Transoral Robotic Surgery and HPV(+) Oropharyngeal SCCA Benjamin Walton, MD Michael Underbrink, MD

The University of Texas Medical Branch Department of Otolaryngology September 18, 2013

Disclosures  None

Learning Objectives  1.

The audience should be able to understand the proper set-up and surgical approach to oropharyngeal tumors.  2. The audience should be able to discuss the prognosis with various treatment options available in HPV-related oropharyngeal cancers.  3. The audience should be able to understand the difference in outcome measures related to TORS versus chemotherapy/radiation.

Background  Epidemiology

of Upper Aerodigestive Tract Cancer is changing (Oropharynx>Larynx)  Its De-escalation Time

The Shifting Revolving Paradigm Surgery

Radiation

Concurrent Chemoradiation

Almeida J et al. Curr Oncol Rep 2012, 14:148-157

Bringing Surgery Back  Surgical

Therapy traditionally wideexposure approaches such as mandibulotomy and trans-pharyngeal surgery  In past 2 decades, surgical approaches evolved to allow resection of oropharyngeal SCCA (OP-SCCA)  Oncological and Functional Outcomes have compared favorably with Standard Treatments

Sticking the Round Peg in the Square Hole

HPV

HPV  Double-stranded

circular DNA virus  Early Region (E) and Late Region (L)  Replicates exclusively in keratinocytes  E6 and E7 important viral oncogenes promoting cell growth by inactivation of p53 and pRb  2 major groups 



HPV 6 and 11 HPV 16 and 18

Staging of the Oropharynx

Staging of the Oropharynx

Courtesy AJCC Cancer Staging System

Courtesy AJCC Cancer Staging System

HPV(+) Oropharyngeal SCCA  HPV-16

causes 90% of HPV-Positive Head and Neck SCCA  Gillison et al. showed 26 or more vaginal sex partners or 6 or more oral sex partners dramatically increases risk; OR = 3.1and OR 3.4 respectively  Differing phenotypic and biological profile of HPV-associated OPSCC leads to superior disease free and overall survival outcomes

Bledsoe et Al Radiation Oncology 2013, 8:174

Survival Effects of HPV  Ang

et al. Performed retrospective analysis of RTOG 0129  Overall Survival of HPV (+) at 3 yrs: 82%  Overall Survival of HPV (-) at 3 yrs: 57.1%  Progression-free Survival in HPV (+): 73.7 %  Progression-free Survival in HPV (-): 43.4%  Locoregional recurrence in HPV (+): 13.6%  Locoregional recurrence in HPV (-): 35.1%

Current Treatment Regiments for HPV(+) Oropharyngeal SCCA  Standard

Therapy is generally once daily XRT in fractions of 2 Gy/fx for a total dose of 70-74 Gy (6 weeks)  Single agent high dose Cisplatin of 100 mg/m2 in 3 doses  Salvage Neck Dissections reserved for PET(+) lymph nodes 3 months s/p treatment or clinically concerning neck masses

Toxicities/Side Effects  Loss

of Taste  Xerostomia  Need for Feeding Tubes/Dysphagia  Febrile Neutropenia  Radiation Dermatitis  Pain

Chemoradiotherapy Toxicities  Machtay

et al. reviewed analysis of three RTOG trials  Rate of severe late toxicities 43% for all treated, 35% in patients with oropharyngael carcinoma  Grade ¾ Laryngeal Toxicity, Feeding tube dependence at 2+ years, and/or treatment related deaths

Acute Toxicity Comparing HPV(+) to HPV(-)  Need

for Feeding Tube (59% vs. 58%; p=

0.97)  Febrile Neutropenia (29% vs. 17%; p= 0.23)  Radiation Dermatitis (p= 0.62), Pain During Treatment (p= 0.57), Pain at 90 Days (p= 0.62) similar

Bledsoe et al Radiation Oncology 2013, 8:174

Late Toxicity Comparing HPV(+) to HPV(-) 6

months post-treatment  Need for Feeding Tube: 0% vs. 24% (p< 0.001)  Trismus: 1% vs. 24% (p= 0.002)  Xerostomia and Dysphagia comparable

Robotic Surgery  Puma

560 robot in 1985 used to perform more precise neurosurgical biopsies  3 years later, trans-urethral resection of prostate  Development aided by NASA and US Army for “telepresence” surgery  FDA approved use of robot in transoral surgery in 2009

TORS Surgery: The Beginning  Preclinical

studies at University of Pennsylvania  O’Malley et al described first series of TORS tongue base resections  UPENN reported first series of TORS cases for radical tonsillectomy on 27 patients  Genden et al (Mount Sinai) reported 20 patients undergoing TORS

Transoral Robotic Surgery of the Oropharynx

Grant N, Atlas of Head and Neck Surgery. 2012, Elsevier.

The “FK” Retractor •Multiple Points of Rotation •Use with Suspension Device

Grant N, Atlas of Head and Neck Surgery. 2012, Elsevier.

Initial General Set-up

Transoral Robotic Base of Tongue Resection

Diagnosis and Management of Unknown Primary Tumors  5-year

actuarial survival for N1/N2/N3 Dz: 69%/58%/30%  Mehta et al reviewed 10 cases of pts with unknown primary SCCA  All pts underwent panendoscopy, PET/CT, and bilateral tonsillectomy without localized primary tumor  9 pts, BOT carpet resection revealed SCCA  1 patient without known primary site

Diagnosis and Management of Unknown Primary Tumors  Identification

of Primary Mucosal Lesion proven vast improvement in 5-year survival  Potential reduction in morbidity by reducing radiation toxicity to other pharyngeal subsites

Tumor Margins   

 

Haughey et al noted presence of positive margin after surgery raised risk of death 2.5 fold to 3.0 fold Collaborative approach between pathologist and surgeon Surgeon delivers specimen to pathology lab and inks with various permanent inks to denote pertinent margins and pinned on cork board If gross margins appeared involved, frozen sections taken or further margins taken After re-resection, operative bed stained with methylene blue to ensure proper orientation

 Orientation

Pathology

of Surgical Specimen in

From: Transoral Robotic Surgery Alone for Oropharyngeal Cancer: An Analysis of Local Control Arch Otolaryngol Head Neck Surg. 2012;138(7):628-634. doi:10.1001/archoto.2012.1166

Figure Legend: Figure. Orientation of transoral robotic surgical specimen for pathologic analysis. A, Surgical specimen inked and pinned to cork board. B, Transection of surgical specimen to assess adequacy of deep margin.

Date of download: 9/15/2013

Copyright © 2012 American Medical Association. All rights reserved.

Transoral Robotic Surgery for Advanced Oropharyngeal Carcinoma (Weinstein et al)  1st

prospective trial of TORS out of UPENN  Data collected from pool of 162 pts  Patients underwent staged neck dissections 3 weeks s/p TORS resection   

Avoid creating connection between neck and pharynx Avoid additional laryngopharyngeal swelling Selective Neck Dissections Levels I- III/IV performed

Adjuvant Radiation Therapy  Post-operative

irradiation without chemotherapy: Questionable surgical margins and presence of 2 or more pathologically positive lymph nodes  Relative indications included T4 disease with infiltrative growth, presence of perineural invasion, presence of 1 pathological lymph node Weinstein et al. Arch Otolarnygol Head Neck Surg. 2010, 11: 1079-1085

Adjuvant Chemo/XRT  Base

concurrent chemo/XRT recs on Bernier et al recommendations from combined analysis of ECOG and RTOG trials  Positive Surgical Margins  Extracapsular Extension (ECE)  Multiple lymph nodes without ECE Weinstein et al. Arch Otolarnygol Head Neck Surg. 2010, 11: 1079-1085

Oncologic Outcomes  47

primary TORS procedures with minimum of 18 month follow-up  No information on HPV status in study  1 positive histologic margin (2%)  Local Disease Control in 46 pts (98%)  Regional control in 45 (96%)  Distant control in 43 pts (91%)  38% of stage III and IV pts avoided chemotherapy Weinstein et al. Arch Otolarnygol Head Neck Surg. 2010, 11: 1079-1085

Weinstein et al. Arch Otolarnygol Head Neck Surg. 2010, 11: 1079-1085

Weinstein et al. Arch Otolarnygol Head Neck Surg. 2010, 11: 1079-1085

Survival  Overall

survival rate: 96% at 1 year and 82% at 2 years  Disease-Specific Survival: 98% at 1 year and 90% at 2 years  Disease-Free Survival: 96% at 1 year and 79% at 2 years Weinstein et al. Arch Otolarnygol Head Neck Surg. 2010, 11: 1079-1085

Long-term Functional and Oncologic Results of Transoral Robotic Surgeyr for Oropharyngeal SCCA (Moore et al)  Moore

et al reviewed 66 pts between 2007 and 2009  65 pt tested for p16, 58 postive (89.2%)  56 of 66 pts clinical stage T1 or T2  Pathologic staging revealed lymph node metastases in 86.4%  Overall staging III-IVB in 87.9%

Treatment Algorithm  Primary

Tumor Resection performed using da Vinci Surgical System  36 (54.5%) patients with clear margins on initial resection  12 (18.2%) patients required second margin excision  18 (27.3%) patients required 3 or more margin excisions on initial operation  1 specimen demonstrated positive margin on final histologic review

Treatment Algorithm  Performed

Neck Dissection in all patients at same time as TORS  56 (84.8%) patients underwent unilateral neck dissection  10 (15.2%) patients underwent bilateral neck dissection

Treatment Outcomes

Long-term Functional and Oncologic Results of Transoral Robotic Surgeyr for Oropharyngeal SCCA (Moore et al)  HPV(+)

smokers with downward trend in

survival  Margin control was important prognostic factor  Only 54% of pts achieved margin control on initial resection  Studies needed to investigate deescalation of therapy in subsets of patients with favorable prognosis

Transoral Robotic Surgery Alone for Oropharyngeal Cancer: An Analysis of Local Control (Weinstein et al)     



30 pts underwent TORS +/- SND without adjuvant therapy (minimum follow-up 18 months 1 local recurrence 3 pts with perineural invasion (10%) 1 pt with lymphovascular invasion (3%) 16 pts with Stage III/IV disease Absence of HPV and p16 analysis  Cohen et al noted HPV(+) in 74% of pts in their series

Weinstein et al. Arch Otolaryngol Head Neck Surg. 2012, 138: 628-634

Selective Neck Dissection and Deintensified Postoperative Radiation and Chemotherapy for Oropharyngeal Cancer: A Subset Analysis of the University of Pennsylvania Transoral Robotic Surgery Trial (Weinstein et al)

 Indications

for post-operative chemoradiation based entirely on pathologic status of nodes  Pts underwent selective neck dissection, levels I-IV most commonly  32 pts between 2005 and 2007  Primary outcome measure was regional recurrence rate  Minimum post-op follow-up of 18 months

Selective Neck Dissection and Deintensified Postoperative Radiation and Chemotherapy for Oropharyngeal Cancer: A Subset Analysis of the University of Pennsylvania Transoral Robotic Surgery Trial (Weinstein et al)

 Contraindications

for SND: stage IVc disease, carotid artery encasement, deep neck structure involvement, skin invasion with dermal metastasis, invasion of SCM, CN XI, or IJ  29 pts underwent ipsilateral neck dissection  2 pts underwent bilateral SND  29% of pts had ECE

Selective Neck Dissection and Deintensified Postoperative Radiation and Chemotherapy for Oropharyngeal Cancer: A Subset Analysis of the University of Pennsylvania Transoral Robotic Surgery Trial (Weinstein et al)

 Clinical

N0 and N1 neck disease was upstaged 33% and 43% respectively on pathology  70% of pts with N2b disease had ECE  14% of pts with N1 disease had ECE  4 of 14 pts with clinical N1 had negative pathologic results

Selective Neck Dissection and Deintensified Postoperative Radiation and Chemotherapy for Oropharyngeal Cancer: A Subset Analysis of the University of Pennsylvania Transoral Robotic Surgery Trial (Weinstein et al)

 Adjuvant

chemoradiation: presence of positive surgical margins, presence of ECE  22.6% pts received no adjuvant therapy  12 pts (50%) received adjuvant radiation  12 pts (50%) received adjuvant chemoradiation

Selective Neck Dissection and Deintensified Postoperative Radiation and Chemotherapy for Oropharyngeal Cancer: A Subset Analysis of the University of Pennsylvania Transoral Robotic Surgery Trial (Weinstein et al)

 Regional

Recurrence: 1  Local Recurrence: 1  Distant Recurrence: 1

Conclusions  Previously

reported, Relapse rates of SND with post-op XRT: 5%-29%  pN2 disease risk of recurrence >20% without XRT, decreased to about 10% with XRT  Study revealed control rate of 100% after SND  

ECE found in 29% of pts pN2b disease is 61% of pts

 Select

pts with clinically low risk N0-1 disease may be observed

Transoral Robotic Surgery and Human Papillomavirus Status: Oncologic Results (Cohen et al)  Review

of 50 pts with OPSCC  37 pts HPV (+); 13 pts HPV (-)  76.9% pts HPV(-) were Stage III/IV  91.9% pts HPV(+) were Stage III/IV

Transoral Robotic Surgery and Human Papillomavirus Status: Oncologic Results (Cohen et al)  Adjuvant

Treatments

 HPV(+)   



56.8% pts received adjuvant Chemo/XRT 27% received XRT alone 5.4% received chemotherapy alone 10.8% received no adjuvant treatment

Transoral Robotic Surgery and Human Papillomavirus Status: Oncologic Results (Cohen et al)  Adjuvant

Treatments

 HPV(-)   

46.2% received adjuvant Chemo/XRT 15.4% received adjuvant XRT 38.5% received no adjuvant therapy

Transoral Robotic Surgery and Human Papillomavirus Status: Oncologic Results (Cohen et al)  Neck  

Dissections

HPV(+): 30/36 pts with path(+) nodal disease (83.3%) HPV(-): 9/12 with path(+) nodal disease (75%)

Cohen et al. Head & Neck. 2011; DOI 10.1002.

Prognostic Factors and Survival Unique to Surgically Treated p16(+) Oropharyngeal Cancer (Haughey and Sinha)  Study

based on TLM and not TORS  Pts with diffusely (+) p16 on IHC  Prospective database w/ primary TLM +/neck dissection +/- adjuvant therapy  Minimum follow-up of 12 months or death  Cox proportional hazard regression analyses to identify variables prognostic for Disease-free survival

Prognostic Factors and Survival Unique to Surgically Treated p16(+) Oropharyngeal Cancer (Haughey and Sinha)  Neck

Dissection: Levels II-IV unless concern for level Ib  Tongue Base and/or Tonsil tumors approaching or extending past midline, or N2c disease: contralateral elective SND

Prognostic Factors and Survival Unique to Surgically Treated p16(+) Oropharyngeal Cancer (Haughey and Sinha)  Adjuvant 

 

Therapy

ECS Multiple or contralateral lymph nodes Positive Margins

 Added

Cisplatin after 2004 for high-risk

cases  Adjuvant XRT at 60 Gy in 30 fractions unless high-risk features 

Positive Margins, Multiple metastatic nodes or ECE – Given 66 to 70 Gy

Prognostic Factors and Survival Unique to Surgically Treated p16(+) Oropharyngeal Cancer (Haughey and Sinha)  Elective

XRT to contralateral neck: 52-54

Gy  Primary site spared XRT if tumor is low stage or negative margin on resection  Pathologic-negative contralateral neck or low risk for contralateral neck; ipsilateral neck alone radiated

Prognostic Factors and Survival Unique to Surgically Treated p16(+) Oropharyngeal Cancer (Haughey and Sinha)  171pts  Median

follow-up of 47 months  3-year Kaplan-Meier estimates for DFS/DSS at 91%/95.5% and 5-year survival at 88%/94.4%  12 total recurrences: 2 local, 4 regional, 6 distant

Prognostic Factors and Survival Unique to Surgically Treated p16(+) Oropharyngeal Cancer (Haughey and Sinha)  cT4

tonsil primary, Ever smoking status, 3+ metastatic nodes, pN2b+ stage, radiation-based adjuvant therapy prognosticator for DFS  Angioinvasion, T3-T4 tumors prognostic for DSS  Smoking not prognostic for DSS  ECE, N stage, margins nonprognostic

Prognostic Factors and Survival Unique to Surgically Treated p16(+) Oropharyngeal Cancer (Haughey and Sinha)  Recurring

theme of changing clinical staging to more accurate pathologic staging

Prognostic Factors and Survival Unique to Surgically Treated p16(+) Oropharyngeal Cancer (Haughey and Sinha)

Favorable Outcomes for TORS 3

year Kaplan-Meier DFS 91% compared to nonsurgical cohorts for DFS 74%/81%/87% in HPV(+) OPSCCA  Since DFS was primary end point including death from all causes, only 7 of 171 (4%) died of disease

Risk Stratification

Patients stratified in three groups based disease-free survival status in each node (low/high/unknown)

Functional Outcomes for TORS  Acute

and Late Toxicities associated with

CCRT  Need for PEG tube and Tracheostomy  Comparing functional results, TORS offers improved outcomes

Tracheostomy Outcomes  Weinstein 

N = 27

 Genden 

et al: 0 (0%)

N = 18

 Iseli 

et al: 2 (7.4%)

et al: 5 (9%) all decannulated by 14 d

N = 54

 Moore

et al: 14 (31%) all decannulated based on stage 

N = 45

Almeida and Genden. Curr Oncol Rep. 2012, 14: 148-157

Gastrostomy Outcomes  Weinstein 

N = 27

 Genden 

et al: 9 (17%) at 12 month

N = 54

 Moore 

et al: 0 (0%)

N = 18

 Iseli 

et al: 27 (100%) peri-operatively

et al: 8 (18%) none at 12 mo

N = 45

Patient-Perceived and Objective Functional Outcomes Following Transoral Robotic Surgery for Early Oropharyngeal Carcinoma (Sinclair et al)  Utilized

MDADI Questionnaire  Prospective Study  42 pts with T1 or T2 OPSCCA; 76% with Stage III Disease  93% underwent staged neck dissection  Pre-op MDADI; Immediate Post-op MDADI, Last Follow-up MDADI

Patient-Perceived and Objective Functional Outcomes Following Transoral Robotic Surgery for Early Oropharyngeal Carcinoma (Sinclair et al) 

 

 

Dysphagia after organ preservation therapy affected by irradiation dose received by pharyngeal constrictor muscles Able to deintensify post-op XRT 31% received post-op chemo. If under organ preservation protocol, 76% in series would have required chemotherapy 45% of pts in series avoided chemotherapy Post-op Chemo only factor predictive of PEG tube retention past 3 months

Current Thoughts  Supported

by literature, HPV-associated OPSCCA with improved prognosis regardless of treatment  Subset of HPV-associated OPSCC with tobacco exposure possibly poorer prognosis  Should HPV status re-stratify and change our treatment regiments?  Will surgical approaches such as TORS improve outcomes in these “intermediate” risk patients?

Is Chemotherapy with Adjuvant XRT Indicated?  Sinha

et al. evaluated 152 p16(+) pts  Evaluated ECS with 2 systems: ECSreport and ECSgraded  Matched patients based on multiple parameters  Primary End-point of DFS and Recurrence  Median Follow-up of 43 months

Is Chemotherapy with Adjuvant XRT Indicated?  ECS

was neither associated with poor disease-free survival nor with other end points  Further analysis revealed no improved disease-free survival using chemotherapy with adjuvant radiotherapy

Reconstruction after TORS  

Almeida et al classified defects from 92 pts into 4 classes Classification system based on anatomical features affecting complications and/or functional outcomes  Site of defect  Number of Subsites Involved  Exposure of Internal Carotid Artery in Pharynx  Communication with oropharynx and neck during concominant neck dissection  More than 50% soft palate resection

•One subsite involved •No adverse features •N =31 (34%)

•Involved more than 1 subsite •No adverse features •N= 45 (49%)

•Only 1 subsite involved •Adverse Feature involved •N=3

•Multiple Subsites Involved •At least 1 adverse features •N=13 (14%)

Reconstruction Algorithm (Almeida et al)

Reconstruction  Soft

palate involvement can result in VPI, hypernasal speech, and reduced speech intelligibility  Small defects closed with superior constrictor advancement flap  Larger defects closed with RFFF

The Future  Improved

survival in HPV (+) patients necessitates a reduction in treatmentrelated toxicities  Decreased Radiation Dose? 

Phase II Trial by Mehrotra et al  Non-smoking

HPV(+), Induction TPF, CR/PR with decreased RT



ECOG 1308: HPV Stage III/IV, Induction TPC, CR with reduced XRT + cetuximab

The Future  Reduce 

Toxicity from Chemotherapy?

De-ESCALaTE HPV Trial  Randomized

Cetuximab



trial of Standard CCRT vs. XRT w/

RTOG 1016  HPV(+)

OPSCC  Accelerated IMRT 70 Gy with Cisplatin vs. Acc. IMRT 70 Gy with Cetuximab

The Future  ORATOR

Study  Prospective Phase II Trial Evaluating QOL as primary end-point  T1-2 Stage, N0-2 nodal stage,