Transcript Transoral Robotic Surgery for Oropharyngeal Carcinoma and HPV Viral Load Marc A. Cohen, MD Research Presentation Faculty Advisors: Dr.

Transoral Robotic Surgery for
Oropharyngeal Carcinoma and
HPV Viral Load
Marc A. Cohen, MD
Research Presentation
Faculty Advisors: Dr. Weinstein
and Dr. O’Malley
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Goals of Study
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Determine margins of resection, oncologic outcomes,
and functional outcomes following primary Transoral
Robotic Surgery (TORS) for oropharyngeal squamous
cell carcinoma (OPSCC)
Determine prevalence of HPV positivity in OPSCC in
patients that undergo TORS
Determine prevalence of cervical nodal metastases in
OPSCC associated with HPV
Assess patient outcomes in reference to HPV status
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Introduction:
Head and Neck Cancer
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There are 500,000 new cases of squamous cell
carcinoma of the head and neck per year.1-3
Overall, 5 year survival is less than 50%1
More than 7,000 in US die from oral cavity /
oropharyngeal cancer per year4
Oncologic outcomes with oropharyngeal squamous cell
carcinoma (OPSCC) are reported along a widely
divergent range.
Currently, most studies with significant power are
investigating various chemoradiation protocols in
OPSCC.
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Divergent Outcomes with OPSCC I
French cohort of stage III and IV OPSCC treated with xrt vs concomitant
chemo/xrt (n=226)
5: Denis, F. et al. J Clin Oncol; 22:69-76 2004
Divergent Outcomes with OPSCC II
ECOG E2399: phase II chemoradiation trial in resectable AJCC III and IV
OPSCC (n=69)
6: Cmelak et al. J Clin Oncol; 25:3971-3977 2007
Divergent Outcomes with OPSCC III
Brazilian cohort of all stage OPSCC treated with chemoradiation (n=361)
7: Pedruzzi et al. Arch Otolaryngol Head Neck Surg 2008;134:1196-1204.
HPV association with HNSCC
In past 10 years, there has been evidence
supporting an association between high
risk human papillomavirus (HPV)
serotypes and HNSCC.8-12
 High risk serotypes (16,18,33) are
conserved and associated with HNSCC
as well as cervical and other carcinomas
of the anogenital tract.9
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HPV associated HNSCC
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HPV associated HNSCC comprise a
distinct clinical entity and pathogenesis
More basaloid features9
 Less p53 mutations13,14
 Younger patients without conventional risk
factors8-10
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• Lifetime number of sexual partners15
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Better prognosis?
Prevalence of HPV
Data using all molecular techniques yields
an association of approximately 9-26% in
all cases of HNSCC with oropharyngeal
squamous cell carcinoma being
associated with 45-70%9,16-19
 Most common serotypes are HPV 16 (8494%), 18 (0-3%), 33 (1-27%)3,16,19-22
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Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Prognosis with HPV status
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There has long been debate about whether
HPV positive lesions are associated with better
patient prognosis.23-29
Recent studies have equated HPV positivity
with decreased recurrence rates, longer
disease free survival, and overall survival.23-26
Lack of field cancerization, intact apoptotic
mechanisms, better immune response to viral
specific antigens, reduced 2nd primary
tumors23,30
ECOG chemoradiation outcomes
in OP SCC with HPV status
30: Fakhry et al. J. Natl Cancer Inst. 2008 100:261-269.
Prognosis with HPV positive OP
SCC treated with CRT
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Worden et al., showed that, “induction
chemotherapy followed by
chemoradiation is an effective treatment
for SCC OP,” especially in those that are
HPV positive. The authors suggest CRT
should be used in SCC OP that are HPV
positive with “alternative treatments”
reserved for those that do not respond to
induction chemotherapy.31
Worden et al
31: Worden et al. J Clin Oncol; 26:3138-3146 2008
Surgical resection of OP lesions
and HPV association
32: Licitra et al. J Clin Oncol; 24:5630-5636 2006
Surgical resection of OP lesions
and HPV viral load
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
33: Cohen et al. Acta Otolaryngol 2008;128:583-9.
Hypotheses
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TORS will be oncologically sound as the primary
therapy in treatment of select oropharyngeal
cancers
The prevalence of HPV positivity in OP lesions will
be 60-70%.
There will be no difference in cervical metastases
in HPV positive and HPV negative lesions.
Patients with both HPV positive and negative
lesions will have favorable prognosis when treated
with TORS.
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Research Design
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This clinical study was a retrospective
analysis of a previously completed
prospective trial evaluating outcomes of
TORS for oropharyngeal squamous cell
carcinoma.
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Patient Inclusion
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At least 18 years old
Presented with therapeutic approaches for a
new squamous cell carcinoma of the
oropharynx evaluated on prior endoscopy and
with pre-operative computed tomography (CT)
and/or magnetic resonance (MR)
Lesions that were anatomically amenable to
transoral robotic surgery
Signed a written informed consent.
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Tumor related contraindications
Unresectability of the tumor or involved
lymph nodes
 Invasion of the mandible
 Bilateral posterior pharyngeal wall
involvement (greater than 50%)
 Carotid artery involvement
 Tumor fixation to the prevertebral fascia.
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Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Additional intervention
Staged cervical lymphadenectomy was
offered to all patients.
 Adjuvant therapy with radiation and/or
chemotherapy as indicated
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Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Clinical Patient Data
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Under IRB approved protocol, patient charts were
evaluated with respect to gender, age, stage, margins
of OP resection, incidence of pN+ in the neck, post
operative radiation, swallowing function, and status of
disease at follow up. This was done in a blinded
fashion, prior to obtaining HPV data.
Statistical analysis was performed using SPSS 16.0.
Nonparametric statistics were performed using
Pearson’s Chi Square and Fisher’s Exact Test (2sided). Kaplan-Meier analysis was performed for
survival with differences assessed by the Log-Rank
method.
Obtaining HPV data
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In an arrangement with SensiGen, LLC, (Ann Arbor,
Michigan) a biotechnology company focused on
molecular diagnosis, we sent paraffin slides of
oropharyngeal squamous cell carcinoma specimens for
testing using real-time PCR technology. This company
has performed HPV assays for other institutions.
Identification of the presence of any of the following HPV
genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
66, 68, 73 (for the 16-plex version) in attomoles.
Measurement of the level of betaglobin DNA present, in
attomoles.
Results: Patient Information
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The first 78 patients with oropharyngeal
squamous cell carcinoma assessed
58 patients with minimum 18 months follow up
 31 patients with HPV evaluation (no minimum
follow up)
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Mean follow up 21 months (2-41)
 HPV assessed in 31 patients
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71% HPV positive, 95% of these HPV-16%
Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870
Patient Characteristics
18 month follow
(n=58)
HPV- (n=9)
HPV+ (n=22)
Mean Age
57.4
55.4
58.6
Females
4 (7%)
0
1 (5%)
Follow up
25 (18-41)
23 (3-36)
21 (2-39)
Site (tonsil, 27(47%), 26(45%)
BOT)
4(44%), 3(33%) 9(41%), 12(55%)
N+ in atrisk necks
44/56 (79%)
6/8 (75%)
17/23 (74%)
ECS
20/53 (38%)
3/8 (38%)
7/22 (32%)
AJCC
(I-IV)
7(12%), 4(7%),
23(40%), 24(41%)
2(22%), 0,
1(5%), 0, 12(55%),
2(22%), 5(55%) 9(41%)
Oncologic Characteristics
following TORS
18 month
cohort (n=58)
HPV- (n=9)
HPV+ (n=22)
Final margins
(close/positive)
5(9%), 0(0%)
1(11%), 0(0%) 0 (0%), 0 (0%)
Local Recurrence
1 (2%)
0
1 (5%)
Neck Recurrence
1 (2%)
1 (11%)
0 (0%)
Distant Metastases
4 (7%)
0 (0%)
1 (5%)
Overall survival at 1
and 2-year
55/58 (95%),
33/41 (81%)
7/7 (100%),
5/6 (83%)
21/22 (95%),
11/14 (79%)
Disease specific
survival 1 and 2-yr
55/56 (98%),
33/36 (92%)
7/7 (100%),
5/5 (100%)
21/21 (100%),
11/12 (92%)
58 patients with 18 months
follow up overall survival
Comparison of overall survival
Worden, F. P. et al. J Clin Oncol; 26:3138-3146 2008
58 patients with 18 month follow
up disease-specific survival
Comparison of disease-specific
survival
31: Worden et al. J Clin Oncol; 26:3138-3146 2008
Overall survival with respect to
post operative adjuvant regimen
P=0.585 (log rank)
Overall survival with respect to
HPV status
P=0.87 (log rank)
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Comparison of outcomes
related to HPV status
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
30: Fakhry et al. J. Natl Cancer Inst. 2008 100:261-269.
31: Worden et al. J Clin Oncol; 26:3138-3146 2008
Swallowing function
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There is a wide range of cited percentage of
people after chemoradiation requiring
gastrostomy tube. This is cited from 3% to
approximately 50%.5,34,35
Ang et al cited the long term need for
gastrostomy tubes in 30% of those with OPSCC
treated with chemoradiation.34
Shiley et al cited the need for gastrostomy tube
in 48% of those with OPSCC treated with
chemoradiation.35
In our cohort 91% (50/55) of at risk patients had
the gastrostomy tube removed.
Conclusions
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TORS appears to be oncologically sound, with
adequate margins of resection as well as
satisfactory preliminary overall and disease
specific survival.
1 and 2 year oncologic data is equal to or
superior to the most recent chemoradiation data.
On preliminary assessment, negative HPV
status does not appear to be a negative
prognostic factor as seen in prior publications.
Swallowing function without gastrostomy tube is
preserved in more than 90% of patients.
Future directions
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With the cohort created, we can follow out for
long term survival data.
We are awaiting quantitative data, with which
we can further analyze patient outcomes.
We can compare outcome data for patients
undergoing surgical resection with those
undergoing primary chemo/xrt.
We can compare function of the those
undergoing surgical resection with those
undergoing chemo/xrt.
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Thank you
Dr. Weinstein
 Dr. O’Malley
 TORS research team
 Department of Otorhinolaryngology: Head
and Neck Surgery

Otorhinolaryngology: Head and Neck Surgery at PENN
Excellence in Patient Care, Education and Research since 1870