Medical interventions for the prevention of platinum-induced hearing loss in children with cancer

  • Review
  • Intervention

Authors

  • Jorrit W van As,

    1. Emma Children's Hospital/Academic Medical Center, c/o Cochrane Childhood Cancer Group, Amsterdam, Netherlands
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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

    Corresponding author
    1. Emma Children's Hospital/Academic Medical Center, Department of Paediatric Oncology, Amsterdam, Netherlands
    • Elvira C van Dalen, Department of Paediatric Oncology, Emma Children's Hospital/Academic Medical Center, PO Box 22660, Amsterdam, 1100 DD, Netherlands. e.c.vandalen@amc.uva.nl.

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Abstract

Background

Platinum-based therapy, including cisplatin, carboplatin and/or oxaliplatin, 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 otoprotective medical interventions have been studied. This review is an update of a previously published Cochrane review.

Objectives

The primary objective was to assess the efficacy of any medical intervention to prevent hearing loss in children with cancer treated with platinum-based therapy (that is including cisplatin, carboplatin and/or oxaliplatin) when compared to placebo, no additional treatment or a different protective medical intervention. Secondary objectives were to determine possible effects of these interventions on anti-tumour efficacy, toxicities other than hearing loss and quality of life.

Search methods

We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (PubMed) (1945 to 17 March 2014) and EMBASE (Ovid) (1980 to 17 March 2014). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2006 to 2013), the American Society of Pediatric Hematology/Oncology (2007 to 2013) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010 to 2013). We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register and the National Institute of Health Register for ongoing trials (www.controlled-trials.com) (searched on 17 March 2014).

Selection criteria

Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating platinum-based therapy together with an otoprotective medical intervention versus platinum-based therapy with placebo, no additional treatment or another protective medical intervention in children with cancer.

Data collection and analysis

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

Main results

We identified two RCTs and one CCT (total number of patients 149) evaluating the use of amifostine versus no additional treatment in the original version of the review; in this update no additional studies were identified. Two studies included children with osteosarcoma, and the other study included children with hepatoblastoma. Patients received cisplatin only or a combination of cisplatin and carboplatin, either administered intra-arterially or intravenously. All studies had methodological limitations. Unfortunately pooling of the results of the included studies was not possible. However, in the individual studies no significant difference was identified in symptomatic ototoxicity only (that is grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (that is grade 1 or higher) between children treated with or without amifostine. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided information on tumour response, defined as the number of patients with a good or partial remission. The available data analysis (data were missing for one patient), best case scenario analysis and worst case scenario analysis all showed a difference in favour of amifostine, but this difference was significant only in the worst case scenario analysis (P = 0.04). No information on survival was available for any of the included study populations. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of patients with adverse effects other than ototoxicity grade 3 or higher. There was a significant difference in favour of the control group in the occurrence of vomiting grade 3 or 4 (risk ratio (RR) 9.04; 95% confidence interval (CI) 1.99 to 41.12; P = 0.004). No significant difference was identified between treatment groups for cardiotoxicity and renal toxicity grade 3 or 4. None of the studies evaluated quality of life. No eligible studies were found for possible otoprotective medical interventions other than amifostine and other types of malignancies.

Authors' conclusions

At the moment there is no evidence from individual studies in children with osteosarcoma or hepatoblastoma treated with different platinum analogues and dosage schedules which underscores the use of amifostine as an otoprotective intervention as compared to no additional treatment. Since pooling of results was not possible and all studies had serious 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'. Based on the currently available evidence, we are not able to give recommendations for clinical practice. No eligible studies were identified for other possible otoprotective medical interventions and other types of malignancies, so no conclusions can be made about their efficacy in preventing ototoxicity in children treated with platinum-based therapy. More high quality research is needed.

Résumé scientifique

Interventions médicales pour la prévention de la perte d'audition induite par le platine chez les enfants atteint d'un cancer

Contexte

Un traitement à base de platine, notamment la cisplatine, la carboplatine et/ou l'oxaliplatine, permet de traiter une variété de malignités pédiatriques. Malheureusement, l'un de ses effets indésirables les plus importants est la survenue de la perte d'audition ou de l'ototoxicité. Afin de prévenir cette ototoxicité, différentes interventions médicales otoprotectrices ont été étudiées. Ceci est une mise à jour d'une revue Cochrane publiée précédemment sur ce sujet.

Objectifs

L'objectif principal était d'évaluer l'efficacité de toute intervention médicale dans la prévention de la perte d'audition chez les enfants cancéreux suivant un traitement à base de platine (c.-à-d. incluant de la cisplatine, de la carboplatine et/ou de l'oxaliplatine), par rapport à un placebo, à l'absence de traitement d'appoint ou à une autre intervention médicale protectrice. Les objectifs secondaires étaient de déterminer les effets éventuels de ces interventions sur l'efficacité antitumorale, les toxicités autres que la perte d'audition et la qualité de vie.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans les bases de données électroniques du registre Cochrane des essais contrôlés (CENTRAL) (Bibliothèque Cochrane 2014, numéro 1), MEDLINE (PubMed) (de 1945 au 17 mars 2014) et EMBASE (Ovid) (de 1980 au 17 mars 2014). Nous avons également effectué des recherches manuelles dans les listes bibliographiques des articles pertinents et les actes de conférence de l'International Society for Paediatric Oncology (de 2006 à 2013), de l'American Society of Pediatric Hematology/Oncology (de 2007 à 2011) et de l'International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (de 2010 à 2013). Nous avons consulté le registre ISRCTN (International Standard Randomized Controlled Trial Number) et le registre National Institute of Health afin d'identifier des essais en cours (www.controlled-trials.com) (recherches effectuées le 17 mars 2014).

Critères de sélection

Des essais contrôlés randomisés (ECR) ou des essais cliniques contrôlés (ECC) comparant un traitement à base de platine avec intervention médicale otoprotectrice à un traitement à base de platine avec placebo, l'absence de traitement supplémentaire ou une autre intervention médicale protectrice chez des enfants atteints d'un cancer.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné les études, évalué les risques de biais des études incluses et extrait des données, y compris les effets indésirables. Des analyses ont été effectuées conformément aux instructions du guide Cochrane sur les revues systématiques des interventions (Cochrane Handbook for Systematic Reviews of Interventions).

Résultats principaux

Pour la version initiale de la revue, nous avions identifié deux ECR et un ECC (avec un total de 149 patients) comparant l'administration d'amifostine à l'absence de traitement supplémentaire ; aucune autre étude n'a été identifiée lors de cette mise à jour. Deux études incluaient des enfants atteints d'un ostéosarcome, et l'autre étude incluait des enfants atteints d'un hépatoblastome. Les patients recevaient uniquement de la cisplatine ou une combinaison de cisplatine et de carboplatine, administrée en intra-artériel ou par intraveineuse. Toutes ces études présentaient des limitations méthodologiques. Malheureusement, il était impossible de grouper les résultats des études incluses. Toutefois, dans les études individuelles, aucune différence significative n'a été identifiée au niveau de l'ototoxicité symptomatique seule (niveau 2 ou supérieur) et de l'ototoxicité symptomatique et asymptomatique combinées (niveau 1 ou supérieur) entre les enfants traités avec ou sans amifostine. Une seule étude, incluant des enfants atteints d'ostéosarcome traités par cisplatine en intra-artériel, fournissait des informations sur la réponse tumorale, définie par le nombre de patients présentant une rémission satisfaisante ou partielle. L'analyse des données disponibles (il manquait certaines données pour un patient) ainsi que les analyses du scénario le plus optimiste et le plus pessimiste montraient toutes une différence en faveur de l'amifostine, mais cette différence était uniquement significative dans l'analyse du scénario le plus pessimiste (P = 0,04). Aucune information sur la survie n'était disponible pour aucune des populations incluses de l'étude. Une seule étude, incluant des enfants atteints d'un ostéosarcome traités par cisplatine en intra-artériel, fournissait des données sur le nombre de patients présentant des effets indésirables autres qu'une ototoxicité de niveau 3 ou supérieur. Il y avait une différence significative en faveur du groupe témoin concernant la survenue de vomissements de niveau 3 ou 4 (risque relatif (RR) 9,04 ; intervalle de confiance (IC) à 95 % de 1,99 à 41,12 ; P = 0,004). Aucune différence significative n'a été identifiée entre les groupes de traitement concernant la cardiotoxicité et la toxicité rénale de niveau 3 ou 4. Aucune des études n'a évalué la qualité de vie. Aucune étude éligible n'a identifié d'éventuelles interventions médicales otoprotectrices autres que l'amifostine et d'autres types de malignités.

Conclusions des auteurs

À l'heure actuelle, il n'existe aucune preuve dans les études individuelles, réalisées chez des enfants atteints d'un ostéosarcome ou d'un hépatoblastome traités par plusieurs analogues du platine et des calendriers posologiques, qui mettent en évidence l'administration d'amifostine comme intervention otoprotectrice par rapport à l'absence de traitement supplémentaire. Étant donné que le regroupement des résultats était impossible et que toutes les études présentaient des limitations méthodologiques notables, aucune conclusion définitive ne peut être émise. Notons que l'expression « aucune preuve d'effet », comme identifiée dans cette revue, est différente de l'expression « preuve d'une absence d'effet ». En fonction des preuves actuellement disponibles, nous ne pouvons émettre aucune recommandation pour la pratique clinique. Aucune étude éligible n'ayant été identifiée pour les autres éventuelles interventions médicales otoprotectrices et les autres types de malignités, aucune conclusion ne peut être émise quant à leur efficacité à prévenir l'ototoxicité chez les enfants suivant un traitement à base de platine. D'autres recherches de qualité supérieure devront être réalisées.

Plain language summary

Drugs to prevent hearing loss in children receiving platinum chemotherapy for cancer

Platinum-based chemotherapy, including cisplatin, carboplatin and/or oxaliplatin, is used in the treatment of 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 hearing loss 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. 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 chemotherapy.

The review authors identified two randomized studies and one controlled study, all comparing amifostine with no additional treatment. Two studies included children with osteosarcoma, the other study included children with hepatoblastoma. All studies had methodological problems. Unfortunately combining the results of the included studies was not possible. At the moment there is no evidence from individual studies showing that the use of amifostine prevents hearing loss. Data on tumour response and adverse effects were available from only one study, so no definitive conclusions can be made. None of the studies assessed survival and quality of life. No adequate studies were identified for other possible drugs to prevent hearing loss and for other types of cancer. Before definitive conclusions can be made about the usefulness of possible drugs to prevent hearing loss (either amifostine or another drug) in children treated with platinum chemotherapy more high quality research is needed.

Résumé simplifié

Médicaments permettant de prévenir la perte d'audition suite à une chimiothérapie au platine chez les enfants atteints d'un cancer

La chimiothérapie au platine, notamment la cisplatine, la carboplatine et/ou l'oxaliplatine, permet de traiter différents types de cancers de l'enfant. Malheureusement, l'un des effets indésirables les plus importants de la chimiothérapie au platine est la perte d'audition. Elle survient non seulement pendant le traitement, mais aussi plusieurs années après la fin du traitement. Bien que la perte d'audition ne soit pas potentiellement mortelle, surtout lors des trois premières années de vie, elle peut entraîner des difficultés au niveau des performances scolaires et du fonctionnement psychologique. La prévention de la perte d'audition induite par le platine est donc très importante et peut améliorer la qualité de vie des enfants atteints d'un cancer et de ses survivants ayant suivi une chimiothérapie au platine.

Les auteurs de la revue ont identifié deux études randomisées et une étude contrôlée, toutes comparaient l'amifostine à l'absence d'un traitement supplémentaire. Ces deux études incluaient des enfants atteints d'un ostéosarcome, l'autre étude incluait des enfants atteints d'un hépatoblastome. Toutes présentaient des problèmes méthodologiques. Malheureusement, il était impossible de combiner les résultats des études incluses. À l'heure actuelle, il n'existe aucune preuve dans les études individuelles montrant que l'administration d'amifostine prévient la perte d'audition. Des données concernant la réponse tumorale et les effets indésirables étaient disponibles dans une seule étude. Par conséquent, il est impossible de tirer des conclusions définitives. Aucune des études n'a évalué la survie et la qualité de vie. Aucune étude adéquate n'a été identifiée concernant d'autres types de cancer et l'administration d'autres médicaments possibles pour prévenir la perte d'audition. D'autres recherches de meilleure qualité devront être réalisées avant de tirer des conclusions définitives sur l'utilité des médicaments possibles pour prévenir la perte d'audition (l'amifostine ou un autre médicament) chez les enfants ayant suivi une chimiothérapie au platine.

Notes de traduction

Traduit par: French Cochrane Centre 8th June, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Summary of findings(Explanation)

Summary of findings for the main comparison. Amifostine compared to no otoprotective intervention 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 and other bias is unclear; low risk of attrition bias and reporting bias.
    3 A small study with a total number of events less than 300 (the threshold rule-of-thumb value stated in the GRADEpro software).
    4 This was a controlled clinical trial.
    5 High risk of selection bias, performance bias, attrition bias and reporting bias; unclear riks of detection bias and other bias.
    6 High risk of attrition and reporting bias; unclear riks of selection bias, performance bias and other bias; low risk of detection bias.

Amifostine compared to no otoprotective intervention for children with cancer treated with platinum-based therapy
Patient or population: children with cancer treated with platinum-based therapy
Settings: pediatric oncology departments
Intervention: amifostine
Comparison: no otoprotective intervention
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
No otoprotective intervention Amifostine
Ototoxicity (that is hearing loss or tinnitus, or both)
Ototoxicity according to NCI CTCv2 criteria with intra-arterial platinum (combined asymptomatic and symptomatic disease)
Exact test method not reported
769 per 1000 1 992 per 1000
(723 to 1000)
RR 1.29
(0.94 to 1.77)
28
(1 study)
⊕⊕⊝⊝
low 2,3

Length of follow-up was not mentioned

When only looking at symptomatic disease also no significant difference between treatment groups was identified (RR 0.87; 95% CI 0.14 to 5.32)

Ototoxicity according to NCI CTCv2 criteria with intravenous platinum (combined asymptomatic and symptomatic disease)
Objective and subjective audiometric evaluations were performed, no further information provided
789 per 1000 1 821 per 1000
(600 to 1000)
RR 1.04
(0.76 to 1.44)
36
(1 study4)
⊕⊕⊝⊝
low 3,5

Length of follow-up was not mentioned

For 3 of the 39 children included in the study (all in the amifostine group) no data on ototoxicity were available. The RR reported here results from the 'available data' analysis. Intention-to-treat analyses (i.e. best case and worst case scenarios) also showed no significant difference between the treatment groups

When only looking at symptomatic disease also no significant difference between treatment groups was identified (available data analysis: RR 0.87; 95% CI 0.14 to 5.32; intention-to-treat analyses (i.e. best case and worst case scenarios) also showed no significant difference between the treatment groups)

Ototoxicity according to modified Brock criteria with intravenous platinum (combined asymptomatic and symptomatic disease)
Audiograms were performed, but no further information provided
556 per 1000 1 594 per 1000
(411 to 861)
RR 1.07
(0.74 to 1.55)
82
(1 study)
⊕⊕⊝⊝
low 3,6

Length of follow-up was not mentioned

It should be noted that these 82 children were part of a larger study group; they were considered in a special interim analysis of the incidence of toxicity. The total number of eligible patients was unclear and as a result we were not able to perform an intention-to-treat analysis. Also, we were not able to check if the ototoxicity results were available for at least 50% of the eligible patients. In the methods section we stated that if that was not the case, we would not report the results due to the associated high risk of attrition bias. We decided to give this study the benefit of the doubt

When only looking at symptomatic disease also no significant difference between treatment groups was identified (RR 1.00; 95% CI 0.57 to 1.75)

Tumour response
Tumour response with intra-arterial platinum (good and partial remission) 583 per 1000 1 933 per 1000
(566 to 1000)
RR 1.6
(0.97 to 2.63)
27
(1 study)
⊕⊕⊝⊝
low 2,3

Length of follow-up was not mentioned

For 1 of the 28 children included in the study (in the control group) no data on tumour response were available. The RR reported here results from the available data analysis. Intention-to-treat analyses also showed no significant difference between the treatment groups in the best case scenario, but in the worst case scenario there was a significant difference in favour of amifostine

The studies using intravenous platinum did not report on this outcome

Survival
Survival (overall and event-free) - not reportedSee commentSee commentNot estimable-See commentNo information on overall and event-free survival was provided
Adverse effects other than ototoxicity
Renal toxicity / vomiting/ cardiotoxicity (all grade 3 or higher according to NCI CTCv2 criteria) with intra-arterial platinumSee commentSee commentSee comment28
(1 study)
See comment

Length of follow-up was not mentioned

Renal toxicity: no significant difference between treatment groups was identified (Fischer’s exact test P = 0.21)

Vomiting: there was a significant difference in favour of the control group (RR 9.04; 95% CI 1.99 to 41.12)

Cardiotoxicity: none of the patients in this study experienced cardiac toxicity grade 3 or 4

The studies using intravenous platinum did not provide adequate data on adverse effects

Quality of Life
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; NCI CTCv2: National Cancer Institute Common Toxicity Criteria version 2
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, including cisplatin, carboplatin and/or oxaliplatin, is used to treat a variety of paediatric malignancies. Unfortunately one of the most important adverse effects is the occurrence of hearing loss (ototoxicity). It usually manifests as bilateral, symmetrical, sensorineural hearing loss first affecting the higher frequencies (≥ 6000 Hz) (McHaney 1983) and 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). The 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 the 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 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 as 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). Also, bolus injections have been reported to be more ototoxic than longer infusion durations (Reddel 1982), although this was not confirmed in a recent Cochrane systematic review (Van As 2014). Additional risk factors are cranial radiotherapy (Schell 1989), younger age (Schell 1989; Li 2004), genetic variants (Ross 2009; Grewal 2010) 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; Cancer in Children 2005) and furosemide (Gallagher 1979).

Description of the intervention

In an effort to prevent or reduce platinum-induced hearing loss, extensive research has been devoted to the identification of medical interventions capable of ameliorating this adverse effect. Cisplatin interacts with cochlear tissues such as the outer hair cells of the organ of Corti, stria vascularis, spiral ligament and spiral ganglionic cells to generate a reactive oxygen species (ROS) response while also depleting the antioxidant enzyme system that would scavenge and neutralize this increase in superoxides. Cisplatin accumulates in the cochlear tissue, integrates into the DNA and causes inefficient and dysfunctional protein and enzyme synthesis. The cochlea, because of its unique anatomical position and isolation, is practically a closed system and is therefore unable to flush out the accumulated toxins with the rapid pace of their generation. This results in ROS overload and a decreased antioxidant system leading to irreversible cell injury (Rybak 2007; Rybak 2009). Thus, antioxidants such as amifostine (Gallegos-Castorena 2007; Fouladi 2008) and sodium thiosulfate (Freyer 2009) might be good treatment options against platinum-induced hearing loss. Furthermore, other medical interventions such as neurotrophins, A1 adenosine receptors and dexamethasone have been studied (Rybak 2009).

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).

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.

This is an update of the first systematic review evaluating all medical interventions for the prevention of platinum-induced hearing loss in children with cancer (Van As 2012).

Objectives

Primary objective

  • To assess the efficacy of any medical intervention to prevent hearing loss in children with cancer and treated with platinum-based therapy (that is including cisplatin, carboplatin and/or oxaliplatin) when compared to placebo, no additional treatment or a different protective medical intervention

Secondary objectives

  • To determine possible effects of these protective medical interventions on the anti-tumour efficacy (that is tumour response and survival) of platinum-based therapy

  • To determine possible effects of these protective medical interventions on toxicities other than hearing loss and quality of life

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating platinum-based therapy together with a protective medical intervention versus platinum-based therapy with placebo, no additional treatment or another protective medical intervention in children with cancer.

Types of participants

Children (aged 0 to 18 years at diagnosis) with any type of childhood malignancy. 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 did not exceed 22 years).

Types of interventions

Platinum-based therapy together with a protective medical intervention versus platinum-based therapy with placebo, no additional treatment or another protective medical intervention.

Treatment other than with cisplatin, carboplatin and/or oxaliplatin and the investigated protective medical intervention should be the same in both treatment groups, including radiotherapy to the head or neck, or both. In both treatment groups the same platinum analogue(s) should have been given with the same infusion duration and individual dose. 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

Primary outcomes

1. Hearing loss (as defined by the authors of the original studies)

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

Secondary outcomes

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

2. Survival (overall survival and event-free survival as defined by the authors of the original study)

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

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

Search methods for identification of studies

See: Cochrane Childhood Cancer Group methods used in reviews (Module CCG)

We did not impose language restrictions.

Electronic searches

We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE in PubMed (from 1945 to 17 March 2014) and EMBASE in Ovid (from 1980 to 17 March 2014).

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 MEDLINE, EMBASE or CENTRAL, either published or unpublished, by searching the reference lists of relevant articles and review articles. We handsearched the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2006 to 2013), the American Society of Pediatric Hematology/Oncology (ASPHO) (from 2007 to 2013) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (from 2010 to 2013). We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register and the National Institute of Health (NIH) Register for ongoing trials (www.controlled-trials.com) (searched on 17 March 2014).

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 the details of the reasons for exclusion of any study considered for the review.

Data extraction and management

Two review authors independently performed data extraction using standardized forms. Data on the characteristics of participants (such as age, stage of disease and renal function), interventions (such as route of delivery, dose and timing of the protective medical intervention, information on the received anti-neoplastic treatment and possible other ototoxic drugs like aminoglycosides and furosemide), outcome measures and length of follow-up 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 the included studies (that is selection bias, performance bias, detection bias, attrition bias, reporting bias and other potential sources of bias). We used the risk of bias items as described in the module of the Childhood Cancer Group (Module CCG), which are 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 the 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). All results were presented with the corresponding 95% confidence interval (CI).

Dealing with missing data

During study selection no relevant data were missing. We attempted to contact the study authors with regard to missing data for data extraction and risk of bias assessment. The primary author of Katzenstein 2009 told us that they were in the process of writing a final manuscript. Some of our requested data might be in there but at the time he was not able to provide us with the additional data. During the update of this review this manuscript was not yet available. We did not receive additional information from Gallegos-Castorena 2007 and Petrilli 2002. We extracted the data by the allocated intervention, irrespective of compliance with the allocated intervention, in order to allow an intention-to-treat analysis. If this was not possible, this was stated and an as treated or available data analysis was performed.

Assessment of heterogeneity

Since pooling of results was not possible, 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' section, we planned to assess reporting bias by constructing a funnel plot when there were a sufficient number of included studies (that is at least 10 studies included in a meta-analysis) because otherwise the power of the test is too low to distinguish chance from real asymmetry (Higgins 2011). Since pooling of results was not possible, this was not applicable.

Data synthesis

We entered data into the Review Manager (RevMan) software as provided by The Cochrane Collaboration; analyses were performed 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 randomized patients (so not optional, or only performed in some centres). When the results of a particular outcome measure were available for less than 50% of the patients of a study, due to the associated high risk of attrition bias, we did not report the results of this outcome measure. We performed pooling of results only if both treatment groups were comparable, including the definition of ototoxicity that was used. Studies for which pooling of results was not possible were summarized descriptively. We used a fixed-effect model throughout the review. For outcomes where only one study was available, we were unable to calculate a RR if one of the treatment groups experienced no events and the Fischer’s exact test was used instead. All RRs, 95% CIs and P values mentioned in the results were calculated in RevMan, with the exception of the Fischer's exact P value (calculated in statcalc.exe).

For each comparison we prepared a summary of findings table using the GRADEprofiler software, in which we presented the following outcomes: ototoxicity (that is hearing loss, tinnitus, or both), tumour response, survival (overall and event-free), 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: study limitations, inconsistency, indirectness, imprecision and publication bias.

Subgroup analysis and investigation of heterogeneity

We planned to analyse data separately for patients treated with cisplatin, carboplatin, oxaliplatin or combinations of these platinum analogues. However, since pooling of results was not possible subgroup analyses were not applicable.

Sensitivity analysis

Since pooling of results was not possible, 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

We ran searches of the electronic databases CENTRAL, MEDLINE (PubMed) and EMBASE (Ovid) in December 2011 for the original version of this review. This search yielded a total of 573 references. Following initial screening of the titles, abstracts, or both, we excluded 551 references which clearly did not meet all criteria required for considering studies for this review. The 22 remaining references were assessed in full, of which three fulfilled all the criteria for considering studies for this review and were thus eligible for inclusion. One reference described an ongoing study (see the Characteristics of ongoing studies table) and the remaining 18 references were excluded for the reasons described in the Characteristics of excluded studies table.

For the update we ran searches of CENTRAL, MEDLINE (PubMed) and EMBASE (Ovid) in March 2014 yielding a total of 138 references which were added to the search results from December 2011. Initial screening of the titles, abstracts, or both, excluded all 138 references as they clearly did not meet the inclusion criteria.

Scanning the reference lists of included articles and reviews and the conference proceedings did not identify any additional eligible studies. By scanning the ongoing trials databases we identified one additional ongoing trial (see the Characteristics of ongoing studies table).

Both ongoing trials were identified at the time of the first version of the review; at the time of the update no full text publications were available.

In summary, the total number of included studies was three. We also identified two ongoing studies. 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

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

We identified two RCTs (Gallegos-Castorena 2007; Katzenstein 2009) and one CCT (Petrilli 2002), all evaluating amifostine as a possible otoprotective intervention. The total number of patients included in these studies was 149: 72 patients received amifostine whereas 77 patients received no otoprotective intervention. Please note that the presented patients in Katzenstein 2009 were considered in a special interim analysis of the incidence of toxicity; the total number of eligible patients was unclear. Patients were aged between 0 and 22 years. In all studies amifostine was given as a 740 mg/m2 dose in a 15 minute infusion immediately prior to the platinum doses; for more detailed information see the Characteristics of included studies table. In two studies patients were diagnosed with an osteosarcoma (Petrilli 2002; Gallegos-Castorena 2007); in the other study the patients were diagnosed with hepatoblastoma (Katzenstein 2009). In one study patients received cisplatin (Gallegos-Castorena 2007), in one study patients received a combination of cisplatin and carboplatin (Petrilli 2002), and in one study patients received either cisplatin or a combination of cisplatin and carboplatin depending on the stage of disease and randomization (Katzenstein 2009). For detailed information on the cumulative platinum doses, individual platinum doses, platinum infusion durations, route of delivery and other agents included in the chemotherapeutic protocols see the Characteristics of included studies table. Regarding other ototoxic drugs, in two studies patients received anthracyclines (that is doxorubicin) (Petrilli 2002; Gallegos-Castorena 2007) and in one study some of the patients received vincristine (Katzenstein 2009); no study stated if patients received gentamycin or furosemide. In two studies patients did not have prior hearing dysfunction and pre-treatment renal impairment (Petrilli 2002; Katzenstein 2009), whereas in the other study this was unclear. In none of the studies patients received prior platinum treatment, prior radiotherapy to the head and neck region, or prior cranial surgery. Genetic variants of platinum ototoxicity were not reported in any of the studies. Finally, none of the studies reported the length of follow-up.

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 per study and the support for the judgements made.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

For evaluating selection bias we have assessed the random sequence generation and the allocation concealment. Both these items, and thus the risk of selection bias, were unclear in two studies (Gallegos-Castorena 2007; Katzenstein 2009). In the other study (Petrilli 2002) there was a high risk of selection bias; randomization was not performed since this was a CCT.

Blinding

For evaluating performance bias we have assessed the blinding of participants and personnel. In two studies the risk of performance bias was unclear (Gallegos-Castorena 2007; Katzenstein 2009). In the other study (Petrilli 2002) the risk of performance bias was high; patients treated with amifostine were consecutive patients so blinding was not possible.

For evaluating detection bias we have evaluated the blinding of outcome assessors for all separate outcomes. For ototoxicity the risk of detection bias was low in one study (Katzenstein 2009) and unclear in two studies (Petrilli 2002; Gallegos-Castorena 2007). Response rate and adverse effects were evaluated in only one study; the risk of detection bias was unclear for both these outcomes (Gallegos-Castorena 2007).

Incomplete outcome data

For evaluating attrition bias we have assessed incomplete outcome data for all separate outcomes. In one study the risk of attrition bias was low for all outcomes, that is ototoxicty, response rate and adverse effects (Gallegos-Castorena 2007). In the other two studies the risk of attrition bias was high for the reported outcome, that is ototoxicity (Petrilli 2002; Katzenstein 2009).

Selective reporting

For evaluating reporting bias we have assessed selective reporting. In one study the risk of reporting bias was low (Gallegos-Castorena 2007). In the other two studies the risk of reporting bias was high (Petrilli 2002; Katzenstein 2009).

Other potential sources of bias

For evaluating other potential sources of bias we have assessed the following items: block randomization 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 analogue 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 the time of platinum treatment between treatment groups, and if an insensitive instrument was used to evaluate ototoxicity. In all three studies the risk of other potential sources of bias was 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 Amifostine compared to no otoprotective intervention for children with cancer treated with platinum-based therapy

Not all articles allowed data extraction for all endpoints (see the Characteristics of included studies table for a more detailed description of the extractable endpoints from each article). All RRs, 95% CIs and P values mentioned below were calculated in RevMan, with the exception of the Fischer's exact P value (calculated in statcalc.exe).

Ototoxicity (that is hearing loss or tinnitus, or both)

Data on ototoxicity could be extracted from all three eligible trials (Petrilli 2002; Gallegos-Castorena 2007; Katzenstein 2009). Unfortunately it was not possible to pool the results of this outcome. Two studies used a comparable definition but in one study patients received their platinum treatment intra-arterially (Gallegos-Castorena 2007) and in the other it was given intravenously (Petrilli 2002). Due to the potential influence of this difference on the occurrence of ototoxicity pooling was not possible. The other study (Katzenstein 2009) initially used the same definition as the other two trials but during the study it was decided that using that definition substantially underestimated the true incidence of significant hearing loss and it was decided to use another definition instead. The authors were not able to provide results using the initial definition and therefore pooling was not possible. For the definitions used in the different studies see Table 1 (for Petrilli 2002; Gallegos-Castorena 2007) and Table 2 (for Katzenstein 2009).

Table 1. NCI CTC version 2 "Inner ear and hearing"*
  1. NCI CTC: National Cancer Institute Common Toxicity Criteria

    *: from NCI CTCv2

Grade Description
0Normal
1Hearing loss on audiometry only
2Tinnitus or hearing loss, not requiring hearing aid or treatment
3Tinnitus or hearing loss, correctable with hearing aid or treatment
4Severe uni- or bilateral hearing loss (deafness), not correctable
Table 2. Modified Brock criteria for the classification of hearing loss*
  1. dB: decibel; kHz: kilohertz

    *: from Katzenstein 2009

Grade of hearing loss Description Potential clinical effects on hearing
0≤20 dB at 1, 2 and 4 kHzNone
1a>40 dB at any frequency from 6 kHz to 12 kHzMeasurable
1b>20 dB but ≤40 dB at any frequency from 3 kHz to 5 kHzMeasurable
2a>40 dB at any frequency from 3 kHz to 5 kHzNoticeable
2b>20 dB but ≤40 dB at 2 kHzNoticeable
3>40 dB at 2 kHzCorrectable with hearing aids
4>40 dB at 1 kHzSpeech comprehension deficits even with hearing aids

Data on ototoxicity (defined as National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 2 or NCI CTCv2) with the use of intra-arterial platinum chemotherapy could be extracted from one study with a total of 28 patients (Gallegos-Castorena 2007). All 15 patients randomized to amifostine had asymptomatic or symptomatic ototoxicity (that is grade 1 and higher); and 10 out of 13 patients in the control group. The analysis showed no significant difference between the treatment groups (RR 1.29; 95% CI 0.94 to 1.77; P = 0.11; see Figure 3). There were two cases of symptomatic ototoxicity (that is grade 2 and higher) among 15 patients randomized to amifostine and two cases among the 13 patients in the control group. The analysis showed no significant difference between the treatment groups (RR 0.87; 95% CI 0.14 to 5.32; P = 0.88; see Figure 4). It should be noted that the patients who suffered from symptomatic ototoxicity were included in both analyses.

Figure 3.

Forest plot of comparison: 1 Amifostine versus no otoprotective intervention, outcome: 1.1 Ototoxicity according to NCI CTC v2 criteria with intra-arterial platinum (combined asymptomatic and symptomatic disease).

Figure 4.

Forest plot of comparison: 1 Amifostine versus no otoprotective intervention, outcome: 1.4 Ototoxicity according to NCI CTC v2 criteria with intra-arterial platinum (symptomatic disease).

Data on ototoxicity (defined as NCI CTCv2) with the use of intravenous platinum chemotherapy could be extracted from one study with a total of 39 patients (Petrilli 2002). For three of the 20 patients in the amifostine group no ototoxicity data were available. The available data analysis of asymptomatic or symptomatic ototoxicity (that is grade 1 and higher) showed no significant difference between the treatment groups (RR 1.04; 95% CI 0.76 to 1.44; P = 0.80; see Figure 5); there were 14 cases among the 17 available patients in the amifostine group and 15 cases among the 19 control patients. 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 17 cases among 20 patients in the amifostine group) was 1.08 (95% CI 0.80 to 1.45; P = 0.63), while the RR for the best case scenario (that is 14 cases among 20 patients in the amifostine group) was 0.89 (95% CI 0.61 to 1.28; P = 0.52). The available data analysis of symptomatic ototoxicity (that is grade 2 or higher) showed no significant difference between the treatment groups (RR 1.32; 95% CI 0.83 to 2.10; P = 0.24; see Figure 6); there were 13 cases among the 17 available patients in the amifostine group and 11 cases among the 19 control patients. 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 16 cases among 20 patients in the amifostine group) was 1.38 (95% CI 0.89 to 2.15; P = 0.15), while the RR for the best case scenario (that is 13 cases among 20 patients in the amifostine group) was 1.12 (95% CI 0.68 to 1.85; P = 0.65). It should be noted that the patients who suffered from symptomatic ototoxicity were included in both analyses.

Figure 5.

Forest plot of comparison: 1 Amifostine versus no otoprotective intervention, outcome: 1.2 Ototoxicity according to NCI CTC v2 criteria with intravenous platinum (combined asymptomatic and symptomatic disease).

Figure 6.

Forest plot of comparison: 1 Amifostine versus no otoprotective intervention, outcome: 1.5 Ototoxicity according to NCI CTC v2 criteria with intravenous platinum (symptomatic disease).

Data on ototoxicity (defined as modified Brock criteria) with the use of intravenous platinum chemotherapy could be extracted from one study; the presented interim analysis included 82 patients (Katzenstein 2009). It should be noted that these 82 children were part of a larger study group; they were considered in a special interim analysis of the incidence of toxicity. The total number of eligible patients was unclear and as a result we were not able to perform an intention-to-treat analysis. Also, we were not able to check if the ototoxicity results were available for at least 50% of the eligible patients. In the methods section we stated that if that was not the case we would not report the results due to the associated high risk of attrition bias. We decided to give this study the benefit of the doubt. There were 22 cases of asymptomatic or symptomatic ototoxicity (that is grade 1a and higher) among 37 patients randomized to amifostine and 25 cases among the 45 patients in the control group. The analysis showed no significant difference between the treatment groups (RR 1.07; 95% CI 0.74 to 1.55; P = 0.72; see Figure 7). There were 14 cases of symptomatic ototoxicity (that is grade 2a and higher) among 37 patients randomized to amifostine and 17 cases among the 45 patients in the control group. The analysis showed no significant difference between treatment groups (RR 1.00; 95% CI 0.57 to 1.75; P = 1.00; see Figure 8). It should be noted that the patients who suffered from symptomatic ototoxicity were included in both analyses.

Figure 7.

Forest plot of comparison: 1 Amifostine versus no otoprotective intervention, outcome: 1.3 Ototoxicity according to modified Brock criteria (combined asymptomatic and symptomatic disease).

Figure 8.

Forest plot of comparison: 1 Amifostine versus no otoprotective intervention, outcome: 1.6 Ototoxicity according to modified Brock criteria (symptomatic disease).

Tumour response

Please note that due to the nature of this outcome (that is the number of patients with a remission) a high event rate is favourable. Therefore, in the figures of the analyses 'favours control' is on the left and 'favours amifostine' is on the right, as opposed to the figures of the other analyses.

Data on tumour response (defined as number of patients with a complete, good or partial response) with the use of intra-arterial platinum chemotherapy could be extracted from one study with a total of 28 patients (Gallegos-Castorena 2007). For one of the 13 patients in the control group no response data were available. The available data analysis of tumour response showed no significant difference between the treatment groups (RR 1.60; 95% CI 0.97 to 2.63; P = 0.06); there were 14 remissions among the 15 patients randomized to amifostine and 7 remissions in the 12 control patients. The intention-to-treat analysis (data not shown) for the best case scenario (that is 8 remissions among 13 patients in the control group) also showed no significant difference between the treatment groups (RR 1.52; 95% CI 0.97 to 2.38; P = 0.07), while the intention-to-treat analysis (data not shown) for the worst case scenario (that is 7 remissions among 13 patients in the control group) showed a significant difference in favour of the amifostine group (RR 1.73; 95% CI 1.03 to 2.92; P = 0.04).

No information on tumour response was provided in Petrilli 2002 and Katzenstein 2009.

Survival

No information on survival (that is event-free survival and overall survival) was provided in Gallegos-Castorena 2007 and Petrilli 2002. Katzenstein 2009 did not provide survival data for the 82 patients included in the interim analysis presented in this manuscript.

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

Since all patients receiving chemotherapy will suffer from side effects, we decided to analyse only the severe and life-threatening effects. We defined these as grade 3 or higher.

In Gallegos-Castorena 2007 (using intra-arterial platinum chemotherapy) there was a significant difference in favour of the control group in the occurence of vomiting grade 3 or 4. All 15 patients in the amifostine group and 1 out of 13 patients in the control group suffered from this toxicity (RR 9.04; 95% CI 1.99 to 41.12; P = 0.004). None of the patients in this study experienced cardiac toxicity grade 3 or 4. We were unable to calculate a RR for renal toxicity grade 3 or 4 since one group experienced no events, but no significant difference between treatment groups was identified; none of the patients in the amifostine group and 2 out of 13 patients in the control group suffered from this toxicity (Fischer’s exact test P = 0.21). They also provided data on amifostine-related toxicity although without stating the exact grading. However, in this review only toxicities evaluated in both treatment groups were eligible so these toxicities were not included.

The adverse effects other than hearing loss and tinnitus (grade 3 or higher) that were reported by Petrilli 2002 and Katzenstein 2009 could not be included in this review. Petrilli 2002 provided data for both treatment groups but as the number of infusions with toxicity present not as the number of patients with toxicity. As a result, we could not adequately analyse these data. They provided data on amifostine infusion-related toxicity, although without stating the exact grading for most toxicities, in (part of) the amifostine group. However, in this review only toxicities evaluated in both treatment groups were eligible, so these toxicities were not included. Katzenstein 2009 provided data on adverse effects in both treatment groups but as the number of courses with toxicity present and not as the number of patients with toxicity. Furthermore, it was not clear if the presented data regarded only the 82 patients included in the interim analysis presented in this manuscript. As a result, we could not adequately analyse these adverse effects data.

Quality of life

None of the studies evaluated quality of life (Petrilli 2002; Gallegos-Castorena 2007; Katzenstein 2009).

Discussion

Platinum-based therapy, including cisplatin, carboplatin and/or oxaliplatin, 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, 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; Gurney 2007; Dean 2008). Prevention of platinum-induced hearing loss is thus very important. This is an update of the first systematic review evaluating all medical interventions for the prevention of platinum-induced hearing loss in children with cancer (Van As 2012).

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

We identified three studies evaluating the use of amifostine versus no otoprotective intervention, two RCTs and one CCT. Two studies included children with osteosarcoma, the other study included children with hepatoblastoma. Patients received cisplatin only or a combination of cisplatin and carboplatin, either administered intra-arterially or intravenously. For other possible otoprotective medical interventions and other types of malignancies no eligible studies were found.

Unfortunately, as is explained in the results, pooling of the results of the included studies was not possible. However, in all individual studies no significant difference was identified in symptomatic ototoxicity only (that is NCI CTC v2 or modified Brock criteria grade 2 or higher) and combined asymptomatic and symptomatic toxicity (that is NCI CTC v2 or modified Brock criteria grade 1 or higher) between patients treated with or without amifostine. None of the included studies provided a description of the exact tests that were used to evaluate ototoxicity so we cannot comment on their appropriateness (for example if age-specific tests were used or if patients were checked for otitis media, common in this age group (Brock 1991)). An important question regarding any otoprotective medical intervention during platinum treatment is whether the otoprotective drug could decrease the ototoxicity by platinum agents without reducing the anti-tumour efficacy (that is the tumour response and survival) and without negative effects on toxicities other than ototoxicity. Only one study provided information on tumour response, defined as the number of patients with a complete, good or partial remission (Gallegos-Castorena 2007). This study included children with osteosarcoma treated with intra-arterial cisplatin. The available data analysis (no response data were available for one patient in the control group), best case scenario analysis and worst case scenario analysis all showed a difference in favour of the amifostine group but only in the worst case scenario analysis (that is the patient with missing data did not have a remission) was this difference significant (P = 0.04). No information on survival was available for any of the included study populations. However, Katzenstein 2009 did provide data on event-free survival, defined as the period from the date chemotherapy was started until evidence of an event (progressive disease, death, diagnosis of a second malignant neoplasm) or date of last contact, whichever occured first, for 184 patients enrolled in this study (instead of only the 82 patients included in the toxicity interim analysis); these 184 patients were not the complete study group. No significant difference between the treatment groups was identified (P = 0.22). Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of patients with adverse effects other than ototoxicity grade 3 or higher (Gallegos-Castorena 2007). There was a significant difference in favour of the control group in the occurrence of vomiting grade 3 or 4 (RR 9.04; 95% CI 1.99 to 41.12; P = 0.004). None of the patients in this study experienced cardiac toxicity grade 3 or 4. No significant difference between the treatment groups was identified for renal toxicity grade 3 or 4. Finally, none of the studies evaluated quality of life (see Summary of findings for the main comparison).

In this review we tried to perform intention-to-treat analyses since they provide the most realistic and unbiased answer to the question of clinical effectiveness (Lachin 2000). However, for Katzenstein 2009 an intention-to-treat analysis was not possible; the presented toxicity interim analysis included 82 patients who were part of a larger study group and the total number of eligible patients was unclear. Therefore, we performed an 'available data' analysis for this study. Also, we were not able to check if the ototoxicity results of this study were available for at least 50% of the eligible patients. In the methods section we stated that if that was not the case we would not report the results due to the associated high risk of attrition bias. We decided to give this study the benefit of the doubt.

'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 patients included in these studies 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. Unfortunately none of the included studies mentioned the length of follow-up.

Furthermore, although according to the protocol for the included studies patients in both treatment groups should have received the same platinum dosage schedule, none of the included studies reported the exact cumulative platinum dose received by the patients in both treatment arms. One study stated that the actually received doses did not differ significantly between treatment groups (Petrilli 2002), but in the other studies it was unclear if the patients in the amifostine and control groups received similar cumulative platinum doses. If patients in the control group received a higher cumulative platinum dose than patients treated with amifostine this could have led to an overestimation of the otoprotective effect of amifostine (and vice versa). This uncertainty should also be kept in mind when interpreting the results of the secondary outcomes (response rate and adverse effects). The same is true for 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; Cancer in Children 2005; Meyer 2009). It was not clear if there were important imbalances between the treatment groups regarding these factors.

The risk of bias in the included studies varied. Often bias could 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 amifostine as an otoprotective medical intervention in children treated with platinum chemotherapy.

We are awaiting the results of the currently ongoing studies evaluating cisplatin chemotherapy with or without sodium thiosulfate in children with different types of tumours, among others childhood liver cancer, germ cell tumour, medulloblastoma, neuroblastoma and osteosarcoma (COG ACCL0431; SIOPEL 6). We are also awaiting the final publication of the study by Katzenstein 2009.

Authors' conclusions

Implications for practice

At the moment there is no evidence from the individual studies (two RCTs and one CCT) in children with osteosarcoma and hepatoblastoma treated with different platinum analogues and dosage schedules which underscores the use of amifostine as an otoprotective intervention as compared to no additional treatment. Since pooling of results was not possible, and all studies had serious 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'. Based on the currently available evidence we are not able to give recommendations for clinical practice.

For other possible otoprotective medical interventions and other types of malignancies no RCTs or CCTs were identified, so no conclusions can be made about their efficacy in preventing ototoxicity in children treated with platinum-based therapy. Based on the currently available evidence we are not able to give recommendations for clinical practice.

Implications for research

Before definitive conclusions can be made about the efficacy of possible otoprotective medical interventions in children (either amifostine or another intervention) 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 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 patients should be sufficient to obtain the power needed for the results to be reliable.

Acknowledgements

We thank Edith Leclercq, the Trials Search Coordinator of the Childhood Cancer Group, for running the searches in CENTRAL, MEDLINE and EMBASE and providing us with the titles and abstracts from the searches. We thank Dr H Katzenstein for providing additional information on his study. We also thank Dr J Dean (Children's Center for Cancer and Blood Disorders Of Northern Virginia) and Prof Dr P Shearer (Department of Paediatric Hematology/Oncology, University of Maryland) who kindly agreed to peer review the first version of the review. Finally, we thank Stichting Kinderen Kankervrij (KiKa), the Netherlands 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 Stichting Kinderen Kankervrij (KiKa).

Data and analyses

Download statistical data

Comparison 1. Amifostine versus no otoprotective intervention
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Ototoxicity according to NCI CTC v2 criteria with intra-arterial platinum (combined asymptomatic and symptomatic disease)128Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.94, 1.77]
2 Ototoxicity according to NCI CTC v2 criteria with intravenous platinum (combined asymptomatic and symptomatic disease)136Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.76, 1.44]
3 Ototoxicity according to modified Brock criteria (combined asymptomatic and symptomatic disease)182Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.74, 1.55]
4 Ototoxicity according to NCI CTC v2 criteria with intra-arterial platinum (symptomatic disease)128Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.14, 5.32]
5 Ototoxicity according to NCI CTC v2 criteria with intravenous platinum (symptomatic disease)136Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.83, 2.10]
6 Ototoxicity according to modified Brock criteria (symptomatic disease)182Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.57, 1.75]
7 Tumour response (good remission and partial remission)127Risk Ratio (M-H, Fixed, 95% CI)1.6 [0.97, 2.63]
8 Adverse effects other than ototoxicity (vomiting grade 3 or higher)128Risk Ratio (M-H, Fixed, 95% CI)9.04 [1.99, 41.12]
Analysis 1.1.

Comparison 1 Amifostine versus no otoprotective intervention, Outcome 1 Ototoxicity according to NCI CTC v2 criteria with intra-arterial platinum (combined asymptomatic and symptomatic disease).

Analysis 1.2.

Comparison 1 Amifostine versus no otoprotective intervention, Outcome 2 Ototoxicity according to NCI CTC v2 criteria with intravenous platinum (combined asymptomatic and symptomatic disease).

Analysis 1.3.

Comparison 1 Amifostine versus no otoprotective intervention, Outcome 3 Ototoxicity according to modified Brock criteria (combined asymptomatic and symptomatic disease).

Analysis 1.4.

Comparison 1 Amifostine versus no otoprotective intervention, Outcome 4 Ototoxicity according to NCI CTC v2 criteria with intra-arterial platinum (symptomatic disease).

Analysis 1.5.

Comparison 1 Amifostine versus no otoprotective intervention, Outcome 5 Ototoxicity according to NCI CTC v2 criteria with intravenous platinum (symptomatic disease).

Analysis 1.6.

Comparison 1 Amifostine versus no otoprotective intervention, Outcome 6 Ototoxicity according to modified Brock criteria (symptomatic disease).

Analysis 1.7.

Comparison 1 Amifostine versus no otoprotective intervention, Outcome 7 Tumour response (good remission and partial remission).

Analysis 1.8.

Comparison 1 Amifostine versus no otoprotective intervention, Outcome 8 Adverse effects other than ototoxicity (vomiting grade 3 or higher).

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 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 textwords 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 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 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]

What's new

DateEventDescription
2 April 2014New citation required but conclusions have not changedUnfortunately, no new studies could be included in this update of the review. As a result the conclusions have not changed. However, as opposed to the original version of the review we have now included a summary of findings table.
2 April 2014New search has been performedThe search for eligible studies was updated to March 2014.

Contributions of authors

Jorrit van As designed the study and 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 studies. He analysed the data and interpreted the results. He wrote and revised the manuscript.

Henk van den Berg critically reviewed the protocol and the review and provided a clinical perspective.

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 studies. 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

  • No sources of support supplied

External sources

  • Stichting Kinderen Kankervrij (KiKa), Netherlands.

Differences between protocol and review

In the protocol we stated that "Children (aged 0 to 18 years at diagnosis) with any type of childhood malignancy" were eligible for inclusion; in order not to exclude relevant data we have added the following: "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 did not exceed 22 years)".

In the update a summary of findings table was included.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Gallegos-Castorena 2007

Methods

Randomized controlled trial; method of randomization not clear.

Performed in Mexico; patients were diagnosed with osteosarcoma between March 1999 and December 2002.

Participants28 children (mean age 11.6 years (range 7 to 15); 14 males and 14 females) with osteosarcoma (stage nm, but in 5 patients metastatic disease, no significant differences in stage of disease between treatment groups; primary disease) treated with surgery (procedure and location nm) and chemotherapy (that is intra-arterial cisplatin (cumulative dose nm, but according to protocol patients should receive 600 mg/m2; individual platinum dose 150 mg/m2; infusion duration nm) and doxorubicin (cumulative dose nm, but according to protocol patients should receive 150 mg/m2)). Other ototoxic drugs: anthracyclines yes (see doxorubicin earlier), vincristine no, gentamycin nm, furosemide nm. No prior platinum treatment. No prior radiotherapy to head and/or neck. No prior cranial surgery. Prior hearing dysfunction nm (baseline tests have been performed, but results not reported). Pre-treatment renal impairment nm (baseline tests have been performed, but results not reported).  
InterventionsAmifostine (740 mg/m2/dose (cumulative dose nm, but according to protocol 2960 mg/m2); intravenous infusion under sedation over 15 minutes immediately prior to each cisplatin dose) (n=15) versus no otoprotective intervention (n=13).
Outcomes

Ototoxicity (according to WHO criteria; it was stated that for the evaluated parameters they did not differ from the NCI system; see also Table 1); audiometry/tympanometry was performed (exact instrument used nm).

Response rate (complete/good remission defined as >90% necrosis after tumorectomy; partial remission defined as 60-90% necrosis after tumorectomy).

Adverse effects grade 3 or higher (according to WHO criteria; it was stated that for the evaluated parameters they did not differ from the NCI system).

Notes

Length of follow-up nm.

Age and gender in intervention and control group nm, but it was stated that the groups were not statistically different.

Cumulative cisplatin dose per treatment group nm. 

Genetic variants nm.

All patients received ondansetron 4 mg/m2/dose 3 times a day and dexamethasone 6 mg/m2/day to prevent nausea and vomiting.

Influence of funders unclear (funding nm).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskIt was stated that patients were randomly assigned to amifostine or no additional treatment, but no further information on the methods of randomization was provided.
Allocation concealment (selection bias)Unclear riskIt was stated that patients were randomly assigned to amifostine or no additional treatment, but no further information on the methods of randomization was provided.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information on blinding of participants and personnel was provided.
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)
All outcomes
Low riskIn all patients all reported outcomes were evaluated, with the exception of response rate, but there was only 1 patient from the control group missing (no histological examination).
Selective reporting (reporting bias)Low riskThere was no protocol mentioned in the manuscript (and we did not search for it), but all expected outcomes are reported.
Other biasUnclear risk

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

Baseline imbalance between treatment groups related to outcome (prior ototoxic treatment, age, sex and/or prior hearing loss): prior ototoxic treatment not reported, age and sex are balanced, prior hearing loss unclear (baseline tests have been performed, but results not reported).

Difference in ototoxic drugs other than platinum analogue between treatment groups (furosemide, gentamycin, anthracyclines, vincristine): cumulative anthracycline dose unclear, but according to protocol patients in both treatment groups should receive the same dose; furosemide and gentamycin not reported; vincristine not given.

Difference in cumulative platinum dose between treatment groups: cumulative dose unclear, but according to protocol patients in both treatment groups should receive the same dose.

Difference in length of follow-up between treatment groups: unclear (length of follow-up nm).

Difference in impaired renal function at time of platinum treatment between treatment groups: unclear.

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

Katzenstein 2009

Methods

Randomized controlled trial; method of randomization not clear.

Unclear where this study was performed; unclear when patients were diagnosed (study was opened in March 1999).

Participants82 children (age range 0 to 11 years; 44 males and 38 females) with hepatoblastoma (21 stage I non pure fetal histology or II, 61 stage III or IV; patients with stage I pure fetal histology were not eligible for this study; unclear if there were significant differences in stage of disease between treatment groups; primary disease) treated with surgery (procedure and location nm) and chemotherapy. Stage I and II patients received 4 cycles of intravenous cisplatin, 5-FU and vincristine (C5V); patients with stage III or IV were either randomized to 6 cycles of C5V or 6 cycles of intravenous cisplatin and carboplatin (CC) (see notes). Cumulative platinum doses not mentioned, but total intended platinum dose in stage I/II patients was 400 mg/m2 of cisplatin (12 mg/kg if < 1 year); individual platinum dose 100 mg/m2; infusion duration 4 hours. In stage III/IV patients treated with C5V the total intended platinum dose was 600 mg/m2 of cisplatin (18 mg/kg if < 1 year); individual platinum dose 100 mg/m2; infusion duration 4 hours and in stage III/IV patients treated with CC the total intended platinum dose was 600 mg/m2 of cisplatin (18 mg/kg if < 1 year); individual platinum dose 100 mg/m2; infusion duration 4 hours and the total intended carboplatin dose was 3640 mg/m2 (120 mg/kg if < 10 kilograms); individual platinum dose 700 mg/m2; infusion duration 1 hour. In case of C5V: cumulative 5-FU doses were nm, but according to protocol patients should receive 600 mg/m2 per cycle (so total 2400 mg/m2 in stage I/II patients and total 3600 mg/m2 in stage III/IV patients); cumulative vincristine doses nm, but according to protocol patients should receive 4.5 mg/m2 per cycle (so total in stage I/II patients 18 mg/m2 and total in stage III/IV patients 27 mg/m2). Other ototoxic drugs: anthracyclines no, vincristine yes for some patients (see above), gentamycin nm, furosemide nm. No prior platinum treatment. No prior radiotherapy to head and/or neck. No prior cranial surgery. No prior hearing dysfunction (on audiogram or auditory brainstem responses before therapy). No pre-treatment renal impairment (that is adequate organ function documented at time of study enrollment).  
Interventions

Amifostine (740 mg/m2/dose (cumulative dose nm, according to the text of the article amifostine was given immediately before cisplatin, but in the abstract it was mentioned that it was given prior to each administration of a platinum agent, that is both before cisplatin and carboplatin); intravenous infusion given over 15 minutes immediately prior to cisplatin) (n=37) versus no otoprotective intervention (n=45).

In the amifostine group 7 patients received CC and 30 patients received C5V; in the control group 11 patients received CC and 34 patients received C5V.

Outcomes Ototoxicity (according to modified Brock criteria: see notes and Table 2); audiograms were performed, no further information provided.
Notes

These 82 children are part of a larger study group. They were considered in a special interim analysis of the incidence of toxicity. The total number of eligible patients is unclear.

Stage III and IV randomization to CC was suspended in January 2002 when the projected improvement in long-term outcome associated with CC was excluded statistically as possible outcome of this trial.

In November 2003 it was decided that using the CTC criteria substantially underestimated the true incidence of significant hearing loss (4% grade 3 or 4 ototoxicity); it was decided that the subgroup of 82 patients should be evaluated using modified Brock criteria.

Length of follow-up nm.

Age and gender in intervention and control group nm, it was not stated if the groups were statistically different or not.

Cumulative cisplatin/carboplatin dose per treatment group nm. 

Genetic variants nm.

All patients received granulocyte colony stimulating factor.

Influence of funders unclear (funders were mentioned).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskIt was stated that patients were randomly assigned to amifostine or no additional treatment, but no further information on the methods of randomization was provided.
Allocation concealment (selection bias)Unclear riskIt was stated that patients were randomly assigned to amifostine or no additional treatment, but no further information on the methods of randomization was provided.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information on blinding of participants and personnel was provided.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskFor the reported outcome (that is hearing loss) outcome assessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
High riskThe patients reported in this manuscript are only a subgroup of all included patients (unclear how many patients were originally included in this study).
Selective reporting (reporting bias)High riskThere was no protocol mentioned in the manuscript (and we did not search for it). However, response was not reported, while in the methods section alpha fetaprotein levels and imaging were mentioned. Also, the definition of hearing loss was adjusted during the study and only results for the last definition were reported.
Other biasUnclear risk

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

Baseline imbalance between treatment groups related to outcome (prior ototoxic treatment, age, sex and/or prior hearing loss): prior ototoxic treatment not reported, age and sex not reported in different treatment groups, no prior hearing loss.

Difference in ototoxic drugs other than platinum analogue between treatment groups (furosemide, gentamycin, anthracyclines, vincristine): furosemide and gentamycin not reported; anthracyclines not given; vincristine unclear if balanced in different treatment groups.

Difference in cumulative platinum dose between treatment groups: unclear if balanced between treatment groups.

Difference in length of follow-up between treatment groups: unclear (length of follow-up nm).

Difference in impaired renal function at time of platinum treatment between treatment groups: unclear.

An insensitive instrument was used to evaluate ototoxicity: unclear (audiograms were performed, but no further information provided).

Petrilli 2002

  1. a

    Nm: not mentioned; n: number; NCI: National Cancer Institute; CTC: Common Toxicity Criteria; WHO: World Health Organization, 5-FU: 5-fluorouracil

Methods

Controlled clinical trial (39 consecutive patients registered in the same protocol: the first 18 patients and the final patient did not receive an otoprotective intervention, whereas the 20 patients in between did); Brazilian Bone Tumor Study Group Protocol IV.

Performed in Brazil; patients were diagnosed with osteosarcoma between June 1996 and December 1997.

Participants39 children (mean age 14.4 years (range 5 to 22); 27 males and 12 females) with osteosarcoma (stage nm, patients were either metastatic or not, no significant differences in stage of disease between treatment groups; primary disease) treated with surgery (procedure and location nm) and intravenous chemotherapy (that is cisplatin (cumulative dose nm, but according to protocol patients should receive 500 mg/m2; individual dose 100 mg/m2; infusion duration nm), carboplatin (cumulative dose nm, but according to protocol patients should receive 2500 mg/m2; individual dose 500 mg/m2; infusion duration nm), doxorubicin (cumulative dose nm, but according to protocol patients should receive 360 mg/m2) and ifosfamide (cumulative dose nm, but according to protocol patients should receive 45 g/m2); for all 4 chemotherapeutic agents the actual recieved doses were not statistically significant different than the protocol doses). Other ototoxic drugs: anthracyclines yes (see doxorubicin earlier), vincristine no, gentamycin nm, furosemide nm. No prior platinum treatment. No prior radiotherapy to head and/or neck. No prior cranial surgery. No prior hearing dysfunction (baseline tests have been performed and without normal hearing patients were not eligible for this study). No pre-treatment renal impairment (baseline tests have been performed and without normal audiometric evaluations at diagnosis patients were not eligible for this study).  
InterventionsAmifostine (740 mg/m2/dose (cumulative dose nm, but according to protocol 7400 mg/m2); 15 minute infusion (intra-arterial or intravenous nm) immediately prior to every cisplatin and carboplatin dose) (n=20) versus no otoprotective intervention (n=19).
Outcomes Ototoxicity (according to NCI CTC version 2 criteria: see also Table 1); objective and subjective audiometric evaluations were performed, no further information provided.
Notes

Length of follow-up nm.

Age and gender in intervention and control group nm, but it was stated that the groups were not statistically different.

Cumulative cisplatin and carboplatin dose per treatment group nm (for more information see information under header Participants). 

Genetic variants nm.

All patients received ondansetron 0.15 mg/kg per dose 3 times a day, dexamethasone 6 mg/m2/day, metoclopramide 1mg/kg per day and dimenhydrinate 2 mg/kg per day to prevent nausea and vomiting.

Influence of funders unclear (funding nm).

This was a pilot study for a larger randomized study.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskControlled clinical trial, so no randomization performed.
Allocation concealment (selection bias)High riskControlled clinical trial, so no randomization performed.
Blinding of participants and personnel (performance bias)
All outcomes
High riskPatients with amifostine were consecutive patients, so blinding was not possible.
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)
All outcomes
High risk3 out of 20 patients in the intervention group missing for almost all outcomes (1 incomplete outcome data, 1 lost to follow-up, 1 nm).
Selective reporting (reporting bias)High riskThere was no protocol mentioned in the manuscript (and we did not search for it), but not all expected outcomes are reported (for example, response rate and hypocalcaemia are missing, while for the latter it was even stated in the discussion of this article that this is one of the most common side effects of amifostine).
Other biasUnclear risk

Block randomization in unblinded trials: not applicable, this is not a randomized trial.

Baseline imbalance between treatment groups related to outcome (prior ototoxic treatment, age, sex and/or prior hearing loss): prior ototoxic treatment not reported, age and sex are balanced, no prior hearing loss.

Difference in ototoxic drugs other than platinum analogue between treatment groups (furosemide, gentamycin, anthracyclines, vincristine): cumulative anthracycline dose unclear, but according to protocol patients in both treatment groups should receive the same dose and the actual recieved doses were not statistically significant different than the protocol doses; furosemide and gentamycin not reported; vincristine not given.

Difference in cumulative platinum dose between treatment groups: cumulative dose unclear, but according to protocol patients in both treatment groups should receive the same dose and the actual recieved doses were not statistically significant different than the protocol doses.

Difference in length of follow-up between treatment groups: unclear (length of follow-up nm).

Difference in impaired renal function at time of platinum treatment between treatment groups: unclear.

An insensitive instrument was used to evaluate ototoxicity: unclear (objective and subjective audiometric evaluations were performed, no further information provided).

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomized controlled trial; CCT: controlled clinical trial

Doolittle 2001Study with historical controls; both children and adults (maximal age 67 years) included (children not presented separately).
Elsendoorn 2001Same study as Weijl 2004 (describing the first 27 patients).
Fouladi 2008Study with historical controls; both children and adults (maximal age 20.16 years) included (children not presented separately); difference in cranial radiotherapy between treatment groups.
Geoerger 2005No otoprotective intervention evaluated.
Grau 1996Both children and adults (maximal age 73 years) included (children not presented separately); unclear if other treatment was the same in the different treatment groups.
Kingston 1986No otoprotective intervention evaluated.
Knight 2008No RCT or CCT, but a case report; no otoprotective intervention.
Ladenstein 2010Ototoxicity not evaluated.
Mahoney 1982Same study as Mahoney 1983.
Mahoney 1983No RCT or CCT; no otoprotective intervention evaluated.
Marina 2005Study with historical controls; unclear if same cumulative platinum dose, infusion duration, individual dose and other treatment in the different treatment groups.
McHaney 1983No RCT or CCT; no otoprotective intervention evaluated
Meyer 2009No RCT or CCT, but a review (no additional studies identified)
Piel 1974No otoprotective intervention evaluated
Skinner 2006No RCT or CCT, but a commentary (no additional studies identified)
Spunt 2007No RCT or CCT; both children and adults (maximal age 21 years) included (children not presented separately)
Sullivan 2009No RCT or CCT, but an editorial (no additional studies identified)
Weijl 2004Both children and adults (maximal age 69 years) included (children not presented separately); significant difference in individual platinum dose between the different treatment groups, unclear if platinum infusion duration and other treatment was the same in the different treatment groups.

Characteristics of ongoing studies [ordered by study ID]

COG ACCL0431

Trial name or titleCOG ACCL0431
MethodsMethod of randomization not clear (patients are stratified according to prior cranial irradiation (yes versus no), age (<5 years versus ≥5 years) and duration of cisplatin infusion (<2 hours versus ≥2 hours))
ParticipantsYoung patients (aged 1 to 18 years) with newly diagnosed hepatoblastoma, germ cell tumor, medulloblastoma, neuroblastoma, osteosarcoma or other malignancy
InterventionsCisplatin containing chemotherapy (according to disease-specific regimens) with or without sodium thiosulfate
OutcomesHearing loss, survival, adverse effects other than hearing loss (that is grade 3 and 4 cytopenia and nephrotoxicity) and genetic variants to predict cisplatin-induced ototoxicity
Starting dateJune 2008
Contact informationProtocol chair DR Freyer
NotesNo full text publication available as per 18 March 2014

SIOPEL 6

Trial name or titleSIOPEL 6
MethodsMethod of randomization not clear (patients are stratified according to country, median age (<15 months versus ≥15 months) and PRETEXT tumor classification (stage I versus stage II versus stage III))
ParticipantsYoung patients (maximal age 18 years) with newly diagnosed standard risk (stage I-III) childhood liver cancer
InterventionsCisplatin chemotherapy with or without sodium thiosulfate
OutcomesHearing loss, tumour response, survival, adverse effects other than hearing loss (not specified) and genetic variants to predict cisplatin-induced ototoxicity
Starting dateDecember 2007
Contact informationPrincipal investigator MD Ronghe
NotesNo full text publication available as per 18 March 2014