High dose chemotherapy and autologous stem cell rescue for children with high risk neuroblastoma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
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Primary objective:
To compare the effectiveness of high dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy for children with high risk neuroblastoma.
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Secondary objectives:
To determine possible effects of these procedures on adverse events and quality of life.
To determine toxicities related to the procedure (like venoocclusive disease of the liver) and late effects (like endocrine disorders or secondary malignancies).
Background
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 the 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 (Goldsby 2004; Brodeur 2006).
Neuroblastoma is one of the most challenging and enigmatic neoplasm 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; Weinstein 2003; Maris 2005). The low risk disease group includes cases younger than 1 year who have stage I, II or IVS disease with favourable histopathology and no MYCN oncogene amplification (Goldsby 2004; Brodeur 2006; Weinstein 2003; Maris 2005). Substantial improvement has been achieved in the cure of cases with low risk resulting in survival rates up to 90% (Goldsby 2004; Brodeur 2006).
High risk neuroblastoma cases are characterized by an age older than 1 year, disseminated disease, MYCN oncogene amplification and unfavourable histopathologic findings (Goldsby 2004; Brodeur 2006; Weinstein 2003; Maris 2005). In these 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 the patients (Goldsby 2004; Brodeur 2006; Weinstein 2003; De Bernardi 2003). In the last two decades higher remission rates are achieved with intensive induction chemotherapy regimens combined with surgical resection and/or external irradiation (Goldsby 2004; Brodeur 2006; Sawaguchi 1990; Castel 1995; Kushner 2004; Laprie 2004; Kaneko 2002). The challenge is to maintain that remission since more than half of patients with high risk develop systemic disease recurrence with or without a recurrence at the primary tumour site (Goldsby 2004; Brodeur 2006; Weinstein 2003; Matthay 1993). Therapy failures are mostly attributed to development of resistance to chemotherapy and minimal residual disease is considered an important cause of recurrence (Keshelava 1998; Reynolds 2001; Burchill 2004; Reynolds 2004).
The idea that further increasing dose intensity may overcome the resistance to drugs provided a rationale for aggressive high dose chemotherapy consolidation protocols (Cheung 1991; Pritchard 1995). Such myeloablative chemotherapy regimens utilize 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 (PBSCs) is the preferred source for rescue as it has several advantages over autologous bone marrow grafts, e.g. the procedure of PBSC collection is easier, the incidence of tumour cell contamination is lower, the yield of stem cells is higher (Brodeur 2006; Ladenstein 1994; Cohn 1997). 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 cell (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 venoocclusive disease of the liver or haemorrhagic cystitis (Bollard 2006). Growth failure, endocrine disorders like gonadal or thyroid dysfunction as well as occurrence of secondary malignancies are among the late complications following high dose chemotherapy and stem cell rescue (Bollard 2006).
Many retrospective and prospective non‐randomised studies supported the use of a myeloablative consolidation in neuroblastoma. Retrospective studies mostly suggested that intensification of consolidation therapy with autologous stem cell rescue following high dose chemotherapy improved survival (Stram 1996; Castel 1995; Di Caro 1994; Philip 1997; Matthay 1995; Verdeguer 2004). The results of non‐randomised pilot studies by the CCG also suggested a modest prolongation of event‐free survival for children with high risk neuroblastoma overall (Matthay 1995).
There are completed and ongoing randomised controlled trials comparing the effectiveness of high dose chemotherapy and stem cell rescue with conventional therapy in high risk neuroblastoma (Matthay 1999; Berthold 2005; Pritchard 2005). At the moment no systematic review on this subject has been carried out.
Objectives
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Primary objective:
To compare the effectiveness of high dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy for children with high risk neuroblastoma.
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Secondary objectives:
To determine possible effects of these procedures on adverse events and quality of life.
To determine toxicities related to the procedure (like venoocclusive disease of the liver) and late effects (like endocrine disorders or secondary malignancies).
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) that compare the effectiveness of high dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy.
When no RCTs are identified, we will include controlled clinical trials (CCTs). A CCT is a study that compares one or more intervention groups to one or more control groups (Cochrane Handbook).
Types of participants
Children (aged 1 to 18 years) with high risk neuroblastoma.
High risk neuroblastoma is defined as a combination of the following characteristics: age >1 year, advanced stage disease, presence of MYCN oncogene amplification, and/or unfavourable histopathologic findings.
Types of interventions
High dose chemotherapy with autologous bone marrow or stem cell rescue versus conventional therapy.
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:
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Event‐free survival (usually defined as the time to recurrence or progression of disease or death of any cause or varying definitions as used by the authors)
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Overall survival (defined as the time to death of any cause)
Secondary outcomes:
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Adverse events (such as stomatitis, diarrhoea, fatigue, anaemia, leukopenia, thrombocytopenia or venoocclusive disease of the liver) and late effects (like endocrine disorders or secondary malignancies)
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Quality of life
Search methods for identification of studies
The following electronic databases will be searched:
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MEDLINE/PubMed (from 1966 to June 2006)
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EMBASE/OVID (from 1980 to June 2006)
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CENTRAL (issue 2, 2006).
(1) For neuroblastoma we will use the following subject headings and text words:
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 will be used:
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 will be used:
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 will use the highly sensitive search strategy as described in the Cochrane Reviewers' Handbook (Cochrane Handbook).
Finally, searches will be combined as (1) AND (2) AND (3) AND (4).
For EMBASE and CENTRAL we will use adaptations of this same strategy.
Information about trials not registered in MEDLINE, EMBASE or the CENTRAL, either published or unpublished, will be located by searching the reference lists of relevant articles and review articles. We also plan to search the conference proceedings of the International Society for Paediatric Oncology (SIOP), American Society for Pediatric Hematology and Oncology (ASPHO) and Advances in Neuroblastoma Research (ANR) from 2002 to 2006, if available electronically and otherwise by hand searching. We will search for ongoing trials by contacting researchers involved in this area and also by scanning the ISRCTN register and the National Institute of Health Register.
Language restriction will not be imposed. The searches will be updated every two years.
Data collection and analysis
STUDY IDENTIFICATION
After employing the search strategy described previously, identification of studies meeting the inclusion criteria will be undertaken by two reviewers independently. Discrepancies will be resolved by consensus. If consensus cannot be reached final resolution will be made using a third party arbitrator. Any study seemingly meeting the inclusion criteria on grounds of the title, or abstract or both will be obtained in full for closer inspection. Details of reasons for exclusion of any study considered for inclusion will be clearly stated. When no RCTs, meeting the inclusion criteria can be found, the level of evidence will be decreased to CCTs.
QUALITY ASSESSMENT OF INCLUDED STUDIES
Assessment of trial quality will be made by two reviewers independently according to the following criteria: method of randomizations, concealment of treatment allocation, blinding of the care provider, blinding of the patients, blinding of the outcome assessor and completeness of follow‐up. Concealment of allocation will be described as adequate, inadequate, or unclear (Schulz 1995). Discrepancies will be resolved by consensus. If consensus cannot be reached final resolution will be made using a third party arbitrator.
DATA EXTRACTION
Data extraction will be performed independently by two reviewers using standardised forms. Data of the characteristics of the participants at time of randomisation (like age, sex, stage of disease, histology, MYCN oncogene amplification, received induction treatment, received external irradiation, remission status at myeloablative treatment and stem cell rescue), 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), of supportive care (like the use of prophylactic antibiotics, growth factors, granulocyte infusions), of outcome measures as described above, and of length of follow‐up will be extracted. In case of disagreement, the abstracts and articles will be re‐examined and discussed until consensus is achieved. If consensus cannot be reached final resolution will be made using a third party arbitrator.
If appropriate, we will contact authors of included articles to obtain information on long‐term follow‐up of patients.
DATA ANALYSIS
The data will be entered in RevMan and analysed according to the guidelines of the Cochrane Handbook (Cochrane Handbook).
Dichotomous variables will be related to risk using the relative risk (RR); continuous outcomes will be related to risk using the mean difference (MD). If possible, data will be extracted by allocation intervention, irrespective of compliance with the allocated intervention, in order to allow an 'intention‐to‐treat' analysis, otherwise 'as treated' analysis will be performed. Heterogeneity will be assessed both by visual inspection of the forest plots and by a formal statistical test for heterogeneity. If there is evidence of significant heterogeneity, the possible reasons for this will be investigated and reported. We will use a random effects model. For the assessment of survival, we will use Parmar's method if hazard ratios have not been explicitly presented in the study. Where possible, data will be separated for different prognostic factors such as disease status at the time of stem cell rescue, MYCN amplification status or serum lactate dehydrogenase levels. The quality of studies included in the analyses will be taken into account in the interpretation of the review's results. We will perform a sensitivity analysis for the used quality criteria. We will construct a funnel plot to graphically ascertain the existence of publication bias.
