the first - generation platinum drug cisplatin is widely and frequently used for the treatment of various cancers . it is an effective drug against many kinds of cancer but also has many associated adverse effects , including ototoxicity , nausea , vomiting , nephrotoxicity , bone - marrow suppression , and hepatotoxicity.1 ) the ototoxicity of cisplatin is known to correlate with its cumulative dose . however , hearing loss ( hl ) after cisplatin treatment is difficult to predict based only on the cumulative dose because there is significant individual variability in susceptibility to ototoxicity.2 ) however , cisplatin - induced ototoxic damage is usually considered irreversible once it has occurred.3 ) these facts justify the mandatory monitoring of ototoxicity to ensure its early detection . numerous previous studies have demonstrated the value of extended high - frequency pure - tone audiometry ( ehf - pta ) for the early detection of cisplatin - induced ototoxicity ( cis - ot ) , because cis - ot begins in the most basal region of the cochlea.3 ) distortion - product otoacoustic emission ( dp - oae ) potentially reflects subclinical cochlear damage because dp - oae amplitude reduction arises from outer - hair - cell damage , which occurs before inner - hair - cell damage . some clinicians advocate the use of dp - oae because this test is not affected by the patient 's age or any deterioration in the patient 's general condition caused by chemotherapy . the first aim of our study was to investigate which of these tests is the more sensitive method for detecting cis - ot . we performed both ehf - pta and dp - oae in every cisplatin - treated patient and compared the ototoxicity detection rates of the two tests . our second aim was to assess the concurrence of ototoxicity and nephrotoxicity in cisplatin - treated patients . serum blood urea nitrogen ( bun ) and serum creatinine ( cr ) levels and the glomerular filtration rate ( gfr ) were measured to detect nephrotoxic complications . this study was performed with the approval of the institutional review board of eulji general hospital and all the participants gave their informed consent . a prospective study was carried out in 17 patients who were undergoing chemotherapy that included cisplatin from may 2011 to august 2013 . seven of these patients discontinued their follow - up voluntarily or dropped out of the study . the data for the 10 patients who completed the tests throughout all their cycles of chemotherapy were collected . all 10 patients were diagnosed with cancer by pathological evaluation , including two with lung cancer , two with gastric cancer , four with gynecological malignancies , one with gall bladder cancer , and one with common bile duct cancer . the hearing levels of the patients were evaluated with ehf - pta and dp - oae . the baseline evaluation was made immediately before chemotherapy commenced and additional tests were performed immediately before each cycle of cisplatin treatment , and one month after the end of treatment . ehf - pta was measured at frequencies of 0.25 , 0.5 , 1 , 2 , 3 , 4 , 8 , 9 , 11.2 , 12.5 , 14 , 16 , 18 , and 20 khz using an ac40 clinical audiometer ( interacoustics , assens , denmark ) . all the patients were tested in both ears , and the pure - tone audiometric thresholds , in decibels hearing level ( db hl ) , were measured through air and bone conduction . the presence or absence of a change in the hearing threshold was based on published clinical guidelines [ american speech - language - hearing association ( asha ) 1994 ] and included : 1 ) 20 db change at any one test frequency ; 2 ) 10 db change at any two consecutive test frequencies ; or 3 ) loss of response at three consecutive test frequencies at which responses were previously obtained ( asha 1994).4 ) navigator pro ( bio - logic systems corp . , mundelein , il , usa ) was used to assess dp - oae . the sound stimulus for dp - oae consisted of two simultaneous permanent pure tones at different frequencies ( f1/f2 ratio=1.22 ) at 60 db spl ( l1>l2 ) , and dp - oae was measured at eight different frequencies : 0.5 , 0.75 , 1 , 1.5 , 2 , 3 , 4 , 6 , and 8 khz . change in dp - oae was defined as a reduction in the signal - to - noise ratio ( snr ) at f2 frequencies below 1 khz , which is the difference between the amplitude of dp - oae and the noise floor at each test f2 frequency . a reduction in snr greater than 14 db was regarded as significant . at f2 frequencies above 1 khz , a reduction in snr greater than 7 db was considered a significant clinical change.5,6 ) serum bun , serum cr , and gfr were tested to monitor nephrotoxicity . statistical analyses were performed with the spss statistical software package ( spss , version 15.0 for windows ; spss inc . , the results of the blood tests before each cycle were compared using multivariate analysis of variance . the correlations between the cumulative dose of cisplatin and the risk factors for developing ototoxicity were calculated using pearson 's correlation analysis . the mean age of the group was 58.710.3 years ( range , 40 - 71 years ) . ( range , 40 - 160 mg / m ) and the mean total infused dose was 610.0286.6 mg / m five patients received six cycles of chemotherapy , two of them received five cycles , another two received four cycles , and one of them received two cycles ( mean , five cycles ; range , 2 - 6 cycles)(table 1 ) . one patient ( subject 10 ) had mixed - type hl on the right side and a ventilation tube was inserted before the study . four of the 10 patients [ subjects 1 , 3 , 5 , and 10 ( left ear only ) , seven of 20 ears ] revealed threshold changes on ehf - pta ( table 2 ) . five ears showed threshold changes below 8 khz ( one ear at 3 khz , two ears at 4 khz , and another two ears at 8 khz ) , and another two ears showed changes at frequencies over 9 khz ( one ear at 9 khz and the other ear at 10 khz ) . one patient ( subject 10 ) with unilateral hl before treatment showed a threshold change at 8 khz on the healthy side only . three ears ( subjects 1 and 10 ) showed threshold changes during chemotherapy and another four ears ( subjects 3 and 5 ) showed threshold changes after therapy ceased ( table 1 , fig . 1 ) . to assess the overall changes in the hearing thresholds after chemotherapy , we plotted the average thresholds for all 10 patients at each frequency . there were no statistical differences in the hearing thresholds before and after treatment for either ear at any frequency measured ( fig . 2 ) . there was no significant correlation between the cumulative dose of cisplatin and the presence of hearing threshold changes on ehf - pta ( p>0.05 ) . there was also no significant correlation between the cumulative dose and the lowest frequency that showed hearing impairment ( p>0.05 ) . five of the 10 patients ( subjects 1 , 3 , 5 , 8 , and 10 , eight of 20 ears ) showed a reduction in dp - oae , but one of the results ( subject 8) was a false positive , in which the dp - oae change only occurred at 2 khz , whereas no change was detected with ehf - pta . the dp - oae results were consistent with the ehf - pta results in two patients ( subjects 1 and 3 , four ears)(table 1 ) . subject 5 showed bilateral hl on ehf - pta , but the dp - oae value only changed in the left ear . in contrast , the dp - oae value changed on both sides in subject 10 , but the threshold change on ehf - pta was only significant in the left ear . the time of detection of hl was the same with both tests , except for subject 10 , in which dp - oae detected hl earlier than ehf - pta . the sensitivity of ehf - pta in detecting cis - ot was 40% ( four of 10 patients ) , as was the sensitivity of dp - oae . average dp - oae changes in each measured frequencies after cisplatin - based chemotherapy were plotted in fig . none of the subjects complained of their newly developed hearing disturbance or any otological problem during or after chemotherapy . only one patient ( subject 1 ) displayed nephrotoxicity according to the laboratory tests , which occurred after the third cycle of chemotherapy , simultaneous with a hearing threshold change . both serum bun and serum cr were elevated and gfr was significantly 
 reduced ( p<0.05 ) . an animal experiment showed that cisplatin causes outer - hair - cell damage from the basal turn.7 ) initially , the first row of outer hair cells is affected , followed by the second and third rows , the inner hair cells , and finally the supporting cells . the progression of damage is typically from the high - frequency - coding cochlear base toward the apex.7,8,9,10,11 ) in the present study , the incidence rate of cis - ot was 40% ( four of 10 patients ) when detected with either ehf - pta or dp - oae . in subject 5 , ehf - pta failed to detect hl in one ear that originally already showed hearing impairment . the time of hl detection was the same in five ears with both tests , but was detected earlier with dp - oae in subject 10 . however , dp - oae generated one false positive result . because this subject presented with a level of reduction at 2 khz on dp - oae only , although ehf - pta detected no threshold change , it is reasonable to regard it as a false positive result . we could draw no conclusion from these data about which test is superior for the early detection of cis - ot . therefore , clinicians should use both tests simultaneously in every cycle of chemotherapy to ensure the detection of ototoxicity . there are no standard criteria for defining changes in dp - oae , and we used the criteria that have been used in many previous studies.5,6 ) asha suggested the clinical criterion that dp - oae changes should show a level reduction 4 db or that a loss of response at two adjacent f2 frequencies indicates a " reduction " on dp - oae.4 ) however , when this criterion was applied in our study , only three of 20 ears ( 15% ) met the criterion ( left ear of subject 1 , both ears of subject 3 ) . this implies that the asha criterion is too strict for the early detection of ototoxicity . the mean incidence of ototoxicity was 33% when patients received a single dose of 50 mg / m cisplatin.12 ) coradini , et al.13 ) reported 52% bilateral hl in cisplatin - treated younger patients ( median age , 12.3 years ; median total dose of cisplatin , 406 mg / m ) using pta , dp - oae , and transient evoked otoacoustic emissions ( te - oae ) . another study using ehf - pta detected hl in 42 of 55 ears ( 76.4% ) after treatment.14 ) in the study of eiamprapai , et al.,6 ) the incidence rate of ototoxicity detected with dp - oae was 77.3% in adult patients after a cumulative dose of cisplatin of 156.177.17 mg / m . another study reported that the incidence of ototoxicity was 81.3% in children ( eight months to 20 years old ) after a cumulative dose of cisplatin of 428106 mg / m , when detected with ehf - pta , dp - oae , and auditory brainstem response.15 ) in the present study , all subjects received chemotherapy by own protocol of the department of oncology , and therapeutic doses of cisplatin were determined by the cell types of tumor and their body surfaces . dp - oae provides a noninvasive and objective measure of cochlear function , because dp - oae is an acoustic response generated by the outer hair cells within the cochlea . in earlier studies published by littman , et al.16 ) and ress , et al.,17 ) several studies reported that dp - oae was a more sensitive monitoring tool for detecting drug - induced ototoxicity than conventional pta or te - oae.18,19 ) however , in this study , we could find the value of ehf - pta in the monitoring ototoxicity . for example , bilateral hearing losses were detected at the frequencies over 9 khz of ehf - pta in subject 1 . moreover , in subject 5 , ehf - pta detected ototoxicity in both ears whereas , dp - oae failed to detect hl on either the two . indeed , many previous studies have shown that ehf - pta is a more sensitive tool for detecting ototoxicity than pta at conventional frequencies , and have suggested that monitoring for ototoxicity must include a threshold evaluation of frequencies above 8 khz.14,20,21 ) however , few studies have compared the sensitivity of ehf - pta and dp - oae in monitoring cis - ot . reavis , et al.22 ) reported that the dp - oae hit rate was 78% in ears with hearing impairment confirmed by ehf - pta ( 0.5 - 20 khz ) . however , a direct comparison between that study and the present study is difficult because they used another criterion to define a " reduction " in dp - oae . in a study of 21 children receiving cisplatin , ehf - pta detected changes earlier than dp - oae in nine patients , whereas an early change was detected by dp - oae in only one patient.15 ) in contrast , in the present study , dp - oae detected a change in one ear earlier than ehf - pta . the difficulty in measuring dp - oae above 8 khz seems to reduce its sensitivity in detecting ototoxicity . nevertheless , dp - oae is a potentially useful tool for monitoring child patients or handicapped people who can not be evaluated with pta . dp - oae could also be used as an accessory tool to support the results of ehf - pta . the protein , kidney injury molecule 1 , which is induced in the renal proximal tubular epithelium after cisplatin therapy , can also be expressed in the cochlea , and caused ototoxic effects in an animal study.23 ) reports of the incidence of cisplatin - induced nephrotoxicity are relatively rare . an increase in the serum cr concentration has been reported in 41% of patients treated with high doses of cisplatin ( 70 - 85 mg / m for each cycle , 5.3 mean cycles).24 ) and mth , et al.25 ) reported that 23 of 38 patients with lung cancer showed pathological increases in serum cr after 2 - 4 cisplatin infusions ( 75 mg / m ) per cycle . from our result , we infer that the incidence of cisplatin - induced nephrotoxicity ( 10% ) is lower than the incidence of ototoxicity ( 40% ) . however , close monitoring must be mandatory for nephrotoxicity , because its consequences are lethal . the purpose of monitoring ototoxicity during cisplatin chemotherapy is the early detection of sensorineural hearing impairment before the patient is him / herself aware of it . if serious ototoxicity is detected , an alternative , less ototoxic drug , such as carboplatin , could be considered before ototoxicity progresses . the timing of the interruption of cisplatin should be considered based on various factors , including the amount of hearing deterioration , the hearing level before chemotherapy , the pathological type or grade of cancer , and the patient 's age . however , to the best of our knowledge , there is no specific criterion for the discontinuation of cisplatin therapy . the average cumulative dose of cisplatin to cause a threshold change in ehf - pta was reported to be 400 or 343.6 mg / m in two different studies.18,26 ) in one study using dp - oae , the snr amplitude decreased significantly when the patients received a cumulative dose of more than 200 mg / m.6 ) in the present study , ototoxicity was detected with ehf - pta and dp - oae after a total cumulative dose of 780 mg / m in two subjects . another subject displayed ototoxicity at a total cumulative dose of 480 mg / m and another at 240 mg / m . the average cumulative dose of cisplatin during which ototoxicity developed was 570261.53 mg / m . however , three subjects who received a cumulative cisplatin dose > 700 mg / m showed no change on either ehf - pta or dp - oae , implying that individual variability , such as genetic factors , affect the development of ototoxicity . in this study , there was no significant correlation between the cumulative dose of cisplatin and the presence of hearing threshold changes , which could be attributable to the small sample size . the four patients with hl after treatment showed threshold changes below 8 khz , but none of them was aware of their hearing impairment during or after chemotherapy . only 10 patients completed all the scheduled follow - up evaluations . because of the severity of the patients ' existing disease , some died during the research period , and some showed very poor compliance with the hearing test . patients who did not feel their hearing was impaired tended to ignore the importance of the follow - up hearing tests . for this reason , seven patients discontinued regular hearing tests during and after their treatment with cisplatin . for the future , the study with larger sample size will be necessary to clarify the effectiveness of ehf - pta and dp - oae for monitoring cisplatin - induced ototoxicity . several investigators argued that both ehf - pta and oae are problematic in patients with hl , particularly in the elderly , because of the limited responses to test due to pre - existing losses of outer hair cells in the cochlear basal region.27,28,29,30 ) for the cases of elderly patients , the baseline testing prior to ototoxic drug administration will be mandatory for the precise interpretation using " change of value " . ress , et al.17 ) studied a greater number of patients including elderly subjects and dp - oae showed effective sensitivity to detect ototoxicity . in the present study , all subjects performed ehf - pta and dp - oae before initial cisplatin infusion and the " change of value " after treatment were calculated . as mentioned several times before it is also easy for oncologists to overlook the monitoring of hearing , because they consider the cancer therapy to be the most important issue . detailed information about cisplatin - induced ototoxicity should be offered to patients and otologists should be involved in establishing a well - organized protocol for hearing tests for all cisplatin - treated patients . in our study , the incidence rate of cis - ot was 40% ( four of 10 patients ) when detected with either ehf - pta or dp - oae . although both ehf - pta and dp - oae showed the same sensitivity in detecting ototoxicity , they did not produce coincident results in all cases . the two hearing tests complement one another , and clinicians should use both tests simultaneously in every cycle of chemotherapy to ensure the detection of ototoxicity .
background and objectivesto compare the effectiveness of monitoring cisplatin - induced ototoxicity in adult patients using extended high - frequency pure - tone audiometry ( ehf - pta ) or distortion - product otoacoustic emission ( dp - oae ) and to evaluate the concurrence of ototoxicity and nephrotoxicity in cisplatin - treated patients.subjects and methodsehf - pta was measured at frequencies of 0.25 , 0.5 , 1 , 2 , 3 , 4 , 6 , 8 , 9 , 11.2 , 12.5 , 14 , 16 , 18 , and 20 khz and dp - oae at frequencies of 0.5 , 0.75 , 1 , 1.5 , 2 , 3 , 4 , 6 , and 8 khz in cisplatin - treated patients ( n=10 ) . 
 baseline evaluations were made immediately before chemotherapy and additional tests were performed before each of six cycles of cisplatin treatment . 
 laboratory tests to monitor nephrotoxicity were included before every cycle of chemotherapy.resultsfour of 10 patients showed threshold changes on ehf - pta . 
 five of 10 patients showed reductions in dp - oae , but one was a false - positive result . 
 the results of ehf - pta and dp - oae were consistent in two patients . 
 only one patient displayed nephrotoxicity on laboratory tests after the third cycle.conclusionsin our study , the incidence rate of cisplatin - induced ototoxicity was 40% with ehf - pta or dp - oae . 
 although both ehf - pta and dp - oae showed the same sensitivity in detecting ototoxicity , they did not produce the same results in all patients . 
 these two hearing tests could be used to complement one another . 
 clinicians should use both tests simultaneously in every cycle of chemotherapy to ensure the detection of ototoxicity .