Guidance regarding COVID-19 for survivors of childhood, adolescent, and young adult cancer: A statement from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19.

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

BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the third update of a previously published Cochrane Review. OBJECTIVES: To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. SEARCH METHODS: We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 14 November 2019), MEDLINE (PubMed) (1945 to 14 November 2019) and Embase (Ovid) (1980 to 14 November 2019). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2019) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2019). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (both searched on 4 November 2019). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified one RCT and no CCTs; in this update no additional eligible studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. AUTHORS' CONCLUSIONS: Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.

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

BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin, oxaliplatin or a combination of these, is used to treat a variety of paediatric malignancies. One of the most significant 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 the third update of a previously published Cochrane Review. OBJECTIVES: To assess the efficacy of medical interventions to prevent hearing loss and to determine possible effects of these interventions on antitumour efficacy, toxicities other than hearing loss and quality of life in children with cancer treated with platinum-based therapy as compared to placebo, no additional treatment or another protective medical intervention. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE (PubMed) and Embase (Ovid) to 8 January 2019. We handsearched reference lists of relevant articles and assessed the conference proceedings of the International Society for Paediatric Oncology (2006 up to and including 2018), the American Society of Pediatric Hematology/Oncology (2007 up to and including 2018) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010 up to and including 2015). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (on 2 January 2019). SELECTION CRITERIA: Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating platinum-based therapy 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, data extraction, risk of bias assessment and GRADE assessment of included studies, including adverse effects. We performed analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified two RCTs and one CCT (total number of participants 149) evaluating the use of amifostine versus no additional treatment in the original version of the review; the updates identified no additional studies. Two studies included children with osteosarcoma, and the other study included children with hepatoblastoma. Children received cisplatin only or a combination of cisplatin and carboplatin, either intra-arterially or intravenously. Pooling of results of the included studies was not possible. From individual studies the effect of amifostine on symptomatic ototoxicity only (i.e. National Cancer Institute Common Toxicity Criteria version 2 (NCICTCv2) or modified Brock grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (i.e. NCICTCv2 or modified Brock grade 1 or higher) were uncertain (low-certainty evidence). Only one study including children with osteosarcoma treated with intra-arterial cisplatin provided information on tumour response, defined as the number of participants with a good or partial remission. The available-data analysis (data were missing for one participant), best-case scenario analysis and worst-case scenario analysis showed a difference in favour of amifostine, although the certainty of evidence for this effect was low. There was no information on survival for any of the included studies. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of participants with adverse effects other than ototoxicity grade 3 or higher (on NCICTCv2 scale). There was low-certainty evidence that grade 3 or 4 vomiting was higher with amifostine (risk ratio (RR) 9.04, 95% confidence interval (CI) 1.99 to 41.12). The effects on cardiotoxicity and renal toxicity grade 3 or 4 were uncertain (low-certainty evidence). None of the studies evaluated quality of life.In the recent update, we also identified one RCT including 109 children with localized hepatoblastoma evaluating the use of sodium thiosulfate versus no additional treatment. Children received intravenous cisplatin only (one child also received carboplatin). There was moderate-certainty evidence that both symptomatic ototoxicity only (i.e. Brock criteria grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (i.e. Brock criteria grade 1 or higher) was lower with sodium thiosulfate (combined asymptomatic and symptomatic ototoxicity: RR 0.52, 95% CI 0.33 to 0.81; symptomatic ototoxicity only: RR 0.39, 95% CI 0.19 to 0.83). The effect of sodium thiosulfate on tumour response (defined as number of participants with a complete or partial response at the end of treatment), overall survival (calculated from time of randomization to death or last follow-up), event-free survival (calculated from time of randomization until disease progression, disease relapse, second primary cancer, death, or last follow-up, whichever came first) and adverse effects other than hearing loss and tinnitus grade 3 or higher (according to National Cancer Institute Common Toxicity Criteria Adverse Effects version 3 (NCICTCAEv3) criteria) was uncertain (low-certainty evidence for all these outcomes). Quality of life was not assessed.We found no eligible studies for possible otoprotective medical interventions other than amifostine and sodium thiosulfate and for 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 that underscores the use of amifostine as an otoprotective intervention as compared to no additional treatment. Since pooling of results was not possible and the evidence was of low certainty, no definitive conclusions can be made. Since we found only one RCT evaluating the use of sodium thiosulfate in children with localized hepatoblastoma treated with cisplatin, no definitive conclusions on benefits and harms can be drawn. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. We identified no eligible studies 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.

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

BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the second update of a previously published Cochrane review. OBJECTIVES: To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. SEARCH METHODS: We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 15 March 2018), MEDLINE (PubMed) (1945 to 15 March 2018) and Embase (Ovid) (1980 to 15 March 2018). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2017) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2017). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 12 March 2018 and 13 March 2018 respectively). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. AUTHORS' CONCLUSIONS: Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.

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

BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin, oxaliplatin or a combination of these, is used to treat a variety of paediatric malignancies. 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 the second update of a previously published Cochrane review. OBJECTIVES: To assess the efficacy of medical interventions to prevent hearing loss and to determine possible effects of these interventions on anti-tumour efficacy, toxicities other than hearing loss and quality of life in children with cancer treated with platinum-based therapy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 6), MEDLINE (PubMed) (1945 to 8 July 2016) and EMBASE (Ovid) (1980 to 8 July 2016). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2006 up to and including 2015), the American Society of Pediatric Hematology/Oncology (2007 up to and including 2016) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010 up to and including 2015). We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register (www.isrctn.com) and the National Institute of Health Register (www.clinicaltrials.gov) for ongoing trials (both searched on 12 July 2016). 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, data extraction, risk of bias assessment and GRADE assessment of included studies, including adverse effects. We performed analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified two RCTs and one CCT (total number of participants 149) evaluating the use of amifostine versus no additional treatment in the original version of the review; the updates identified no additional studies. Two studies included children with osteosarcoma, and the other study included children with hepatoblastoma. Children received cisplatin only or a combination of cisplatin and carboplatin, either intra-arterially or intravenously. Pooling of results of the included studies was not possible. However, in the individual studies there was no significant difference 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 participants with a good or partial remission. The available data analysis (data were missing for one participant), 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). There was no information on survival for any of the included studies. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of participants 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). There was no significant difference between treatment groups for cardiotoxicity and renal toxicity grade 3 or 4. None of the studies evaluated quality of life. The quality of evidence for the different outcomes was low. We found no eligible studies 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 that 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 unable to give recommendations for clinical practice. We identified no eligible studies 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.

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

BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is an update of a previously published Cochrane review. OBJECTIVES: To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. SEARCH METHODS: We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 4), MEDLINE (PubMed) (1945 to 18 May 2016) and EMBASE (Ovid) (1980 to 18 May 2016). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2015) and the American Society of Pediatric Hematology/Oncology (2014 and 2015). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 20 May 2016 and 24 May 2016 respectively). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. AUTHORS' CONCLUSIONS: Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed.

Platinum-induced hearing loss after treatment for childhood cancer.

BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin, oxaliplatin or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. There is a wide variation in the reported prevalence of platinum-induced ototoxicity and the associated risk factors. More insight into the prevalence of and risk factors for platinum-induced hearing loss is essential in order to develop less ototoxic treatment protocols for the future treatment of children with cancer and to develop adequate follow-up protocols for childhood cancer survivors treated with platinum-based therapy. OBJECTIVES: To evaluate the existing evidence on the association between childhood cancer treatment including platinum analogues and the occurrence of hearing loss. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 8), MEDLINE (PubMed) (1945 to 23 September 2015) and EMBASE (Ovid) (1980 to 23 September 2015). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2008 to 2014), the American Society of Pediatric Hematology/Oncology (2008 to 2015) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010 to 2015). Experts in the field provided information on additional studies. SELECTION CRITERIA: All study designs, except case reports, case series (i.e. a description of non-consecutive participants) and studies including fewer than 100 participants treated with platinum-based therapy who had an ototoxicity assessment, examining the association between childhood cancer treatment including platinum analogues and the occurrence of hearing loss. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection. One review author performed data extraction and risk of bias assessment, which was checked by another review author. MAIN RESULTS: We identified 13 eligible cohort studies including 2837 participants with a hearing test after treatment with a platinum analogue for different types of childhood cancers. All studies had methodological limitations, with regard to both internal (risk of bias) and external validity. Participants were treated with cisplatin, carboplatin or both, in varying doses. The reported prevalence of hearing loss varied considerably between 0% and 90.1%; none of the studies provided data on tinnitus. Three studies reported a prevalence of 0%, but none of these studies provided a definition for hearing loss and there might be substantial or even complete overlap in included participants between these three studies. When only studies that did provide a definition for hearing loss were included, the prevalence of hearing loss still varied widely between 1.7% and 90.1%. All studies were very heterogeneous with regard to, for example, definitions of hearing loss, used diagnostic tests, participant characteristics, (prior) anti-tumour treatment, other ototoxic drugs and length of follow-up. Therefore, pooling of results was not possible.Only two studies included a control group of people who had not received platinum treatment. In one study, the prevalence of hearing loss was 67.1% (95% confidence interval (CI) 59.3% to 74.1%) in platinum-treated participants, while in the control participants it was 7.4% (95% CI 6.2% to 8.8%). However, hearing loss was detected by screening in survivors treated with platinum analogues and by clinical presentation in control participants. It is uncertain what the effect of this difference in follow-up/diagnostic testing was. In the other study, the prevalence of hearing loss was 20.1% (95% CI 17.4% to 23.2%) in platinum-treated participants and 0.4% (95% CI 0.12% to 1.6%) in control participants. As neither study was a randomized controlled trial or controlled clinical trial, the calculation of a risk ratio was not feasible as it is very likely that both groups differed more than only the platinum treatment.Only two studies evaluated possible risk factors using multivariable analysis. One study identified a significantly higher risk of hearing loss in people treated with cisplatin 400 mg/m(2) plus carboplatin 1700 mg/m(2) as compared to treatment with cisplatin 400 mg/m(2) or less, irrespective of the definition of hearing loss. They also identified a significantly higher risk of hearing loss in people treated with non-anthracycline aminoglycosides antibiotics (using a surrogate marker) as compared to people not treated with them, for three out of four definitions of hearing loss. The other study reported that age at treatment (odds ratio less than 1 for each single-unit increase) and single maximum cisplatin dose (odds ratio greater than 1 for each single-unit increase) were significant predictors for hearing loss, while gender was not. AUTHORS' CONCLUSIONS: This systematic review shows that children treated with platinum analogues are at risk for developing hearing loss, but the exact prevalence and risk factors remain unclear. There were no data available for tinnitus. Based on the currently available evidence we can only advise that children treated with platinum analogues are screened for ototoxicity in order to make it possible to diagnose hearing loss early and to take appropriate measures. However, we are unable to give recommendations for specific follow-up protocols including frequency of testing. Counselling regarding the prevention of noise pollution can be considered, such as the use of noise-limiting equipment, avoiding careers with excess noise and ototoxic medication. Before definitive conclusions on the prevalence and associated risk factors of platinum-induced ototoxicity can be made, more high-quality research is needed. Accurate and transparent reporting of findings will make it possible for readers to appraise the results of these studies critically.

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

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.

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

BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. OBJECTIVES: To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. SEARCH METHODS: We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 12), MEDLINE (PubMed) (1945 to 4 December 2013) and EMBASE (Ovid) (1980 to 4 December 2013). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2009 to 2013). We scanned ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/en/) for ongoing trials (both searched on 13 December 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified one RCT and no CCTs. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (RR 1.39; 95% CI 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12; 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. AUTHORS' CONCLUSIONS: Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed.

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

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. OBJECTIVES: The primary objective was to assess the efficacy of different otoprotective medical interventions in preventing hearing loss in children with cancer treated with platinum-based therapy. 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 2011, Issue 4), MEDLINE (PubMed) (1945 to 22 December 2011) and EMBASE (Ovid) (1980 to 22 December 2011). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2006 to 2011), the American Society of Pediatric Hematology/Oncology (2007 to 2011) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010). 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 20 December 2011). 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 of 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. 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. All studies had methodological limitations. Unfortunately, pooling of the results of included studies was not possible. However, in all 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 (RR 9.04; 95% 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 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 eligible studies were identified, 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.

Methotrexate for high-grade osteosarcoma in children and young adults.

BACKGROUND: The majority of the currently used treatment protocols for osteosarcoma are based on a combination of doxorubicin, cisplatin, methotrexate (MTX) and/or ifosfamide, of which MTX seems to be one of the most active drugs. However, in the literature, this has not been unambiguously proven. OBJECTIVES: To compare the effectiveness of treatment including MTX with treatment without MTX for children and young adults (up to 21 years) with primary high-grade osteosarcoma. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 4, 2010), MEDLINE (1966 to January 2011) and EMBASE (1980 to January 2011). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of treatment including MTX with treatment without MTX in the treatment of paediatric high-grade osteosarcoma. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed the study selection. One reviewer performed the data extraction and quality assessment, which was checked by another reviewer. MAIN RESULTS: We could not identify any studies in which the only difference between the treatment groups was the use of MTX.We did identify a RCT comparing MTX with cisplatin (n=30 children). The risk of bias in this study was difficult to assess due to a lack of reporting. Survival could not be evaluated, but no evidence of a significant difference in response rate between the treatment groups was identified (RR=0.44; 95% CI 0.17 to 1.13; P=0.09). A significant difference in the occurrence of toxicities in favour of MTX was identified, but with regard to quality of life treatment with cisplatin seemed to give better results.For other combinations of treatment including and not including MTX no studies were identified. AUTHORS' CONCLUSIONS: Since no RCTs or CCTs in which only the use of MTX differed between the treatment groups were identified, no definitive conclusions can be made about the effects on antitumour efficacy, toxicities and quality of life of the addition of MTX to treatment of children and young adults with primary high-grade osteosarcoma. The same is true for combinations of treatment including and not including MTX other than treatment with MTX versus treatment with cisplatin. Only 1 RCT comparing MTX with cisplatin treatment was available and therefore, no definitive conclusions can be made about the effectiveness of these agents in children and young adults with primary high-grade osteosarcoma. Furthermore, this study was performed in a different treatment era. Nowadays single agent treatment of osteosarcoma is considered inadequate. Based on the currently available evidence, we are not able to give recommendations for the use of MTX in clinical practice. More high quality research is needed.