PURPOSE Cisplatin is a component of many high-risk neuroblastoma (HRNBL) induction regimens and causes irreversible destruction of cochlear hair cells. Historical cisplatin-induced hearing loss (CIHL) rates in patients with HRNBL range from 13% to 95%, with considerable heterogeneity due to treatment, assessment timing, and audiologic grading scales. Contemporary rates of CIHL in this vulnerable population are unknown. The purpose of this study was to describe the prevalence of end-induction CIHL using international consensus grading among patients with HRNBL enrolled on the Children's Oncology Group (COG) study ANBL1531. METHODS Enrolled patients were randomized or assigned therapy that included a total of 360 mg/m 2 of cisplatin during induction. Audiologic evaluations were completed at baseline and end of induction (EOI). A subset of trial centers submitted EOI audiograms, which were centrally graded using the International Society of Pediatric Oncology (SIOP) ototoxicity grading scale. Evaluable participants were those with interpretable audiology results for frequencies 2-8 kHz available for central review. Communication-impacting CIHL was defined as SIOP grade ≥2. RESULTS Among evaluable patients (n = 87), 56% (49/87) had SIOP grade >2 CIHL in the better ear following induction chemotherapy and 69% (51/74 of patients with ear-specific testing) had SIOP >2 hearing loss in the worse ear. There were no statistically significant differences in CIHL across patient demographic factors. A higher rate of CIHL was observed among patients receiving concurrent ALK inhibitor therapy (11/14, 79%), but this did not reach statistical significance. CONCLUSION In this contemporary HRNBL cohort with central audiometry using uniform SIOP ototoxicity grading, communication-impacting CIHL affected over half of patients at EOI. Otoprotection strategies are urgently needed for patients with HRNBL who receive cisplatin.

Background/Objectives: Cisplatin-exposed pediatric cancer patients are at increased risk of ototoxicity, particularly those under 5 years of age. In this group, audiological monitoring is challenging, as interpretation of otoacoustic emissions (OAEs) and tympanometry, used to supplement behavioral audiometry, is subject to interindividual variability. This study aimed to identify key challenges and establish an international consensus on optimal testing procedures and interpretation criteria for assessing early cochlear damage. Methods: Audiological data from 11 children (<5 years) exposed to cisplatin in utero were evaluated. An international panel of 10 pediatric oncology audiology experts reviewed tympanometry, transient evoked OAEs (TEOAEs), and distortion product OAEs (DPOAEs). Areas of disagreement were analyzed, and consensus was sought regarding testing conditions, interpretation, and clinical application. Results: Agreement on cochlear status was good in 10/22 ears, moderate in 3/22 ears, and poor in 9/22 ears, highlighting substantial variability in interpretation. Consensus was achieved on minimal technical and interpretative requirements for OAE testing in this population. The panel proposes a classification framework integrating OAEs and tympanometry to guide clinical follow-up. Importantly, normal OAE results were not considered sufficient to exclude ototoxic damage or mild hearing loss. Conclusions: OAEs, particularly DPOAEs, are valuable as a screening tool in ototoxicity monitoring programs for young children, provided that testing conditions and interpretation are standardized. However, OAEs alone are insufficient for definitive assessment. Longitudinal monitoring and confirmatory testing with behavioral audiometry or ABR/ASSR remain essential. Further validation of the proposed classification system is warranted.

OBJECTIVES:Sodium thiosulfate (STS) has recently been approved as an otoprotectant for systemic use in pediatric cancer patients receiving cisplatin treatment for localized, nonmetastatic solid tumors by the Food and Drug Administration, European Medicines Agency, and Medicines and Healthcare Products Regulatory Agency. While incorporating STS into the current standard of care pediatric practice, questions about uniform, timely, and safe administration are raised that may benefit from additional guidance. DESIGN:Recognizing that advancing clinical practice presents multiple challenges, an international onco-ototoxicity prevention task force, including experts in pediatric oncology, audiology, and pharmacology, was established to identify potential barriers to the implementation of otoprotection and to offer practical solutions for clinical services for children exposed to cisplatin, based on available evidence, as well as consensus where data are less robust. This task force held several online meetings and a working group session at the annual SIOPE meeting in Milan in May 2024, where the challenges for implementing STS were outlined and addressed. RESULTS:Nine key challenges were identified, including, for example, the timing of both cisplatin infusion and STS administration, the optimal integration of STS into existing treatment protocols, potential drug interactions, and relevant economic considerations. CONCLUSION:In this article, we propose practical steps to address these challenges, informed by the existing literature and expert opinion, incorporating recommendation statements from the international onco-ototoxicity prevention task force on behalf of the SIOP Supportive Care Network, to facilitate the implementation of STS in children with localized, nonmetastatic disease.

Cisplatin-induced hearing loss (CIHL) in pediatric cancer patients is an irreversible and highly prevalent adverse effect with a devastating impact on quality of life. Sodium thiosulfate (STS) has recently been approved for systemic administration as an otoprotective agent in children. However, implementation of systemic STS has its challenges, and there is currently limited evidence to support local STS for children. This review investigates the potential value of locally administered otoprotective agents other than STS with a focus on future pediatric implementation. We conducted a systematic review on the efficacy and safety of locally applied non-STS otoprotective agents in in vivo settings. This included a summary of investigated drug delivery methods and administration routes. We identified 70 preclinical and eight clinical studies. Agents were categorized based on their biological mechanisms: anti-inflammatory, chemical deactivators, calcium blockers, biologicals, and miscellaneous mechanisms. Preclinical studies investigated 45 different agents. Dexamethasone and N-acetylcysteine were identified as efficacious agents recurrently and progressed to clinical trials. Dexamethasone was investigated in three randomized clinical trials (RCTs) and three non-randomized clinical studies and showed statistically significant but not clinically relevant benefit in two trials. N-acetylcysteine was investigated in two clinical trials and one RCT and was minimally effective in the RCT and in one clinical study. Our review did not identify available studies of local alternative otoprotective agents that could reliably replace systemic STS in terms of safety and efficacy for pediatric patients. Further research on the optimal dosage, delivery method, and timing of otoprotective agents is needed.

Supplementary Fig. 5 Progression-free survival in NAC treated and observation patients

Supplementary Fig. 2 Cumulative incidence of SIOP Grade ≥2 hearing loss

Ototoxicity is among the adverse events related to cancer treatment that can have far-reaching consequences and negative impacts on quality-of-life for cancer patients and survivors of all ages. Ototoxicity management (OtoM) comprises the prevention, diagnosis, monitoring, and treatment, including rehabilitation and therapeutic intervention, of individuals who experience hearing loss, tinnitus, or balance/vestibular difficulties following exposures to ototoxic agents, including platinum chemotherapy (cisplatin, carboplatin) and cranial radiation. Despite the well-established physical, socioeconomic, and psychological consequences of hearing and balance dysfunction, there are no widely adopted standards for clinical management of cancer treatment-related ototoxicity. Consensus recommendations and a roadmap are needed to guide development of effective and feasible OtoM programs, direct research efforts, address the needs of caregivers and patients at all stages of cancer care and survivorship. Here we review current evidence and propose near-term to longer-term goals to advance OtoM in five strategic areas: (1) beneficiary awareness, empowerment, and engagement, (2) workforce enhancement, (3) program development, (4) policy, funding, and sustainability, and (5) research and evaluation. The goal is to identify needs and establish a roadmap to guide worldwide adoption of standardized OtoM for cancer treatment and improved outcomes for patients and survivors.

BackgroundCranial orthosis is a widely accepted treatment approach for moderate to severe deformational plagiocephaly. Custom-fit helmets molded tightly to the head are worn for 23 hours a day for several months2. This poses a challenge for children with concurrent conductive hearing loss who benefit from hearing devices, specifically bone anchored hearing aids (baha), that are intended to contact the skull directly1. We theorized the bone conducted signals could be transferred through the helmet to the baha device given its tight fit to the cranium.MethodsThis is a pilot study in which we present a case report of three patients in whom baha with headbands were used over their helmet therapy. Feedback management settings were adjusted to account for this. Given the age and development of the children, aided testing was performed.ResultsGood aided benefit was seen with using baha placement over the helmet. Optimal results were achieved with placement of the processor on the flat section of the helmet near the ear pinna. One patient, however, did not tolerate stimulus well and the baha was discontinued. For the other two patients, the baha over the helmet was utilized until they completed helmet therapy. Baha program settings were re-measured/adjusted when the device was used without the helmet. Parents reported positive responses when their child was wearing the baha compared to without.ConclusionPlacement of the baha with headband over a molding helmet is an important alternative method for patients with concurrent deformational plagiocephaly and conductive hearing loss. This modification allows for earlier baha implementation to facilitate auditory and language development, and minimize communication delays, while permitting optimal head reshaping without compromising speech development or head shape.

Supplementary Fig. 3 Change in serum glutathione concentrations following NAC infusion

Supplementary Fig. 4 Evaluation of long-term storage of serum specimens (NAC assay)

BACKGROUND:Childhood cancer survivors treated with platinum-based chemotherapy are at risk of treatment-induced hearing loss. Accurate evaluation of hearing thresholds has historically been limited to clinical audiometry, which is logistically challenging and expensive to include in epidemiologic studies. We evaluated the feasibility of using a remote, tablet-based hearing assessment in a cohort of pediatric germ cell tumor survivors treated with platinum-based chemotherapy. METHODS:Survivors from the GCT Outcomes and Late effects Data (GOLD) study were recruited to the pilot study (n = 100). Study personnel conducted remote hearing assessments of standard and extended high frequency thresholds using validated tablet-based audiometry (SHOEBOX, Inc.). T tests and Wilcoxon rank-sum tests evaluated differences in assessment characteristics between children and adults. Agreement between self-reported and measured hearing loss was calculated using Cohen κ. RESULTS:We were able to reach 136/168 (81%) eligible participants, of which 100 (74%) agreed to participate. Successful completion of the remote hearing assessment was high [97%; 20 children (ages 7-17), 77 adults (ages 18-31)]. The mean assessment length was 37.6 minutes, and the mean turnaround time was 8.3 days. We observed hearing loss at standard frequencies in 21% of participants. Agreement between self-reported and measured hearing loss was significant (P value = 1.41 × 10-7), with 83.5% concordance. CONCLUSIONS:Hearing loss measured using the remote assessment aligns with self-reporting and rates of hearing loss reported in the literature for this population. IMPACT:Remote application of tablet-based audiometry is a feasible and efficacious method for measuring hearing in epidemiologic studies with participants spread across large geographic areas.

Purpose: Ototoxic medications and chemical agents in the workplace can put individuals' hearing and vestibular health at risk for permanent injury. Proactive ototoxicity management (OtoM) strategies aim to minimize exposure, avoid onset of symptoms, provide ongoing monitoring, and manage auditory and vestibular changes as the clinical needs of the patient evolve. During a 2021 American Speech-Language-Hearing Association Special Interest Groups Open House, members of the International Ototoxicity Management Group discussed how best to integrate OtoM into routine clinical practice, what tools to use, and what special considerations need to be understood to best support patients and their families. Here, we have summarized their viewpoints to encourage widespread adoption of improved OtoM services for at-risk individuals. Conclusions: The field of audiology needs to move to a place where we better understand the full extent of ototoxicity and can agree on expanding minimum guidelines that can be implemented more universally to mitigate, detect, and manage the damage from ototoxic exposures. Only recently has our field seen a therapeutic drug that can protect against ototoxicity; however, the population served is restricted only to children receiving treatment for nonmetastatic carcinoma. This is hopefully just the beginning of future therapeutic interventions to come, but, in the meantime, ototoxicity resulting from other medications in different patient populations and chemical agents persists.

Purpose Cisplatin-induced hearing loss (CIHL) is a common late effect after childhood cancer treatment having profound, lifelong consequences that lower quality of life. The recent identification of intravenous sodium thiosulfate (STS) as an effective agent for preventing pediatric CIHL represents a paradigm shift that has created new opportunities for expanding STS usage and developing additional otoprotectants. The purpose of this paper is to discuss key considerations and recommendations for the design and implementation of future pediatric otoprotection trials. Methods An approach synthesizing published data and collective experience was used. Results Key issues were identified in the categories of translational research, trial designs for systemic and intratympanic agents, measurement of ototoxicity, and biostatistical challenges. Conclusions Future pediatric otoprotection trials should emphasize (1) deep integration of preclinical and early-phase studies; (2) an embedded or free-standing design for systemic agents based on mechanistic considerations; (3) use of suitable audiologic testing batteries for children, SIOP grading criteria, and submission of raw audiologic data for central review; and (4) novel endpoints and innovative study designs that maximize trial efficiency for limited sample sizes. Additional recommendations include routine collection of DNA specimens for assessing modifying effects of genetic susceptibility and meaningful inclusion of patient/family advocates for informing trial development. Implications for Cancer Survivors Changing the historical paradigm from acceptance to prevention of pediatric CIHL through expanded research with existing and emerging otoprotectants will dramatically improve quality of life for future childhood cancer survivors exposed to cisplatin.

In two randomized trials (Children's Oncology Group ACCL0431 and International Childhood Liver Tumour Strategy Group SIOPEL-6), sodium thiosulfate (STS) demonstrated efficacy in preventing cisplatin-induced hearing loss (CIHL). However, the measures used in those trials have been superseded by the consensus International Society of Paediatric Oncology (SIOP) Ototoxicity Scale. To provide benchmark data for STS efficacy when using this contemporary scale, we reanalyzed ACCL0431 hearing outcomes with the SIOP scale and using multiple timepoints. Compared to the control arm, STS significantly reduced CIHL when assessed by the SIOP scale across these different approaches. These results provide critical data to inform treatment discussions and support future potential trial designs comparing otoprotectants.

Pediatric Blood & CancerVolume 70, Issue 5 e30248 COMMENTARYOpen Access Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it Penelope Brock, Corresponding Author Penelope Brock [email protected] orcid.org/0000-0003-1239-6316 Department of Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Correspondence Penelope R. Brock, Department of Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Email: [email protected]Search for more papers by this authorAnnelot Meijer, Annelot Meijer Department of Pediatric Oncology, Prinses Maxima Centrum, Utrecht, The NetherlandsSearch for more papers by this authorPer Kogner, Per Kogner Department of Pediatric Oncology and Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorMarc Ansari, Marc Ansari Pediatric Hematology and Oncology, Geneva University Hospital, Geneva, SwitzerlandSearch for more papers by this authorMichael Capra, Michael Capra Paediatric Oncology, Our Lady's Children's Hospital, Dublin, IrelandSearch for more papers by this authorJames Geller, James Geller orcid.org/0000-0001-5181-116X Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USASearch for more papers by this authorMarry van den Heuvel-Eibrink, Marry van den Heuvel-Eibrink Department of Pediatric Oncology, Prinses Maxima Centrum, Utrecht, The NetherlandsSearch for more papers by this authorKristin Knight, Kristin Knight Department of Pediatric Audiology, Oregon Health and Science University, Portland, Oregon, USASearch for more papers by this authorMariana Kruger, Mariana Kruger orcid.org/0000-0002-6838-0180 Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, South AfricaSearch for more papers by this authorSusan Lindemulder, Susan Lindemulder Department of Pediatric Oncology, Oregon Health and Science University, Portland, Oregon, USASearch for more papers by this authorRudolf Maibach, Rudolf Maibach Department of Statistics, International Breast Cancer Study Group, Bern, SwitzerlandSearch for more papers by this authorAllison O'Neill, Allison O'Neill orcid.org/0000-0002-8957-3870 Children's Cancer and Blood Disorders Center, Dana Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorVassilios Papadakis, Vassilios Papadakis orcid.org/0000-0002-1821-7799 Department of Pediatric Oncology, Agia Sofia Children's Hospital, Athens, GreeceSearch for more papers by this authorKaukab Rajput, Kaukab Rajput Department of Paediatric Audiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UKSearch for more papers by this authorArchie Bleyer, Archie Bleyer orcid.org/0000-0001-7738-5146 Radiation Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USASearch for more papers by this authorEric Bouffet, Eric Bouffet orcid.org/0000-0002-6832-6539 Division of Pediatric Neuro-Oncology, The Hospital for Sick Children, Toronto, Ontario, CanadaSearch for more papers by this authorMichael Sullivan, Michael Sullivan Children's Cancer Centre and Department of Paediatric Oncology, Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this author Penelope Brock, Corresponding Author Penelope Brock [email protected] orcid.org/0000-0003-1239-6316 Department of Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Correspondence Penelope R. Brock, Department of Paediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Email: [email protected]Search for more papers by this authorAnnelot Meijer, Annelot Meijer Department of Pediatric Oncology, Prinses Maxima Centrum, Utrecht, The NetherlandsSearch for more papers by this authorPer Kogner, Per Kogner Department of Pediatric Oncology and Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorMarc Ansari, Marc Ansari Pediatric Hematology and Oncology, Geneva University Hospital, Geneva, SwitzerlandSearch for more papers by this authorMichael Capra, Michael Capra Paediatric Oncology, Our Lady's Children's Hospital, Dublin, IrelandSearch for more papers by this authorJames Geller, James Geller orcid.org/0000-0001-5181-116X Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USASearch for more papers by this authorMarry van den Heuvel-Eibrink, Marry van den Heuvel-Eibrink Department of Pediatric Oncology, Prinses Maxima Centrum, Utrecht, The NetherlandsSearch for more papers by this authorKristin Knight, Kristin Knight Department of Pediatric Audiology, Oregon Health and Science University, Portland, Oregon, USASearch for more papers by this authorMariana Kruger, Mariana Kruger orcid.org/0000-0002-6838-0180 Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, South AfricaSearch for more papers by this authorSusan Lindemulder, Susan Lindemulder Department of Pediatric Oncology, Oregon Health and Science University, Portland, Oregon, USASearch for more papers by this authorRudolf Maibach, Rudolf Maibach Department of Statistics, International Breast Cancer Study Group, Bern, SwitzerlandSearch for more papers by this authorAllison O'Neill, Allison O'Neill orcid.org/0000-0002-8957-3870 Children's Cancer and Blood Disorders Center, Dana Farber Cancer Institute, Boston, Massachusetts, USASearch for more papers by this authorVassilios Papadakis, Vassilios Papadakis orcid.org/0000-0002-1821-7799 Department of Pediatric Oncology, Agia Sofia Children's Hospital, Athens, GreeceSearch for more papers by this authorKaukab Rajput, Kaukab Rajput Department of Paediatric Audiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UKSearch for more papers by this authorArchie Bleyer, Archie Bleyer orcid.org/0000-0001-7738-5146 Radiation Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USASearch for more papers by this authorEric Bouffet, Eric Bouffet orcid.org/0000-0002-6832-6539 Division of Pediatric Neuro-Oncology, The Hospital for Sick Children, Toronto, Ontario, CanadaSearch for more papers by this authorMichael Sullivan, Michael Sullivan Children's Cancer Centre and Department of Paediatric Oncology, Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this author First published: 11 February 2023 https://doi.org/10.1002/pbc.30248 Senior authors Archie Bleyer, Eric Bouffet, and Michael Sullivan contributed equally to this work. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abbreviations ACCL0431 American Cancer Control Liver (study number) 0431 CIHL cisplatin-induced hearing loss EFS event-free survival OS overall survival QoL quality of life SIOPEL 6 International Society of Pediatric Oncology Epithelial Liver (group study number) 6 STS sodium thiosulfate 1 INTRODUCTION Cisplatin is an essential chemotherapeutic agent for children treated with hepatic tumors, neuroblastoma, medulloblastoma, germ cell tumors, and osteosarcoma. Unfortunately, cisplatin-induced hearing loss (CIHL) occurs in about 50% of treated children,1-3 and is more frequent and more severe in those aged less than or equal to 5 years.4, 5 CIHL develops during the early stages of therapy,4 is irreversible,6 and in infants and young children causes speech and language deficits, impaired academic skills, and lower quality of life.7, 8 Prevention of CIHL has been variously approached by different disease clinical trial groups, some opting for individual cisplatin dose reduction or cisplatin replacement, but often without a solid evidence base. In other tumor groups, cisplatin dose reduction is being studied in randomized clinical trials. Either way, cisplatin remains an important treatment agent, particularly for children with high-risk and/or metastatic disease. Several otoprotective agents have been promising preclinically, but sodium thiosulfate (STS) has the best proven protection in clinical trials.9 STS induces antioxidant production to counter reactive oxygen species responsible for CIHL development.10 The licensing of STS (as PEDMARK) by the Food and Drug Administration (FDA), for use in children over 1 month as cisplatin otoprotectant, is a breakthrough, because the impact of permanent bilateral hearing loss is debilitating and costly. But the FDA has only approved STS for use in "localized, nonmetastatic" disease; so how has this current situation of limiting its application occurred? This commentary aims to help clinicians understand why STS has been restricted to localized cancer, how this situation has arisen, and guide the use of STS in the future. 2 RANDOMIZED CLINICAL TRIALS WITH STS AND THE MISCONCEPTION THAT ENSUED The efficacy of STS to reduce the incidence and severity of CIHL in children with cancer was studied in two randomized clinical trials: ACCL0431 (American Cancer Control Liver [study number] 0431) and SIOPEL 6 (International Society of Pediatric Oncology Epithelial Liver [group study number] 6).11, 12 Secondary end points were event-free survival (EFS) and overall survival (OS). In these two trials, STS was administered intravenously over 15 minutes, after an interval of 6 hours from the end of the cisplatin infusion. As demonstrated in pharmacokinetic studies, it is safe to administer STS at a time when active cisplatin is out of circulation.13 The trials were differently designed. ACCL0431 was a hearing trial, where children with any tumor were randomized to receive either cisplatin alone, or cisplatin and STS, and were stratified by age and cisplatin infusion time. They were not matched by tumor type, disease stage, clinical risk group or treatment, and disease prognostic factors were not collected. SIOPEL 6 was a randomized clinical trial for children with standard-risk hepatoblastoma stratified by clinical risk group and age and treated with six cycles of either single agent cisplatin alone, or cisplatin and STS, with delayed surgical resection. Patients were closely matched by tumor type, prognostic group, and treatment received. Both trials showed that STS significantly reduced hearing loss by ∼50% and as secondary end point; neither trial showed a statistically significant difference in EFS or OS between their treatment arms. However, in ACCL0431, a discernable, though statistically nonsignificant, trend toward lower OS in the STS-treated group prompted an unplanned, post hoc survival analysis using retrospective stratification of participants by initial extent of disease (localized or disseminated). No difference in EFS/OS was noted among patients retrospectively classified as having localized disease but among those retrospectively classified as having disseminated disease, a significantly lower OS was noted. But, in a subsequent comparison of expected outcomes, taken from historic published outcomes for a mixed disseminated tumor group, the control group with disseminated disease was found to have an unexpectedly favorable outcome, whereas the STS group with disseminated disease had the expected outcome.14, 15 Following the initial publication of ACCL0431, a misinterpretation about STS became widely spread; namely, that it was safe in localized disease but not safe in patients with metastatic disease. The more obvious conclusion is that the two arms of the ACCL0431 trial were not matched for tumor type or any prognostic factor. Crucially, the plausible reason for this observation was not tumor protection, but mismatched cohorts unmatched by tumor type, biology, pathology, stage, or treatment received. There are several hypotheses as to why the concern about STS, administered 6 hours after cisplatin, and thus not interfering with the antitumor activity of the chemotherapy, is unjustified. With regard to the ACCL0431 trial, these include: (a) overall tumor recurrence rate, which was equal in the STS group and the control group; (b) extent of disease was not a predetermined aim of the study; (c) the study design created large heterogeneity in tumor type and stage; (d) the number of each tumor type in the study was small; (e) the trial did not meet stopping rules that included tumor protection; and (f) most importantly, differences in treatment regimens and prognostic factors could have contributed, and likely did, to the retrospective deduction of tumor protection. 3 STS: TO USE OR NOT TO USE Following publication of the ACCL0431 study, a widely held assumption has been made that STS administration can lead to reduced tumor control in children with disseminated disease, but without a biologically plausible rationale. It is clear from the mechanism of action of STS that if administered too early, while cisplatin is still active it is likely to have an adverse effect, but this should apply equally regardless of tumor stage. Thus a 6-hour delay after the cisplatin infusion before STS is administered is crucial. Fortunately, STS can still protect the inner ear from cisplatin's longer duration adverse effect on hearing, even when delayed by 6 hours. We suggest that the misinterpretation of the post hoc analysis in the ACCL0431 study risks wider misunderstanding with serious consequences; namely, that STS will only be used in children with localized cancers. We are concerned that this issue may exclude children who will most benefit from STS otoprotection, those with high-risk cancer requiring high-dose cisplatin. We identify several issues that may challenge oncologists, patients, and their families confronted with this dilemma. 1) It is essential that adequate information is given to parents and young adults to increase awareness of the potential of otoprotection and/or any other CIHL reduction policy, and that they can advocate for their children or themselves once properly informed. Factors that might influence decision-making around the use of STS could be the impact of the disease or treatment on other faculties (e.g., vision or balance), the potential of alternative treatments to cisplatin, the potential hearing support available should hearing loss occur, and other key elements of the benefit/risk discussion. 2) Clinical trials of STS are needed in small groups of children with metastatic disease, preferably by specific tumor groups, to study efficacy, safety, pharmacokinetics, and disease response. These should be supported by additional biological and imaging studies to investigate changes in response to treatment, to understand whether STS alters antitumor efficacy. 3) Hearing loss can negatively influence the child's development, neuro-cognition, behavior, and quality of life (QoL),7, 16-18 which added to brain irradiation could further reduce intelligence quotient (IQ).19 Comparative and longitudinal studies on the impact of CIHL in children with cancer treated with and without STS are needed. 4) Future STS trials require central review of biology, pathology, radiology, and audiology, allowing for careful matching of patients by diagnosis, clinical risk group, biological subset, and treatment received. For the extent of disease, the term "metastatic" is preferred to "disseminated" to indicate the spread of cancer cells away from the primary tumor. 5) Issues around the best use of cisplatin, potentially fractionating the dose where possible,20 and reducing the infusion time to capture the optimal STS window for hearing protection, need to be addressed using a rigorous disease-based approach. 6) Pediatric oncology has developed over decades through evidence-based medicine. However, in certain areas, particularly where toxicity is concerned, well-intentioned forms of treatment adaptation have been introduced and have become normalized without the necessary evidence base (e.g., cisplatin dose reduction for individual patients who develop hearing loss). Now that prevention is a possibility, it is time to carefully consider the risk/benefit analysis for each child/young person. Is the risk of potential reduced tumor efficacy from STS more real than that of individual dose reduction? What is the financial burden for the family of introducing STS versus lifelong hearing support? What is the benefit of protection versus no hope of hearing aid support for patients in low- and mid-income countries? There are precedents where treatment has been unnecessarily withheld from children, such as growth hormones in children treated for brain tumors for fear of recurrence. Will history repeat itself? 4 CONCLUSION We need to design and support reliable, well-executed studies on appropriately delayed STS in children with metastatic disease for whom cisplatin is an essential therapy. In the meantime, we need to be brave enough to face the question together with each child and family: do we introduce appropriately delayed STS as a cisplatin otoprotectant in those most likely to benefit? And do we act in the best interest of the child and recognize the limitations of post hoc evidence and address the serious compromise of lifelong CIHL now that we have an effective antidote? ACKNOWLEDGMENTS Thanks to all participating families and patients in the above-mentioned clinical trials and to national charities for funding clinical trial research. CONFLICT OF INTEREST STATEMENT Penelope R. Brock and James Geller are consultants for Fennec Pharmaceuticals. There are no other known conflicts of interest. REFERENCES 1Knight KR, Kraemer DF, Winter C, et al. Early changes in auditory function as a result of platinum chemotherapy: use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncol. 2007; 25(10): 1190- 1195. 2Clemens E, de Vries AC, Pluijm SF, et al. Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: a DCOG late-effects study. Eur J Cancer. 2016; 69: 77- 85. 3Kushner BH, Budnick A, Kramer K, et al. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer. 2006; 107(2): 417- 422. 4Meijer AJM, Li KH, Brooks B, et al. 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Supplementary Fig. 1 Treatment schema & Sampling Timepoints