every 4 weeks as above |
|
| Outcomes | OS (definition nm) Adverse effects (nm on which criteria they were based) |
|
| Notes | In this review, only children with medulloblastoma were included. There were 34 evaluable children, but it is unclear how many children with medulloblastoma were originally included in this study Length of follow‐up nm (maximal follow‐up was 24 months) Number of children who stopped chemotherapy or RT prematurely or who did not receive the full doses nm |
|
CCNU: lomustine; CNS: central nervous system; CSA: craniospinal axis; CSRT: craniospinal radiotherapy; CT: computed tomography; DFS: disease‐free survival; EFS: event‐free survival; Gy: gray; HART: hyperfractionated accelerated radiotherapy; ITT: intention to treat; MOPP: mechlorethamine, vincristine, procarbazine and prednisone; MRI: magnetic resonance imaging; nm: not mentioned; OS: overall survival; PNET: primitive neuroectodermal tumour; RT: radiotherapy; WHO: World Health Organization.
Characteristics of excluded studies [ordered by year of study]
| Study | Reason for exclusion |
|---|---|
| Neidhardt 1982 | All participants received chemotherapy. They were randomised for maintenance chemotherapy |
| Neidhardt 1987b | Description of the design of the Bailey 1995 CT vs no CT; Bailey 1995 RTvslowRT/CT study |
| Neidhardt 1987a | Preliminary results of a study included in this review (Bailey 1995 CT vs no CT; Bailey 1995 RTvslowRT/CT) |
| Rogers 2011 | Participants treated according to the same protocol as Taylor 2003/4 and overlap with participants in the Taylor 2003/4 is likely; the primary outcome of this review (i.e. survival) was not presented and only a very small subgroup of eligible participants (26%) was described with regard to alopecia |
Differences between protocol and review
None.
Contributions of authors
Erna Michiels designed the study and wrote the protocol; identified the studies meeting the inclusion criteria; performed data extraction and risk of bias assessment of the included studies; searched for unpublished and ongoing studies; contributed to the interpretation of the results; wrote and revised the review.
Antoinette Schouten ‐ van Meeteren critically reviewed the protocol; identified the studies meeting the inclusion criteria; performed data extraction and risk of bias assessment of the included studies; contributed to the interpretation of the results; critically reviewed the manuscript.
François Doz critically reviewed the protocol and the manuscript.
Geert Janssens critically reviewed the manuscript.
Elvira van Dalen designed the study and wrote the protocol; helped with developing the search strategy; identified studies meeting the inclusion criteria; searched for unpublished and ongoing studies; analysed the data; contributed to the interpretation of the results; wrote and revised the review.
All authors approved the final version.
Sources of support
Internal sources
No sources of support supplied
External sources
Dutch Cochrane Centre, Netherlands.
Stichting Kinderen Kankervrij (KIKA), Netherlands.
Declarations of interest
None known.
New
References
References to studies included in this review
Abd El‐Aal 2005 {published data only}
- Abd El‐Aal HH, Mokhtar MM, Habib EE, El‐Kashef AT, Fahmy ES. Medulloblastoma: conventional radiation therapy in comparison to chemoradiation therapy in the post‐operative treatment of high‐risk patients. Journal of the Egyptian National Cancer Institute 2005;17(4):301‐7. [PubMed] [Google Scholar]
Bailey 1995 CT vs no CT {published data only}
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