Different infusion durations for preventing platinum-induced hearing loss in children with cancer

  • Protocol
  • Intervention

Authors

  • Jorrit W van As,

    Corresponding author
    1. Emma Children's Hospital / Academic Medical Center, c/o Cochrane Childhood Cancer Group, Amsterdam, Netherlands
    • Jorrit W van As, c/o Cochrane Childhood Cancer Group, Emma Children's Hospital / Academic Medical Center, PO Box 22660, Amsterdam, 1100 DD, Netherlands. Jorritvas@gmail.com.

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  • Henk van den Berg,

    1. Emma Children's Hospital / Academic Medical Center, Department of Paediatric Oncology, Amsterdam, Netherlands
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  • Elvira C van Dalen

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

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

To assess the effects of any platinum infusion duration to prevent hearing loss and/or tinnitus in children with cancer treated with platinum-based therapy (i.e. including cisplatin, carboplatin and/or oxaliplatin) when compared to another infusion duration. We will also assess possible effects of these infusion durations on anti-tumour efficacy (i.e. tumour response and survival) of platinum-based therapy, on adverse effects other than hearing loss and/or tinnitus and on quality of life.

Background

Description of the condition

Platinum-based therapy, that is therapy including cisplatin, carboplatin and/or oxaliplatin, is used to treat a variety of paediatric cancers. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. It usually manifests itself by bilateral, symmetrical, sensorineural hearing loss first affecting the higher frequencies (≥ 6000 Hz) (McHaney 1983) and it is often accompanied by tinnitus (Reddel 1982).

There is a wide variation in the reported frequency of platinum-induced hearing loss, but the frequency has been described to be as high as 88% (McHaney 1983). Hearing loss not only develops during platinum-based therapy but also years after completion of the therapy (Bertolini 2004; Knight 2005). This might be explained by the prolonged retention of platinum in the body; up to 20 years after treatment circulating platinum is still detectable in plasma (Gietema 2000). Platinum-induced hearing loss seems to be irreversible, and worsening of hearing loss occurs during follow-up (McHaney 1983; Bertolini 2004).

Different risk factors for hearing loss have been identified, such as the type of platinum analogue used. Cisplatin seems to cause substantially more hearing loss than carboplatin, and the highest incidence of hearing loss has been found in patients who received both cisplatin and carboplatin (Bertolini 2004; Dean 2008). The ototoxicity of oxaliplatin compared to the other platinum analogues is not as well established, but oxaliplatin seems to be the least ototoxic (Eloxatin SPC). Furthermore, the incidence of platinum-induced hearing loss seems to be dose-dependent, increasing with higher cumulative doses (McHaney 1983; Schell 1989; Bertolini 2004; Li 2004) and with higher individual doses (Reddel 1982; Li 2004). Different dosing formulas, like dose per body surface area or per kilogram bodyweight, can influence the platinum doses actually received, especially in infants (Leahey 2012; Qaddoumi 2012). Cranial radiotherapy (Schell 1989), younger age (Schell 1989; Li 2004; Qaddoumi 2012), genetic variants (Ross 2009; Grewal 2010; Langer 2013) and other host-specific factors (Veal 2001), impaired renal function at the time of platinum treatment (Skinner 2004), and other ototoxic drugs like aminoglycosides (Skinner 2004; Jenney 2005) and furosemide (Gallagher 1979) have been reported as additional risk factors. Finally, it has been suggested that different infusion durations (such as bolus and continuous infusions) have different levels of ototoxicity (Reddel 1982).

Why it is important to do this review

Although platinum-induced hearing loss is not life-threatening, loss of hearing, especially during the first three years of life and even when only borderline to mild, can have important implications. It can negatively impact speech and language development, which may lead to difficulties with school performance and psychosocial functioning (Gregg 2004; Skinner 2004; Dean 2008). This is even more true for children who suffer dual sensory loss, like retinoblastoma or optic pathway glioma patients.

Prevention of platinum-induced hearing loss is thus very important and might improve the quality of life of childhood cancer patients and survivors treated with platinum-based therapy. A recent systematic review has shown that at present there is no evidence which underscores the use of medical interventions, such as amifostine, to prevent the occurrence of platinum-induced ototoxicity (Van As 2012). It is thus important to identify other options, such as different platinum infusion durations.

This is, to our knowledge, the first systematic review evaluating all evidence on the use of different platinum infusion durations for the prevention of platinum-induced hearing loss in children with cancer.

Objectives

To assess the effects of any platinum infusion duration to prevent hearing loss and/or tinnitus in children with cancer treated with platinum-based therapy (i.e. including cisplatin, carboplatin and/or oxaliplatin) when compared to another infusion duration. We will also assess possible effects of these infusion durations on anti-tumour efficacy (i.e. tumour response and survival) of platinum-based therapy, on adverse effects other than hearing loss and/or tinnitus and on quality of life.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) or controlled clinical trials (CCTs).

Types of participants

Children (aged 0 to 18 years at diagnosis) with any type of childhood malignancy treated with a platinum analogue.

Studies including both children and adults are only eligible for inclusion in this review if the majority of participants are children (that is either more than 90% children or the maximal age of participants does not exceed 22 years).

Types of interventions

Platinum-based therapy using one platinum infusion duration compared to the same platinum-based therapy using another platinum infusion duration.

Only the platinum infusion duration may differ between the treatment groups; all other treatment, including type of platinum analogue(s), the individual platinum dose and radiotherapy to the head and neck should be the same in both treatment groups. In the design of the study it should have been the intention to treat both treatment groups with the same cumulative dose of cisplatin, carboplatin and/or oxaliplatin.

Types of outcome measures

Outcomes listed here are not used as criteria for including studies, but are the outcomes of interest within studies identified for inclusion. Hearing loss and tinnitus will be included irrespective of time of occurrence after platinum-based therapy.

Primary outcomes
  1. Hearing loss (as defined by the authors of the original study)

  2. Tinnitus (as defined by the authors of the original study)

  3. Overall survival (as defined by the authors of the original study)

Secondary outcomes
  1. Event-free survival (as defined by the authors of the original study)

  2. Tumour response (complete and partial remission as defined by the authors of the original study)

  3. Adverse effects (grade 3 or higher according to the criteria used by the authors of the original study) other than hearing loss and tinnitus.

  4. Quality of life (as defined by the authors of the original study)

Search methods for identification of studies

We will not impose language restrictions. Searches will be updated every two years. The Cochrane Childhood Cancer Review Group will run the searches in CENTRAL, MEDLINE and EMBASE; all other searches will be run by the review authors.

Electronic searches

We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), MEDLINE in PubMed (from 1945 to present) and EMBASE in Ovid (from 1980 to present).

The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are shown in the appendices (Appendix 1; Appendix 2; Appendix 3).

Searching other resources

We will locate information about trials not registered in CENTRAL, MEDLINE or EMBASE, either published or unpublished, by searching the reference lists of included studies and review articles. We will handsearch the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2009 to 2013). We will scan ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/en/) for ongoing trials.

Data collection and analysis

Selection of studies

After employing the search strategy described previously, two review authors will independently identify studies meeting the inclusion criteria for this review. Discrepancies between authors will be resolved by discussion. If this is impossible, we will achieve final resolution using a third-party arbitrator. We will obtain in full any study which seems to meet the inclusion criteria on the grounds of the title or abstract, or both, for closer inspection. We will clearly state details of the reasons for exclusion of any study considered for the review. We will include a flow chart of the selection of studies in the review. If there are multiple reports of the same study we will use the most recent report as the primary publication; the other available reports will be checked for data not reported in the primary publication.

Data extraction and management

Two review authors will independently perform data extraction using standardised forms. Data on the characteristics of participants (such as age, sex, type of malignancy, stage of disease, prior hearing loss, genetic variants and renal function at time of platinum treatment), interventions (such as information on the received antineoplastic treatment and possible other ototoxic drugs like aminoglycosides and furosemide), outcome measures, length of follow-up and details of funding sources and the declaration of interests for each included study will be extracted. Discrepancies between authors will be resolved by discussion. If this is impossible, we will achieve final resolution using a third-party arbitrator.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias in included studies (that is selection bias, performance bias, detection bias (for each outcome separately), attrition bias (for each outcome separately), reporting bias and other bias). We will use the 'Risk of bias' items and definitions of low risk, unclear risk and high risk as described in the module of the Cochrane Childhood Cancer Group (Kremer 2008), which is based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Discrepancies between authors will be resolved by discussion. If this is impossible, we will achieve final resolution using a third-party arbitrator. The risk of bias in included studies will be taken into account in the interpretation of the review's results.

Measures of treatment effect

Dichotomous variables will be analysed using risk ratios (RR). Continuous outcomes will be analysed using mean differences (MD) if all studies use the same scale; otherwise standardised mean differences (SMD) will be used. Survival will be analysed using hazard ratios (HR). We will use Parmar's method if HRs have not been explicitly presented in the study (Parmar 1998). We will present all results with the corresponding 95% confidence interval (CI).

Dealing with missing data

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. We will extract data by the allocated intervention, irrespective of compliance with the allocated intervention, in order to allow an intention-to-treat analysis. If this is not possible, this will be stated and we will perform an 'as treated' analysis.

Assessment of heterogeneity

We will assess heterogeneity both by visual inspection of the forest plots and by a formal statistical test for heterogeneity, that is the I² statistic. In the absence of significant heterogeneity (I² < 50%) (Higgins 2011), we will use a fixed-effect model for the estimation of treatment effects. Otherwise, we will explore possible reasons for the occurrence of heterogeneity and take appropriate measures, such as using a random-effects model.

Assessment of reporting biases

In addition to the evaluation of reporting bias as described in the Assessment of risk of bias in included studies section, we will assess reporting bias by constructing a funnel plot where there is a sufficient number of included studies (that is at least 10 studies included in a meta-analysis). When there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011).

Data synthesis

We will enter data into the Cochrane Collaboration Review Manager software and undertake analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will include outcome measures only if it was the intention of the study to perform the necessary assessments in all randomised patients (that is, not only optional or only performed in some centres). When the results of a particular outcome measure are available for less than 50% of the patients of a study, due to the associated high risk of attrition bias we will not report the results of this outcome measure. We will pool results only if both treatment groups are comparable, including the definition of outcomes used. Studies for which pooling of results is not possible will be summarised descriptively. We do not expect multi-arm studies (i.e. including more than two treatment groups); however, if these studies are included we will take appropriate measures as described in the Cochrane Handbook (Higgins 2011).

For each comparison we will prepare a 'Summary of findings' table using the GRADEprofiler software in which we plan to present the following outcomes: hearing loss, tinnitus, overall survival, event-free survival, tumour response, adverse effects other than ototoxicity and quality of life. The quality of the evidence will be assessed by two independent review authors using the five GRADE considerations, i.e. study limitations, inconsistency, indirectness, imprecision and publication bias.

Subgroup analysis and investigation of heterogeneity

If possible we will analyse data separately for patients treated with cisplatin, carboplatin, oxaliplatin or combinations of these platinum analogues.

Sensitivity analysis

For all outcomes for which pooling is possible we will perform sensitivity analyses for all 'Risk of bias' criteria separately. We will exclude studies with a high risk of bias and studies for which the risk of bias is unclear in sensitivity analyses, and compare the results of studies with a low risk of bias with the results of all available studies.

Acknowledgements

We thank Edith Leclercq for her help with developing the search strategies for the different databases. We also thank Dr ACH de Vries (Department of Pediatric Oncology, Sophia Children’s Hospital/Erasmus Medical Center, Rotterdam, the Netherlands) and an undisclosed person who kindly agreed to peer review our protocol.

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 Hearing loss the following text words will be used:

Deafness OR hearing loss OR Loss, Hearing OR hearing disorders OR auditory OR hearing impairment OR hearing impairments OR hearing impairment* OR hear* OR audiologic OR audiometry OR audiometr* OR audiogram OR ototoxicology OR ototoxic* OR hypoacusis OR hypoacuses OR hypoacus* OR ototoxicity OR deaf* OR cochleotoxicity

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

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 cis-Dichlorodiammineplatinum(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

3. For Carboplatin the following text words will be used:

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* OR Platinum OR Platinum Compounds OR platinum*

4. For Oxaliplatin and other platinum compounds the following text words will be used:

Oxaliplatin OR oxaliplatin* OR oxaliplatine OR platinum(II)-1,2-cyclohexanediamine oxalate OR 1,2-diaminocyclohexane platinum oxalate OR oxalato-(1,2-cyclohexanediamine)platinum II OR cis-oxalato-(trans-l)-1,2-diaminocyclohexane-platinum(II) OR Eloxatine OR Eloxatin OR oxaliplatin, (SP-4-2-(1S-trans))-isomer OR oxaliplatin, (SP-4-3-(cis))-isomer OR ACT 078 OR ACT-078 OR oxaliplatin, (SP-4-2-(1R-trans))-isomer OR 63121-00-6 OR 61825-94-3 OR dacotin OR dacplat OR jm-83 OR l-ohp OR oxalatoplatinum OR rp 54780 OR sr-96669 OR Platinum OR Platinum Compounds OR platinum* OR organoplatinum compounds

5. For Children the following text words will be used:

Infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat* 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

Final search 1 AND (2 OR 3 OR 4) AND 5

The search will be performed in title, abstract or keywords

*=zero or more characters

Appendix 2. Search strategy for MEDLINE (PubMed)

1. ForHearing loss the following MeSH headings and text words will be used:

Deafness OR hearing loss OR Loss, Hearing OR hearing disorder OR hearing disorders OR auditory OR hearing impairment OR hearing impairments OR hearing impairment* OR hear* OR audiology OR audiologic OR audiometry OR audiometr* OR audiogram OR audiography OR ototoxicology OR ototoxic* OR hypoacusis OR hypoacuses OR hypoacus* OR ototoxicity OR deaf* OR cochleotoxicity

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

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 cis-Dichlorodiammineplatinum(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

3. ForCarboplatin the following MeSH headings and text words will be used:

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*

4. For Oxaliplatin and other platinum compounds the following MeSH headings and textwords will be used:

Oxaliplatin OR oxaliplatin* OR 1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II) OR oxaliplatine OR platinum(II)-1,2-cyclohexanediamine oxalate OR 1,2-diaminocyclohexane platinum oxalate OR oxalato-(1,2-cyclohexanediamine)platinum II OR cis-oxalato-(trans-l)-1,2-diaminocyclohexane-platinum(II) OR Eloxatine OR Eloxatin OR oxaliplatin, (SP-4-2-(1S-trans))-isomer OR oxaliplatin, (SP-4-3-(cis))-isomer OR ACT 078 OR ACT-078 OR oxaliplatin, (SP-4-2-(1R-trans))-isomer OR 63121-00-6 OR 61825-94-3 OR dacotin OR dacplat OR jm-83 OR l-ohp OR oxalatoplatinum OR rp 54780 OR sr-96669 OR Platinum OR Platinum Compounds OR platinum* OR organoplatinum compounds [mh]

5. ForChildren the following MeSH headings and text words will be used:

Infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* 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 OR infant, newborn

6. ForRCTs/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 OR 3 OR 4) AND 5 AND 6

[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 Hearing loss the following Emtree terms and text words will be used:

1. exp hearing impairment/
2. (deafness or deaf$ or hearing impairment or hearing impairments or hearing impairment$).mp.
3. hearing loss.mp. or exp hearing loss/
4. exp hearing disorder/
5. (hearing disorder or hearing disorders).mp.
6. hear$.mp.
7. auditory.mp.
8. exp audiology/ or audiologic$.mp.
9. exp audiometry/
10. (audiometry or audiometr$ or audiogram).mp.
11. exp audiography/
12. (ototoxicology or ototoxic$ or ototoxicity).mp.
13. exp OTOTOXICITY/
14. exp HYPOACUSIS/
15. (hypoacusis or hypoacuses or hypoacus$).mp.
16. cochleotoxicity.mp.
17. or/1-16

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

1. exp CISPLATIN DERIVATIVE/ or exp CISPLATIN/ or cisplatin.mp.
2. cis-Diamminedichloroplatinum.mp.
3. Platinum Diamminodichloride.mp.
4. (cis-Platinum or cis Platinum or Dichlorodiammineplatinum or cis-Diamminedichloroplatinum or cis Diamminedichloroplatinum or cis-Dichlorodiammineplatinum).mp.
5. (Platinol or Platidiam or Platino or NSC-119875 or Biocisplatinum or CDDP or CACP).mp.
6. (cisplatin$ or abiplatin or neoplatin or cis-DDP).mp.
7. or/1-6

3. For Carboplatin the following Emtree terms and text words will be used:

1. carboplatin.mp. or exp CARBOPLATIN/
2. (CBDCA or Carbosin or Carbotec or Ercar).mp.
3. (JM-8 or JM 8 or JM8).mp.
4. (NSC-241240 or NSC 241240 or NSC241240).mp.
5. (Neocarbo ot Paraplatin or Carboplat or Paraplatine).mp.
6. (Platinwas or Ribocarbo or Blastocarb or nealorin).mp.
7. (carboplatin$ or Platinum or Platinum Compounds or platinum$).mp.
8. or/1-7

4. For Oxaliplatin and other platinum compounds the following Emtree terms and textwords will be used:

1. Oxaliplatin.mp. or exp OXALIPLATIN/
2. (oxaliplatin$ or oxaliplatine).mp.
3. 1,2-diaminocyclohexane platinum oxalate.mp. or exp platinum 1,2 diaminocyclohexane/
4. (Eloxatine or Eloxatin).mp.
5. ("ACT 078" or ACT-078).mp.
6. (dacotin or dacplat or jm-83 or l-ohp or oxalatoplatinum or rp 54780 or sr-96669).mp.
7. (oxalato 1,2 cyclohexanediamine platinum or platinum 1,2 cyclohexanediamine oxalate or platinum 1,2 diaminocyclohexane oxalate or platinum oxalate 1,2 diaminocyclohexane).mp.
8. transplastin.mp.
9. Organoplatinum Compounds.mp. or exp platinum complex/
10. 61825-94-3.rn.
11. or/1-10

5. For Children the following Emtree terms and text words will be used:

1. infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/
2. adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/
3. primary school/ or high school/ or kindergarten/ or nursery school/ or school/
4. or/1-3
5. (infant$ or newborn$ or (new adj born$) or baby or baby$ or babies or neonate$ or perinat$ or postnat$).mp.
6. (child$ or (school adj child$) or schoolchild$ or (school adj age$) or schoolage$ or (pre adj school$) or preschool$).mp.
7. (kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp.
8. (minors$ or (under adj ag$) or underage$ or juvenil$ or youth$).mp.
9. (puber$ or pubescen$ or prepubescen$ or prepubert$).mp.
10. (pediatric$ or paediatric$ or peadiatric$).mp.
11. (school or schools or (high adj school$) or highschool$ or (primary adj school$) or (nursery adj school$) or (elementary adj school) or (secondary adj school$) or kindergar$).mp.
12. or/5-11
13. 4 or 12

6. For RCTs/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 OR 3 OR 4) AND 5 AND 6

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

Declarations of interest

None known

Sources of support

Internal sources

  • Dutch Cochrane Centre, Netherlands.

External sources

  • Stichting Kinderen Kankervrij (KiKa), Netherlands.

Ancillary