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

  • Review
  • 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

Background

Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied.

Objectives

To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life.

Search methods

We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 12), MEDLINE (PubMed) (1945 to 4 December 2013) and EMBASE (Ovid) (1980 to 4 December 2013). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2009 to 2013). We scanned 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 (both searched on 13 December 2013).

Selection criteria

Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups.

Data collection and analysis

Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.

Main results

We identified one RCT and no CCTs. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (RR 1.39; 95% CI 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12; 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues.

Authors' conclusions

Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed.

Résumé scientifique

Différentes durées de perfusion pour prévenir la perte d'audition induite par le platine chez les enfants atteints d'un cancer

Contexte

Un traitement à base de platine, notamment le cisplatine, le carboplatine et l'oxaliplatine, ou une combinaison de ceux-ci, est utilisé pour traiter une variété de malignités pédiatriques. Malheureusement, l'un des effets indésirables les plus importants est la survenue d'une perte auditive ou ototoxicité. Dans un effort visant à prévenir cette ototoxicité, différentes durées de perfusion à base de platine ont été étudiées.

Objectifs

Évaluer les effets de différentes durées de perfusion de platine pour prévenir la perte d'audition ou les acouphènes, ou les deux, chez des enfants atteints d'un cancer. Les objectifs secondaires étaient d'évaluer les effets éventuels de ces durées de perfusion sur : a) l'efficacité antitumorale du traitement à base de platine, b) des effets indésirables autres que la perte d'audition ou les acouphènes, et c) la qualité de vie.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans les bases de données électroniques suivantes : registre Cochrane des essais contrôlés (CENTRAL 2013, numéro 12), MEDLINE (PubMed) (de 1945 au 4 décembre 2013) et EMBASE (Ovid) (de 1980 au 4 décembre 2013). En outre, nous avons effectué une recherche manuelle dans les références bibliographiques des articles pertinents et les actes de conférence de l'International Society for Paediatric Oncology (de 2009 à 2013). Nous avons passé au crible ClinicalTrials.gov (www.clinicaltrials.gov) et le système d'enregistrement international des essais cliniques (ICTRP) de l'Organisation mondiale de la Santé (OMS) (http://www.who.int/ictrp/en/) pour les essais en cours (les deux ont eté consultés le 13 décembre 2013).

Critères de sélection

Essais contrôlés randomisés (ECR) ou essais cliniques contrôlés (ECC) comparant différentes durées de perfusion de platine chez des enfants atteints d'un cancer. Seule la durée de perfusion de platine pouvait différer entre les groupes de traitement.

Recueil et analyse des données

Deux auteurs de la revue ont procédé indépendamment à la sélection des études, à l'évaluation du risque de biais et à l'évaluation GRADE des études incluses, et ont extrait les données, notamment les effets indésirables. Des analyses ont été effectuées conformément aux recommandations du Manuel Cochrane pour les revues systématique des interventions en santé (Cochrane Handbook for Systematic Reviews of Interventions).

Résultats principaux

Nous avons identifié un ECR et aucun ECC. L'ECR (nombre total d'enfants = 91) a évalué l'utilisation d'une perfusion continue de cisplatine (N = 43) par rapport à une perfusion d'une heure du cisplatine en bolus (N = 48) chez des enfants présentant un neuroblastome. Pour la perfusion continue, le cisplatine était administré aux jours 1 à 5 du cycle, mais il est difficile de savoir si la durée de la perfusion était un total de 5 jours. Des limitations méthodologiques étaient présentes. Seuls les résultats de peu de temps après le traitement d'induction ont été fournis. Aucune preuve probante d'une différence en termes de perte auditive (définie comme une atteinte symptomatique et asymptomatique combinées) entre les différentes durées de perfusion n'a été identifiée car les résultats étaient imprécis (RR 1,39 ; IC à 95 % de 0,47 à 4,13, preuves de faible qualité). Bien que le nombre d'enfants n'était pas fourni, il était indiqué que la réponse tumorale était équivalente dans les deux bras de traitement. En ce qui concerne les effets indésirables autres que l'ototoxicité, nous n'avons pu évaluer que les décès toxiques. De nouveau, l'intervalle de confiance de l'effet estimé était trop large pour exclure des différences entre les groupes de traitement (RR 1,12 ; IC à 95 % de 0,07 à 17,31, preuves de faible qualité). Aucune donnée n'était disponible pour les autres résultats intéressants (c'est à dire les acouphènes, la survie globale, la survie sans événement et la qualité de vie) ou pour d'autres (combinaisons de) durées de perfusion ou d'autres analogues du platine.

Conclusions des auteurs

Étant donné qu'un seul ECR éligible évaluant l'utilisation d'une perfusion continue de cisplatine versus une perfusion d'une heure du cisplatine en bolus a été identifié, et qu'il présentait des limitations méthodologiques, aucune conclusion définitive ne peut être faite. Il convient de noter que l'expression « aucune preuve d'effet », comme identifiée dans cette revue, est différente de l'expression « preuve d'une absence d'effet ». Pour d'autres (combinaisons de) durées de perfusion ou d'autres analogues du platine aucune étude éligible n'a été identifiée. Davantage de recherches de haute qualité sont nécessaires.

Plain language summary

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

Platinum-based chemotherapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat different types of childhood cancer. Unfortunately, one of the most important adverse effects of platinum chemotherapy is hearing loss. This can occur not only during treatment but also years after the end of treatment. Although it is not life-threatening, the loss of hearing, especially during the first three years of life, may lead to difficulties with school performance and psychosocial functioning. Therefore, prevention of platinum-induced hearing loss is very important and might improve the quality of life of children undergoing cancer treatment and those who have survived treatment with platinum-based chemotherapy.

The review authors identified one randomised study comparing a continuous cisplatin infusion with a one hour cisplatin bolus infusion in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the treatment cycle but it is not clear if the infusion duration was a total of 5 days. The study had methodological problems and only results from shortly after induction therapy were available. At the moment there is no evidence showing that the use of a different cisplatin infusion duration prevents hearing loss or adversely affects tumour response and adverse effects. No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. We need more high quality research before definite conclusions can be made about the usefulness of different platinum infusion durations to prevent hearing loss in children with cancer.

Résumé simplifié

Différentes durées de perfusion pour prévenir la perte d'audition induite par le platine chez les enfants atteints d'un cancer

La chimiothérapie à base de platine, comprenant le cisplatine, le carboplatine et l'oxaliplatine ou d'une combinaison de ceux-ci, est utilisée pour traiter différents types de cancers de l'enfant. Malheureusement, l'un des effets indésirables les plus importants de la chimiothérapie avec platine est la perte d'audition. Elle peut se produire non seulement pendant le traitement, mais aussi plusieurs années après la fin du traitement. Bien qu'elle ne mette pas en jeu le pronostic vital, la perte d'audition, en particulier au cours des trois premières années de la vie, peut conduire à des difficultés au niveau des performances scolaires et du fonctionnement psychosocial. Par conséquent, la prévention de la perte d'audition induite par le platine est très importante et pourrait améliorer la qualité de vie des enfants subissant un traitement anticancéreux et ceux qui ont survécu à un traitement avec une chimiothérapie à base de platine.

Les auteurs de la revue ont identifié une étude randomisée comparant une perfusion continue de cisplatine avec une perfusion d'une heure du cisplatine en bolus chez des enfants présentant un neuroblastome. Pour la perfusion continue, le cisplatine était administré aux jours 1 à 5 du cycle de traitement, mais il n'est pas clair si la durée de la perfusion était de 5 jours au total. L'étude avaient des problèmes méthodologiques et seuls les résultats de peu de temps après le traitement d'induction étaient disponibles. Actuellement, il n'existe aucune preuve montrant que l'utilisation d'une durée de perfusion de cisplatine différente prévient la perte d'audition ou a un impact négatif sur la réponse tumorale et les effets indésirables. Aucune donnée n'était disponible pour les autres résultats intéressants (c'est à dire les acouphènes, la survie globale, la survie sans événement et la qualité de vie) ou pour d'autres (combinaisons de) durées de perfusion ou d'autres analogues du platine. Nous avons besoin de plus de recherches de haute qualité avant de pouvoir tirer des conclusions définitives quant à l'utilité de différentes durées de perfusion de platine pour prévenir la perte d'audition chez les enfants atteints d'un cancer.

Notes de traduction

Traduit par: French Cochrane Centre 9th November, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Summary of findings(Explanation)

Summary of findings for the main comparison. Continuous platinum infusion compared to bolus platinum infusion for children with cancer treated with platinum-based therapy
  1. 1 The assumed risk is based on the prevalence in the control group of the included study.
    2 Presence of selection bias, performance bias, detection bias, attrition bias for outcome tumour response and other bias is unclear; high risk of attrition bias for outcome hearing loss; low risk of attrition bias for outcome adverse effects toxic death.
    3 A small study with a total number of events less than 300 (the threshold rule-of-thumb value stated in the GRADEpro software)

Continuous platinum infusion compared to bolus platinum infusion for children with cancer treated with platinum-based therapy
Patient or population: children with cancer treated with platinum-based therapy
Settings: paediatric oncology departments
Intervention: continuous platinum infusion (cisplatin was administered on days 1 to 5 of the cycle, but it is unclear if the infusion duration was thus 5 days)
Comparison: bolus platinum infusion (one hour)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Bolus platinum infusion Continuous platinum infusion
Hearing loss (asymptomatic and symptomatic disease)
exact test method not reported
139 per 1000 1 193 per 1000
(65 to 574)
RR 1.39
(0.47 to 4.13)
67
(1 study)
⊕⊕⊝⊝
low 2,3

Length of follow-up was not mentioned, but the median duration of induction was 102 days in the continuous infusion arm and 107 days in the bolus infusion arm (no significant difference) and only results from shortly after induction therapy were provided.

For 24 of the 91 children included in the study no data on hearing loss were available (12 in each treatment group). The RR presented here results from the 'available data' analysis. Intention-to-treat analyses (i.e. worst and best case scenarios) also showed no significant difference between the treatment groups.

Tinnitus - not reportedSee commentSee commentNot estimable-See commentNo information on tinnitus was provided.
Overall survival - not reportedSee commentSee commentNot estimable-See commentNo information on overall survival was provided.
Event-free survival - not reportedSee commentSee commentNot estimable-See commentNo information on event-free survival was provided.
Tumour response (complete or partial remission)See commentSee commentNot estimable (see comments)Unclear
(1 study)
⊕⊕⊝⊝
low 2,3

The number of children with a complete or partial remission was not provided, but it was stated that tumour response was equivalent in both treatment arms.

Length of follow-up was not mentioned, but the median duration of induction was 102 days in the continuous infusion arm and 107 days in the bolus infusion arm (no significant difference) and only results from shortly after induction therapy were provided.

Adverse effects: toxic death (no definition provided) 21 per 1000 1 23 per 1000
(1 to 361)
RR 1.12
(0.07 to 17.31)
91
(1 study)
⊕⊕⊝⊝
low 2,3
Length of follow-up was not mentioned, but the median duration of induction was 102 days in the continuous infusion arm and 107 days in the bolus infusion arm (no significant difference) and only results from shortly after induction therapy were provided.
Quality of life - not reportedSee commentSee commentNot estimable-See commentNo information on quality of life was provided.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Platinum-based therapy, that is therapy including cisplatin, carboplatin or oxaliplatin, or a combination of these, 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. This 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). Therefore, it is 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 different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) 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 were only eligible for inclusion in this review if the majority of participants were children (that is either more than 90% children or the maximal age of participants did not exceed 22 years).

Types of interventions

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

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

Types of outcome measures

Outcomes listed here were not used as criteria for including studies, but are the outcomes of interest within studies identified for inclusion. Hearing loss and tinnitus were 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 did not impose language restrictions. The Cochrane Childhood Cancer Review Group ran the searches in CENTRAL, MEDLINE and EMBASE; all other searches were run by the review authors.

Electronic searches

We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013 Issue 12), MEDLINE in PubMed (from 1945 to 4 December 2013) and EMBASE in Ovid (from 1980 to 4 December 2013).

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 located 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 handsearched the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2009 to 2013). We scanned 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 (both searched on 13 December 2013).

Data collection and analysis

Selection of studies

After employing the search strategy described previously, two review authors independently identified studies meeting the inclusion criteria for this review. Discrepancies between authors were resolved by discussion. No third-party arbitration was needed. We obtained in full any study which seemed to meet the inclusion criteria on the grounds of the title or abstract, or both, for closer inspection. We clearly stated details of the reasons for exclusion of any study considered for the review. We have included a flow chart of the selection of studies in the review.

Data extraction and management

Two review authors independently performed 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, details of funding sources and the declaration of interests for each included study were extracted. Discrepancies between authors were resolved by discussion. No third-party arbitration was needed.

Assessment of risk of bias in included studies

Two review authors independently assessed 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 used 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 Review Group (Kremer 2008), which is based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Discrepancies between authors were resolved by discussion. No third-party arbitration was needed. The risk of bias in included studies was taken into account in the interpretation of the review's results.

Measures of treatment effect

Dichotomous variables were analysed using risk ratios (RR). We presented all results with the corresponding 95% confidence interval (CI).

Dealing with missing data

During study selection no relevant data were missing. We attempted to contact the authors of Coze 1997 with regard to missing data for data extraction and risk of bias assessment, but unfortunately we did not receive a response. We extracted data by the allocated intervention, irrespective of compliance, in order to allow an intention-to-treat analysis. If this was not possible, this was stated and an 'available data' analysis was performed.

Assessment of heterogeneity

Since only one study was included in the review, the assessment of heterogeneity (both by visual inspection of the forest plots and by a formal statistical test for heterogeneity, that is the I² statistic (Higgins 2011)) was not applicable.

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 planned to assess reporting bias by constructing a funnel plot. This is only really possible when there are at least 10 studies included in a meta-analysis because otherwise the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011). Since only one study was included in the review this was not possible.

Data synthesis

We entered data into the Cochrane Collaboration Review Manager software and undertook analyses according to the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We included outcome measures only if it was the intention of the study to perform the necessary assessments in all randomised participants (that is, not only optional or only performed in some centres). When the results of a particular outcome measure were available for less than 50% of the participants of a study, due to the associated high risk of attrition bias we did not report the results of this outcome measure. Since only one study was included in the review pooling of results was not applicable. Results were summarised descriptively. We used a fixed-effect model throughout the review.

For each comparison we prepared a 'Summary of findings' table using the GRADEprofiler software in which we presented the following outcomes: hearing loss, tinnitus, overall survival, event-free survival, tumour response, adverse effects other than ototoxicity (grade 3 or higher) and quality of life. The quality of the evidence was 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

We planned to analyse data separately for children treated with cisplatin, carboplatin, oxaliplatin or combinations of these platinum analogues. However, all children included in the review were treated with cisplatin and as a result subgroup analyses were not possible.

Sensitivity analysis

Since only one study was included in the review, sensitivity analyses for risk of bias items (that is excluding studies with a high risk of bias and studies for which the risk of bias was unclear and comparing the results of studies with a low risk of bias with the results of all available studies) were not applicable.

Results

Description of studies

Results of the search

Running the searches in the electronic databases of CENTRAL, MEDLINE (PubMed) and EMBASE (Ovid) yielded a total of 681 references. Following initial screening of the titles, abstracts, or both, we excluded 678 references which clearly did not meet all criteria required for considering studies for this review. The three remaining references were assessed in full, of which one fulfilled all the criteria for considering studies for this review and was thus eligible for inclusion. The other 2 references were excluded for the reasons described in the Characteristics of excluded studies table.

Scanning the reference lists of the included article and reviews, conference proceedings and ongoing trials databases did not identify any additional eligible (ongoing) studies.

In summary, the total number of included studies was one. No ongoing studies were identified. See Figure 1 for a flow diagram of the selection of studies for this systematic review.

Figure 1.

Flow diagram of selection of studies

Included studies

Characteristics of the included study are summarised below. For more detailed information see the Characteristics of included studies table.

We identified one RCT (Coze 1997) evaluating a continuous cisplatin infusion versus a one hour bolus cisplatin infusion. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle, but it is unclear if the infusion duration was thus 5 days. The total number of randomised children was 91; 43 were randomised to the continuous infusion group and 48 to the bolus infusion group. Please note that this randomisation was part of a larger study; the total number of eligible participants was unclear. All participants had a newly diagnosed neuroblastoma stage 4 and were aged > 1 year at diagnosis. For detailed information on treatment see the Characteristics of included studies table. Treatment other than induction therapy was not included in the manuscript. Regarding other ototoxic drugs, participants received anthracyclines (i.e. doxorubicin) and vincristine; it was not stated if participants received gentamycin or furosemide. It was also unclear if participants had prior hearing dysfunction; at least some of the participants had pre-treatment renal impairment. Participants did not receive prior platinum treatment, prior radiotherapy to the head and neck region or prior cranial surgery. Genetic variants of platinum ototoxicity were not reported. The length of follow-up was not mentioned. Only results from shortly after induction therapy were provided.

Risk of bias in included studies

See the risk of bias section of the Characteristics of included studies table and Figure 2 for the exact scores and the support for the judgements made.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

For evaluating selection bias we have assessed the random sequence generation and the allocation concealment. Both of these items, and thus the risk of selection bias, were unclear.

Blinding

For evaluating performance bias we have assessed the blinding of participants and personnel. The study did not provide information on blinding of participants and personnel, but since children in both treatment groups received their platinum therapy with different infusion durations this was most likely not the case. However, we judged the risk of performance bias as unclear.

For evaluating detection bias we assessed the blinding of outcome assessors for all separate outcomes. For all reported outcomes, that is ototoxicity, tumour response and adverse effects (toxic death), no information on blinding of outcome assessors was provided and the risk of detection bias was thus unclear.

Incomplete outcome data

For evaluating attrition bias we assessed incomplete outcome data for all separate outcomes. The risk of attrition bias was high for ototoxicity, unclear for tumour response and low for adverse effects (toxic death).

Selective reporting

For evaluating reporting bias we assessed selective reporting. There was no study protocol mentioned in the manuscript (and we did not separately search for it), but all expected outcomes were reported taking into consideration the fact that only short-term outcomes following induction therapy were reported. We judged the risk of reporting bias to be low.

Other potential sources of bias

For evaluating other potential sources of bias we assessed the following items: block randomisation in unblinded trials, baseline imbalance between treatment groups related to outcome (prior ototoxic treatment, age, sex, prior hearing loss), difference in ototoxic drugs other than platinum analogues between treatment groups (furosemide, gentamycin, anthracyclines, vincristine), difference in cumulative platinum dose between treatment groups, difference in length of follow-up between treatment groups, difference in impaired renal function at time of platinum treatment between treatment groups, if an insensitive instrument was used to evaluate ototoxicity, and if there was inappropriate influence of funders. All these items, and thus the risk of other bias, were unclear. For a more detailed description of all different items see the risk of bias section of the Characteristics of included studies table.

Effects of interventions

See: Summary of findings for the main comparison Continuous platinum infusion compared to bolus platinum infusion for children with cancer treated with platinum-based therapy

Coze 1997 did not allow data extraction for all outcome measures (see the Characteristics of included studies table for a more detailed description of the extractable outcome measures).

Hearing loss

Coze 1997 provided data on hearing loss (see additional table 1 for the used definitions; based on the available information we were not able to distinguish between asymptomatic and symptomatic hearing loss).

For 24 of the 91 children no data on hearing loss were available (12 in each treatment group). The 'available data' analysis of asymptomatic and symptomatic hearing loss (that is grade B and higher) showed no significant difference between the treatment groups (RR 1.39; 95% CI 0.47 to 4.13; P = 0.55; see Figure 3). There were 6 cases among the 31 available children in the continuous infusion group and 5 cases among the 36 available children in the bolus infusion group. Intention-to-treat analyses (data not shown) also showed no significant difference between the treatment groups: the RR for the worst case scenario (that is 18 cases among the 43 children in the continuous infusion group and 17 cases among the 48 children in the bolus infusion group) was 1.18 (95% CI 0.70 to 1.99; P = 0.53), while the RR for the best case scenario (that is 6 cases among the 43 children in the continuous infusion group and 5 cases among the 48 children in the bolus infusion group) was 1.34 (95% CI 0.44 to 4.08; P = 0.61).

Figure 3.

Forest plot of comparison: 1 Continuous platinum infusion versus bolus platinum infusion, outcome: 1.1 Hearing loss (asymptomatic and symptomatic disease).

Tinnitus

No information on tinnitus was provided.

Overall survival

No information on overall survival was provided.

Event-free survival

No information on event-free survival was provided.

Tumour response

The number of children with a complete or partial remission (according to International Neuroblastoma Response Criteria) was not provided, but it was stated that tumour response was equivalent in both treatment arms. However, it was not mentioned in how many children this outcome was assessed.

Adverse effects (grade 3 or higher) other than hearing loss and tinnitus

In the methods section of Coze 1997 it was stated that toxicities were graded according to the World Health Organization (WHO) criteria (WHO 1979). However, the information reported in the results section was not completely in accordance with the WHO criteria, thus making grading impossible. We did not receive clarification from the authors and as a result we were only able to include results on toxic death (death is always higher than grade 3; for the other reported adverse effects grading was not possible).

The analysis of toxic death (no definition provided) showed no significant difference between the treatment groups (RR 1.12; 95% CI 0.07 to 17.31; P = 0.94; see Figure 4). There was 1 toxic death among the 43 children in the continuous infusion group and 1 toxic death among the 48 children in the bolus infusion group.

Figure 4.

Forest plot of comparison: 1 Continuous platinum infusion versus bolus platinum infusion, outcome: 1.2 Adverse effects: toxic death.

Quality of life

No information on quality of life was provided.

Discussion

Summary of main results

Platinum-based therapy is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity (McHaney 1983). Although it is not life-threatening, loss of hearing can have important implications, for example difficulties with school performance and psychosocial functioning (Gregg 2004; Skinner 2004; Dean 2008). Thus, prevention of platinum-induced hearing loss is very important. 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.

To adequately ascertain the efficacy of different platinum infusion durations, the best study design - provided that the design and execution are correct - is an RCT in which the only difference between the intervention and control group is the platinum infusion duration. CCTs can also provide reliable information, keeping in mind their limitations, but other study designs (including historical control groups) were not eligible for this review due to the high risk of bias associated with such designs.

We identified one RCT evaluating the use of a continuous cisplatin infusion versus a one hour bolus cisplatin infusion in children with newly diagnosed neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle, but it is unclear if the infusion duration was a total of 5 days. The total number of randomised children was 91; 43 were randomised to the continuous infusion group and 48 to the bolus infusion group. This randomisation was part of a larger study; the total number of eligible participants was unclear.

No significant difference in hearing loss (asymptomatic and symptomatic disease combined) between the different infusion durations was identified. An important question regarding any possible otoprotective measure during platinum treatment is whether it could decrease the ototoxicity of platinum agents without reducing the anti-tumour efficacy (that is tumour response and survival) and without negative effects on other toxicities or quality of life. The number of children with a complete or partial remission was not provided and it was unclear in how many children this outcome was assessed. However, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects of grade 3 or higher, other than ototoxicity, we were only able to assess toxic deaths. Again, no significant difference between the treatment groups was identified. No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) (see Summary of findings for the main comparison).

For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified.

Overall completeness and applicability of evidence

'No evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. The reason that no significant difference between treatment groups was identified could be the fact that the number of children included in this study was too small to detect a difference (that is low power). Also, hearing loss not only develops during platinum-based therapy but also years after completion of the therapy (Bertolini 2004; Knight 2005), so the length of follow-up could have been too short to detect a difference between the treatment groups since only results from shortly after induction therapy were provided.

It was stated that participants received a continuous cisplatin infusion and that cisplatin was administered on days 1 to 5 of the cycle, but it is unclear if the infusion duration was thus 5 days. No further information on the exact infusion duration was provided, making it impossible to use the results of this study in clinical practice. Also, the study did not provide a description of the exact test that was used to evaluate hearing loss so we cannot comment on its appropriateness (for example if age-specific tests were used or if children were checked for otitis media, common in this age group (Brock 1991)). Furthermore, the study was executed between 1987 and 1992. Since then supportive care and anti-cancer treatments have improved substantially and the applicability of its results to current clinical practice is unclear. Finally, data were not available for all outcomes of interest. As a result we cannot draw conclusions regarding those outcomes, but they are of course important for clinical practice.

Quality of the evidence

In the included study, bias could often not be ruled out due to lack of reporting. However, at this time this is the best available evidence based on RCTs and CCTs evaluating different platinum infusion durations in children with cancer.

It should be noted that although children in both treatment groups should have received the same platinum dosage schedule, the included study did not report the exact cumulative platinum dose received. If children in the bolus infusion group received a higher cumulative platinum dose than those treated with a continuous infusion, this could have led to an overestimation of the otoprotective effect of the continuous infusion (and vice versa). This uncertainty should also be kept in mind when interpreting the results of the other outcomes (response rate and adverse effects). The same is true for prior hearing loss, impaired renal function at the time of platinum treatment and the use of other ototoxic drugs like aminoglycosides (anthracyclines, gentamycin), vincristine and furosemide (Gallagher 1979; Skinner 2004; Jenney 2005; Meyer 2009). It was not clear if there were important imbalances between the treatment groups regarding these factors.

Potential biases in the review process

This systematic review used a very broad search strategy for identifying eligible studies. Thus, although it is unlikely that eligible studies were missed, it is never possible to completely rule out reporting bias. The search strategy included search terms for ototoxicity and as a result it is possible that for outcomes other than hearing loss and tinnitus more studies are available than the one identified in this review.

Authors' conclusions

Implications for practice

Since only one RCT evaluating the use of a continuous cisplatin infusion versus a one hour bolus cisplatin infusion was identified, no definitive conclusions can be made. For the continuous infusion, cisplatin was administered on days 1 to 5 of the treatment cycle but it is not clear if the infusion duration was a total of 5 days. Methodological limitations were present. No clear evidence of a difference in hearing loss between the different treatment groups was identified. However, results were imprecise. Tumour response was reported by the study to be equivalent in both treatment arms. With regard to adverse effects of grade 3 or higher other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude a difference between the treatment groups. It should be noted that 'no evidence of effect', as identified in this review is not the same as 'evidence of no effect'. No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life). Based on the currently available evidence, we are unable to draw conclusions on the benefits or harms of either infusion duration.

For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified, so no conclusions can be drawn.

Implications for research

Before definitive conclusions can be made about the efficacy of different platinum infusion durations to diminish ototoxicity in children treated with platinum-based therapy, more high quality research is needed. Future trials should preferably be RCTs. They should be performed in homogeneous study populations (with regard to, for example, tumour diagnosis and type of platinum analogues) and have a long-term follow-up. Also, valid outcome definitions (including ototoxicity, anti-tumour efficacy, adverse effects and quality of life) should be used. Appropriate age-specific hearing tests should be used to assess ototoxicity and it should be described how exactly these tests were performed. Possible risk factors for ototoxicity should be taken into account. The number of included children should be sufficient to obtain the power needed for the results to be reliable.

Acknowledgements

We thank Edith Leclercq (Trials Search Coordinator of the Cochrane Childhood Cancer Group) for her help with developing the search strategies for the different databases and running these searches. 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. Dr ACH de Vries also peer reviewed the final review, as did Dr KE Warren (Pediatric Oncology Branch of the National Cancer Institute, Bethesda, USA) and an undisclosed person; we thank all these peer reviewers. Finally, we thank Stichting Kinderen Kankervrij (KiKa) for the financial support which made it possible to perform this systematic review. The editorial base of the Cochrane Childhood Cancer Group is funded by KiKa.

Data and analyses

Download statistical data

Comparison 1. Continuous platinum infusion versus bolus platinum infusion
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Hearing loss (asymptomatic and symptomatic disease)167Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.47, 4.13]
2 Adverse effects: toxic death191Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.07, 17.31]
Analysis 1.1.

Comparison 1 Continuous platinum infusion versus bolus platinum infusion, Outcome 1 Hearing loss (asymptomatic and symptomatic disease).

Analysis 1.2.

Comparison 1 Continuous platinum infusion versus bolus platinum infusion, Outcome 2 Adverse effects: toxic death.

Appendices

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

1. For Hearing loss the following text words were 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 were 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 were 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 were 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 were 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 was 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 were 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 were 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 were 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 text words were 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 were 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 were 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 were 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 were 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 were 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 or 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 text words were 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 were 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 were used:

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

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]

Contributions of authors

Jorrit van As wrote the protocol. He identified the studies meeting the inclusion criteria. He performed the data extraction, risk of bias assessment and GRADE assessment of the included study. He analysed the data and interpreted the results. He wrote and revised the manuscript.

Henk van den Berg critically reviewed the protocol. He contributed to the interpretation of the results. He critically reviewed the manuscript.

Elvira van Dalen designed the study and critically reviewed the protocol. She developed the search strategy in collaboration with the Trials Search Coordinator of the Childhood Cancer Group. She identified the studies meeting the inclusion criteria. She searched for unpublished and ongoing studies. She performed the data extraction, risk of bias assessment and GRADE assessment of the included study. She analysed the data and interpreted the results. She wrote and revised the manuscript.

All authors approved the final version.

Declarations of interest

None known.

Sources of support

Internal sources

  • Dutch Cochrane Centre, Netherlands.

External sources

  • Stichting Kinderen Kankervrij (KiKa), Netherlands.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Coze 1997

  1. a

    INRC: International Neuroblastoma Response Criteria; INSS: International Neuroblastoma Staging System; nm: not mentioned.

Methods

Randomised controlled trial; method of randomisation not clear.

Twenty-one institutions from the French Society of Pediatric Oncology (not limited to France, for example also institutions from Belgium and Switzerland) participated between October 1987 and November 1992.

Participants

91 children (aged > 1 year at diagnosis, no further information provided; sex nm; both age and sex were equivalent in the treatment arms) with newly diagnosed neuroblastoma (stage 4 according to INSS criteria). They received induction therapy consisting of chemotherapy and surgical removal of the primary tumour at the end of induction chemotherapy unless local investigator considered surgery inadvisable. Radiotherapy nm. Treatment other than induction therapy was not included in the article.

Chemotherapy consisted of intravenous cisplatin (cumulative dose nm, but according to treatment protocol participants should receive 400 mg/m2; individual platinum dose 40 mg/m2), cyclophosphamide (cumulative dose nm, but according to treatment protocol participants should receive 3000mg/m2), vincristine (cumulative dose nm, but according to treatment protocol participants should receive 15 mg/m2), etoposide (cumulative dose nm, but according to treatment protocol participants should receive 1000 mg/m2) and doxorubicin (cumulative dose nm, but according to treatment protocol participants should receive 120 mg/m2).

Completion of scheduled chemotherapy: 41 out of 43 children (95%) in the continuous infusion arm and 47 out of 48 children (98%) in the bolus infusion arm. Reasons for not completing chemotherapy: 1 toxic death in each arm and 1 "no response" in the continuous infusion arm.

Other ototoxic drugs: anthracyclines yes (see doxorubicin earlier), vincristine yes (see earlier), gentamycin nm (prophylactic use of antibiotics was not recommended; in case of febrile neutropenia empiric antibiotics were given, but no information provided on agents or number of children), furosemide nm.

No prior platinum treatment. No prior radiotherapy to head or neck, or both. No prior cranial surgery. Prior hearing dysfunction nm. Pre-treatment renal impairment defined as creatinine clearance ≤ 90 ml/min/1.73 m2 in at least 2 children (both in the bolus infusion arm; no further information provided).

InterventionsCisplatin by continuous infusion (cisplatin was administered on days 1 to 5 of the cycle, but it is unclear if the infusion duration was thus 5 days) (N = 43) versus 1 hour bolus (N = 48).
Outcomes

Ototoxicity (according to the Brock criteria (see Table 1)); measured by audiometry (exact instrument used nm).

Tumour response (according to INRC criteria).

Adverse effects (no definition provided).

Notes

This randomised study was part of a larger study; the total number of participants eligible for the infusion duration randomisation is unclear.

Length of follow-up nm, but the median duration of induction was 102 days in the continuous infusion arm and 107 days in the bolus infusion arm (no significant difference) and only results from shortly after induction therapy were provided.

Cumulative cisplatin dose per treatment group nm.

Genetic variants for hearing loss nm.

Influence of funders not reported; this study was supported in part by grants from the Association pour la Recherche sur le Cancer, Villejuif, France. No declaration of interest of the authors was provided.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskIt was stated that this was a randomised study, but no further information on the methods of randomisation was provided.
Allocation concealment (selection bias)Unclear riskIt was stated that this was a randomised study, but no further information on the methods of randomisation was provided.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information on blinding of participants and personnel was provided. Since children in both treatment groups received their platinum therapy with different infusion durations this was most likely not the case.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information on blinding of outcome assessors was provided (for all reported outcomes).
Incomplete outcome data (attrition bias): ototoxicityHigh riskThis outcome was assessed in only 67 out of 91 children (74%).
Incomplete outcome data (attrition bias): tumour responseUnclear riskIt was not mentioned in how many children this outcome was assessed.
Incomplete outcome data (attrition bias): toxic deathLow riskThis outcome was assessed in all 91 children.
Selective reporting (reporting bias)Low riskThere was no protocol mentioned in the manuscript (and we did not search for it), but all expected outcomes were reported (taking into consideration the fact that only short-term outcomes following induction therapy were reported).
Other biasUnclear risk

Block randomization in unblinded trials: unclear (information on both method of randomisation and blinding was not provided).

Baseline imbalance between treatment arms related to outcome (prior ototoxic treatment, age, sex and/or prior hearing loss): unclear (no prior ototoxic treatment, age and sex are balanced, prior hearing loss unclear).

Difference in ototoxic drugs other than platinum analogues between treatment arms (furosemide, gentamycin, anthracyclines, vincristine): unclear (for all these agents).

Difference in cumulative platinum dose between treatment arms: unclear (not reported).

Difference in length of follow-up between treatment arms: unclear (not reported).

Difference in impaired renal function at time of platinum treatment between groups: unclear (not reported).

An insensitive instrument was used to evaluate ototoxicity: unclear (exact test method not reported).

Inappropriate influence of funders: unclear (no information provided).

Table 1. Brock criteria for the classification of hearing loss*
  1. * As reported in the methods section of the included study (Coze 1997). Coze et al refer to Brock 1987 for these criteria. However, Brock et al define grade E as "Severe, bilateral hearing loss greater than 40 dB at 8000 Hz" (so identical to grade B).

    dB: decibel; Hz: Hertz

Grade Description
ANone: bilateral hearing loss, less than 40 dB in all frequencies
BMild: bilateral hearing loss, greater than 40 dB at 8000 Hz
CModerate: bilateral hearing loss, greater than 40 dB at 6000 Hz
DMarked: bilateral hearing loss, greater than 40 dB at 4000 Hz
ESevere: bilateral hearing loss, greater than 40 dB at 2000 Hz

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomised controlled trial; CCT: controlled clinical trial.

Bergeron 2005Not an RCT or CCT; no evaluation of different platinum infusion durations.
Lanvers-Kaminsky 2006Not an RCT or CCT; more than only the platinum infusion duration different between treatment groups.