transoral robotic surgery for oropharyngeal carcinoma and hpv viral load marc a. cohen, md research...

Transoral Robotic Surgery for Oropharyngeal Carcinoma and

HPV Viral Load

Marc A. Cohen, MDResearch 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 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


Introduction:Head and Neck Cancer 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.


Divergent Outcomes with OPSCC IFrench 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 IIECOG 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 IIIBrazilian 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

HPV associated HNSCC

HPV associated HNSCC comprise a distinct clinical entity and pathogenesis More basaloid features9

Less p53 mutations13,14

Younger patients without conventional risk factors8-10

• Lifetime number of sexual partners15

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 (84-94%), 18 (0-3%), 33 (1-27%)3,16,19-22


Prognosis with HPV status 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

30: Fakhry et al. J. Natl Cancer Inst. 2008 100:261-269.

ECOG chemoradiation outcomes in OP SCC with HPV status

Prognosis with HPV positive OP SCC treated with CRT 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

31: Worden et al. J Clin Oncol; 26:3138-3146 2008

Worden et al

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 aTIFF (Uncompressed) decompressor

are needed to see this picture.

33: Cohen et al. Acta Otolaryngol 2008;128:583-9.

Hypotheses 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.


Research Design

This clinical study was a retrospective analysis of a previously completed prospective trial evaluating outcomes of TORS for oropharyngeal squamous cell carcinoma.


Patient Inclusion 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.


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.


Additional intervention

Staged cervical lymphadenectomy was offered to all patients.

Adjuvant therapy with radiation and/or chemotherapy as indicated


Clinical Patient Data

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 (2-sided). Kaplan-Meier analysis was performed for survival with differences assessed by the Log-Rank method.

Obtaining HPV data 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 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) Mean follow up 21 months (2-41) HPV assessed in 31 patients

71% HPV positive, 95% of these HPV-16%


Patient Characteristics18 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, BOT)

27(47%), 26(45%) 4(44%), 3(33%) 9(41%), 12(55%)

N+ in at-risk 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, 2(22%), 5(55%)

1(5%), 0, 12(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)



Comparison of outcomes related to HPV status



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 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 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 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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Head Neck Surg 1994;120:743-748. 29. Snijders PJ, Scholes AG, Hart CA, et al. Prevalence of mucosotropic human papillomaviruses in squamous-cell carcinoma of the head and neck. Int J Cancer

1996;66:464-9. 30. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective

clinical trial. J Natl Cancer Inst 2008;100:261-9. 31. Worden FP, Kumar B, Lee SJ, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively

associated with HPV16 copy number. J Clin Onol 2008;26:3138-46. 32. Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis affects prognosis in patients with surgically treated oropharyngeal

squamous cell carcinoma. J Clin Oncol 2006;24:5630-36. 33. Cohen MA, Basha SR, Reichenbach DK, et al. Increased viral load correlates with improved survival in HPV-16-associated tonsil carcinoma patients. Acta

Otolaryngol 2008;128:583-9. 34. Ang KK, Harris H, Garden AS, et al. Concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: radiation therapy oncology

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2006;134:

References II

Thank you

Dr. Weinstein Dr. O’Malley TORS research team Department of Otorhinolaryngology: Head

and Neck Surgery


transoral robotic surgery for oropharyngeal carcinoma and hpv viral load marc a. cohen, md research...

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