Relationship between cisplatin administration and the development of ototoxicity.
OBJECTIVE
To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non-small-cell lung carcinoma patients.


METHODS
Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation scheme. Patients were randomly assigned to receive treatment once a week for 6 weeks or once every 2 weeks for 4 weeks. The following cohorts of patients were treated with a reversed schedule once every 2 weeks, in which cisplatin was followed by gemcitabine. The dose-intensity of cisplatin was equal in both schedules. Audiometric evaluations were obtained for each ear at several frequencies. Mean hearing loss after cisplatin treatment was computed for each dose level at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Pure tone averages (PTAs) were also calculated. The pharmacokinetics of cisplatin was determined to study the correlation among the maximum drug concentration, the area under the curve of unbound platinum, and the development of ototoxicity.


RESULTS
A total of 328 audiograms were analyzed. At the higher frequencies, a more severe hearing impairment was recorded. Most patients showed a decrease in hearing thresholds at dosages above 60 mg/m2 cisplatin at the higher frequencies. PTAs at 1, 2, and 4 kHz show a mean hearing loss of 19 dB after cisplatin administration at dosages above 90 mg/m2. Threshold shifts at 8 and 12.5 kHz after cisplatin administration were experienced at dosages above 60 mg/m2.


CONCLUSIONS
Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m2. It is more pronounced when cisplatin is given once every 2 weeks.
Rademaker-Lakhai
Jeany M
JM
Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital and Department of Audiology, Academic Medical Center, Amsterdam, The Netherlands. jeanyrademaker@quicknet.nl
Crul
Mirjam
M
Zuur
Lot
L
Baas
Paul
P
Beijnen
Jos H
JH
Simis
Yvonne J W
YJ
van Zandwijk
Nico
N
Schellens
Jan H M
JH
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001299:Audiometry; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D006309:Hearing / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced*; D006316:Hearing Loss, High-Frequency / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine