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High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma

  1. Bilgehan Yalçin1,*,
  2. Leontien CM Kremer2,
  3. Huib N Caron2,
  4. Elvira C van Dalen2

Editorial Group: Cochrane Childhood Cancer Group

Published Online: 22 AUG 2013

Assessed as up-to-date: 24 DEC 2012

DOI: 10.1002/14651858.CD006301.pub3


How to Cite

Yalçin B, Kremer LCM, Caron HN, van Dalen EC. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006301. DOI: 10.1002/14651858.CD006301.pub3.

Author Information

  1. 1

    Hacettepe University Faculty of Medicine, Pediatric Oncology, Ankara, Turkey

  2. 2

    Emma Children's Hospital / Academic Medical Center, Department of Paediatric Oncology, Amsterdam, Netherlands

*Bilgehan Yalçin, Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, 06100, Turkey. yalcinb@hacettepe.edu.tr. bilgehanyalcin@yahoo.com.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 22 AUG 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Neuroblastoma is the most common extracranial solid tumour in children comprising 8% to 10% of all childhood cancers. The incidence is nearly 10 per 1,000,000 children under the age of 15 years and 90% of cases are diagnosed in the first 10 years of life. Children with neuroblastoma mostly present with abdominal disease and more than half of the cases have advanced disease (defined as stage III or IV disease) (Aydin 2009; Brodeur 2006; Goldsby 2004).

Neuroblastoma is one of the most challenging and enigmatic neoplasms of childhood because of its biological heterogeneity and contrasting patterns of clinical behaviour. Some young infants with favourable disease may experience complete spontaneous regression while older children with metastatic disease mostly relapse despite initial response to chemotherapy.

The prognosis and management of children with neuroblastoma is highly dependent on clinical, histopathological and biological characteristics, and they are stratified into risk groups based on prognostic factors (Goldsby 2004; Maris 2005; Maris 2007; Weinstein 2003). For pre-treatment risk stratification traditionally an age of one year was used as a cut-off point. The low-risk disease group included cases younger than one year who had stage I, II or IV-S disease with favourable histopathology and no MYCN oncogene amplification (Brodeur 2006; Goldsby 2004; Maris 2005; Maris 2007; Weinstein 2003).

High-risk neuroblastoma cases were traditionally characterised by an age older than one year, disseminated disease, MYCN oncogene amplification and unfavourable histopathologic findings (Brodeur 2006; Goldsby 2004; Maris 2005; Weinstein 2003). However, in recent years a new neuroblastoma risk classification system has been developed by the International Neuroblastoma Risk Group (INRG) Task Force resulting in standardized approaches for the initial evaluation and treatment stratification of neuroblastoma patients (Cohn 2009). In this INRG classification system an age cut-off of 18 months is used for pre-treatment risk stratification, as opposed to the traditional cut-off of one year. In many of the currently published studies patients with what is now understood to be intermediate-risk disease were classified as high-risk patients. Consequently the relevance of the results of these studies to current practice can be questioned.

Substantial improvement has been achieved in the cure of patients with low-risk neuroblastoma resulting in survival rates up to 90% (Brodeur 2006; Goldsby 2004). In high-risk cases, despite intensified combination chemotherapies, surgery, radiotherapy and the use of differentiation agents, prognosis improved only modestly with long-term survival in less than one-third of patients (Brodeur 2006; De Bernardi 2003; Goldsby 2004; Weinstein 2003). In the last two decades higher remission rates have been achieved with intensive induction chemotherapy regimens combined with surgical resection, external irradiation or both (Brodeur 2006; Castel 1995; Goldsby 2004; Kaneko 2002; Kushner 2004; Laprie 2004; Sawaguchi 1990). The challenge is to maintain remission since more than half of patients with high-risk disease develop systemic disease recurrence with or without a relapse at the primary tumour site (Brodeur 2006; Goldsby 2004; Matthay 1993; Weinstein 2003). AntiGD2 antibody-based immunotherapy has been shown to improve event-free and overall survival in high-risk neuroblastoma patients in remission after multimodality treatment (Yu 2010). Therapy failures are mostly attributed to development of resistance to chemotherapy and minimal residual disease is considered an important cause of recurrence (Burchill 2004; Keshelava 1998; Reynolds 2001; Reynolds 2004).

The idea that further increasing dose intensity may overcome chemotherapy resistance has provided a rationale for aggressive high-dose chemotherapy consolidation protocols (Cheung 1991; Pritchard 1995). Such myeloablative chemotherapy regimens utilise effective high-dose drug combinations which can be safely escalated to levels above those causing bone marrow ablation. Rapid bone marrow reconstitution can be achieved by autologous stem cell rescue. Autologous peripheral blood stem cells (PBSC) are the preferred source for rescue as this has several advantages over autologous bone marrow grafts. For example, the procedure of PBSC collection is easier, the incidence of tumour cell contamination is lower, and the yield of stem cells is higher (Brodeur 2006; Cohn 1997; Ladenstein 1994). A possible limitation of using autologous products is the risk of tumour cell contamination in the graft, which has been shown to contribute to relapse. Considerable efforts have been made to detect and remove tumour (negative purging) or select progenitor cells (positive purging) before reinfusion (Ladenstein 2004). Disease status prior to stem cell rescue has a crucial influence on final outcome. Patients in complete, very good partial or partial remission have a better prognosis, while those with stable disease or no response have a poor outcome (Ladenstein 2004).

Patients undergoing stem cell rescue may experience toxicities related to conditioning regimens like veno-occlusive disease of the liver or haemorrhagic cystitis (Bollard 2006). Growth failure, endocrine disorders such as gonadal or thyroid dysfunction, hearing impairment, renal impairment, orthopedic complications as well as the occurrence of secondary malignancies are among the late complications following high-dose chemotherapy and stem cell rescue (Bollard 2006; Trahair 2007).

Many retrospective and prospective non-randomised studies support the use of a myeloablative consolidation in neuroblastoma. Retrospective studies mostly suggest that intensification of consolidation therapy with autologous stem cell rescue following high-dose chemotherapy improves survival (Castel 1995; Di Caro 1994; Matthay 1995; Philip 1997; Stram 1996; Verdeguer 2004). The results of non-randomised pilot studies by the Children's Cancer Group also suggest a modest prolongation of event-free survival for children with high-risk neuroblastoma (Matthay 1995).

This is an update of the first systematic review evaluating the current state of evidence on the efficacy of high-dose chemotherapy and autologous haematopoietic stem cell rescue compared with conventional therapy in patients diagnosed with high-risk neuroblastoma (Yalçin 2010).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Primary objective

To compare the efficacy of high-dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy in children with high-risk neuroblastoma.

 

Secondary objectives

To determine adverse effects (e.g. veno-occlusive disease of the liver) and late effects (e.g. endocrine disorders or secondary malignancies) related to the procedure and possible effects of these procedures on quality of life.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCTs) that compared the efficacy of high-dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy were considered for inclusion.

 

Types of participants

Participants included children (aged < 21 years) with high-risk neuroblastoma. High-risk neuroblastoma is defined as a combination of the following characteristics: unfavourable age (as defined by the authors of the included studies), advanced stage disease (as defined by the authors of the included studies), presence of MYCN oncogene amplification, or unfavourable histopathologic findings (as defined by the authors of the included studies) or both. 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 group.

 

Types of interventions

Interventions included high-dose chemotherapy with autologous bone marrow or stem cell rescue versus conventional therapy (i.e. either conventional chemotherapy or no further treatment). High-dose chemotherapy is defined as chemotherapy sufficient to require stem cell rescue. Conventional chemotherapy is defined as chemotherapy at a lower dose than the high-dose chemotherapy without the need for stem cell rescue.

 

Types of outcome measures

 

Primary outcomes

  • Event-free survival (usually defined as the time to recurrence or progression of disease or death from any cause or varying definitions, as used by the authors).
  • Overall survival (defined as the time to death from any cause).

 

Secondary outcomes

  • Adverse events (e.g. stomatitis, diarrhoea, fatigue, anaemia, leukopenia, thrombocytopenia or veno-occlusive disease of the liver) and late effects (e.g. endocrine disorders or secondary malignancies).
  • Quality of life.

 

Search methods for identification of studies

We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, issue 6), MEDLINE/PubMed (from 1966 to June 2012) and EMBASE/Ovid (from 1980 to June 2012). The search strategies for the different electronic databases (using a combination of controlled vocabulary and text word terms) are shown in Appendix 1, Appendix 2 and Appendix 3.

We located information about trials not registered in CENTRAL, MEDLINE or EMBASE, either published or unpublished, by searching the reference lists of relevant articles and review articles. We also scanned the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2002 to 2011), the American Society for Pediatric Hematology and Oncology (ASPHO) (from 2002 to 2012), Advances in Neuroblastoma Research (ANR) (from 2002 to 2012) and the American Society for Clinical Oncology (ASCO) (from 2008 to 2012), if available electronically and otherwise by handsearching. 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). We imposed no language restriction.

 

Data collection and analysis

 

Study identification

Two authors independently screened the search results to identify studies meeting the inclusion criteria. We obtained full manuscripts for any study that appeared to meet the inclusion criteria based on title, or abstract or both for closer inspection. We clearly reported reasons for exclusion for any study considered for the review. Discrepancies between authors were resolved by consensus. No third party arbitration was needed.

 

Assessment of risk of bias in included studies

Two authors independently performed assessment of risk of bias in the included studies, according to the following criteria: concealment of treatment allocation, blinding of the care provider, blinding of the patients, blinding of the outcome assessor (for each outcome separately), intention-to-treat analyses (for each outcome separately) and completeness of follow up (for each outcome separately). We have used the definitions as recommended by the Cochrane Childhood Cancer Group at the time of the original version of the review (see  Table 1). Discrepancies between authors were resolved by consensus. No third party arbitration was needed.

 

Data extraction

Two authors independently extracted data using standardised forms. We extracted the following data:

  • the characteristics of the participants at the time of randomisation (such as age, sex, stage of disease, histology, MYCN oncogene amplification, received induction treatment, received external irradiation, remission status at myeloablative treatment and stem cell rescue);
  • the characteristics of interventions (details of myeloablative therapy: drugs used, routes of delivery, dose, timing, use of total body irradiation; details of the stem cell rescue: timing and methods of cell harvest, timing of stem cell rescue, number of cells infused, contamination with tumour cells);
  • details of supportive care (such as the use of prophylactic antibiotics, growth factors, granulocyte infusions);
  • details of outcome measures as described above; and
  • length of follow up.

In case of disagreement between authors, we re-examined the abstracts and articles and discussed these until consensus was achieved. No third party arbitration was needed.

 

Data analysis

We entered data into Review Manager and analysed data according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We pooled studies for meta-analysis when appropriate. The risk ratio (RR) was calculated for dichotomous outcomes along with the corresponding 95% confidence interval (CI). For the assessment of survival, we used the generic inverse variance function of RevMan to combine logs of the hazard ratios (HR) and estimate corresponding 95% CI. We used Parmar's method if hazard ratios were not reported in the study (Parmar 1998). We extracted data by allocation intervention, irrespective of compliance with the allocated intervention, in order to allow for an 'intention-to-treat' analysis. 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 > 50%) (Higgins 2005), this was reported. We used a random-effects model for the estimation of treatment effects throughout the review. Where possible, we presented data separately for different prognostic factors such as disease status at the time of stem cell rescue, MYCN amplification status and serum lactate dehydrogenase levels. For all outcomes for which pooling was possible we performed sensitivity analyses for all quality criteria separately. We excluded low quality studies and studies for which the quality was unclear and compared the results of the good quality studies with the results of all available studies. The quality of studies included in the analyses was taken into account in the interpretation of the results of the review. We planned to construct a funnel plot to graphically ascertain the existence of publication bias. However, as a rule of thumb, 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 three trials could be included in the review, we did not construct funnel plots.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

We ran searches of the electronic databases CENTRAL, MEDLINE/PubMed and EMBASE/Ovid in January 2009 for the original version of this review. This search yielded a total of 1463 references. Initial screening excluded 1427 references which clearly did not meet all the criteria for considering studies for this review. We obtained 36 references in full for closer inspection. Three studies fulfilled all the criteria for considering studies for this review and were included in the review (Berthold 2005; Matthay 1999; Pritchard 2005). We excluded the remaining 33 articles for reasons described in the Characteristics of excluded studies table.

For the update we ran searches of CENTRAL, MEDLINE/PubMed and EMBASE/Ovid in June 2012 yielding a total of 266 references which were added to the search results from January 2009. Initial screening excluded 265 references which clearly did not meet the inclusion criteria. We obtained one full text study for closer inspection. It fulfilled the inclusion criteria and was thus included. This study provides additional follow-up data for the Matthay 1999 study.

We scanned the reference lists of relevant articles and reviews and conference proceedings (i.e. SIOP, ASPHO and ASCO) and did not identify any additional eligible studies. One trial was added to the Characteristics of excluded studies table. By scanning of the ANR conference proceedings we identified one study that has not been published in full yet and is awaiting further assessment (see Characteristics of studies awaiting classification table). This study provides additional follow-up for the Berthold 2005 study. No eligible ongoing trials were identified.

In summary, the total number of included RCTs was three (described in four publications). Characteristics of included studies are summarised below (for further details see the Characteristics of included studies table). We also identified one study awaiting assessment.

All three eligible RCTs were multi-centre studies, two of which were based in Europe (Berthold 2005; Pritchard 2005) and one in North America (Matthay 1999). Patients were recruited between January 1982 (Pritchard 2005) and November 2002 (Berthold 2005). The total number of patients included in the three studies was 739; 370 children received high-dose chemotherapy and stem cell rescue, whereas 369 children received either conventional chemotherapy (Berthold 2005; Matthay 1999) or no further treatment (Pritchard 2005). All trials used different induction regimens (i.e. different chemotherapeutic agents and different (cumulative) dosages) and different myeloablative treatments. In Berthold 2005 and Matthay 1999 there were also differences in treatment patients received in the study itself (for example, external radiotherapy, therapeutic MIBG-I131, immunotherapy and retinoic acid treatment). See the Characteristics of included studies table for further details. All patients were diagnosed with high-risk neuroblastoma. The definitions of high-risk neuroblastoma differed between studies (See Characteristics of included studies table). Matthay 1999 included newly diagnosed patients. It was unclear if the patients in the other studies were newly diagnosed. None of the studies reported the exact age of the participants; only the number of cases above and below one year of age was reported.

 

Risk of bias in included studies

See  Table 2 summarises the risk of bias scores for each included study.

We judged allocation concealment to be adequate in two studies (Berthold 2005; Pritchard 2005), whereas in one study this was unclear (Matthay 1999).

Care providers and patients were not blinded to treatment in two studies (Berthold 2005; Matthay 1999), whereas in one study this was unclear (Pritchard 2005). However, it should be noted that due to the nature of the interventions blinding of care providers and patients was virtually impossible.

For blinding of the outcome assessor we scored each outcome separately, with the exception of overall survival, since for that outcome blinding was not relevant. Three studies evaluated event-free survival. In Matthay 1999 the outcome assessor was blinded to treatment. However, for the additional follow-up data of this study this was unclear. In two studies it was unclear if the outcome assessor evaluating event-free survival was blinded. Two studies evaluated adverse effects. In the Matthay 1999 study the outcome assessor was blinded to treatment assignment. However, for the additional follow-up data of this study it was unclear if the outcome assessor evaluating adverse events was blinded. In the Berthold 2005 study this was unclear.

The presence of an intention-to-treat (ITT) analysis was also scored for each outcome separately. For both overall survival and event-free survival all three studies evaluating these outcomes used an ITT analysis. For adverse effects both studies evaluating this outcome used an ITT analysis.

Completeness of follow-up was also scored for each outcome separately. For both overall survival and event-free survival the completeness of follow-up was unclear in all three studies evaluating these outcomes. The same was true for adverse effects (evaluated in two studies), with the exception of treatment-related death. In one study no patients were lost to follow-up (Berthold 2005), whereas in the other study more than 20% of patients were lost to follow-up (Matthay 1999).

In summary, selection bias (based on concealment of allocation) could not be ruled out in 33.3% of included studies. Performance bias (based on blinding of the care provider and patient) could not be ruled out in any of the included studies. Detection bias (based on blinding of the outcome assessor) could not be ruled out in 66.7% (100% when including the additional follow-up data) of included studies evaluating event-free survival and in 50% (100% when including the additional follow-up data) of included studies evaluating adverse effects. The assessment of the risk of attrition bias was based on the use of an ITT analysis and completeness of follow-up. All included studies used an ITT analysis for all evaluated outcomes. For overall survival, event-free survival and adverse effects (with the exception of treatment-related death) completeness of follow-up was unclear in 100% of included studies. For treatment-related death loss to follow up was more than 20% in 50% of the included studies.

 

Effects of interventions

 

Event-free survival

Data on event-free survival were extracted from three trials (Berthold 2005; Matthay 1999; Pritchard 2005) with a total of 739 patients (see Figure 1). Two of these trials included secondary malignant disease as an event (Berthold 2005; Matthay 1999), whereas the other did not (Pritchard 2005; see the Characteristics of included studies table for the exact definitions). However, since only a very small percentage of patients developed secondary malignant disease (see the description of adverse effects later on), we were able to pool the results of these three trials. There was a statistically significant difference in event-free survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (HR 0.78, 95% CI 0.67 to 0.90, P = 0.0006). No heterogeneity was detected for this comparison (I2 = 0%).

 FigureFigure 1. Forest plot of comparison: 1 Myeloablative therapy versus control, outcome: 1.1 Event-free survival without additional follow-up data.

The meta-analysis of the two trials including secondary malignant disease as an event also showed a statistically significant difference in event-free survival in favour of myeloablative therapy over conventional chemotherapy (HR 0.79; 95% CI 0.67 to 0.92, P = 0.002, 674 patients). No heterogeneity was detected for this comparison (I2 = 0%). The study not including secondary malignant disease as an event showed no statistically significant difference between myeloablative therapy and no further treatment (HR 0.73, 95% CI 0.49 to 1.07, P = 0.11, 65 patients).

Additional follow-up data from the Matthay 1999 study have been published. The length of follow-up was not reported, but the median follow-up of patients alive without an event was 7.7 years (range 130 days to 12.8 years). Relapse was included as an event in the follow-up study, as opposed to the original publication. The results of this meta-analysis of three trials including additional follow-up data were in line with the earlier data. There was a statistically significant difference in event-free survival in favour of the myeloablative therapy group over conventional chemotherapy or no further treatment (HR 0.79, 95% CI 0.70 to 0.90, P = 0.0003, 739 patients). No heterogeneity was detected for this comparison (I2 = 0%). When additional follow-up data were included the meta-analysis of the two trials including secondary malignant disease as an event again showed a statistically significant difference in event-free survival in favour of the myeloablative therapy group over conventional chemotherapy (HR 0.80, 95% CI 0.70 to 0.92, P = 0.001, 674 patients). No heterogeneity was detected for this comparison (I2 = 0%). The results of the analysis of the study not including secondary malignant disease as an event did not change, since no new data were available (i.e. no significant difference between the treatment groups). See Figure 2.

 FigureFigure 2. Forest plot of comparison: 1 Myeloablative therapy versus control, outcome: 1.2 Event-free survival including additional follow-up data of Matthay 1999.

The above mentioned HRs were calculated using the complete follow-up period of the trials. The individual studies also reported three or five-year event-free survival rates. Berthold 2005 and Matthay 1999 reported significantly better three-year event-free survival rates in the myeloablative therapy group compared to conventional chemotherapy (P = 0.0221 and P = 0.034 respectively). Pritchard 2005 found no statistically significant difference in five-year event-free survival between the treatment groups (P = 0.08). Additional follow-up data from Matthay 1999 showed a statistically significant difference in 5-year event-free survival in favour of the myeloablative therapy group (P = 0.0434).

It should be noted that the individual studies all used different starting points for event-free survival, either years since randomisation or years from diagnosis. In the Matthay 1999 study randomisation was performed a median of 60 days after diagnosis. Pritchard 2005 did not report the time of randomisation but the decision to randomise was made five to nine months after diagnosis. In the Berthold 2005 study randomisation was performed a median of 39 days after diagnosis.

 

Subgroups

Subgroups are summarised descriptively (i.e. as reported in the individual studies).

Berthold 2005 performed subgroup analyses based on commonly accepted risk factors. Three-year event-free survival was significantly better in the myeloablative therapy group compared to conventional chemotherapy: (1) in patients who had a complete remission or very good partial remission to induction chemotherapy/before randomisation (P = 0.0083); (2) in patients with raised serum concentration of lactate dehydrogenase (P = 0.0357; cut-off value not reported); and (3) in patients receiving antibody treatment (P = 0.0061). By contrast, no statistically significant difference in three-year event-free survival was identified between the treatment groups: (1) in patients who had partial remission, mixed remission or stable disease before randomisation (P = 0.1809); (2) in patients treated with retinoic acid (P = 0.9732); (3) in patients with MYCN amplification with stage I, II, III, or IV-S disease or with stage IV disease aged younger than one year (P = 0.2183); (4) in patients with MYCN amplification (P = 0.0669); (5) in patients without MYCN amplification (P = 0.0643); (6) in patients with normal concentrations of serum lactate dehydrogenase (P = 0.3132; cut-off value not mentioned); and (7) in patients with stage IV disease and age more than one year (P = 0.0549).

Matthay 1999 performed subgroup analyses based on stage IV disease, MYCN amplification, unfavourable histopathological findings, a serum ferritin level of at least 143 ng per millilitre, a partial response to initial chemotherapy (as compared to complete response or nearly complete response), age at diagnosis more than two years and, among stage IV patients, bone metastases at diagnosis, and the presence at diagnosis of more than 100 tumour cells per 105 normal nucleated bone marrow cells. Matthay 1999 reported that event-free survival among patients assigned to myeloablative therapy was longer in each subgroup (univariate analysis) than that among patients assigned to conventional chemotherapy (no P values reported). This difference in event-free survival was most pronounced among the subgroups of patients who were older than two years at diagnosis (P = 0.01) and among patients with MYCN amplification (P = 0.03). Additional follow-up data showed no statistically significant difference between treatment groups in event-free survival in patients with stage IV disease.

Pritchard 2005 reported significantly better five-year event-free survival in patients aged more than one year with stage IV disease assigned to the myeloablative therapy group (P = 0.01).

 

Overall survival

Data on overall survival were reported in three trials (Berthold 2005; Matthay 1999; Pritchard 2005). The results from two of these trials could be pooled (Berthold 2005; Pritchard 2005). There was a statistically significant difference in overall survival in favour of the myeloablative therapy group over conventional chemotherapy or no further treatment (HR 0.74, 95% CI 0.57 to 0.98, P = 0.04, 360 patients). No heterogeneity was detected for this comparison (I2 = 0%). See Figure 3. The other study (Matthay 1999) only provided descriptive results: overall survival was similar for both regimens (n = 379 patients).

 FigureFigure 3. Forest plot of comparison: 1 Myeloablative therapy versus control, outcome: 1.3 Overall survival without additional follow-up data.

As opposed to the original publication, the additional follow-up data from the Matthay 1999 study included information on overall survival. The length of follow-up was not mentioned, but the median follow-up of patients alive without an event was 7.7 years (range 130 days to 12.8 years). In contrast to the earlier results, the meta-analysis including the additional follow-up data showed no statistically significant difference in overall survival between treatment groups (HR = 0.86, 95% CI 0.73 to 1.01, P = 0.06, 739 patients). No heterogeneity was detected (I2 = 0%) (Figure 4).

 FigureFigure 4. Forest plot of comparison: 1 Myeloablative therapy versus control, outcome: 1.4 Overall survival including additional follow-up data of Matthay 1999.

The above mentioned HR is calculated using the complete follow-up period of the trials. The individual studies also reported three or five-year overall survival rates. Berthold 2005 and Matthay 1999 found no statistically significant difference in three-year overall survival between the treatment groups (P = 0.0875 and P = 0.87 respectively). Pritchard 2005 found no statistically significant difference in five-year overall survival between the treatment groups (P = 0.1). Additional follow-up data from Matthay 1999 showed no statistically significant difference in 5-year overall survival between the treatment groups (P = 0.3917). However, at 5 years overall survival was significantly better in the myeloablative therapy group compared to the conventional chemotherapy group (P < 0.0001 by test of the log(-log(.)) transformation).

It should be noted that the individual studies all used different starting points for event-free survival, either years since randomisation or years from diagnosis. In the Matthay 1999 study randomisation was performed a median of 60 days after diagnosis. Pritchard 2005 did not report the time of randomisation but the decision to randomise was made five to nine months after diagnosis. In the Berthold 2005 study randomisation was performed a median of 39 days after diagnosis.

 

Subgroups

Subgroups are summarised descriptively (i.e. as reported in the individual studies).

Berthold 2005 performed subgroup analyses based on commonly accepted risk factors. Three-year overall survival was significantly better in the myeloablative therapy group compared to conventional chemotherapy: (1) in patients who had a complete remission or very good partial remission before randomisation (P = 0.0436), or (2) in patients receiving antibody treatment (P = 0.0221). By contrast, no significant difference in three-year event-free survival was identified between the treatment groups in the following subgroups: (1) in patients who had partial remission, mixed remission or stable disease before randomisation (P = 0.1311); (2) in patients treated with retinoic acid (P = 0.8918); (3) in patients with MYCN amplification with stage I, II, III or IV-S disease or with stage IV disease aged younger than one year (P = 0.2287); (4) in patients with MYCN amplification (P = 0.1658); (5) in patients without MYCN amplification (P = 0.1921); (6) in patients with normal concentrations of serum lactate dehydrogenase (P = 0.1985; cut-off value not reported); (7) in patients with raised serum concentration of lactate dehydrogenase (P = 0.1247; cut-off value not reported); and (8) in patients with stage IV disease and age more than one year (P = 0.1820).

Matthay 1999 did not report any subgroup analyses regarding overall survival in the original manuscript. Using additional follow-up data a subgroup analysis of patients with stage IV disease found no statistically significant difference in overall survival between the treatment groups.

Pritchard 2005 reported that five-year overall survival in patients aged more than one year with stage IV disease was significantly better in the myeloablative therapy group than in the no further treatment group (P = 0.03).

 

Adverse effects

Since all patients receiving antineoplastic treatment will suffer from adverse events, we decided to analyse only severe and life-threatening effects. We defined this as toxicity grade three or higher. Only adverse effects occurring from the start of the randomised treatment (i.e. myeloablative therapy or control) were eligible for inclusion in this review. See Figure 5 and Figure 6.

 FigureFigure 5. Forest plot of comparison: 1 Myeloablative therapy versus control, outcome: 1.5 Adverse effects grade 3 or higher without additional follow-up data.
 FigureFigure 6. Forest plot of comparison: 1 Myeloablative therapy versus control, outcome: 1.6 Adverse effects grade 3 or higher including additional follow-up of Matthay 1999.

 

Treatment-related death

Data on treatment-related death could be extracted from two trials with a total of 574 patients (Berthold 2005; Matthay 1999). There were 12 deaths among 278 patients randomised to the myeloablative therapy group and five among 296 in the control group. There was no statistically significant difference in treatment-related death between the treatment groups (RR 2.53, 95% CI 0.17 to 37.12, P = 0.50). However, unexplained heterogeneity was detected (I2 = 78%). It should be noted that it was not possible to perform an intention-to-treat analysis using the Matthay 1999 data, therefore we performed an as-treated analysis.

When additional follow-up data from Matthay 1999 were included in the meta-analysis there was still no statistically significant difference in treatment-related death between the treatment groups (RR 1.08, 95% CI 0.65 to 1.78, P = 0.78). There were 25 deaths among 271 patients in the myeloablative group compared to 26 among 284 patients in the control group (RR 1.08, 95% CI 0.65 to 1.78, P = 0.78). No unexplained heterogeneity was detected for this comparison (I2 = 0%). Again, it was not possible to perform an intention-to-treat analysis for the study of Matthay 1999, so an as-treated analysis was performed.

 

Secondary malignant disease

Data on secondary malignant disease could be extracted from two trials with a total of 674 patients (Berthold 2005; Matthay 1999). There were two cases of secondary malignant disease among 338 patients in the myeloablative group (i.e. one acute myeloid leukaemia and one unknown malignancy) compared to two cases among 336 conventional chemotherapy patients (i.e. one acute lymphoblastic leukaemia and one unknown malignancy). The meta-analysis showed no statistically significant difference between the treatment groups (RR 0.99; 95% CI 0.14 to 7.00, P = 0.99). No heterogeneity was detected for this comparison (I2 = 0%).

When additional follow-up data from the Matthay 1999 study were included in the meta-analysis there was still no statistically significant difference between the treatment groups (RR 1.48, 95% CI 0.24 to 9.01, P = 0.67). There were three cases of secondary malignant disease among 338 patients in the myeloablative therapy group (i.e. two cases of acute myeloid leukaemia and one follicular carcinoma of the thyroid) compared to two among 336 patients in the conventional chemotherapy group (i.e. both acute lymphoblastic leukaemia). No unexplained heterogeneity was detected for this comparison (I2 = 0%).

 

Other adverse effects

Data on serious infections, sepsis, renal effects, interstitial pneumonitis and veno-occlusive disease could be extracted from one trial with a total of 379 patients (Matthay 1999). There was 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 (see Figure 5 and Figure 6 for more information). These toxicity data did not change with additional follow-up.

 

Quality of life

None of the studies evaluated quality of life.

 

Sensitivity analyses

The results of the sensitivity analyses for the risk of bias criteria were consistent among the trials and did not differ from the overall analyses.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Neuroblastoma is the most common extracranial solid tumour in children. Unfortunately, despite the development of new treatment options, the prognosis of high-risk patients is poor; and disease recurs in more than half of patients (Brodeur 2006; Goldsby 2004; Matthay 1993; Weinstein 2003). High-dose chemotherapy and stem cell transplantation might increase survival in these patients. This systematic review evaluated the current state of evidence on the efficacy of high-dose chemotherapy and autologous haematopoietic stem cell rescue compared with conventional therapy in patients diagnosed with high-risk neuroblastoma. Only randomised controlled trials (RCTs) were included since it is widely recognised that a RCT is the only study design which can be used to obtain unbiased evidence on the use of different treatment options, provided that the design and execution of the RCTs are adequate.

We identified three RCTs that compared high-dose chemotherapy and autologous haematopoietic stem cell rescue (i.e. myeloablative therapy) with conventional chemotherapy or no further treatment (Berthold 2005; Matthay 1999; Pritchard 2005). The updated literature search identified a manuscript reporting additional follow-up data from the Matthay 1999 study. The exact length of follow-up was not reported, but the median follow-up of patients alive without an event was 7.7 years (range 130 days to 12.8 years). Even though all patients were diagnosed with high-risk neuroblastoma, definitions of high-risk patients differed between the studies, as did the required response to induction therapy to be eligible for randomisation. The three included RCTs used an age of one year as the cut-off point for pre-treatment risk stratification. 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. Randomisation was performed at different time intervals since diagnosis. All trials used different induction treatments, myeloablative treatments and control treatments. Also, in two trials the received treatment slightly differed between patients, but we assumed that as a result of randomisation these differences in treatment were evenly distributed in both treatment groups. Two studies used bone marrow cells (Matthay 1999; Pritchard 2005) and one study used peripheral blood cells (Berthold 2005) for stem cell transplant (See the Characteristics of included studies table for further information).

The individual studies reported three or five-year event-free survival. In the Berthold 2005 and Matthay 1999 studies (including the additional follow-up data from Matthay 1999) a statistically significant difference in favour of myeloablative therapy was identified. In the Pritchard 2005 study this difference was not statistically significant. Our meta-analysis using their complete follow-up period also showed a statistically significant difference in event-free survival in favour of the myeloablative therapy group (HR 0.78, 95% CI 0.67 to 0.90, P = 0.0006). When the two studies in which secondary malignant disease was included as an event were analysed separately (Berthold 2005; Matthay 1999), this finding was confirmed. In the study which did not include secondary malignant disease as an event, no statistically significant difference in event-free survival between the treatment groups was identified (Pritchard 2005). However, the direction of the result of this study was the same as the overall result of all trials. The results of the meta-analysis of event-free survival did not change when additional follow-up data from Matthay 1999 were included in the analysis.

The individual studies also reported three or five-year overall survival. In all three studies (including the additional follow-up data from Matthay 1999) no statistically significant difference between the treatment groups was identified. In the Matthay 1999 study overall survival at five years was significantly better in the myeloablative therapy group than the conventional chemotherapy group (P < 0.0001 by test of the log(-log(.)) transformation). Our original meta-analysis using the complete follow-up period showed a statistically significant difference in overall survival in favour of the myeloablative therapy group (HR 0.74, 95% CI 0.57 to 0.98, P = 0.04; 2 studies, 360 patients). However, when additional follow-up data from Matthay 1999 was included in the meta-analysis the overall result was no longer statistically significant (HR 0.86, 95% CI 0.73 to 1.01, P = 0.43; 3 studies, 739 patients). A possible explanation could be the mortality caused by different late effects (e.g. as described by Mertens 2001; Reulen 2010). Another possible explanation could be that treatment options for progressive disease or relapse in patients who received myeloablative therapy are more limited than in patients who received conventional therapy or no further treatment. However, more data are needed for a definitive conclusion.

For two evaluated adverse effects (toxicity grade three or higher) it was possible to perform a meta-analysis. No statistically significant differences in secondary malignant disease or treatment-related death were identified between the treatment groups (both with the original data and with the inclusion of additional follow-up data from Matthay 1999). While unexplained heterogeneity was detected in the original analysis of treatment-related death, this was not the case when additional follow-up data were included. Serious infections, sepsis, renal effects, interstitial pneumonitis and veno-occlusive disease were only evaluated in the Matthay 1999 study. There was a significantly higher incidence of renal effects, interstitial pneumonitis and veno-occlusive disease in the myeloablative therapy group, whereas for serious infections and sepsis no statistically significant differences between the treatment groups were identified. These toxicity data did not change with additional follow-up. None of the included studies evaluated quality of life.

In the individual studies different subgroups were evaluated, but the results were not univocal in all studies. As a result, no definitive conclusions can be made regarding the effect of myeloablative therapy or conventional treatment in the different subgroups.

In this review we performed intention-to-treat (ITT) analyses, since they provide the most realistic and unbiased answer to the question of clinical effectiveness (Lachin 2000; Lee 1991). However, for treatment-related death it was not possible to perform an ITT analysis using the Matthay 1999 data and we therefore performed an as-treated analysis.

'No evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. The reason that some studies did not identify a statistically significant difference between study groups could be the fact that the number of patients included in these studies was too small to detect a difference between the treatment groups (i.e. low power). Furthermore, the length of follow-up could have been too short to detect a significant difference between the treatment groups.

The risk of bias in the included studies was difficult to assess due to a lack of reporting. As a result, the presence of selection bias, performance bias, detection bias and attrition bias could not be ruled out. However, at the moment this is the best available evidence from RCTs comparing the efficacy of high-dose chemotherapy and autologous haematopoietic stem cell rescue with conventional therapy in patients diagnosed with high-risk neuroblastoma. With regard to performance bias, it should be noted that due to the nature of the interventions blinding of care providers and patients was virtually impossible.

The results of myeloablative therapy must be viewed in the context of the different treatment regimens used in the included studies. The included studies differed in terms of the preceding therapy (e.g. induction chemotherapy, surgery and radiotherapy), the myeloablative regimen with or without total body irradiation, the stem cells (e.g. whether purging was used or not, and the origin of the stem cells, i.e. bone marrow or peripheral blood) and the presence and type of consolidation chemotherapy. As a result, in this systematic review we can only provide conclusions on the concept of myeloablative treatment versus conventional or no further treatment treatment. We cannot make conclusions with regard to specific versions of these treatments. However, the concept seems to work in terms of event-free survival, both for all randomised patients treated with myeloablative therapy and for specific subgroups. For overall survival there is currently no evidence of effect. No definitive conclusions can be made regarding adverse effects and quality of life.

We are awaiting the full text publication of the study published as a conference abstract (Hero 2010), which presented additional follow-up data from the Berthold 2005 study. Hero 2010 reported that myeloablative therapy proved to be effective with respect to long-term outcome, but is complicated by acute and long-term toxicity. However, as it is known that information provided in conference abstracts is often substantially different from information provided in subsequent full text publications (Yoon 2012), these results were not included in the analyses of this systematic review.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

Our original meta-analyses of both event-free and overall survival showed a statistically significant difference in favour of myeloablative therapy. However, when additional follow-up data from Matthay 1999 were included in the meta-analyses the difference in event-free survival remained statistically significant, but the difference in overall survival was no longer statistically significant. A possible explanation could be that treatment options for progressive disease or relapse in patients who received myeloablative therapy are more limited than in patients who received conventional therapy or no further treatment. Another possible explanation could be the mortality caused by different late effects. Nonetheless, more data are needed for a definitive conclusion. Data on adverse effects were very limited, but significantly more events in the myeloablative therapy group were identified for renal effects, interstitial pneumonitis and veno-occlusive disease. The fact that no significant differences in the occurrence of other adverse effects between treatment groups were identified could be the result of low power or too short a follow-up period. No information on quality of life was provided. No definitive conclusions regarding the effect of myeloablative therapy or conventional treatment in different subgroups can be made.

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 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 over estimated due to the inclusion of patients with intermediate-risk disease.

Based on the currently available evidence, we cannot make recommendations for the use of high-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma in clinical practice. This systematic review only allows a conclusion on the concept of myeloablative treatment; no conclusions regarding the best treatment strategy can be made.

 
Implications for research

Future trials on the use of high-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma should focus on identifying the most optimal induction therapy and myeloablative regimen, with regard to survival, (late) adverse effects and quality of life. The best study design to answer these questions is a randomised controlled trial (RCT). RCTs should be performed in homogeneous study populations (e.g. stage of disease) and have a long-term follow up. Different risk groups, using the most recent definitions, should be taken into account. The number of included patients should be sufficient to obtain the power needed for the results to be reliable.

Also, it will be very interesting to examine additional data from the RCTs already performed. We are awaiting the full text publication of additional follow-up data from the Berthold 2005 study. The performance of an individual patient data analysis including only patients that are classified as high-risk according to the latest definition is another possibility to assess the efficacy of high-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Leontien Kremer and Elvira van Dalen, the Co-ordinating Editors of the Childhood Cancer Group, are both co-authors of this review and therefore they could not act as Co-ordinating Editor for this review. Marianne van de Wetering (Department of Paediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands) was willing to take on this task, for which we would like to thank her. Also, we would like to thank Edith Leclercq, the Trials Search Co-ordinator of the Childhood Cancer Group, for running the search strategy in the different databases and providing us with the titles and abstracts of the searches, Marcello DiNisio for translating an Italian article and, the Foundation of Paediatric Cancer Research (SKK), the Netherlands and Stichting Kinderen Kankervrij (KIKA), the Netherlands, for the financial support which made it possible to perform this systematic review. Finally, we thank Dr. Maria Antonietta de Ioris (Department of Paediatric Oncology-Hematology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy) and two undisclosed peer reviewers, all of whom kindly agreed to peer review our manuscript. The editorial base of the Cochrane Childhood Cancer Group is funded by Kinderen Kankervrij (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, the United Kingdom.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Myeloablative therapy versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Event-free survival without additional follow-up data3739Hazard Ratio (Random, 95% CI)0.78 [0.67, 0.90]

    1.1 Event-free survival including secondary malignant disease as an event without additional follow-up data
2674Hazard Ratio (Random, 95% CI)0.79 [0.67, 0.92]

    1.2 Event-free survival not including secondary malignant disease as an event without additional follow-up data
165Hazard Ratio (Random, 95% CI)0.73 [0.49, 1.07]

 2 Event-free survival including additional follow-up data of Matthay 19993739Hazard Ratio (Random, 95% CI)0.79 [0.70, 0.90]

    2.1 Event-free survival including additional follow-up data and secondary malignant disease as an event
2674Hazard Ratio (Random, 95% CI)0.80 [0.70, 0.92]

    2.2 Event-free survival including additional follow-up data and not including secondary malignant disease as an event
165Hazard Ratio (Random, 95% CI)0.73 [0.49, 1.07]

 3 Overall survival without additional follow-up data2360Hazard Ratio (Random, 95% CI)0.74 [0.57, 0.98]

 4 Overall survival including additional follow-up data of Matthay 19993739Hazard Ratio (Random, 95% CI)0.86 [0.73, 1.01]

 5 Adverse effects grade 3 or higher without additional follow-up data2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Treatment-related death
2574Risk Ratio (M-H, Random, 95% CI)2.53 [0.17, 37.12]

    5.2 Secondary malignant disease
2674Risk Ratio (M-H, Random, 95% CI)0.99 [0.14, 7.00]

    5.3 Serious infections
1379Risk Ratio (M-H, Random, 95% CI)1.02 [0.84, 1.23]

    5.4 Sepsis
1379Risk Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.30]

    5.5 Renal effects
1379Risk Ratio (M-H, Random, 95% CI)2.28 [1.28, 4.04]

    5.6 Interstitial pneumonitis
1379Risk Ratio (M-H, Random, 95% CI)9.55 [2.26, 40.43]

    5.7 Veno-occlusive disease
1379Risk Ratio (M-H, Random, 95% CI)35.18 [2.13, 580.88]

 6 Adverse effects grade 3 or higher including additional follow-up of Matthay 19992Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Treatment-related death
2555Risk Ratio (M-H, Random, 95% CI)1.08 [0.65, 1.78]

    6.2 Secondary malignant disease
2674Risk Ratio (M-H, Random, 95% CI)1.48 [0.24, 9.01]

    6.3 Serious infections
1379Risk Ratio (M-H, Random, 95% CI)1.02 [0.84, 1.23]

    6.4 Sepsis
1379Risk Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.30]

    6.5 Renal effects
1379Risk Ratio (M-H, Random, 95% CI)2.28 [1.28, 4.04]

    6.6 Interstitial pneumonitis
1379Risk Ratio (M-H, Random, 95% CI)9.55 [2.26, 40.43]

    6.7 Veno-occlusive disease
1379Risk Ratio (M-H, Random, 95% CI)35.18 [2.13, 580.88]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. Search strategy for Central Register of Controlled Trials (CENTRAL)

(1) For neuroblastoma we have used the following subject headings and text words (both in the original version of the review and the update):

(neuroblastoma OR neuroblastomas OR ganglioneuroblastoma OR ganglioneuroblastomas OR neuroepithelioma OR olfactory esthesioneuroblastoma OR neuroblast*) in Clinical Trials

(2) For bone marrow and stem cell rescue the following subject headings and text words were used (both in the original version of the review and the update):

(stem cell rescue OR bone marrow rescue OR bone marrow transplantation OR bone marrow grafting OR bone marrow cell transplantation OR stem cell transplantation OR stem cell transplantations OR hematopoietic stem cell transplantation OR peripheral blood stem cell transplantation OR peripheral stem cell transplantation OR cord blood stem cell transplantation OR placental blood stem cell transplantation OR umbilical cord stem cell transplantation OR autograft OR autografts OR autologous transplantation OR autotransplant OR autotransplants OR ABMT OR transplant* OR autolog* OR BMT OR myeloablative therapy OR myeloablative agonist OR myeloablative agonists OR myeloablativ* OR mega therapy OR high-dose therapy OR high dose therapy) in Clinical Trials

(3) For children the following subject headings and text words were used (both in the original version of the review and the update):

(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) in Clinical Trials

Finally, searches were combined as (1) AND (2) AND (3).

The search was performed in title, abstract or keywords.

[* = zero or more characters]

 

Appendix 2. Search strategy for MEDLINE/PubMed

(1) For neuroblastoma we have used the following subject headings and text words (both in the original version of the review and the update):

neuroblastoma OR neuroblastomas OR ganglioneuroblastoma OR ganglioneuroblastomas OR neuroepithelioma OR esthesioneuroblastoma, olfactory OR neuroblast*

(2) For bone marrow and stem cell rescue the following subject headings and text words were used (both in the original version of the review and the update) :

stem cell rescue OR bone marrow rescue OR bone marrow transplantation OR bone marrow grafting OR bone marrow cell transplantation OR stem cell transplantation OR stem cell transplantations OR hematopoietic stem cell transplantation OR peripheral blood stem cell transplantation OR peripheral stem cell transplantation OR cord blood stem cell transplantation OR placental blood stem cell transplantation OR umbilical cord stem cell transplantation OR autograft OR autografts OR transplantation, autologous OR autotransplant OR autotransplants OR ABMT OR transplant* OR autolog* OR BMT OR myeloablative therapy OR myeloablative agonist OR myeloablative agonists OR myeloablativ* OR mega therapy OR high-dose therapy OR high dose therapy

(3) For children the following subject headings and text words were used (both in the original version of the review and the update):

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 OR schools, nursery

(4) For identifying RCTs and CCTs we used the highly sensitive search strategy as described in the Cochrane Handbook for Systematic Reviews of Interventons (Higgins 2005 for the original version and Higgins 2008 for the update).

Finally, searches were combined as (1) AND (2) AND (3) AND (4).

[pt = publication type; tiab = title, abstract; sh = subject heading; mh = MeSH term; *=zero or more characters; RCT = randomized controlled trial; CCT = controlled clinical trial]

 

Appendix 3. Search strategy for EMBASE/Ovid

(1) For neuroblastoma we have used the following subject headings and text words (both in the original version of the review and the update):

(neuroblastoma or neuroblastomas or ganglioneuroblastoma or ganglioneuroblastomas or neuroepithelioma or olfactory esthesioneuroblastoma or neuroblast$ or neuroganglioblastoma).mp or neuroblastoma/ or olfactory neuroepithelioma/ or neuroepithelioma/ or esthesioneuroblastoma/ or neuroblastoma cell/

(2) For bone marrow and stem cell rescue the following subject headings and text words were used (both in the original version of the review and the update):

(stem cell rescue or bone marrow rescue).mp or (bone marrow transplantation or bone marrow grafting).mp or (bone marrow cell transplantation or stem cell transplantation or stem cell transplantations).mp or (hematopoietic stem cell transplantation or peripheral blood stem cell transplantation).mp or (peripheral stem cell transplantation or cord blood stem cell transplantation).mp or (placental blood stem cell transplantation or umbilical cord stem cell transplantation).mp or (autograft or autografts).mp or (autologous transplantation or autotransplant or autotransplants).mp or (BMT or ABMT or PBSCT).mp or transplant$.mp or autolog$.mp or (bone marrow transplant or bone marrow transfusion or bone marrow graft).mp or myeloablative therapy.mp or (myeloablative agonist or myeloablative agonists).mp or myeloablativ$.mp or mega therapy.mp or (high-dose therapy or high dose therapy).mp or autologous bone marrow transplantation/ or allogenic bone marrow transplantation/ or bone marrow transplantation/ or bone marrow rescue/ or myeloablative agent/ or stem cell transplantation/ or allogenic bone marrow transplantation/ or allogeneic stem cell transplantation/ or autologous stem cell transplantation/ or peripheral blood stem cell transplantation/ or cord blood stem cell transplantation/ or hematopoietic stem cell transplantation/ or autograft/ or autotransplantation/ or allotransplantation/

(3) For children the following subject headings and text words were used (both in the original version of the review and the update):

Infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/ or adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/ or primary school/ or high school/ or kindergarten/ or nursery school/ or school/ or infant$.mp or newborn$.mp or new born$.mp or (baby or baby$ or babies).mp or neonate$.mp or child$.mp or (school child$ or schoolchild$).mp or (school age$ or schoolage$).mp or (pre school$ or preschool$).mp or (kid or kids).mp or toddler$.mp or adoles$.mp or teen$.mp or boy$.mp or girl$.mp or minors$.mp or (under ag$ or underage$).mp or juvenil$.mp or youth$.mp or puber$.mp or pubescen$.mp or prepubescen$.mp or prepubert$.mp or (pediatric$ or paediatric$ or peadiatric$).mp or (school or schools).mp or (high school$ or highschool$).mp or primary school$.mp or nursery school$.mp or elementary school.mp or secondary school$.mp or kindergar$.mp

(4) For RCTs and CCTs the following subject headings and text words were used (in the original version of the review):

(a) clinical trial/ or controlled study/ or randomized controlled trial/ or double blind procedure/ or single blind procedure/ or comparative study/ or randomization/ or prospective study/ or placebo/ or phase 2 clinical trial/ or phase 3 clinical study.mp or phase 4 clinical study.mp or phase 3 clinical trial/ or phase 4 clinical trial/ or allocat$.mp or blind$.mp or control$.mp or placebo$.mp or prospectiv$.mp or random$.mp or ((singl$ or doubl$ or trebl$ or tripl$) and (blind$ or mask$)).mp or (versus or vs).mp or (randomized controlled trial$ or randomised controlled trial$).mp or controlled clinical trial$.mp or clinical trial$.mp

(b) human/ or nonhuman/ or animal/ or animal experiment/

(c) (b) not human/

(d) (a) not (c)

For the update the following subject headings and text words were used:

1. Randomized Controlled Trial/
2. Controlled Clinical Trial/
3. randomized.ti,ab.
4. placebo.ti,ab.
5. randomly.ti,ab.
6. trial.ti,ab.
7. groups.ti,ab.
8. drug therapy.sh.
9. or/1-8
10. Human/
11. 9 and 10

Finally, searches were combined as (1) AND (2) AND (3) AND (4).

[mp = title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name; sh = subject heading; ti,ab = title, abstract; / = Emtree term; $=zero or more characters; RCT = randomised controlled trial; CCT = controlled clinical trial].

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Last assessed as up-to-date: 24 December 2012.


DateEventDescription

28 November 2012New citation required and conclusions have changedSummary of most important changes in the update:

The search for eligible studies was updated to June 2012. Additional follow-up data of one of the three already included RCTs were available. For overall survival the results changed from a significant difference in favour of myeloablative therapy into no significant difference between the treatment groups.

It should be noted that all included studies used an age of one year as the cut-off point for pre-treatment risk stratification. 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.

28 November 2012New search has been performedThe search for eligible studies was updated to June 2012.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Bilgehan Yalçin designed the study and wrote the protocol. He identified studies meeting the inclusion criteria. He searched for unpublished and ongoing studies. He performed the data extraction and risk of bias assessment of the included studies. He contributed to the interpretation of the results. He critically reviewed the review.

Leontien CM Kremer designed the study and critically reviewed the protocol. She contributed to the interpretation of the results. She critically reviewed the review.

Huib N Caron designed the study and critically reviewed the protocol. He contributed to the interpretation of the results. He critically reviewed the review.

Elvira C van Dalen designed the study and wrote the protocol. She developed the search strategy. She identified the studies meeting the inclusion criteria. She searched for unpublished and ongoing studies. She performed the data extraction and risk of bias assessment of the included studies. She analyzed the data and interpreted the results. She wrote and revised the review.

All authors approved the final version.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Foundation of Pediatric Cancer Research (SKK) Amsterdam, Netherlands.
  • Stichting Kinderen Kankervrij (KIKA), Netherlands.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

For the update of this review we extended the search strategy as described in the protocol: we also included the conference proceedings of the American Society of Clinical Oncology (ASCO).

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
  22. References to other published versions of this review
Berthold 2005 {published data only}
  • Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J, et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncology 2005;6:649-58.
Matthay 1999 {published data only}
  • Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. Journal of Clinical Oncology 2009;27(7):1007-13.
  • Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. New England Journal of Medicine 1999;341:1165-73.
Pritchard 2005 {published data only}

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
  22. References to other published versions of this review
Adkins 2004 {published data only}
  • Adkins ES, Sawin R, Gerbing RB, London WB, Matthay KK, Haase GM. Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer Group study. Journal of Pediatric Surgery 2004;39:931-6.
Berthold 1990 {published data only}
  • Berthold F, Burdach S, Kremens B, Lampert F, Niethammer D, Riehm H, et al. The role of chemotherapy in the treatment of children with neuroblastoma stage IV: the GPO (German Pediatric Oncology Society) experience. Klinische Pädiatrie 1990;202:262-9.
Castel 2001 {published data only}
  • Castel V, Cañete A, Navarro S, García-Miguel P, Melero C, Acha T, et al. Outcome of high-risk neuroblastoma using a dose intensity approach: improvement in initial but not in long-term results. Medical and Pediatric Oncology 2001;37:537-42.
Castel 2002 {published data only}
Dini 1989 {published data only}
  • Dini G, Philip T, Hartmann O, Pinkerton R, Chauvin F, Garaventa A, et al. Bone marrow transplantation for neuroblastoma: a review of 509 cases. EBMT Group. Bone Marrow Transplant 1989;4(Suppl 4):42-6.
Dini 1991a {published data only}
  • Dini G, Lanino E, Garaventa A, Paolucci P, Amici A, Locatelli F, et al. Unpurged ABMT for neuroblastoma: AIEOP-BMT experience. Bone Marrow Transplant 1991;7(Suppl 2):92.
Dini 1991b {published data only}
  • Dini G, Lanino E, Garaventa A, Paolucci P, Amici A, Locatelli F, et al. Unpurged autologous bone marrow transplantation for neuroblastoma: the AIEOP-BMT group experience. Bone Marrow Transplant 1991;7(Suppl 3):109-11.
Garaventa 1993 {published data only}
  • Garaventa A, Ladenstein R, Chauvin F, Lanino E, Philip I, Corciulo P, et al. High-dose chemotherapy with autologous bone marrow rescue in advanced stage IV neuroblastoma. European Journal of Cancer 1993;29A:487-91.
Haas-Kogan 2003 {published data only}
  • Haas-Kogan DA, Swift PS, Selch M, Haase GM, Seeger RC, Gerbing RB, et al. Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. International Journal of Radiation Oncology, Biology, Physics 2003;56:28-39.
Hartmann 1985 {published data only}
  • Hartmann O, Zucker JM, Pinkerton R, Philip T, Beaujean F, Bernard JL, et al. Metastatic neuroblastoma in children older than one year old at diagnosis. Treatment with intensive chemo-radiotherapy and autologous bone marrow transplant. Revue Française de Transfusion et Immuno-Hématologie 1985;28:539-46.
Kaneko 1999 {published data only}
  • Kaneko M, Tsuchida Y, Uchino J, Takeda T, Iwafuchi M, Ohnuma N, et al. Treatment results of advanced neuroblastoma with the first Japanese study group protocol. Study Group of Japan for Treatment of Advanced Neuroblastoma. Journal of Pediatric Hematology/Oncology 1999;21:190-7.
Klingebiel 1994 {published data only}
  • Klingebiel T, Handgretinger R, Herter M, Lang P, Dopfer R, Scheel-Walter H, et al. Peripheral stem cell transplantation in neuroblastoma stage 4 with the use of [131I-m]IBG. Progress in Clinical and Biological Research 1994;385:309-17.
Ladenstein 1991 {published data only}
  • Ladenstein R, Lasset C, Bouffet E, Brunat-Mentigny M, Biron P, Philip I, et al. A single center experience with bone marrow transplantation for high risk neuroblastoma. Bone Marrow Transplant 1991;7(Suppl 2):93.
Ladenstein 1996 {published data only}
Madon 1985 {published data only}
  • Madon E, Pastore G, Cordero di Montezemolo L, Brach del Prever A, Lanino E. Italian multicenter experience in the treatment of neuroblastoma and soft tissue sarcoma. Minerva Pediatrica 1985;37:603-10.
Matthay 1995 {published data only}
  • Matthay KK, O'Leary MC, Ramsay NK, Villablanca J, Reynolds CP, Atkinson JB, et al. Role of myeloablative therapy in improved outcome for high risk neuroblastoma: review of recent Children's Cancer Group results. European Journal of Cancer 1995;31A:572-5.
Matthay 1996 {published data only}
  • Matthay KK. Impact of myeloablative therapy with bone marrow transplantation in advanced neuroblastoma. Bone Marrow Transplant 1996;18(Suppl 3):S21-4.
Matthay 1998 {published data only}
  • Matthay KK, Perez C, Seeger RC, Brodeur GM, Shimada H, Atkinson JB, et al. Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. Journal of Clinical Oncology 1998;16:1256-64.
Mugishima 1999 {published data only}
  • Mugishima H. High-dose chemotherapy and hematopoietic stem cell transplant in the treatment of advanced neuroblastoma. Gan To Kagaku Ryoho 1999;26:1056-67.
Ohnuma 1995 {published data only}
  • Ohnuma N, Takahashi H, Kaneko M, Uchino J, Takeda T, Iwafuchi M, et al. Treatment combined with bone marrow transplantation for advanced neuroblastoma: an analysis of patients who were pretreated intensively with the protocol of the Study Group of Japan. Medical and Pediatric Oncology 1995;24:181-7.
Olgun 2008 {published data only}
  • Olgun N, Gunes D, Aksoylar S, Varan A, Erbay A, Hazar V, et al. The Turkish Pediatric Oncology Group Neuroblastoma 2003 (TPOG-NB-2003): treatment results of the high risk group (abstract D110). Pediatric Blood and Cancer. 2008:140.
Paolucci 1989 {published data only}
  • Paolucci P, Mancini AF, Rosito P, Vecchi V, Vivarelli F, Granchi D, et al. Intensification of induction prior to intensification of consolidation and bone marrow rescue in disseminated neuroblastoma. Bone Marrow Transplant 1989;4(Suppl 4):151-2.
Philip 1991 {published data only}
  • Philip T, Zucker JM, Bernard JL, Lutz P, Bordigoni P, Plouvier E, et al. The LMCE1 unselected group of stage IV neuroblastoma revisited with a median follow up of 59 months after ABMT. Progress in Clinical and Biological Research 1991;366:517-25.
Pinkerton 1991 {published data only}
  • Pinkerton CR. ENSG 1-randomised study of high-dose melphalan in neuroblastoma. Bone Marrow Transplant 1991;7(Suppl 3):112-3.
Saarinen 1996 {published data only}
  • Saarinen UM, Wikström S, Mäkipernaa A, Lanning M, Perkkiö M, Hovi L, et al. In vivo purging of bone marrow in children with poor-risk neuroblastoma for marrow collection and autologous bone marrow transplantation. Journal of Clinical Oncology 1996;14:2791-802.
Sawaguchi 1989 {published data only}
  • Sawaguchi S, Kaneko M, Nakajo T, Sawada T, Takahashi H, Tsuchida Y. A preliminary treatment report of the Study Group of Japan for Advanced Neuroblastoma. Nippon Gan Chiryo Gakkai Shi 1989;24:1020-6.
Sawaguchi 1990 {published data only}
  • Sawaguchi S, Kaneko M, Uchino J, Takeda T, Iwafuchi M, Matsuyama S, et al. Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy. A report from the Study Group of Japan. Cancer 1990;66:1879-87.
Schmidt 2005 {published data only}
  • Schmidt ML, Lal A, Seeger RC, Maris JM, Shimada H, O'Leary M, et al. Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. Journal of Clinical Oncology 2005;23:6474-80.
Seeger 1991 {published data only}
  • Seeger RC, Villablanca JG, Matthay KK, Harris R, Moss TJ, Feig SA, et al. Intensive chemoradiotherapy and autologous bone marrow transplantation for poor prognosis neuroblastoma. Progress in Clinical and Biological Research 1991;366:527-33.
Seeger 2000 {published data only}
  • Seeger RC, Reynolds CP, Gallego R, Stram DO, Gerbing RB, Matthay KK. Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children's Cancer Group Study. Journal of Clinical Oncology 2000;18:4067-76.
Shuster 1991 {published data only}
  • Shuster JJ, Cantor AB, McWilliams N, Pole JG, Castleberry RP, Marcus R, et al. The prognostic significance of autologous bone marrow transplant in advanced neuroblastoma. Journal of Clinical Oncology 1991;9:1045-9.
Stram 1994 {published data only}
  • Stram DO, Matthay KK, O'Leary M, Reynolds CP, Seeger RC. Myeloablative chemoradiotherapy versus continued chemotherapy for high risk neuroblastoma. Progress in Clinical and Biological Research 1994;385:287-91.
Stram 1996 {published data only}
  • Stram DO, Matthay KK, O'Leary M, Reynolds CP, Haase GM, Atkinson JB, et al. Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastoma: a report of two concurrent Children's Cancer Group studies. Journal of Clinical Oncology 1996;14:2417-26.
Zucker 1991 {published data only}
  • Zucker JM, Philip T, Bernard JL, Michon J, Bouffet E, Gentet JC, et al. Single or double consolidation treatment according to remission status after initial therapy in metastatic neuroblastoma: first results of LMCE 3 study in 40 patients. Bone Marrow Transplant 1991;7(Suppl 2):91.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
  22. References to other published versions of this review
Aydin 2009
  • Aydin GB, Kutluk MT, Yalçin B, Büyükpamukçu M, Kale G, Varan A, et al. Neuroblastoma in Turkish children: experience of a single center. Journal of Pediatric Hematology and Oncology 2009;31:471-80.
Bollard 2006
  • Bollard CM, Krance RA, Heslop HE. Hematopoietic stem cell transplantation in pediatric oncology. In: Pizzo PA, Poplack DG editor(s). Principles and practice of pediatric oncology. 5th Edition. Philadelphia: Lippincott Williams & Wilkins, 2006:476-500.
Brodeur 1988
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Brodeur 1993
  • Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 1993;11:1466-77.
Brodeur 2006
  • Brodeur GM, Maris JM. Neuroblastoma. In: Pizzo PA, Poplack DG editor(s). Principles and practice of pediatric oncology. 5th Edition. Philadelphia: Lippincott Williams & Wilkins, 2006:933-70.
Burchill 2004
Castel 1995
  • Castel V, García-Miguel P, Melero C, Navajas A, Navarro S, Molina J, et al. On behalf of the Spanish Neuroblastoma Study Group. The treatment of advanced neuroblastoma. Results of the Spanish Neuroblastoma Study Group (SNSG) Studies. European Journal of Cancer 1995;31A:642-5.
Cheung 1991
  • Cheung NK, Heller G. Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. Journal of Clinical Oncology 1991;9:1050-8.
Cohn 1997
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Cohn 2009
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De Bernardi 2003
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Di Caro 1994
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Evans 1971
Goldsby 2004
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Higgins 2008
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Kaneko 2002
  • Kaneko M, Tsuchida Y, Mugishima H, Ohnuma N, Yamamoto K, Kawa K, et al. Intensified chemotherapy increases the survival rates in patients with stage 4 neuroblastoma with MYCN amplification. Journal of Pediatric Hematology/Oncology 2002;24:613-21.
Keshelava 1998
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Kushner 2004
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Lachin 2000
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Maris 2005
Maris 2007
Matthay 1993
  • Matthay KK, Atkinson JB, Stram DO, Selch M, Reynolds CP, Seeger RC. Patterns of relapse after autologous purged bone marrow transplantation for neuroblastoma: a Children's Cancer Group pilot study. Journal of Clinical Oncology 1993;11:2226-33.
Matthay 2009
  • Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. Journal of Clinical Oncology 2009;27:1007-13.
Mertens 2001
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Parmar 1998
Philip 1997
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Reynolds 2001
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Reynolds 2004
Shimada 1984
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Trahair 2007
  • Trahair TN, Vowels MR, Johnston K, Cohn RJ, Russell SJ, Neville KA, et al. Long-term outcomes in children with high-risk neuroblastoma treated with autologous stem cell transplantation. Bone Marrow Transplantation 2007;40(8):741-6.
Verdeguer 2004
  • Verdeguer A, Munoz A, Canete A, Pardo N, Martinez A, Donat J, et al. Long-term results of high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma patients: a report of the Spanish working party for BMT in children (Getmon). Pediatric Hematology and Oncology 2004;21:495-504.
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Yu 2010
  • Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. New England Journal of Medicine 2010;363(14):1324-34.

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
  22. References to other published versions of this review
Yalçin 2006
  • Yalçin B, Kremer LC, Caron HN, van Dalen EC. High dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database of Systematic Reviews 2006, Issue 4. [DOI: 10.1002/14651858.CD006301]
Yalçin 2010
  • Yalçin B, Kremer LC, Caron HN, van Dalen EC. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database of Systematic Reviews 2010, Issue 5. [DOI: 10.1002/14651858.CD006301.pub2]