What Is Cancer? Cancer Statistics. Cancer Disparities. Cancer Causes and Prevention. Risk Factors. Cancer Prevention Overview. Cancer Screening Overview.
Screening Tests. Diagnosis and Staging. Questions to Ask about Your Diagnosis. Types of Cancer Treatment. Side Effects of Cancer Treatment. Clinical Trials Information. A to Z List of Cancer Drugs. Questions to Ask about Your Treatment. Feelings and Cancer. Adjusting to Cancer.
Day-to-Day Life. Support for Caregivers. Questions to Ask About Cancer. Choices for Care. Talking about Your Advanced Cancer. Planning for Advanced Cancer. Advanced Cancer and Caregivers.
Questions to Ask about Advanced Cancer. Managing Cancer Care. Finding Health Care Services. Advance Directives. Using Trusted Resources. Coronavirus Information for Patients. Clinical Trials during Coronavirus. Adolescents and Young Adults with Cancer. Emotional Support for Young People with Cancer. Cancers by Body Location. Late Effects of Childhood Cancer Treatment. RI was involved in the study design. MK was involved in the analysis of the data and manuscript editing.
MS was involved in the study conception, data analysis, and editing the manuscript. DA was involved in the study conception and design, interpretation of the data, drafting and revising the manuscript. All authors read and approved the final manuscript. Correspondence to D. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.
If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Reprints and Permissions. Santucci, N. Insight into the current practice of ototoxicity monitoring during cisplatin therapy. Download citation. Received : 03 December Accepted : 22 February Published : 25 March Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Original research article Open Access Published: 25 March Insight into the current practice of ototoxicity monitoring during cisplatin therapy N.
Santucci 1 , B. Garber 2 , R. Ivory 3 , M. Kuhn 2 , M. Abstract Background The aim of this study is to evaluate the current state of ototoxicity monitoring for patients receiving cisplatin chemotherapy in an academic medical center with particular attention to how closely monitoring adheres to national ototoxicity guidelines.
Results Three hundred seventy-nine patients met study criteria, of which Conclusions There is poor adherence to national ototoxicity monitoring guidelines at a large academic medical center.
Graphical abstract. Introduction Platinum-based agents are standard curative and palliative chemotherapies used for a wide range of malignancies in both the pediatric and adult population. Results Characteristics of cohort We reviewed patient medical records. Discussion According to the American Cancer Society, an estimated 1.
Conclusion Despite well-established ototoxicity monitoring guidelines, it seems that clinical practice may not reflect these recommendations. Availability of data and materials The data generated and analyzed during the study are available from the corresponding author on reasonable request.
References 1. PubMed Google Scholar 3. Article PubMed Google Scholar 8. Article PubMed Google Scholar 9. Article PubMed Google Scholar Google Scholar Acknowledgements None. Funding No funding was received for this study. Garber, M. Stephen Authors N. Santucci View author publications. View author publications. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. About this article. Cite this article Santucci, N.
Copy to clipboard. Contact us Submission enquiries: Access here and click Contact Us General enquiries: info biomedcentral. Autophagy differs from caspase-dependent apoptosis in that it is stimulated by oxidative and nitrosative stress Filomeni et al. Both activation and inhibition of autophagy can reduce cisplatin-induced ototoxicity. For example, inhibition of ROS generation significantly prevents autophagy activation and apoptosis in response to cisplatin exposure Yin et al.
Further, enhancing autophagy can alleviate cisplatin-induced ototoxicity in rats Liu et al. Meanwhile, some genotypes GSTs, SLC22A2 occur significantly more often among patients without ototoxicity, which show a protection against cisplatin-induced ototoxicity. These observations were made on small cohorts and independent replication is required. Nitrative stress could be another important factor in cisplatin-induced ototoxicity.
Cisplatin treatment induces the nitration and degradation of cochlear protein LMO4 within the Organ of Corti, spiral ganglion, and stria vascularis Jamesdaniel et al. Other nitrated proteins in the cochlear sensory epithelium have been discovered by proteomic analysis Jamesdaniel et al. Furthermore, the activation of the iNOS pathway and the generation of nitric oxide is believed to facilitate ototoxicity Watanabe et al. Another programmed cell death pathway, necroptosis, has been demonstrated to contribute to cisplatin ototoxicity Choi et al.
Animal models are necessary for the study of cisplatin-induced ototoxicity. In addition to zebrafish used for screening and optimizing potent therapeutic agents Kros and Steyger, , other in vivo animal models, particularly rodents mice, rats, and guinea pigs , are utilized for histological analysis of auditory structures and physiological function.
Cisplatin-induced hearing loss is associated not only with dosage, but also with the administration protocol. Whether used in single high dose or multiple low dose, one cycle or multiple cycles, consecutively or separately, different choices have different mortality rates and levels of hearing damage Hughes et al. The purpose of each is to establish a viable and stable ototoxicity model.
However, this approach is not similar to clinical chemotherapy in which cisplatin is administered as a single intravenous dose every 4 to 6 weeks with as many as six repetitions. Multi-dose administrations that mimic clinical regimens are essential. Three cycles of cisplatin with day intervals has been established Roy et al. Table 1 Summarized effects of otoprotective drugs on cisplatin-induced ototoxicity in various animal models and by differing delivery routes. Significant ototoxic differences have been found for different rodent species.
For example, guinea pigs exhibit an increased sensitivity to cisplatin compared with mice Poirrier et al. It suggests the need for careful selection of animal species.
The large inter-animal variability observed with systemic drug administration can be overcome by direct administration of cisplatin into the cochlea via an osmotic minipump system Wolters et al. Although this intracochlear application is not clinically practical, which is the major drawback of this protocol, the animal model is ideally suitable for studies on otoprotective interventions.
Additionally, the trans-tympanic route lowers morbidity and dose-dependent cochlear or vestibular toxicity Callejo et al. In recent decades, preclinical pharmacological strategies have assessed means by which to reduce the ototoxic effects of cisplatin. These assessments have been based on the underlying mechanisms identified above.
The following describes promising small molecule compounds, novel delivery systems, and routes of delivery in a variety of experimental animal models. Various studies have assessed the potential protective effects of compounds. These include blockade of cisplatin entry into the cochlear fluid or hair cells.
Further, antioxidants are among the most extensively studied agents due to the importance of ROS in ototoxicity. However, a concern exists that the chemotherapeutic efficacy of cisplatin may be reduced Block et al.
Reductions in inflammatory cytokine levels have been another target for drug development by which to protect from cisplatin-induced hearing loss. Finally, strategies to reduce apoptosis or other forms of cell death have shown great promise.
Table 1 identifies otoprotective candidates evaluated in the last 10 year, as well as operative pathways by which cochlear cell cytotoxicity is induced. One of the most important choices for a protective intervention is the route of drug delivery. The amount and distribution of drug depends both on the substance applied and on the application protocol.
Pharmacological therapy to the inner ear can be divided into two forms: systemic or local administration. Both have pros and cons. Systemic administration is a practical and less invasive method for delivery by oral, intravenous, intraperitoneal I. As shown in Table 1 , these methods of administration are preferable and have protective effects against cisplatin-induced ototoxicity.
Among these compounds, many have been applied systemically before the injection of cisplatin for a single dose Paeoniflorin, Levosimendan or multi doses Curcumin, Dunnione , while some are used after cisplatin injection Ginkgolide B, N-acetylcysteine.
For low-frequency hearing loss, associated with the cochlear apex, systemic administration provides for relatively uniform drug distribution along the cochlea. For high-frequency hearing loss local administration is appropriate Wang et al. However, there are two challenges. The first is to overcome biological barriers that restrict access to the inner ear.
These are the blood-perilymph, blood-endolymph, perilymph-endolymph, and middle-inner ear barriers Zou et al. The second is off target side effects of systemic administration and the possibility of drug clearance prior to target site access.
Unwanted side effects include hematological changes Freyer et al. Further, the development of 3D computer simulated delivery and sampling procedures have provided a valuable tool to interpret the amount and distribution of drug within the ear Salt and Plontke, Drugs are commonly applied to the round window RW niche where it contacts both the round window membrane RWM and the stapes footplate.
If not cleared through the eustachian tube, higher drug concentrations are found in the scala vestibuli rather than the scala tympani.
A decreasing basal-apical drug concentration gradient along the cochlea may limit the therapeutic effect of the drug Plontke et al. Caution must be exercised in that vestibulotoxicity can develop with prolonged drug retention Salt et al.
Moreover, multi-cycle intratumor administration may be required, which can damage tissue and bone and is expensive. The RW is also a site for chronic drug delivery by a combination of micropump and catheter over a long time course, which provides predictable duration of delivery and consistent drug concentration Sale et al. Potential adverse local effects are middle ear granulation Plontke et al. Furthermore, obstruction pseudomembrane, fibrous, or fat plug of the RWM Alzamil and Linthicum, is another obstacle to local delivery.
Intracochlear administration has the advantage of passage through physiological barriers. Compared with I. Varied approaches have been developed to improve efficacy including the use of sealing materials to reduce leakage while injecting through the RWM Plontke et al. Gene therapy and cell transplantation by intracochlear delivery hold future promise for treatment Salt and Plontke, To summarize, the most suitable protocol for treating cisplatin-induced ototoxicity is intratympanic injection to be delivered 1h before each cisplatin injection, due to superior perilymph concentrations within 1 h of administration Chandrasekhar et al.
While the major obstacle is the trama of middle ear and intratympanic pain, which can be relieved by advanced technique of endoscope and analgesia. Many strategies for both systemic and local delivery to the inner ear have been developed to improve local effectiveness and to reduce systemic side effects. Innovations in drug delivery systems, including nanoparticles, hydrogels, and environmental stimuli systems have been applied to the inner ear.
After intratympanic administration, drug can reach the cochlea through the RWM by diffusion of the drug-loaded NPs or by diffusion of the free drug released from NPs Mader et al. However, particle size, surface chemistry, and cell-penetrating peptides CPPs all have impact on cochlear drug delivery in vivo Cai et al.
Various materials have been used for NP construction, including lipids, inorganic materials such as gold, carbon or iron , proteins, and polymeric systems Morachis et al. Each have a different capacity to reduce cisplatin-induced ototoxicity. For example, Martin-Saldana Martin-Saldana et al. Biodegradable and biocompatible solid lipid nanoparticles SLNs are able to increase glucocorticoid dose to the inner ear, improving protection Cervantes et al.
Moreover, modification to NP surfaces can improve desirable attributes. Solutions administered intratympanically tend to be absorbed through the eustachian tube and cleared through the middle ear mucosa, which provides limited temporal exposure to the inner ear. This obstacle is overcome by the use of hydrogel. OTO poloxamer hydrogel containing dexamethasone provides a sustained-exposure to dexamethasone and alleviates cisplatin-induced ototoxicity Fernandez et al.
A Diltiazem calcium-channel blocker -loaded chitosan-glycerophosphate CGP hydrogel has been used as a vehicle to provide controlled and sustained delivery to the inner ear Naples et al. In addition, hydrogel itself can be cross-linked with functional reagents, such as genipin or STS, with potential therapeutic effect Videhult Pierre et al.
For example, silk fibroin and homogenously deacetylated chitosan formulations undergo spontaneous transformation from an aqueous phase to gel and provide rapid transport to the inner ear and prolonged release through the RWM Chen et al. In spite of these attractive properties, there is a concern for subsequent conductive hearing loss due to hydrogel attachment to the RWM.
A clinical trial has demonstrated I. The major constraint on effective nanoparticle delivery is their poor cellular internalization. Given this, environmental stimuli systems may increase their effective delivery. The stimuli systems can be divided into endogenous redox, pH, enzyme and exogenous light, heat, magnetic field, and ultrasound types Morachis et al. The former ones occur inherently and are beneficial for clinical application.
A designed pH-sensitive polymeric nanoparticle system, triggered by an acid environment due to increased ROS and inflammation, can release encapsulated dexamethasone and ameliorate hearing loss by intratympanic administration Martin-Saldana et al.
Endogenous stimuli are favored by systemic administration and only activated for regulated release at specific sites Movahedi et al. In a magnetic field, nano-constructs consisting of superparamagnetic iron oxide nanoparticles SPIONs entrapped within glutathione micelles can be used to sequester extracellular cisplatin before it enters a cell Martin-Saldana et al. NPs with encapsulated prednisolone can be delivered magnetically to the cochlea with substantial reduction in hearing loss Ramaswamy et al.
In vitro , a photosensitive substance, 4-azidosalicylate activated by UV light, has been used to disable prestin in in isolated OHCs, resulting in permanent electromotility inhibition Fisher et al.
Although optogenetic applications have not been used to treat cisplatin-induced ototoxicity, possibilities have been described DiGuiseppi and Zuo, Drug delivery carriers are also suitable for use with cisplatin, including NPs, liposomes, micelles Baba et al. These can selectively and effectively accumulate in solid tumors, enhancing anticancer potential and reducing toxicity. Although an extensive number of preclinical studies have explored protective interventions to reduce cisplatin-induced ototoxicity, there are no generally established clinical guidelines.
The challenges for translation of preclinical to clinical trials are: 1 differences in morphology and physiology between the human cochlea and that of experimental animals Laurell, ; 2 identification of ototoxic susceptible patients in that international standards among classification systems do not exist Knight et al.
Several well-studied laboratory protective approaches have been extended to the clinic. Two randomized controlled trials RCTs have verified the otoprotective effect of intratympanic dexamethasone and N-acetylcysteine, which included attenuation of hearing loss and alleviation of OHC dysfunction Marshak et al. Another antioxidant, amifostine, significantly reduced cisplatin-induced serious hearing loss in patients with average-risk medulloblastoma Fouladi et al.
Some trials have had contradictory results Yoo et al. Therefore, a larger scale research, employing various concentrations to be delivered in precise timing, is required. Notably, sodium thiosulfate is a promising agent. In a recent multicenter, randomized, phase 3 clinical trial NCT Brock et al. Similarly, in another clinical trial NCT Freyer et al. These results suggest a new era with encouraging possibilities in cases of inevitable cisplatin chemotherapy due to its efficacy and safety.
To reduce cisplatin-induced ototoxicity, there are challenges, including 1 an incomplete understanding of the underlying mechanisms of ototoxicity, 2 selection of an optimal strategy when to use and by which route among many alternatives, 3 translation to clinical application. There is a need to identify the pathogenic basis for cisplatin-induced ototoxicity. This identification will guide future advances in effective otoprotective agents.
Moreover, identification of pharmacogenomic markers may reduce cisplatin-induced ototoxicity by identifying patients at greatest risk, or who require closer audiologic monitoring, or may benefit from another platinum derivative, or require a reduced drug dosage.
In all cases, interference with antitumor efficacy must be considered. Importantly, an internationally approved strategy needs to be implemented for clinical practice. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Alzamil, K. Extraneous round window membranes and plugs: possible effect on intratympanic therapy. The vertical axis is the level of sound in decibels - termed dB HL Hearing Level where the quietest levels are at the top.
Where there is no conductive hearing loss the air - and bone conduction thresholds are more or less the same, but when there is a hearing loss the air conduction thresholds are depressed further. Overlaying any audiogram onto this can indicate which sounds are audible and those which would be inaudible, which can illustrate the functional implications of various configurations of hearing loss.
The speech banana. For the results of audiometry to be reliable, the child has to understand the instructions and has to be motivated to comply. For children younger than 5 years of age, audiometry is generally too challenging. Therefore, several other behavioural tests are available to estimate hearing thresholds in children.
Visual reinforcement audiometry is applied to estimate hearing thresholds in young children 6 months to 3 years of age. A visual reinforcer, such as an animated toy or picture is used to generate and maintain a head turn response to the sound stimulus presented through a speaker or ear phones.
To measure hearing thresholds in children aged 3 to 5 years, conditioned play audiometry may be applied. The child is conditioned to respond to a sound by performing an action putting blocks in a box or stacking rings on a stick [ 30 ]. Conventional audiometry has been considered the gold standard for obtaining hearing thresholds between 0. The child presses a button in response to the sound stimulus. Additionally, the extended high frequencies EHF up to 16 kHz may be tested for identification of early ototoxic damage.
EHF testing is less widely applied as special calibration of the equipment is required A. Meier et al. For infants up to 6 months of age, behavioural tests are too inaccurate for hearing threshold estimation. To asses hearing of children of this age, objective tests are available and widely used in programs for new born hearing screening. OAEs reflect the function of outer hair cells and are only produced in ears with normal hearing or a mild loss of 20—30 dB HL.
Presence of an OAE response confirms normal or near-normal hearing. Absence of a response indicates the possibility of a hearing loss and the need for follow-up testing, though it is often due to temporary factors such as excessive head movement or middle ear fluid. The main follow-up test in this age group is auditory brainstem response ABR testing.
The electrodes detect field potentials generated by the lower auditory pathways cochlea and brainstem , producing a characteristic waveform response. The intensity of the stimuli is reduced until the waves are no longer visible, providing a close approximation to behavioural hearing thresholds. When the equipment is well calibrated and click stimuli are used, hearing thresholds around 3 kHz can be estimated, type of hearing loss can be determined conductive or sensorineural and integrity of the VIIIth cranial nerve and lower brainstem can be assessed.
ABR is preferably measured during sleep, but in some situations sedation must be applied [ 30 ], A. As cisplatin-induced ototoxicity in children may have a negative impact on speech-language development and quality of life, early detection of hearing loss by audiological assessments is important.
Monitoring during and after cancer therapy facilitates audiological management including counselling of patients and family, and support of hearing function if necessary hearing aids, assistive listening devices, speech and language therapy [ 33 ].
During therapy, monitoring may also provide the opportunity to modify cisplatin dose, depending highly on the availability of an evidence-based alternative, and whether or not cisplatin is the backbone of treatment. For example, dose adjustment may not be applicable in patients with liver tumours, for whom cisplatin is the key component of survival [ 34 ]. A baseline assessment before start of cisplatin treatment, where possible, is important to identify pre-existing hearing loss, and is accompanied by questions on medical history including previous ear and hearing problems, family history, a check for dysmorphic features and presence of tinnitus.
The timing of monitoring and the testing schedule during cancer therapy highly depends on the protocol and patient-specific circumstances. Serial assessments can be considered for patients who receive cisplatin, including a check of middle ear and inner ear function, and presence of tinnitus.
A post-treatment assessment is used to identify hearing loss or to record progressive changes in hearing status, often performed within three months after cessation of treatment A. It may be necessary to continue monitoring up to several years after treatment to detect a delayed onset of hearing loss. Surveillance is advised annually for young survivors, every other year for older children, and every five years for adolescents and young adult survivors [ 35 ].
When cisplatin was first used in young children at GOSH there were no appropriate grading scales with which to compare ototoxicity measurements taken from children receiving the same or different treatments including cisplatin. These approaches can be used in older children where baseline hearing can be established.
In very young sick children it is difficult to get a reliable baseline and the tests used at a very young age are not the same as the tests used later on. Sue Bellman, the audiologist at the time at GOSH studied the particular pattern of hearing loss which the children were developing. She designed a scale which was published by Brock in and became known as the Brock grading [ 7 ]. Brock grading was later thought not to be sensitive enough and was developed further and a new scale published by Kay Chang in [ 36 ].
Grading can be done from the audiogram locally but when comparison of grading is required for the purposes of studying the toxicity of one treatment regimen with another in a clinical trial then central review of audiograms is necessary to assure consistency and quality.
This is particularly the case in international clinical trials where the audiogram needs to be uploaded to the trial database for review. The developmental and psychological impacts of deafness on children are diverse and substantial. In addition to the primary influence of hearing loss on the acquisition of language and literacy skills, children with any degree of hearing loss are at increased risk of experiencing social, emotional and behavioural difficulties as well as potential influences on quality of life, identity and self-esteem.
All these consequences are well documented for children with congenital hearing loss, with research typically focusing on children with severe or profound deafness, and recently, those who have received cochlear implants. Research findings reveal a highly complex picture, with a large number of factors interacting to result in the difficulties presented by any individual child, including for example their language and communication skills, the cause of their deafness, their educational provision, and parental socio-economic status.
The picture is somewhat less clear for children who have a mild or moderate hearing loss often referred to as minimal hearing loss, and the largest group of children affected by ototoxicity , or those who acquired a loss during childhood due to illness directly for example meningitis , or as in the case of ototoxicity, due to the treatment of illness.
However, there is increasingly empirical evidence that is relevant in relation to the developmental and psychological impacts of ototoxicity-induced hearing loss. The most significant impact of hearing loss is during infancy and early childhood, when language skills are developing at their fastest but delays may go unrecognised or untreated until the child enters school [ 37 ]. Thus age of exposure to ototoxic drugs is of particular importance, since even if the hearing loss is confined to the high frequencies, it can have subtle but significant impacts on speech perception and therefore speech production and intelligibility [ 38 , 39 ].
Audibility and recognition of high-frequency speech sounds s, f, th, sh, h, k, and t and perception of fricative phonemes e. Delays in language development acquired at this time may be hard to reverse, even with appropriate amplification and speech therapy [ 40 ]. A review of the literature on minimal hearing loss comprising 69 articles, 6 of which included children with high-frequency hearing loss concluded that although some individuals appeared to have no observable speech-language or academic difficulties, others experience considerable problems [ 37 ].
Those children that perform in the normal, average range on tests of language skills and academic attainments may in fact be under-performing in relation to their cognitive potential IQ. In addition, children who appear not to have been negatively affected in terms of language and academic development, may still present with significant psychosocial problems.
As a group, children with any degree of hearing loss, as well as those specifically with minimal hearing loss, exhibit higher rates of behaviour problems such as noncompliance, aggression, hyperactivity, impulsivity, and inattention than their hearing peers. They also have more emotional problems such as lower energy levels, higher stress and poorer self-esteem.
The psychosocial impact of hearing loss is also seen in terms of the effect on quality of life. A systematic review of 41 articles [ 41 ], showed that children with hearing loss generally report a lower quality of life than their normally-hearing peers. Their meta-analysis on four studies employing the Paediatric Quality of Life Inventory PedsQL , revealed statistically and clinically significant differences in PedsQL scores between children with normal hearing and those with hearing loss, in the Social and School domains.
Recently, a study reported detrimental effects of hearing loss on quality of life in children and adolescents who suffered hearing loss following ototoxic treatment compared with those whose hearing was unaffected [ 11 ].
All the areas assessed were impacted, including the ability to communicate with family and peers, level of independence, interactions with peers and emotional well-being. Long-term follow-up of childhood cancer survivors indicates significant hearing loss as predictive of poorer outcomes for school, employment and independent living [ 42 ].
As a result of these developmental and psychosocial consequences of ototoxicity-induced hearing loss it is essential that children are not only closely monitored in terms of their hearing thresholds, but also the wider language, learning, social, emotional and behavioural impacts. A range of interventions may be needed, including speech and language therapy, classroom and teaching accommodations and strategies to maximise access to speech and peer interactions, as well as therapeutic interventions to address emotional and behavioural problems.
As child cancer services develop and more gain children access cancer care, it will be necessary to develop policy and services to address the long term effects of chance treatment [ 43 ].
Cisplatin, is included in the WHO Essential Medicines List for Children , but severe acquired hearing loss in child cancer survivors may have very significant impact on learning and future education opportunities of survivors and increase the health burden in families [ 44 , 45 ]. Adding cisplatin as childhood cancer treatment may therefore increase the prevalence of hearing loss, which increases the need for early identification in the context of limited resources. Community health care workers have been successfully trained to assist and implement screening for hearing loss in communities, which should be used to assist in continuous assessment of hearing in children, surviving childhood cancer after cisplatin treatment and return to their communities [ 45 ].
These identified children should be referred back to the major urban treatment centres for further more sophisticated hearing assessment and management. However, it should be noted that in Sub-Saharan Africa, and in the most populous parts of South East Asia there is a general lack of audiologists and limited access to testing and hearing support, which may hamper rehabilitation. These resource-constricted countries should therefore establish partnerships with developed countries and non-governmental organisations to assist them in the management of childhood cancer survivors with hearing loss due to cisplatin [ 48 ].
A parent with a child going through treatment is always trying to find the balance between a desperate longing for their child to be cancer free whilst enduring the least possible short and long-term side effects. At the start of treatment, when doctors explain the risks of potential hearing loss when using cisplatin, it can be hard to fully appreciate and understand the long-term impact for your child.
0コメント