HEAD & NECK SURGERY - Stanford University School of Medicine

S T ANFORD U NIVERSITY D EPARTMENT OF O TOLARYNGOLOGY– HEAD & N ECK S URGERY
R ESEARCH P ROGRAMS
THE EVALUATION, MANAGE-
MENT, AND PREVENTION
OF CISPLATIN OTOTOXICITY IN
PEDIATRIC PATIENTS.
Kay Chang, MD
Cisplatin is a commonly administered
chemotherapeutic agent in multiple
pediatric neoplasms. The ototoxicity of
this agent is well-documented, though
poorly characterized. Reports of ototoxicity
rates in children vary from 1% to 82%.
This disparity is due to extreme variability
between institutions in the audiologic
assessment of sick pediatric patients, as
well as the lack of a well established and
clinically validated classification for
degrees of ototoxicity. The Common Terminology
Criteria for Adverse Events
(CTCAE v3.0) widely used by oncologists,
fails to classify ototoxicity in a clinically
consistent, or relevant manner.
Due to a lack of a robust grading system
for ototoxicity, it is difficult to design ototoxicity
studies in patients that can be
easily compared to other studies. I have
developed a more clinically useful grading
system for pediatric ototoxicity and
have validated it to a large 5-year cohort
of children treated by the Lucile Packard
Children’s Hospital (LPCH) at Stanford
Pediatric Oncology department. By examining
details such as dose delivery schedule
and co-administered drugs, a number
of interesting revelations regarding optimal
methods of reducing ototoxicity in
children have been discovered, and will
be presented at the next ASCO meeting.
As an active member of the Children’s
Oncology Group (COG), a national organization
involved in improving the oncologic
care of children, I have been intimately
involved in the ototoxicity
assessment of multiple large multi-institutional
studies administered by COG
12
20
15
10
5
0
dB
-5
-10
-15
-20
-25
Post-Treatment DPOAEs
2000 2378 2828 3364 4000 4757 5657 6727 8000 9514 11314 13454 16000
Hz
(including the Intergroup Hepatoblastoma
Study P9645 and the ARAR0331
Nasopharyngeal Carcinoma Study). This
grading system has been a valuable tool
and has helped to improve methodologies
for accurately assessing and characterizing
ototoxic effects. This is particularly
important since children seem to be
much more susceptible to ototoxicity
than adults. Furthermore, while the effects
of ototoxicity may be quite limited in
adults who have mastered speech and
language, in pre-lingual young children,
ototoxicity may result in severe speech
delay and the inability to ever assume a
normal role in society. So while the children
may be cured of their cancer, they
really never fully recover from their treatment
to live normal unhindered lives.
While accurately monitoring cisplatin
ototoxicity may provide some insights
into improved dosing strategies for
reducing adverse effects in children, a
more exciting approach is actual prevention
of ototoxicity by administering various
“otoprotective” agents. In the course
of investigating the protective effect of
the anti-oxidant N-acetylcysteine in the
guinea pig cochlea, my laboratory discovered
a novel otoprotective effect
induced by the transtympanic administration
of lactate to the middle ear. In
this experiment, guinea pigs treated with
cisplatin that were administered either
lactated Ringer’s solution or N-acetylcysteine
had significantly improved cochlear
function, as measured by DPOAE, compared
to the normal saline and negative
control groups (see figure). Currently,
with the collaboration the LPCH Pediatric
Oncology department, standardized protocols
utilizing my grading scale are
being developed to investigate these as
well as other otoprotective agents, including
EPO and several gene therapy
agents. Our goal is with these
efforts is to eliminate this most
devastating late-effect of chemotherapy
in young children.
Legend
IR
N-AC
NS
Control
Mean post-treatment DPOAE data. Stimulus
parameters were L2 = 55 dB and F2 ranging
from 2 to 16 kHz. Error bars represent one
SEM, and are plotted for the Control and LR
groups; however they were comparable
across all 4 groups (average SEM across frequencies
measured 2.88, 3.27, 2.93, and 2.78
for the 4 groups). The light dotted line at the
bottom of the graph represents the average
noise floor during emission recording.
CLINICAL RESEARCH IN SLEEP
SURGERY
Richard L. Goode, MD, Jose E. Barrera, MD,
Nelson Powell, MD, Robert Riley, MD
The Division of sleep surgery aims to
develop improved diagnostic methods
in evaluating site of obstruction in sleep
apnea patients. We are taking two
approaches to improve our understanding
of the anatomic reasons for collapse
of the upper airway in obstructive sleep
apnea. A protocol which is being coordinated
with Dr. Gerald Popelka will utilize
cine real-time MRI scanning of the upper
airway in patients with sleep disordered
breathing and normal volunteers, and
correlate these findings with the endoscopic
evaluation of patients before and
after surgery. Electroencephalogram,
actigraphy, and pulse oximetry data in
combination with MRI images will be
collected from patients with upper airway
resistance syndrome, obstructive
sleep apnea, and normal controls. We expect
to be able to significantly improve
our understanding of the anatomic reasons
for a given patient’s obstructive
symptoms, and thus improve clinical
staging and surgical decision-making.
Real time MRI scan
Our second project aims to evaluate
functional obstruction during sleep as a
measure of pressure manometry. The use
of a multi-site pressure probe tube that
is worn during sleep will be utilized to
determine the site of obstruction based
on pressure changes across five transducers
within the probe tube precisely
located in the upper airway. We hope to
characterize what causes multi-site
obstruction and to what degree patients
with with obstructive sleep apnea are
affected.