Abstract
Background
Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor; more than half of patients experience disease recurrence. High-dose chemotherapy and haematopoietic stem cell rescue (i.e. myeloablative therapy) might improve survival. This review is an update of a previously published Cochrane review.
Objectives
The primary objective was to compare the efficacy of myeloablative therapy with conventional therapy in children with high-risk neuroblastoma. Secondary objectives were to determine possible effects of these interventions on adverse events, late effects and quality of life.
Search methods
We searched the electronic databases CENTRAL (The Cochrane Library 2012, issue 6), MEDLINE/PubMed (1966 to June 2012) and EMBASE/Ovid (1980 to June 2012). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2002 to 2011), American Society for Pediatric Hematology and Oncology (ASPHO) (from 2002 to 2012), Advances in Neuroblastoma Research (ANR) (from 2002 to 2012) and American Society for Clinical Oncology (ASCO) (from 2008 to 2012). We searched for ongoing trials by scanning the ISRCTN register and the National Institute of Health Register (http://www.controlled-trials.com; both screened July 2012).
Selection criteria
Randomised controlled trials (RCTs) comparing the efficacy of myeloablative therapy with conventional therapy in high-risk neuroblastoma patients.
Data collection and analysis
Two authors independently performed study selection, data extraction and risk of bias assessment. If appropriate, we pooled studies. The risk ratio (RR) and 95% confidence interval (CI) was calculated for dichotomous outcomes. For the assessment of survival data, we calculated the hazard ratio (HR) and 95% CI. We used Parmar’s method if hazard ratios were not reported in the study. We used a random-effects model.
Main results
We identified three RCTs including 739 children. They all used an age of one year as the cut-off point for pre-treatment risk stratification. The updated search identified a manuscript reporting additional follow-up data for one of these RCTs. There was a statistically significant difference in event-free survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (3 studies, 739 patients; HR 0.78, 95% CI 0.67 to 0.90). There was a statistically significant difference in overall survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (2 studies, 360 patients; HR 0.74, 95% CI 0.57 to 0.98). However, when additional follow-up data were included in the analyses the difference in event-free survival remained statistically significant (3 studies. 739 patients; HR 0.79, 95% CI 0.70 to 0.90), but the difference in overall survival was no longer statistically significant (2 studies, 360 patients; HR 0.86, 95% CI 0.73 to 1.01). The meta-analysis of secondary malignant disease and treatment-related death did not show any statistically significant differences between the treatment groups. Data from one study (379 patients) showed a significantly higher incidence of renal effects, interstitial pneumonitis and veno-occlusive disease in the myeloablative group compared to conventional chemotherapy, whereas for serious infections and sepsis no significant difference between the treatment groups was identified. No information on quality of life was reported. In the individual studies we evaluated different subgroups, but the results were not univocal in all studies. All studies had some methodological limitations.
Authors’ conclusions
Based on the currently available evidence, myeloablative therapy seems to work in terms of event-free survival. For overall survival there is currently no evidence of effect when additional follow-up data are included. No definitive conclusions can be made regarding adverse effects and quality of life, although possible higher levels of adverse effects should be kept in mind. A definitive conclusion regarding the effect of myeloablative therapy in different subgroups is not possible. This systematic review only allows a conclusion on the concept of myeloablative therapy; no conclusions can be made regarding the best treatment strategy. Future trials on the use of myeloablative therapy for high-risk neuroblastoma should focus on identifying the most optimal induction and/or myeloablative regimen. The best study design to answer these questions is a RCT. These RCTs should be performed in homogeneous study populations (e.g. stage of disease and patient age) and have a long-term follow-up. Different risk groups, using the most recent definitions, should be taken into account.
It should be kept in mind that recently the age cut-off for high risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate-risk disease have been included in the high-risk groups. Consequently the relevance of the results of these studies to the current practice can be questioned. Survival rates may be overestimated due to the inclusion of patients with intermediate-risk disease.
Plain language summary
High-dose chemotherapy and stem cell transplant compared to conventional therapy for children with high-risk neuroblastoma
Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients still remains poor; in more than half of patients the disease returns. High-dose chemotherapy and haematopoietic stem cell rescue, also known as myeloablative therapy, might improve the survival of these patients. A well-informed decision on the use of myeloablative therapy in the treatment of children with high-risk neuroblastoma should be based on high quality evidence of effectiveness for treating tumours and side effects.
This systematic review focused on randomised studies comparing the effectiveness of myeloablative therapy with conventional therapy in children with high-risk neuroblastoma. The authors found three studies including 739 patients. These studies provide evidence that myeloablative therapy improves event-free survival (that is, the time until a certain event like for example tumour progression, a second tumour develops or death from any cause occurs). For overall survival (that is, the time until a patient dies from any cause, so not only from the tumour or its treatment, but for example, also from a car accident) there is no evidence of a better outcome in patients treated with myeloablative therapy. Side effects such as renal (kidney) effects, interstitial pneumonitis (a type of lung disease) and veno-occlusive disease (a condition in which some of the small veins in the liver are obstructed) were more common in patients treated with myeloablative therapy than conventional chemotherapy. It should be noted that this systematic review only allows a conclusion on the concept of myeloablative therapy; no conclusions regarding the best treatment strategy with regard to, for example, types of chemotherapeutic agents and the use of radiation therapy, could be made. More high quality research is needed.
It should be noted that recently the age cut-off for high-risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate-risk disease were included in the high-risk groups. Consequently the relevance of the results of these studies to the current practice can be questioned. Survival rates may be overestimated due to the inclusion of patients with intermediate-risk disease.
