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Effects of Difluoromethylornithine Chemoprevention on Audiometry Thresholds and Otoacoustic Emissions
Karen J. Doyle, MD, PhD;
Christine E. McLaren, PhD;
Janet E. Shanks, PhD;
Cheryl M. Galus, MA;
Frank L. Meyskens, MD
Arch Otolaryngol Head Neck Surg. 2001;127:553-558.
ABSTRACT
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Objectives To determine the effects of long-term, low-dose difluoromethylornithine
(DFMO) on audiometric thresholds and distortion product otoacoustic emission
(DPOAE) levels in humans.
Design A prospective, randomized, placebo-controlled phase 2 clinical trial
of DFMO in participants with a prior adenomatous colonic polyp.
Setting Academic tertiary care referral center.
Participants One hundred twenty-three volunteer subjects with colorectal polyps and
normal hearing for the frequencies 250 through 2000 Hz.
Interventions Subjects were randomized to receive placebo or oral DFMO at daily dosages
between 0.075 and 0.4 g/m2 of body surface area for 12 months.
Outcome Measures Pure-tone audiometric thresholds for the frequencies 250, 500, 1000,
2000, 3000, 4000, 6000, and 8000 Hz and DPOAE levels were measured at baseline
and 1, 3, 6, 9, and 12 months after starting treatment with DFMO or placebo
and 3 months after cessation of treatment if there was a suggestion of possible
changes at the 12-month measurement.
Results At these low dosages, there was little evidence for shifts in auditory
pure-tone thresholds, and there were no statistically significant shifts in
DPOAE levels. For auditory pure-tone thresholds, there was a subtle, approximately
2- to 3-dB hearing level decrease in hearing sensitivity for the 2 higher
DFMO dosages, but only at the 2 lowest frequencies, 250 and 500 Hz.
Conclusions Administration of low-dose DFMO for 12 months did not produce hearing
loss, in contrast to prior studies that used higher dosages.
INTRODUCTION
AUDIOLOGIC monitoring for the purpose of prevention of hearing loss
is often used for known ototoxic medications such as the aminoglycoside antibiotics
and cisplatin. Such monitoring usually consists of behavioral pure-tone testing
at baseline and during the treatment regimen.1
More recently, evoked otoacoustic emissions (OAE) testing has been compared
with behavioral pure-tone monitoring in hopes that OAE testing would detect
sensory damage before the onset of permanent pure-tone threshold shifts.2 The OAEs are sounds emanating from the cochlea that
are recorded from the external ear canal.3
Intermodulation distortion product (DPOAE) levels can be recorded in OAE to
2-tone stimulation.4 The DPOAEs, like the other
evoked OAEs, are reproducible and are vulnerable to insults that damage cochlear
outer hair cells.5 Their usefulness in measuring
ototoxicity has been suggested because they are objective (ie, they do not
require subjective responses from the patient), they provide information at
different frequencies, and they may be measured in a few minutes.6
The polyamines putrescine, spermidine, and spermine are organic cations
involved in the process of cell growth and differentiation.7
A specific inhibitor of ornithine decarboxylase and polyamine synthesis,  -difluoromethylornithine
(DFMO), has been used at high dosages in cancer chemotherapy and, more recently,
at lower dosages in cancer chemoprevention.8, 9
In several studies, DFMO has been found to be ototoxic at higher dosages.
For example, at dosages of 8 g/m2 in continuous infusion for colon
cancer chemotherapy over 28 days, Ajani et al8
found reversible hearing loss in some patients. Croghan et al10
assessed the ototoxic effects of DFMO administered to 58 patients treated
with dosages ranging from 2 to 12 g/m2 per day for metastatic melanoma.
In this study, 75% of patients who received total doses of more than 250 g/m2 developed hearing loss of more than 30 dB, across the frequency range
of 500 to 8000 Hz. These studies created concern that ototoxic effects could
limit the usefulness of DFMO in cancer chemoprevention.
Two studies were designed to investigate whether DFMO administered at
low dosages produced hearing loss, while concurrently investigating the minimum
dosage of DFMO required to lower polyamine content in tissues. One study,
by Pasic et al,11 observed an average pure-tone
audiometric shift of 16.8 dB in patients taking DFMO for 6 to 12 months at
the highest tested dosages (2, 3, and 5 g/m2 per day).11 Only 3 of 32 subjects receiving the lowest dosage
(500 mg/m2) developed pure-tone shifts of more than 15 dB at 2
frequencies. Pasic et al also demonstrated that the hearing loss was reversible
in all subjects, with a median recovery time of 58 days following drug cessation.
In an earlier study, the present investigators used much smaller daily dosages
of DFMO (0.075, 0.20, or 0.40 g/m2 per day) in a year-long chemoprevention
trial of 123 patients12 and found that dosages
of 0.2 and 0.4 g/m2 reduced polyamine levels to 34% and 10%, respectively,
of levels observed in the placebo group. Pure-tone audiometry was performed
in all subjects at baseline and at 3-month intervals throughout the study.
In the present article, the results of pure-tone audiometric and DPOAE testing
are reported for patients in the earlier study.
SUBJECTS AND METHODS
SUBJECTS
Difluoromethylornithine or placebo was administered to 123 volunteer
subjects at the University of California, Irvine (University of California,
Irvine, Medical Center and Long Beach Veterans Affairs Medical Center). Subjects
were randomly assigned in a double-blinded fashion to receive either daily
oral placebo or 1 of 3 dosages of DFMO (0.075, 0.20, or 0.40 g/m2
per day). Men and women aged 40 to 80 years (median, 65 years) who met the
following criteria were included in the study: history of colon polyp removal
without familial polyposis, colon resection of greater than 40 cm, history
of cancer within 5 years, or other chronic medical problems. Audiologic criteria
required that subjects have no worse than 20-dB hearing level (HL) thresholds
for the frequencies 250, 500, 1000, and 2000 Hz. All patients signed a consent
form approved by the institutional review boards of the University of California,
Irvine, Medical Center or the Long Beach Veterans Affairs Medical Center.
PURE-TONE AUDIOMETRY
Bilateral pure-tone air-conduction audiograms were performed in a sound-treated
booth by an audiologist at baseline and 1, 3, 6, 9, and 12 months after the
onset of DFMO treatment in all study participants and 3 months after drug
discontinuation in 15 patients who experienced a more than 15-dB increase
in baseline threshold at any frequency. At baseline, air-conduction and bone-conduction
pure-tone testing was completed for the frequencies 250, 500, 1000, 2000,
3000, 4000 Hz, and air-conduction thresholds were obtained for the frequencies
6000 and 8000 Hz. Following completion of the trial, baseline thresholds were
compared with 12-month thresholds.
DISTORTION PRODUCT OTOACOUSTIC EMISSIONS
Distortion product otoacoustic emissions were measured concurrently
with pure-tone threshold measurements. The DPOAE testing was carried out in
a quiet room using the Otodynamic Analyzer ILO92 (Otodynamics Ltd, Hatfield,
England). For tone pairs of frequencies f1
and f2, each was presented through the
probe at a 75-dB sound pressure level (SPL) (equilevel and f2/f1 = 1.22), with f2 values of 1000, 1600, 2000, 3200, 4000, and
5100 Hz. Emissions of 2(f1-f2) were measured and plotted as DP-grams (graphs of emission
amplitudes in dB SPL as a function of f2
frequency).
STATISTICAL ANALYSIS
Pure-Tone Audiometry
Pure-tone air-conduction thresholds were recorded for each ear of each
study subject, and a total of 5 pure-tone audiograms were collected over the
12-month period. Although periodic testing provided close subject monitoring,
the baseline and 12-month thresholds were compared to determine the greatest
effects of the dosing regimen. For each patient with incomplete data, the
baseline thresholds were compared with the final threshold measurements for
that patient. For most test frequencies, the hearing threshold levels at baseline
and the final threshold measurements were higher for the placebo group than
for the DFMO groups; thus, all statistical comparisons were based on the average
change from baseline. The mean and SD for the change in HL in the last audiometric
test following baseline was computed for each patient and for each ear at
each of the 8 test frequencies. For each frequency, regression analysis was
used with the mean change in decibels as the dependent variable and dosage
group as the explanatory variable.
Paired t tests were applied to examine the
difference in mean change between the right and left ears at the same frequency
for each dosage group. At P .05, differences were
found for only 4 of 32 comparisons—at the 3000-, 4000-, and 6000-Hz
frequencies for the placebo group and at the 6000-Hz frequency for the 0.2-g/m2 group. A major natural loss would be presbycusis (aging), which is
bilateral. Because unilateral loss is uncommon and usually traumatic, the
mean change from baseline for left and right ears was computed for each subject
and each frequency. An analysis of variance followed by a post hoc Dunnett
test was then performed to compare the mean change from baseline for the control
group with that of the 3 dosage groups. Multiple regression analysis was used,
with mean change in decibels as the dependent variable and dosage group, age,
sex, and race as the explanatory variables. For each frequency, the overall
F test of significance of the model and t tests for
slope parameters were performed.
Pure-Tone Recovery
Pure-tone threshold data were also analyzed from a subset of 14 patients
who had measurements taken at baseline, at the end of drug administration
at 12 months, and following recovery at 15 months. For each subject and each
frequency, the mean change from baseline for the left and right ears was computed.
Repeated-measures analysis of variance followed by the Dunnett test was used
to compare the mean change from baseline for the control group vs that of
the 3 dosage groups.
Distortion Product Otoacoustic Emissions
In the analysis of the DPOAE data, the baseline DPOAE levels in decibels
SPL for each f2 value tested were compared
with the corresponding 12-month DPOAE level or the DPOAE level at final measurement.
For each subject, a 3-level categorical variable was created, and the differences
between the baseline and 12-month DPOAE levels were recorded as "no change,"
"decrease," or "increase." The DPOAE values for the left and right ears were
considered separately. For each ear and each f2 value, a Fisher exact test was applied to examine the association
between dosage group and change category.
RESULTS
Pure-tone audiometry was performed at baseline and in at least 1 subsequent
month for 111 (90%) of 123 patients. Table
1 shows the number of patients, by dosage group, who had pure-tone
threshold measurements at baseline and the number of patients who had their
final measurement made at months 1, 3, 6, 9, 12, and 15. Patients from all
4 groups dropped out for different reasons. Table 1 shows that patients were more likely to drop out of the
study as the dosage increased. One patient from the 0.4-g/m2 dosage
group who met the toxicity criterion (>20-dB HL increase in threshold at any
frequency) was dropped from the study after 9 months because of hearing loss.
No other patients were removed because of hearing loss, although 4 patients
from the 2 higher-dosage groups were dropped from the study because of symptoms
of dizziness and imbalance that resolved following discontinuation of the
drug.
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Table 1. Number of Patients Audiologically Tested, by Dosage Group,
at Baseline and in the Final Month of Testing*
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PURE-TONE AUDIOMETRY
For each ear and each of the 8 test frequencies, regression analysis
was used to examine the mean change in decibels across dosage groups. The P value for the trend of the regression slope parameter
was computed. Those with P.05 had a positive
slope, giving evidence for a trend toward worsening thresholds in the highest-dosage
group. For the right ear, at a frequency of 250 Hz, there was an estimated
hearing loss of 2.2 dB HL, on average, for each 0.1-g/m2 increase
in dosage (95% confidence interval [CI], 0.3-4.1 dB HL). Similarly, at 500
and 3000 Hz, the estimated average hearing losses were 1.7 dB HL (95% CI,
0.0-3.3 dB HL) and 2.7 dB HL (95% CI, 0.8-4.6 dB HL), respectively. For the
left ear, the average hearing losses were 1.9 dB HL (95% CI, 0.3-3.5 dB HL)
at 250 Hz and 1.4 dB HL (95% CI, 0.0-2.8 dB HL) at 500 Hz for each 0.1-g/m2 increase in dosage. Although significant trends were found for low
frequencies, we note that the probability of false-positive results likely
increased, given that multiple significance tests were applied to data from
the same dosage groups.
For each subject and each frequency, the mean change from baseline for
the left and right ears was computed. Analysis-of-variance results are given
in Table 2, with the average change
from baseline for the 2 ears as the dependent variable for each frequency.
Dosage levels were significant at 250 and 500 Hz (P
= .005 and P = .02, respectively), but nonsignificant
at other frequencies. Figure 1 shows
the mean change from baseline pure-tone threshold for the average of the left
and right ears at 250 and 500 Hz as a function of dosage. Figure 1A shows that for 250 Hz, there was an average 2–dB
HL worsening of threshold for each 0.1-g/m2 increase in DFMO dosage
(95% CI, 0.6-3.5 dB HL; P for trend, .01), adjusting
for age, sex, and race. Figure 1B
demonstrates an average 1.5–dB HL increase in threshold at 500 Hz for
each 0.1-g/m2 increase in DFMO dosage (95% CI, 0.2-2.8 dB HL; P for trend, .02), adjusting for age, sex, and race. The
variability within each dosage group obscured any mean change between the
treatment and placebo groups, with the exception of 250 Hz (0.4 g/m2 per day different from placebo, P = .01) and
500 Hz (0.2 g/m2 per day different from placebo, P = .02).
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Table 2. Mean Change From Baseline in Hearing Threshold*
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Figure 1. Mean change in pure-tone threshold
from baseline for the average of left and right ears at 250 Hz (A) and 500
Hz (B) as a function of dosage. P values for trend
were adjusted for age, sex, and race.
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PURE-TONE THRESHOLD RECOVERY
Thresholds for the 8 pure-tone frequencies were averaged for the left
and right ears for the subset of 14 patients who had pure-tone threshold measurements
at baseline, at the end of drug administration (12 months), and following
recovery (15 months). Of the 14 patients, 2 were from the placebo group, 4
were from the 0.075-g/m2dosage group, 3 were from the 0.2-g/m2 dosage group, and 5 were from the 0.4-g/m2 dosage group.
The hypothesis was that hearing thresholds would return to baseline levels
following cessation of DFMO treatment. Figure
2 shows the mean hearing thresholds across time for all 4 study
groups measured at 250 (A), 500 (B), 1000 (C), 2000 (D), 3000 (E), 4000 (F),
6000 (G), and 8000 (H) Hz:
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Figure 2. Mean hearing thresholds across
time for all 4 study groups (placebo and difuoromethylornithine, 0.075, 0.2,
and 0.4 g/m2) at 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000
Hz. HL indicates hearing level.
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- For the placebo group, follow-up mean thresholds at 5 of the 8
frequency levels (500, 1000, 3000, 6000, and 8000 Hz) were equivalent to or
lower than baseline thresholds.
- For the 0.075-g/m2 dosage group, follow-up mean thresholds
at 4 of 8 frequencies (250, 1000, 3000, and 6000 Hz) were equivalent to or
lower than baseline thresholds.
- For the 0.2-g/m2 dosage group, follow-up mean thresholds
at 2 of 8 frequencies (3000 and 4000 Hz) were equivalent to or lower than
baseline thresholds.
- For the 0.4-g/m2 dosage group, follow-up mean thresholds
from 2 of 8 frequency levels (6000 and 8000 Hz) were equivalent to or lower
than baseline thresholds.
Overall, results from graphical analysis suggest that at the lower frequencies,
recovery had not occurred by 3 months after the end of drug administration,
whereas at the higher frequencies, recovery had occurred. However, paired t tests indicated no statistically significant differences
from baseline to the 15-month follow-up at any of the 8 frequencies tested.
Analysis of variance of the mean change in hearing threshold from baseline
to the 15-month follow-up indicated no dosage effect at any of the 8 frequencies
tested.
DISTORTION PRODUCT OTOACOUSTIC EMISSIONS
We emphasize qualitative rather than quantitative analysis for the DPOAE
test results. Statistical analysis was problematic, because emissions were
often absent or nondetectable above the noise floor, even at baseline. Most
patients experienced a decrease in DPOAE level from baseline, had no change
from baseline, or had nondetectable DPOAEs both before and after treatment.
These data did not provide any evidence that DPOAE levels were significantly
affected by DFMO at any dosage compared with placebo.
These observations were confirmed by analysis of corresponding baseline
and 12-month DPOAE levels categorized as no change, decrease, or increase.
Patients who had a pretreatment value greater than the posttreatment value
or a measurable pretreatment value but a nondetectable posttreatment value
were considered to have had a decrease in amplitude over time. Patients who
had equal pretreatment and posttreatment values or with nondetectable DPOAEs
measured both before and after treatment were considered to have had no change.
Patients who had a pretreatment value less than the posttreatment value or
a nondetectable posttreatment value and a measurable pretreatment value were
considered to have had an increase in amplitude over time. There was no significant
association between the change in amplitude and dosage for the left and right
ears (Fisher exact test), with the exception of the level of the DPOAE level
at 4000 Hz for the left ear (Figure 3)
(P = .008), because most patients in the 0.2-g/m2 dosage group had no change in DPOAE. Overall 67% (64/96) of patients
experienced no change in DPOAE, compared with 18% (17/96) who experienced
a decrease in DPOAE and 15% (14/96) who experienced an increase in DPOAE.
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Figure 3. Mean change in DPOAE (distortion-product
otoacoustic emission) levels for the left ear at 4000 Hz.
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COMMENT
Overall, the results demonstrate that 1 year of chemoprevention with
DFMO at the low dosage (0.4 g/m2 per day) used in this study
did not produce hearing loss. All of the dosages employed in this study were
lower than those used in earlier DFMO treatment studies; thus, the results
do not disagree with those of earlier reports. Pasic et al11
measured pure-tone auditory thresholds in 66 subjects in a cancer chemoprevention
trial.11 The subjects received placebo or DFMO
at dosages between 0.5 and 3 g/m2 for 6 to 12 months. The magnitude
and incidence of threshold shifts correlated with the daily DFMO dosage, and
the shifts occurred predominantly at low frequencies. The extent of threshold
shifts was greater for higher than for lower dosages, averaging 16.8 dB at
the 3 highest daily dosages. Finally, the time between DFMO treatment and
the onset of hearing loss was strongly associated with increasing daily dosages,
in that subjects receiving higher daily dosages demonstrated hearing loss
earlier than those given lower daily dosages. Ten of the 13 subjects in the
study by Pasic et al11 who underwent a threshold
shift of 15 dB or greater at 2 or more frequencies underwent regular pure-tone
threshold measurements after DFMO therapy was stopped. All threshold shifts
were reversible, and recovery occurred after a median of 58 days. Pasic et
al11 concluded that DFMO administration is
associated with a predictable shift in auditory thresholds. In the present
study, we used lower DFMO dosages than Pasic et al, and there was little evidence
for shifts in auditory pure-tone thresholds. Instead, a subtle, approximately
2- to 3-dB, decrease in sensitivity occurred only at the 2 higher dosages
for the 2 lowest frequencies tested. Like Pasic and colleagues, who found
a lesser incidence of hearing loss with their lowest-dose regimen of 0.5 g/m2, in our study, we found that 1 patient receiving the highest-dosage
regimen had clinically significant hearing loss that necessitated his removal
from the study. This patient's hearing returned to baseline levels after 3
months. In combination, these studies suggest that a dosage of DFMO of about
0.5 g/m2 is near the threshold for audiometric change as a function
of drug administration time, at least for a period of 12 months.
In an earlier study, Plinkert and Krober13
compared pure-tone audiometry with click-evoked OAEs in 29 patients receiving
cisplatin chemotherapy. They found that amplitude loss of click-evoked OAEs
was a more sensitive tool for the early detection of cochlear dysfunction
than pure-tone audiometry, because amplitude loss of click-evoked OAEs was
noted earlier than losses of pure-tone thresholds. The authors concluded that
measurement of OAEs permitted the diagnosis of cochlear lesions induced by
cisplatin before they became clinically manifest. Other researchers have investigated
the role of DPOAEs in the measurement of ototoxic effects.14, 15
However, no formal guidelines have been formulated for OAE testing in ototoxic
monitoring because OAE testing is a new tool that has been incompletely studied.
In the present study, which found no significant pure-tone threshold shifts
with low-dose DFMO, DPOAEs were of less use for monitoring hearing changes,
mainly because in this older subject population, they were frequently absent,
even at baseline.
CONCLUSIONS
Many studies have been performed to investigate the ototoxic characteristics
of medications such as aminoglycoside antibiotics and the chemotherapeutic
agent cisplatin.16, 17, 18
Such studies describe the minimum dosages and minimum cumulative doses that
produce ototoxic effects, the typical patterns of hearing loss, and other
factors that interact with the agent in question. The American Speech, Language,
and Hearing Association has published guidelines for audiologic testing of
individuals receiving ototoxic drug therapy.1
The current recommendations include baseline pure-tone air-conduction threshold
testing at octave intervals from 250 to 6000 Hz. However, the monitoring schedule
depends on the medication given because drugs differ in the rapidity with
which therapeutic schedules produce hearing loss. The National Cancer Institute
is currently creating recommendations for pure-tone audiometric monitoring
in chemoprevention trials. Because chemoprevention requires long-term dosing
compared with traditional cancer-treatment regimens, monitoring must be carried
out over long periods. In addition, higher levels of toxic effects are acceptable
in cancer-treatment regimens than would be acceptable in chemoprevention,
since the latter patients do not actually have cancer. A decrease in hearing
as measured by pure-tone threshold assessment of DFMO does not seem to occur
at dosages lower than 0.5 g/m2. This dosage probably can be used
safely in long-term chemoprevention trials, as other adverse effects did not
occur more frequently in the present study compared with placebo.7 Since the duration of all trials reported has been
1 year, the effect on hearing in longer-term studies will need to be periodically
monitored in investigative trials.
AUTHOR INFORMATION
Accepted for publication February 6, 2001.
This work was supported in part by grant R01 CA 59024 (Dr Meyskens)
from the National Institutes of Health, Bethesda, Md.
We thank Khan Nguyen, MS, and Kuo-Tung Li, MS, for assistance with statistical
and graphical analyses.
From the Department of Otolaryngology (Drs Doyle, Shanks and Ms Galus)
and the Department of Medicine and the Chao Family Comprehensive Cancer Center
(Drs McLaren and Meyskens), University of California, Irvine, and the Department
of Audiology, Veterans Affairs Medical Center, Long Beach, Calif (Dr Shanks).
Corresponding author and reprints: Karen J. Doyle, MD, PhD, Department
of Otolaryngology–Head and Neck Surgery, University of California Davis
Medical Center, 2521 Stockton Blvd, Suite 7200, Sacramento, CA 95817 (e-mail:
karen.doyle{at}ucdmc.ucdavis.edu).
REFERENCES
| |
1. American Speech-Language-Hearing Association. Guidelines for the audiologic management of individuals receiving cochleotoxic
drug therapy. ASHA. 1994;36 (suppl 12):11-19.
2. Zorowka PG, Schmitt HJ, Gutjahr P. Evoked otoacoustic emissions and pure tone threshold audiometry in
patients receiving cisplatinum therapy. Int J Pediatr Otorhinolaryngol. 1993;25:73-80.
FULL TEXT
|
ISI
| PUBMED
3. Kemp DT. Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am. 1978;64:1386-1391.
FULL TEXT
|
ISI
| PUBMED
4. Lonsbury-Martin BL, Harris FP, Stagner BB, Hawkins MD, Martin GK. Distortion product emissions in humans, I: basic properties in normally
hearing subjects. Ann Otol Rhinol Laryngol Suppl. 1990;147:3-14.
PUBMED
5. Lasky RE, Snodgrass E, Hecox K. Distortion-product otoacoustic emission input/output functions as a
function of frequency in human adults. J Am Acad Audiol. 1994;5:183-194.
PUBMED
6. Balkany T, Telischi FF, McCoy MJ, et al. Otoacoustic emissions in otologic practice. Am J Otol. 1994;15:29-38.
7. Pegg AE, McCann PP. Polyamine metabolism and function [review]. Am J Physiol. 1982;243:C212-C221.
8. Ajani JA, Ota DM, Grossie VB, et al. Evaluation of continuous-infusion -difluoromethylornithine therapy
for colorectal carcinoma. Cancer Chemother Pharmacol. 1990;26:223-226.
ISI
| PUBMED
9. Meyskens FL Jr, Gerner EW. Development of difluoromethylornithine (DFMO) as a chemoprevention
agent [review]. Clin Cancer Res. 1999;5:945-951.
FREE FULL TEXT
10. Croghan MK, Aickin MG, Meyskens FL. Dose-related -difluoromethyl-ornithine ototoxicity. Am J Clin Oncol. 1991;14:331-335.
ISI
| PUBMED
11. Pasic TR, Heisey D, Love RR. Alpha-difluoromethylornithine ototoxicity: chemoprevention clinical
trial results. Arch Otolaryngol Head Neck Surg. 1997;123:1281-1286.
FREE FULL TEXT
12. Meyskens FL, Gerner EW, Emerson S, et al. Effect of -difluoromethylornithine on rectal mucosal levels
of polyamines in a randomized, double-blinded trial for colon cancer prevention. J Natl Cancer Inst. 1998;90:1212-1218.
FREE FULL TEXT
13. Plinkert PK, Krober S. Early detection of cisplatin-induced ototoxicity by evoked otoacoustic
emissions [in German]. Laryngorhinootologie. 1991;70:457-462.
FULL TEXT
| PUBMED
14. Hotz MA, Harris FP, Probst R. Otoacoustic emissions: an approach for monitoring aminoglycoside-induced
ototoxicity. Laryngoscope. 1994;104:1130-1134.
ISI
| PUBMED
15. Allen GC, Tiu C, Koike K, Ritchey AK, Kurs-Lasky M, Wax MK. Transient-evoked otoacoustic emissions in children after cisplatin
chemotherapy. Otolaryngol Head Neck Surg. 1998;118:584-588.
FULL TEXT
|
ISI
| PUBMED
16. Boheim K, Bichler E. Cisplatin-induced ototoxicity: audiometric findings and experimental
cochlear pathology. Arch Otorhinolaryngol. 1985;242:1-6.
FULL TEXT
| PUBMED
17. Schaefer SD, Post JD, Close LG, et al. Ototoxicity of low- and moderate-dose cisplatin. Cancer. 1985;56:1934-1939.
FULL TEXT
|
ISI
| PUBMED
18. Waters GS, Ahmad M, Katsarkas A, et al. Ototoxicity due to cis-diamminedichloroplatinum in the treatment of
ovarian cancer: influence of dosage and schedule of administration. Ear Hear. 1991;12:91-102.
ISI
| PUBMED
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