Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 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
Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 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?
Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 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
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 • 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 33: Cohen et al. Acta Otolaryngol 2008;128:583-9.
Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 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.
Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 Research Design • 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 • 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.
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
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.
Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 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%
Comparison of overall survival Worden, F. P. et al. J Clin Oncol; 26:3138-3146 2008
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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Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870 Thank you • Dr. Weinstein • Dr. O’Malley • TORS research team • Department of Otorhinolaryngology: Head and Neck Surgery