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Intervention Protocol

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Retinoic acid post consolidation therapy for high-risk neuroblastoma

  1. Frank Peinemann1,*,
  2. Carmen Bartel2,
  3. Ulrich Grouven3,
  4. Frank Berthold4

Editorial Group: Cochrane Childhood Cancer Group

Published Online: 31 JUL 2013

DOI: 10.1002/14651858.CD010685


How to Cite

Peinemann F, Bartel C, Grouven U, Berthold F. Retinoic acid post consolidation therapy for high-risk neuroblastoma (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD010685. DOI: 10.1002/14651858.CD010685.

Author Information

  1. 1

    Children's Hospital, University of Cologne, Cologne, NW, Germany

  2. 2

    Cologne, Germany

  3. 3

    Hannover Medical School, Hannover, Germany

  4. 4

    Children's Hospital, University of Cologne, Pediatric Oncology and Hematology, Cologne, Germany

*Frank Peinemann, Children's Hospital, University of Cologne, Kerpener Str. 62, Cologne, NW, 50937, Germany. pubmedprjournal@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 31 JUL 2013

SEARCH

This is not the most recent version of the article. View current version (29 JAN 2015)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Neuroblastoma is a rare malignant disease and mainly affects infants and very young children (GARD 2011). Tumours develop in the sympathetic nervous system such as adrenal medullary tissue or paraspinal ganglia and may be localised or metastatic at diagnosis (Cole 2012). The median age at diagnosis is 17 months and the incidence rate of neuroblastoma is age dependent with an incidence rate of 64 per million children in the first year of life reducing to 29 per million children in the second year of life (Goodman 2012). The incidence rate in adults is less than 1 per million per year but adults have a considerably worse prognosis (Esiashvili 2007). Cohn 2009 proposed the International Neuroblastoma Risk Group classification system, which is shown in  Table 1. Of 8800 patients with neuroblastoma, 36.1% had high-risk neuroblastoma. Patients in the high-risk group had a five-year event-free survival of less than 50%. Time to event was defined as time from diagnosis until time of first occurrence of relapse, progression, secondary malignancy, or death, or until time of last contact if none of these occurred. Matthay 2012 addresses new approaches with targeted therapy that may improve the outcome in patients with high-risk neuroblastoma.

An abdominal mass is the most common presentation of neuroblastoma. In general, neuroblastoma occurs at a single location, usually the medulla of the adrenal gland or along the paravertebral sympathetic chain. As approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis, organ-specific symptoms may be caused by the local presence of metastases, such as eye problems associated with retrobulbar tumours, pancytopenia associated with bone marrow infiltration, abdominal distension and respiratory problems associated with liver enlargement, paralysis and Horner syndrome associated with ganglion involvement (NCI PDQ 2012). Furthermore, there are general signs and symptoms like tiredness, weakness or pain. Some neuroblastoma regress spontaneously without therapy while others progress with a fatal outcome despite therapy. One study of infants younger than 12 months showed nearly half of the study population within three years of follow up had a spontaneous regression at diagnosis (Hero 2008). A tumour mass may be confirmed by ultrasound, X-rays, computed tomography, or magnetic resonance imaging. Guidelines for using imaging methods have been developed in response to the increased importance of image-defined factors in staging and risk assessment (Brisse 2011).

The International Neuroblastoma Staging System provides the current definitions for diagnosis, the stages 1, 2A, 2B, 3, 4 and 4S that are shown in  Table 2, and treatment response that is shown in  Table 3 (Brodeur 1993). The International Neuroblastoma Risk Group classification system provides the current definitions for the very low, low, intermediate, and high risk group that is shown in  Table 1 (Cohn 2009). The authors estimated the event-free survival for each of the four risk groups and tested the clinical importance of 13 potential prognostic factors.

 

Description of the intervention

Retinoic acid is a derivative of vitamin A (retinol) that includes 13-cis retinoic acid, also known as isotretinoin, among others. Retinoic acid regulates growth and development of epithelial cells. Retinoic acid inhibits growth of human neuroblastoma cells (Sidell 1982). Retinoic acid reduces morphological signs characteristic for several malignant human neuroblastoma cell lines (Sidell 1983). In a phase I clinical trial, 13-cis retinoic acid was used in children with neuroblastoma after autologous hematopoietic stem cell transplantation without signs of myelosuppression (Villablanca 1995). In a phase III clinical trial, 13-cis retinoic acid improved event-free survival for patients with high-risk neuroblastoma (Matthay 1999).

The test intervention of this review is the addition of retinoic acid as part of a therapy that comes after the consolidation therapy. Consolidation therapy that precedes retinoic acid includes either high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation or standard chemotherapy. Matthay 1999 recommended that "retinoic acid should form the basis for the treatment of patients with high-risk neuroblastoma". Yalcin 2010 included three randomised controlled trials (RCTs) in a Cochrane review including Matthay 1999, and showed a significant difference in favour of myeloablative therapy for both overall survival and event-free survival compared to conventional therapy in children with high-risk neuroblastoma.

Retinoic acid has been associated with several adverse events. Grissom 1996 reported hypervitaminosis A in a single patient. Turman 1999 reported two cases with bone marrow transplant nephropathy. Villablanca 1993 observed hypercalcaemia in 12 of 39 patients and a dose-limiting toxicity in three of those. Olson 1983 reported dry skin, dry mucous membranes, conjunctivitis, and hypertriglyceridaemia after vitamin A or retinoids.

 

How the intervention might work

Retinoic acid induces the differentiation of human neuroblastoma cell lines and stops uncontrolled cell growth in vitro (Reynolds 2003). High dose of retinoic acid might reduce relapse rate after intensive chemotherapy with or without autologous hematopoietic stem cell transplantation in patients with high-risk neuroblastoma.

 

Why it is important to do this review

Many patients may have an improved survival if retinoic acid is added to the post consolidation therapy. But it is possible that a considerable number of patients may not respond to the addition of retinoic acid. This review is important to evaluate the evidence base for the efficacy and the possible adverse events associated with this treatment.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The primary aim of this study is to evaluate whether patients with high-risk neuroblastoma have an additional benefit in terms of overall survival if retinoic acid is added to the post consolidation therapy and whether retinoic acid has dose-limiting treatment-related severe adverse events.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

RCTs.

 

Types of participants

Patients with high-risk neuroblastoma according to the International Neuroblastoma Risk Group or the Children's Oncology Group classification of risk groups shown in  Table 1 and  Table 4.

 

Types of interventions

  • Intervention
    • Addition of retinoic acid as part of a post consolidation therapy after high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation
  • Comparator
    • Placebo retinoic acid or no addition of retinoic acid to post consolidation therapy as described above

 

Types of outcome measures

The outcomes listed here are a list of the outcomes of interest within whichever studies are included and not used as criteria for including studies.

 

Primary outcomes

  • Overall survival: the event is death by any cause from start of retinoic acid treatment.
  • Treatment-related mortality: incidence of deaths that were classified as treatment related or the participants died of treatment complications.

 

Secondary outcomes

  • Progression-free survival: time staying free of disease progression from start of retinoic acid treatment; patients may still have the disease but their disease is stable or showed a partial response to treatment; the events are death from all causes or any progression of the disease
  • Event-free survival: time staying free of any of a particular group of defined events from start of retinoic acid treatment; patients may still have the disease; the events are death from all causes, any sign of the disease in participants who had a complete response to treatment, any relapse or progression of the disease, or events that were defined by the individual study protocol
  • Early toxicity: adverse events within 90 days of the therapy; incidence of all reported adverse events, severe events (grades 3 and 4 of toxicity), and incidence of toxicity-related discontinuation of treatment will be extracted. Results may be pooled if the definitions are similar. Examples of possibly reported classifications: the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTEP 2010); WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (ICSSC 2003)
  • Late toxicity including secondary malignancy
  • Health-related quality of life measured by validated questionnaires

 

Search methods for identification of studies

Search methods as suggested in the Cochrane Handbook for Systematic Reviews of Interventions and by the Cochrane Childhood Cancer Review Group will be used (Higgins 2011; Kremer 2008). The search will be updated every two years. No language restrictions will be applied.

 

Electronic searches

We plan to conduct an electronic literature database search in the Cochrane Central Register of Controlled Trials (CENTRAL) including articles published in the latest issue (Appendix 1). We plan to search in MEDLINE (PubMed) including articles published from 1946 to present by using the search strategy shown in Appendix 2, and in EMBASE (Ovid) including articles published from 1980 to present (Appendix 3). The terms and the syntax used for the search in MEDLINE will be tailored to the requirements of the other two databases. The Cochrane Childhood Cancer Group will run the searches in the three mentioned electronic databases.

We plan to search for ongoing trials by scanning the online registries ClinicalTrials.gov (http://clinicaltrials.gov/) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (http://apps.who.int/trialsearch/) using the term "neuroblastoma" in the field condition and "retinoic acid" in the field intervention.

We plan to search for abstracts presented at the last five consecutive annual meetings from 2008 to 2012 of the American Society of Clinical Oncology, the International Society of Paediatric Oncology, and the Advances in Neuroblastoma Research available for online searching. We will request an online search using the term "neuroblastoma AND retinoic AND acid" in the search fields title as well as abstract.

 

Searching other resources

We plan to search information about trials not registered in electronic databases in reference lists of relevant articles and review articles. We plan to contact authors to replenish missing information.

 

Data collection and analysis

 

Selection of studies

While preparing this systematic review, we endorse the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, adhere to its principles and conform to its checklist (Moher 2009). All titles and abstracts retrieved by electronic searching will be downloaded to the reference management database EndNote 2012, duplicates will be removed and the remaining references will be examined by two review authors independently (FP, CB). We will include a study selection flow chart in the review. The full text of potentially relevant references will be obtained. The eligibility of retrieved papers will be assessed independently by two authors (FP, CB). Disagreements will be resolved by discussion between the two reviewers and consultation with a third author (FB) if necessary. Reasons for exclusion will be documented. If we identify multiple reports of one study we will use the latest results. We will check the multiple reports for possible duplicate data, will address the issue, and will not include duplicate data in the analysis.

 

Data extraction and management

Two authors (FP, CB) will abstract study characteristics and outcomes independently, including information on study design, subject characteristics, interventions, follow up, treatment outcomes, and adverse events. We will resolve differences between reviewers by discussion or by appeal to a third author (UG). For included studies, data on characteristics of patients (inclusion criteria, age, stage, co-morbidity, previous treatment, number enrolled in each arm) and interventions (type of retinoic acid, dose applied, duration of therapy), risk of bias, duration of follow-up, outcomes and deviations from protocol will be abstracted independently by two authors (FP, CB) onto a data extraction form specifically designed for the review.

For time to event data such as survival, we will extract the hazard ratio (HR) and its standard error or confidence interval from trial reports; if these are not reported, we will attempt to estimate the logHR and its standard error using the methods of Parmar 1998. For dichotomous outcomes (e.g. adverse events or treatment-related mortality) we will extract the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a relative risk (RR). For continuous outcomes (e.g. quality of life measures), we will extract the final value or change from baseline and corresponding standard deviation of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow-up, in order to estimate the mean difference (MD) or standardised mean difference (SMD) between treatment arms. Where possible, all data extracted will be those relevant to an intention-to-treat analysis, in which all participants will be analysed in groups to which they were assigned. If not possible this will be stated. The time points at which outcomes were collected and reported will be noted.

 

Assessment of risk of bias in included studies

Two authors (FP, UG) will independently appraise the risk of bias in the included studies. We will resolve differences between reviewers by discussion or by appeal to a third author (CB). We will use the items listed in the Cochrane Childhood Cancer Group manual (Kremer 2008), which is based on the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011), but some adjustments have been made:

  1. Random sequence generation (selection bias),
  2. Allocation concealment (selection bias),
  3. Blinding of participants (performance bias),
  4. Blinding of personnel (performance bias),
  5. Other potential threats to validity, if relevant: for each outcome separately (performance bias),
  6. Blinding of outcome assessment (detection bias) will be done for each outcome separately,
  7. Other potential threats to validity, if relevant: for each outcome separately (detection bias),
  8. Incomplete outcome data such as missing data for each outcome separately (attrition bias),
  9. Selective reporting such as not reporting pre-specified outcomes (reporting bias), and
  10. Other sources of bias such as bias related to the specific study design (other bias).

We will apply the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). In general, a "Low risk" of bias is judged if plausible bias is unlikely to seriously alter the results, for example, participants and investigators enrolling participants could not foresee assignment. A "High risk" of bias is judged if plausible bias seriously weakens confidence in the results, for example, participants or investigators enrolling participants could possibly foresee assignments. "Unclear" risk of bias is judged if plausible bias raises some doubt about the results, for example, the method of concealment is not described or not described in sufficient detail to allow a definite judgement. In case a trial will not provide data on all outcomes included in the review, we will choose the option "Unclear" for the outcomes that were not reported and leave the description field empty. This row of the table will not be included in the publication of the review. In addition to the risk of bias tables, we will include "Methodological Quality" summaries. The results of the risk of bias assessment will be taken into account when interpreting the results of the review.

 

Measures of treatment effect

For meta-analyses of time to event data, the primary effect measure will be the HR. If the hazard ratio is not directly given in the publication, we intend to estimate hazard ratios according to methods proposed by Parmar 1998 and Tierney 2007. We plan to calculate RR with 95% confidence intervals (CIs) for dichotomous outcomes. In case of rare events, Peto odds ratios are planned to be used instead. Continuous data will be analysed and presented using the MD, if all results are measured on the same scale (e.g. length of hospital stay). If this is not the case (e.g. pain or quality of life), SMD will be used.

 

Unit of analysis issues

No unit of analysis issues are expected.

 

Dealing with missing data

We will conform to the Cochrane Collaboration's principal options for dealing with missing data (Higgins 2011). If data are missing or only imputed data are reported we will contact trial authors to request data on the outcomes among participants who were assessed. When relevant data regarding study selection, data extraction and risk of bias assessment are missing, we will attempt to contact the study authors to retrieve the missing data.

 

Assessment of heterogeneity

We plan to assess heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (I2) (Higgins 2003) and, if possible, by subgroup analyses. If there will be evidence of substantial heterogeneity, we plan to investigate and report the possible reasons for this. An I2greater than 50% will be considered to indicate substantial heterogeneity.

 

Assessment of reporting biases

We plan to conform to the Cochrane Collaboration's criteria to evaluate reporting biases such as publication bias, time lag bias, multiple (duplicate) publication bias, location bias, citation bias, language bias, outcome reporting bias (Higgins 2011).

 

Data synthesis

We plan to analyse the data using the Review Manager 2013. This will be done by one author (FP) and checked by another (UG). If sufficient, clinically similar studies are available, their results will be pooled in meta-analyses. If any trials have multiple treatment groups, the 'shared' comparison group will be divided into the number of treatment groups and comparisons between each treatment group and the split comparison group will be treated as independent comparisons. Random effects models with inverse variance weighting will be used for all meta-analyses (DerSimonian 1986).

We will use GRADEpro 2008 to create t"Summary of findings" tables as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We plan to present overall survival, treatment-related mortality, early toxicity, late toxicity, and health-related quality of life provided that data will be presented for both treatment arms.

 

Subgroup analysis and investigation of heterogeneity

We plan a subgroup analysis on age (younger than 18 months vs. older than 18 months) since the International Neuroblastoma Risk Group has established 18 months as the optimal cut-off for age. We plan also a subgroup analysis on MYCN gene amplification (with vs. without MYCN amplification).

 

Sensitivity analysis

We plan to conduct sensitivity analyses of studies with low risk of bias vs. studies with high or uncertain risk of bias.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

We thank Edith Leclercq for her help with developing the search strategies for the different databases. The editorial base of the Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KiKa).

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. Search strategy for CENTRAL (The Cochrane Library)

1. For Retinoic acid the following text words will be used:

retinoic acid OR retinoic acids OR Retinoid* OR Retinoid OR Retinoids OR tretinoin OR Vitamin A Acid OR trans-Retinoic Acid OR trans Retinoic Acid OR all-trans-Retinoic Acid OR all trans Retinoic Acid OR beta-all-trans-Retinoic Acid OR beta all trans Retinoic Acid OR 13-cis-RA OR 13-cis-retinoic acid OR 4759-48-2 OR Retin-A OR Retin A OR Vesanoid OR isotretinoin OR ATRA OR Accutane OR Airol OR Dermairol

2. For Neuroblastoma the following text words will be used:

neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas OR ganglioneuroblast* OR neuroepithelioma OR neuroepitheliomas OR neuroepitheliom* OR esthesioneuroblastoma OR esthesioneuroblastomas OR esthesioneuroblastom* OR schwannian

Final search 1 and 2
The search will be performed in title, abstract or keywords

[*=zero or more characters]

 

Appendix 2. Search strategy for MEDLINE (PubMed)

1. For Retinoic acid the following MeSH headings and text words will be used:

retinoic acid OR retinoic acids OR Retinoid* OR Retinoid OR Retinoids OR tretinoin OR Vitamin A Acid OR Acid, Vitamin A OR trans-Retinoic Acid OR Acid, trans-Retinoic OR trans Retinoic Acid OR all-trans-Retinoic Acid OR Acid, all-trans-Retinoic OR all trans Retinoic Acid OR beta-all-trans-Retinoic Acid OR beta all trans Retinoic Acid OR 3-cis-RA OR 13-cis-retinoic acid OR 4759-48-2 OR Retin-A OR Retin A OR Vesanoid OR isotretinoin OR ATRA OR Accutane OR Airol OR Dermairol

2. For Neuroblastoma the following MeSH headings and text words will be used:

neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas OR ganglioneuroblast* OR neuroepithelioma OR neuroepitheliomas OR neuroepitheliom* OR esthesioneuroblastoma OR esthesioneuroblastomas OR esthesioneuroblastom* OR schwannian

3. For RCTs and CCTs the following MeSH headings and text words will be used:

((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) AND (humans[mh])

Final search 1 and 2 and 3

[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 Retinoic acid the following Emtree terms and text words will be used:

1. exp retinoic acid/
2. (retinoic acid or retinoic acids).mp.
3. (retinoid* or retinoid or retinoids).mp.
4. tretinoin.mp.
5. Vitamin A Acid.mp.
6. (trans-retinoic Acid or trans retinoic Acid or all-trans-Retinoic Acid or all trans Retinoic Acid).mp.
7. (beta-all-trans-retinoic acid or beta all trans retinoic acid or 3-cis-RA or 13-cis-retinoic acid).mp.
8. 4759-48-2.rn.
9. (Retin-A or Retin A or Vesanoid or isotretinoin or ATRA or Accutane or Airol or Dermairol).mp.
10. or/1-9

2. For Neuroblastoma the following Emtree terms and text words will be used:

1. exp neuroblastoma/
2. (neuroblastoma or neuroblastomas or neuroblast$).mp.
3. (ganglioneuroblastoma or ganglioneuroblastomas or ganglioneuroblast$).mp.
4. (neuroepithelioma or neuroepitheliomas or neuroepitheliom$).mp.
5. exp esthesioneuroblastoma/
6. (esthesioneuroblastoma or esthesioneuroblastomas or esthesioneuroblastoma$).mp.
7. schwannian.mp.
8. or/1-7

3. For RCTs and CCTs the following Emtree terms and text words will be 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

Final search 1 and 2 and 3

[mp = title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

All authors approved the final version of the protocol.

FP: concept, primary manuscript preparation

CB: manuscript review

FB: providing a clinical perspective

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The authors declare that they have no conflict of interest.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • University of Cologne, Germany.
    Provision of the full-texts of articles

 

External sources

  • No sources of support supplied

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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