Rapid COJEC versus standard induction therapies for high-risk neuroblastoma

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The aim of this study is to compare survival, treatment response and dose-limiting treatment-related severe adverse events in patients with high-risk neuroblastoma receiving induction therapy with either rapid COJEC or a standard schedule.

Background

Description of the condition

Neuroblastoma is a rare malignant disease that affects mainly infants and very young children (GARD 2013). Tumours develop in the sympathetic nervous system (e.g. in the 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, falling 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). The International Neuroblastoma Risk Group classification system, proposed by Cohn 2009,is shown in Table 1. The authors of Cohn 2009 estimated the event-free survival for each of the four risk groups and tested the clinical importance of 13 potential prognostic factors. The Children's Oncology Group assignment to low, intermediate, and high risk group, published by the National Cancer Institute (NCI) at the National Institutes of Health (NIH) (NCI PDQ 2013), is shown in Table 2.

Table 1. The International Neuroblastoma Risk Group (INRG) consensus pretreatment classification schema
  1. Reference: Cohn 2009

    The International Neuroblastoma Risk Group (INRG) consensus classification schema includes the criteria INRG stage, age, histologic category, grade of tumour differentiation, MYCN status, presence/absence of 11q aberrations and tumour cell ploidy. Sixteen statistically and/or clinically different pretreatment groups of patients (lettered A through R) have been identified using these criteria. The categories are designated as very low (A, B, C), low (D, E, F), intermediate (G, H, I, J), or high (K, N, O, P, Q, R) pretreatment risk subsets.

    Abbreviations: INRG: International Neuroblastoma Risk Group; MYCN: the official gene symbol approved by the Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC), which is a short abbreviated form of the gene name 'v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog';

INRG stageAge (months)Histologic categoryGrade of tumour differentiationMYCN11q aberrationPloidyPretreatment risk group
CodeInterpretation
L1/L2 Ganglioneuroma maturing; ganglioneuroblastoma intermixed    AVery low
L1 Any, except ganglioneuroma or ganglioneuroblastoma Not amplified  BVery low
Amplified  KHigh
L2< 18Any, except ganglioneuroma or ganglioneuroblastoma Not amplifiedNo DLow
Yes GIntermediate
≥ 18Ganglioneuroblastoma nodular; neuroblastomaDifferentiatingNot amplifiedNo ELow
Yes HIntermediate
Poorly differentiated or undifferentiatedNot amplified  HIntermediate
 Amplified  NHigh
M< 18  Not amplified HyperdiploidFLow
< 12  Not amplified DiploidIIntermediate
12 to < 18  Not amplified DiploidJIntermediate
< 18  Amplified  OHigh
≥ 18     PHigh
MS< 18  Not amplifiedNo CVery low
Yes QHigh
Amplified  RHigh
Table 2. Children's Oncology Group (COG) assignment to low, intermediate, and high risk group
  1. Reference: NCI PDQ 2013

    DNA index: favourable > 1 (hyperdiploid) or < 1 (hypodiploid); unfavourable = 1 (diploid)

    Abbreviations: COG: Children's Oncology Group; d: days; DNA: deoxyribonucleic acid; INPC: International Neuroblastoma Pathology Committee (also called Shimada system); INSS: The International Neuroblastoma Staging System; MYCN: the official gene symbol approved by the Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC), which is a short abbreviated form of the gene name 'v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog'; y: years

INSS stage Age MYCN INPC classification DNA index Risk group
10 to 21 yAnyAnyAnyLow
2A/2B< 365 dAnyAnyAnyLow
≥ 365 d to 21 yNon-amplifiedAny-Low
≥ 365 d to 21 yAmplifiedFavourable-Low
≥ 365 d to 21 yAmplifiedUnfavourable-High
3< 365 dNon-amplifiedAnyAnyIntermediate
< 365 dAmplifiedAnyAnyHigh
≥ 365 d to 21 yNon-amplifiedFavourable-Intermediate
≥ 365 d to 21 yNon-amplifiedUnfavourable-High
≥ 365 d to 21 yAmplifiedAny-High
4< 548 dNon-amplifiedAnyAnyIntermediate
< 365 dAmplifiedAnyAnyHigh
≥ 548 d to 21 yAnyAny-High
4S< 365 dNon-amplifiedFavourable> 1Low
< 365 dNon-amplifiedAny= 1Intermediate
< 365 dNon-amplifiedUnfavourableAnyIntermediate
< 365 dAmplifiedAnyAnyHigh

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, and paralysis and Horner syndrome associated with ganglion involvement (NCI PDQ 2013). Furthermore, neuroblastoma is associated with general signs and symptoms such as tiredness, weakness or pain. Some neuroblastomas regress spontaneously without therapy, whereas others progress, having a fatal outcome despite therapy. One study in infants aged younger than 12 months showed that nearly half of the study population within three years of diagnosis had a spontaneous regression at follow up (Hero 2008). A tumour mass may be confirmed on ultrasound, X-ray, 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). International Neuroblastoma Staging System (INSS) for neuroblastoma is shown in Table 3; INSS definitions of treatment response are shown in Table 4 (Brodeur 1993).

Table 3. The International Neuroblastoma Staging System (INSS)
  1. Reference: Brodeur 1993

    Note: Multifocal primary tumours (e.g. bilateral adrenal primary tumours) should be staged according to the greatest extent of disease, as defined above, and followed by a subscript letter M (e.g. 3M).
    1The midline is defined as the vertebral column. Tumours originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
    2Marrow involvement in stage 4S should be minimal (i.e. < 10% of total nucleated cells identified as malignant on bone marrow biopsy or on marrow aspirate). More extensive marrow involvement would be considered to be stage 4. An MIBG (meta-iodobenzylguanidine) scan (if performed) should be negative in the marrow.

    Abbreviations: INSS: The International Neuroblastoma Staging System;

Stage Definition
1Localised tumour with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumour microscopically (nodes attached to and removed with the primary tumour may be positive).
2ALocalised tumour with incomplete gross excision; representative ipsilateral non-adherent lymph nodes negative for tumour microscopically.
2BLocalised tumour with or without complete gross excision, with ipsilateral non-adherent lymph nodes positive for tumour. Enlarged contralateral lymph nodes must be negative microscopically.
3Unresectable unilateral tumour infiltrating across the midline,1 with or without regional lymph node involvement; or localised unilateral tumour with contralateral regional lymph node involvement; or midline tumour with bilateral extension by infiltration (unresectable) or by lymph node involvement.
4Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defined for stage 4S).
4SLocalised primary tumour (as defined for stages 1, 2A or 2B), with dissemination limited to skin, liver and/or bone marrow2 (limited to infants < 1 year of age).
Table 4. Response to treatment
  1. Reference: Brodeur 1993

Response Primary tumour Metastatic sites
Complete responseNo tumourNo tumour; catecholamines normal.
Very good partial responseDecreased by 90% to 99%No tumour; catecholamines normal; residual 99Tc bone changes allowed.
Partial responseDecreased by more than 50%All measurable sites decreased by greater than 50%. Bones and bone marrow: number of positive bone sites decreased by greater than 50%; no more than one positive bone marrow site allowed.
Minimal responseNo new lesions; more than 50% reduction in any measurable lesion (primary or metastases) with less than 50% reduction in any other; less than 25% increase in any existing lesion.
No responseNo new lesions; less than 50% reduction but less than 25% increase in any existing lesion.
Progressive diseaseAny new lesion; greater than 25% increase in any measurable lesion ; previous negative marrow positive for tumour.

Description of the intervention

Intervention

The rapid COJEC schedule comprises the chemotherapeutic agents cisplatin (represented by the first C of the acronym, otherwise abbreviated P), vincristine (O), carboplatin (J), etoposide (E) and cyclophosphamide (C). The schedule is administered in eight cycles separated by intervals of 10 days and is completed within 70 days from the first to the last drug administered. One example of a COJEC chemotherapeutic regimen has been reported by Pearson 2008.

In patients with high-risk neuroblastoma, the aim of the rapid COJEC schedule is to administer higher single doses of selected drugs than standard schedules over a substantially shorter treatment period, with shorter intervals between cycles. Shorter intervals and higher doses increase the dose intensity of chemotherapy, making possible earlier myeloablative autologous haematopoietic stem cell transplantation and, possibly, improving survival. However, increased toxicity such as neutropenia may compromise any favourable effect.

Comparators

Various standard cumulative chemotherapy schedules are available for induction therapy in patients with high-risk neuroblastoma prior to myeloablative autologous haematopoietic stem cell transplantation. Standard induction chemotherapy schedules are characterised by several successive administrations of drugs, and the time intervals between the drug applications are planned to allow the bone marrow time to recover and to prevent high-grade toxicities. Severe adverse events associated with such schedules are mainly haematological and include neutropenia (Ladenstein 2010). Examples of standard induction chemotherapy schedules available for use in patients with high-risk neuroblastoma include:

  1. the OPEC/OJEC schedule, comprising cisplatin (P), vincristine (O), carboplatin (J), etoposide (E) and cyclophosphamide (C), is administered in seven cycles separated by intervals of 21 days and is completed within 126 days from the first to the last drug administered. One example of a chemotherapeutic OPEC/OJEC regimen has been reported by Pearson 2008;

  2. the Children's Oncology Group (COG) schedule, comprising three cycles of cisplatin, etoposide, doxorubicin and ifosfamide. One example of a chemotherapeutic COG regimen has been reported by Matthay 1999 and again recently by Matthay 2009.

  3. the Gesellschaft für Pädiatrische Onkologie und Hämatologie (in English: Association for Pediatric Oncology and Hematology) (GPOH) schedule, comprising the alternating of so-called N5 and N6 cycles. One example of a chemotherapeutic GPOH regimen has been reported by Berthold 2005 and was used in the NB2004 trial (GPOH 2007).

How the intervention might work

The administration of drugs in short intervals and at high, tolerated doses could interfere with the recovery of cancer cells from toxic chemotherapteutic doses and could result in more cancer cell death. The substantially reduced total time of drug administration might lower the risk of drug resistance. These possible advantages, taken together, could lead to more effective treatment and improved patient survival.

Why it is important to do this review

Rapid COJEC could improve patient survival compared with standard induction therapy, but could also give rise to more frequent and more severe adverse events than standard induction therapy. The efficacy of, and adverse events associated with, this therapy should be confirmed in randomised controlled trials. As the rapid COJEC schedule could be investigated in future studies, this review is important in order to evaluate the evidence base for the efficacy and possible adverse events associated with this treatment.

Objectives

The aim of this study is to compare survival, treatment response and dose-limiting treatment-related severe adverse events in patients with high-risk neuroblastoma receiving induction therapy with either rapid COJEC or a standard schedule.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials.

Types of participants

Patients with high-risk neuroblastoma according to the International Neuroblastoma Risk Group (Table 1) or the COG (Table 2) classification systems.

Types of interventions

Intervention

We plan to include studies investigating the use of rapid COJEC as induction chemotherapy.

Comparators

We plan to include studies investigating different standard induction chemotherapy options, including:

  1. the OPEC/OJEC schedule;

  2. the COG schedule; and

  3. the GPOH schedule.

Rapid COJEC induction chemotherapy is associated with a substantially shorter treatment period, shorter intervals between cycles and higher single doses of selected drugs than standard schedules. We plan to assess the role of the intervention on the induction period and on the initial treatment response. Consequently, the treatment initiated after the induction period will need to be identical for both the intervention and comparator schedules.

Types of outcome measures

The outcomes listed below are outcomes of interest in the studies included in this review rather than inclusion criteria for studies.

Primary outcomes
  • Complete response versus other responses such as partial or no response.

  • Early toxicity: adverse events within 90 days of the therapy; incidence of all reported adverse events and severe (grade 3 and 4) events; and incidence of toxicity-related discontinuations from treatment. Results may be pooled if similar definitions are used in studies. Examples of potentially used classification systems: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 2013) and WHO toxicity grading scale for determining the severity of adverse events (ICSSC 2003).

  • Treatment-related mortality: incidence of deaths during the induction period that are classified as treatment related or attributed to treatment complications.

Secondary outcomes
  • Overall survival (OS): death from any cause from the start of rapid COJEC or standard induction therapy.

  • Progression-free survival (PFS): time free of disease progression (death from all causes or any disease progression) from the start of rapid COJEC or standard induction therapy; patients may still have the disease but their disease is stable or showed a partial response to treatment

  • Event-free survival (EFS): time free of any of a group of defined events (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 defined by the individual study protocol) from the start of rapid COJEC or standard induction therapy; patients may still have the disease.

  • Late non-haematological toxicity such as organ toxicity and secondary malignancy.

  • Health-related quality of life measured by validated questionnaires and compared between the intervention and control groups.

Search methods for identification of studies

Search methods as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011) and by the Cochrane Childhood Cancer Review Group (Kremer 2008) will be used. The search will be updated every 2 years. No language restrictions will be applied.

Electronic searches

We plan to conduct an electronic literature database search in The Cochrane Library (Cochrane Central Register of Controlled Trials (CENTRAL)) including articles published in the latest issue (Appendix 1). We plan to search in MEDLINE (PubMed format) for articles published from 1946 to the present by using the search strategy shown in Appendix 2, and in EMBASE (Ovid format) for articles published from 1980 to the 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 (ClinicalTrials.gov 2013) and World Health Organization International Clinical Trials Registry Platform (ICTRP 2013), using the term 'neuroblastoma' in the field condition and 'rapid cojec' 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 (ASCO), the International Society of Paediatric Oncology (SIOP) and the Advances in Neuroblastoma Research (ANR) that are available for online searching. We will request an online search using the term 'neuroblastoma' AND 'rapid' AND 'cojec' in the search fields 'title' and 'abstract'.

Searching other resources

We plan to search for information about trials not registered in electronic databases in the reference lists of relevant articles and review articles. We plan to ask authors to provide any missing information.

Data collection and analysis

Selection of studies

While preparing this systematic review, we intend to endorse the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 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 Version X3 (Thomson Reuters Corp 2013), duplicates will be removed and the remaining references will be examined by two review authors independently (FP, DAT). We will include a study selection flow chart in the review.

Those studies that clearly do not meet the inclusion criteria will be excluded and copies of the full text of potentially relevant references will be obtained. The eligibility of retrieved papers will be assessed independently by two authors (FP, DAT). Disagreements will be resolved by discussion between the two reviewers and consultation with a third review author (FB), if necessary. Reasons for exclusion will be documented. If we identify multiple reports of one study we will use the most-up-to-date 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 reviewers (FP, DAT) 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 review author (FB). For included studies, data on characteristics of patients (inclusion criteria, age, stage, comorbidity, previous treatment, number enrolled in each arm) and interventions (type of rapid COJEC and standard induction therapy, dose applied, duration of therapy), risk of bias, duration of follow up, outcomes and deviations from protocol will be abstracted independently by two reviewers (FP, DAT) into 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 (CI) from trial reports; if these are not reported, we will attempt to estimate the log (HR) and its standard error using the methods of Parmar 1998 and Tierney 2007. For dichotomous outcomes (e.g. response, adverse events and 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 standard 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 the groups to which they were assigned. If this is 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 reviewers will independently appraise the risk of bias in the included studies (FP, DAT). We will resolve differences between reviewers by discussion or by appeal to a third review author (FB). We will use the items listed in the Cochrane Childhood Cancer Group module (Kremer 2008), which is based on The Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011a), but with some adjustments:

  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) 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 prespecified 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 criteria for judging risk of bias (Higgins 2011b). In general, a 'low risk' of bias will be attributed if plausible bias is unlikely to have a marked affect on the results; for example, participants and investigators enrolling participants could not foresee assignment. A 'high risk' of bias will be attributed if plausible bias seriously weakens confidence in the results; for example, participants or investigators enrolling participants could possibly foresee assignments. An 'unclear' risk of bias will be attributed if plausible bias raises some doubts about the results; for example, the method of concealment is not described or not described in sufficient detail to allow a definite judgement. In cases where a trial does not provide data on all the outcomes included in the review, we will attribute an 'unclear' risk to the outcomes that are not reported and leave the description field empty. This row of the 'Risk of bias' table will not be included in the published version of the review. In addition to a 'Risk of bias' table, we will include a methodological quality summary. 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 HR is not stated in the publication, we intend to estimate it according to methods proposed by Parmar 1998 and Tierney 2007. We plan to calculate RRs with 95% CIs for dichotomous outcomes. In case of rare events, we plan to use Peto odds ratios instead. Continuous data will be analysed and presented as MDs provided all the 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), SMDs 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 2011c). If data are missing, or imputed data only 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 that cannot be ascribed to sampling variation (I2 statistic) (Higgins 2003) and, if possible, by subgroup analyses. If there is evidence of substantial heterogeneity, we plan to investigate and report the possible reasons for this. An I2 statistic greater than 50% will be considered to indicate substantial heterogeneity.

Assessment of reporting biases

We plan to conform to The Cochrane Collaboration's criteria for evaluating the reporting of bias, such as publication bias, time lag bias, multiple (duplicate) publication bias, location bias, citation bias, language bias and outcome reporting bias (Sterne 2011).

Data synthesis

We plan to analyse data using Review Manager 2011. This will be done by one review author (FP) and checked by another review author (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 3.2 software (GRADEpro 2008) to create a 'Summary of findings' table, as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). We plan to analyse data for overall survival, treatment-related mortality, progression-free survival, event-free survival, early toxicity, late toxicity and health-related quality of life.

Subgroup analysis and investigation of heterogeneity

We plan a subgroup analysis based on age (< 1 year vs. >= 1 year). Patients younger than 1 year have a better prognosis than older children. A considerable proportion of patients younger than 1 year have tumour features that are associated with spontaneous regression. As a consequence, the INSS limits stage 4S to infants younger than 1 year of age (Brodeur 1993) and the COG assignment uses the age of 365 days as a cut-off for stage and risk group assignments (NCI PDQ 2013).

Sensitivity analysis

We plan to conduct sensitivity analyses by excluding studies judged to be at high or unclear risk of bias with regard to each 'risk of bias' item separately.

Acknowledgements

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

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

1. For COJEC the following text words will be used:

induction therapy OR consolidation therapy OR OPEC OR OJEC OR COJEC OR rapid COJEC OR (carboplatin AND cisplatin AND cyclophosphamide AND etoposide AND vincristine)

For carboplatin, cisplatin, cyclophosphamide, etoposide and vincristine the following search strategies will be applied:

Carboplatin

Carboplatin OR cis-Diammine(cyclobutanedicarboxylato)platinum II OR CBDCA OR Carbosin OR Pharmachemie Brand of Carboplatin OR Carbotec OR Columbia Brand of Carboplatin OR Ercar OR Almirall Brand of Carboplatin OR JM-8 OR JM 8 OR JM8 OR Neocarbo OR Neocorp Brand of Carboplatin OR NSC-241240 OR NSC 241240 OR NSC241240 OR Paraplatin OR Carboplat OR Paraplatine OR Bristol-Myers Squibb Brand of Carboplatin OR Platinwas OR Chiesi Brand of Carboplatin OR Ribocarbo OR ribosepharm Brand of Carboplatin OR Blastocarb OR Lemery Brand of Carboplatin OR Nealorin OR Prasfarma Brand of Carboplatin OR carboplatin*

Cisplatinum

Cisplatin OR cis-Diamminedichloroplatinum(II) OR Platinum Diamminodichloride OR Diamminodichloride, Platinum OR cis-Platinum OR cis Platinum OR Dichlorodiammineplatinum OR cis-Diamminedichloroplatinum OR cis Diamminedichloroplatinum OR cisDichlorodiammineplatinum(II) OR Platinol OR Platidiam OR Platino OR NSC-119875 OR Biocisplatinum OR CDDP OR CACP OR cisplatin* OR abiplatin OR neoplatin OR cis-DDP

Cyclophosphamide

cyclophosphamide OR cyclophosphane OR cytophosphan OR B-518 OR cyclophosphamide monohydrate OR monohydrate, cyclophosphamide OR endoxan OR cytoxan OR neosar OR procytox OR sendoxan OR NSC-26271 OR NSC 26271 OR NSC26271 OR cyclophosphamide, (R)-isomer OR cyclophosphamide, (S)-isomer OR cyclophosphamide, (+)-isomer OR endox* OR cyclophospha*

Etoposide

etoposide OR etoposid* OR Eposide OR Eposin OR 33419-42-0

Vincristine

vincristine OR vincristin* OR 57-22-7

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 PubMed

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

induction therapy[tiab] OR consolidation therapy[tiab] OR OPEC OR OJEC OR COJEC OR rapid COJEC OR (carboplatin AND cisplatin AND cyclophosphamide AND etoposide AND vincristine).

For carboplatin, cisplatin, cyclophosphamide, etoposide and vincristine the following search strategies will be applied:

Carboplatin

Carboplatin OR cis-Diammine(cyclobutanedicarboxylato)platinum II OR CBDCA OR Carbosin OR Pharmachemie Brand of Carboplatin OR Carbotec OR Columbia Brand of Carboplatin OR Ercar OR Almirall Brand of Carboplatin OR JM-8 OR JM 8 OR JM8 OR Neocarbo OR Neocorp Brand of Carboplatin OR NSC-241240 OR NSC 241240 OR NSC241240 OR Paraplatin OR Carboplat OR Paraplatine OR Bristol-Myers Squibb Brand of Carboplatin OR Platinwas OR Chiesi Brand of Carboplatin OR Ribocarbo OR ribosepharm Brand of Carboplatin OR Blastocarb OR Lemery Brand of Carboplatin OR Nealorin OR Prasfarma Brand of Carboplatin OR carboplatin*

Cisplatinum

Cisplatin OR cis-Diamminedichloroplatinum(II) OR Platinum Diamminodichloride OR Diamminodichloride, Platinum OR cis-Platinum OR cis Platinum OR Dichlorodiammineplatinum OR cis-Diamminedichloroplatinum OR cis Diamminedichloroplatinum OR cisDichlorodiammineplatinum(II) OR Platinol OR Platidiam OR Platino OR NSC-119875 OR Biocisplatinum OR CDDP OR CACP OR cisplatin* OR abiplatin OR neoplatin OR cis-DDP

Cyclophosphamide

cyclophosphamide OR cyclophosphane OR cytophosphan OR B-518 OR cyclophosphamide monohydrate OR monohydrate, cyclophosphamide OR endoxan OR cytoxan OR neosar OR procytox OR sendoxan OR NSC-26271 OR NSC 26271 OR NSC26271 OR cyclophosphamide, (R)-isomer OR cyclophosphamide, (S)-isomer OR cyclophosphamide, (+)-isomer OR endox* OR cyclophospha*

Etoposide

etoposide OR etoposid* OR Eposide OR Eposin OR 33419-42-0

Vincristine

vincristine OR vincristin* OR 57-22-7

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 COJEC the following Emtree terms and text words will be used:

1. (induction therapy or consolidation therapy).mp.

2. (OPEC or OJEC or COJEC or rapid COJEC).mp.

3. (Carboplatin or CBDCA or Carbosin or Pharmachemie Brand of Carboplatin or Carbotec or Columbia Brand of Carboplatin or Ercar or Almirall Brand of Carboplatin or JM-8 or JM 8 or JM8 or Neocarbo or Neocorp Brand of Carboplatin or NSC-241240 or NSC 241240 or NSC241240 or Paraplatin or Carboplat or Paraplatine or Bristol-Myers Squibb Brand of Carboplatin or Platinwas or Chiesi Brand of Carboplatin or Ribocarbo or ribosepharm Brand of Carboplatin or Blastocarb or Lemery Brand of Carboplatin or Nealorin or Prasfarma Brand of Carboplatin or carboplatin$).mp.

4. (Cisplatin or cis-Diamminedichloroplatinum or Platinum Diamminodichloride or Diamminodichloride, Platinum or cis-Platinum or cis Platinum or Dichlorodiammineplatinum or cis-Diamminedichloroplatinum or cis Diamminedichloroplatinum or cisDichlorodiammineplatinum or Platinol or Platidiam or Platino or NSC-119875 or Biocisplatinum or CDDP or CACP or cisplatin$ or abiplatin or neoplatin or cis-DDP).mp.

5. (cyclophosphamide or cyclophosphane or cytophosphan or B-518 or cyclophosphamide monohydrate or endoxan or cytoxan or neosar or procytox or sendoxan or NSC-26271 or NSC 26271 or NSC26271 or cyclophosphamide derivative or endox$ or cyclophospha$ or cyclofosfa$ or 50-18-0).mp.

6. (etoposide or etoposid$ or Eposide or Eposin or 33419-42-0).mp.

7. (vincristine or vincristin$ or 57-22-7).mp.

8. (1 OR 2 OR (3 AND 4 AND 5 AND 6 AND 7))

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; ti,ab = title, abstract, / = Emtree term; sh = subject heading; $ = zero or more characters; RCT = randomized controlled trial; CCT = controlled clinical trial]

Contributions of authors

All authors approved the final version of the protocol.

FP: concept, data assessment, primary manuscript preparation

DAT: study selection, data assessment, manuscript review

FB: providing a clinical perspective

Declarations of interest

The authors declare that they have no conflicts of interest.

Sources of support

Internal sources

  • University of Cologne, Germany.

    Provision of the full texts of articles

External sources

  • No sources of support supplied

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