Trans-Oral Robotic Surgery What is the Benefit? · Director Trans-Oral Robotic Surgery. Department of Otolaryngology / Head & Neck Surgery. 27 July 2017. Winship Cancer Institute

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Trans-Oral Robotic Surgery What is the Benefit?

Radiation RulesMihir R. PatelDirector Trans-Oral Robotic SurgeryDepartment of Otolaryngology / Head & Neck Surgery27 July 2017

2Winship Cancer Institute | Emory University

Early Treatment Paradigms

DE-Revolution

Impact of ENE

TORS for Unknown Primary

TORS at EMORY

Summary

Outline – Benefit of TORS


HPV-Related OPSCC Demographic

Marur S, et al. Curr Opin Oncol. 2014;26(3):252-258.


HPV-Related OPSCC: Cancer Cured

• Cured of cancer at age 55• 20 years of post-RT related morbidities

• 2nd primary• Carotid vascular disease• ? immune system

• lymphopenia > 60 mos.• T-cells CD4+ / CD8+• B-cells

• 56 Gy leads to fibrosis of pharyngeal constrictor

• Dysphagia• Xerostomia


CRT

• Standard treatment for OPSCC• RT 70 Gy

• OP & Bilateral Cervical Nodes• Early/ Late Complications

• Mucositis, Xerostomia, Dysphagia, Tissue Fibrosis

• High dose Cisplatin added to RT regimen 70 Gy

• 29% PEG dependency @ 2yrs• > 30% constrictor 70 Gy • > 50% = stricture / aspiration

• late toxicity in OP• 56% = CRT• 30% = RT

TORS

• Morbidity• 0% Orocutaneous fistula• 2% Tongue swelling/

numbness• 8% Bleeding

• 3% (5 cases to OR)• 1% MI

• Swallow Function• 9% Dysphagia• 7% PEG

• 5% excluding 3 salvage cases

• Margins• 4% positive

Early Data: What is the trade off?

Machtay M, et al. J Clin Oncol. 2008;26(21):3582-3589. Weinstein GS, et al. Laryngoscope. 2012;122(8):1701-1707.


Optima: A phase II dose and volume de-escalation trial for high- and low-risk HPV+ oropharynx cancers

Patient Selection: HPV+ OPC low-risk (≤T3, ≤N2B, ≤10 PYH) OR high-risk (T4 or ≥N2C or > 10 PYH)

• 3 cycles induction carboplatin + nab-paclitaxel1) Low-risk ≥ 50% - low-dose RT 50Gy 2) Low-risk 30-50% - low-dose CRT 45Gy 3) High-risk poor response - CRT 75Gy

• CRT = paclitaxel, 5-FU, hydroxyurea, + 1.5Gy BID RT • Primary site biopsy + neck dissection post de-escalated treatment (RT50, CRT45)

Primary endpoint - 2-year PFS Secondary endpoints - pathologic complete response (pCR) rate and toxicity

Results: 62 patients enrolled: 28 low-risk

• Low-Risk: 71.4% RT50 21.4% CRT45 • 2-year PFS and OS were both 100% for low-risk• Grade ≥3 mucositis 15.8% - RT50 46.4% - CRT45 60.0% - CRT75 (p = .033) • Grade ≥3 dermatitis 0% - RT50 21.4% - CRT45 30.0% - CRT75 (p = .056)• PEG-tube dependency post-treatment

• 3 months 0% - RT50 14.8% - CRT45 70.0% - CRT75 (p < .001)• 6 months 0% - RT50 3.7% - CRT45 20.0% - CRT75 (p = .066)

• pCR rate: 94.4% RT50 92.3% CRT45 Melotek J, et al. J Clin Oncol. 2017;35(suppl): Abstract 6066.


TORS De-Intensification


A personalized approach using hypoxia resolution to guide curative-intent radiation dose-reduction to 30 Gy: a novel de-escalation paradigm for HPV-associated oropharynx cancers (OPC)

Patient Selection: HPV+ OPC low-risk: ≤T3, ≤N2B, ≤10 PYH Primary tumors were excised and analyzed for DNA repair foci ex-vivo

• pre-RT dynamic 18F-FMISO (fluoromisonidazole) PET to assess tumor hypoxia (defined as > 1.2 tumor to muscle SUV ratio) in cervical lymph nodes

• No hypoxia after initiation of CRT• 30Gy over 3 weeks - tumor bed + neck• 2 cycles of concurrent high-dose cisplatin or carboplatin/ 5-FU

• If persistent hypoxia• Standard dose of 70Gy over 7 weeks with chemo

• Neck dissection (ND) was done 4-months post CRT • Weekly DWI MRI, ctDNA, whole exome & RNA sequencing were performed

Results: 19 patients – 3 T0, 11 T1, 5 T2; 5 N1, 3 N2a, 11 N2b

• pre-RT 18F-FMISO scans• 6 No hypoxia – 30Gy• 13 + hypoxia• 12 intra-treatment 18F-FMISO scans

• 3 were + hypoxia - 70Gy CRT • 15 patients de-escalated to 30Gy • complete pathologic response in 8 of 9 patients• To date, 18 of 19 patients (95%-6 pending ND) remain disease free

Riaz N, et al. J Clin Oncol. 2017;35(suppl): Abstract 6076.


• Straight Forward– advanced lesions surgically contraindicated (ie T3 / 4)– advanced nodal disease (ie N2c / N3)– lesions with high chance of avoiding adjuvant therapy (ie T1 / T2N1)

• In Between– p16+/- smokers amenable to TORS– p16+ non-smokers requiring postoperative radiation (ie N2a / b)

• Difficult– p16+ Low-Risk T1/2 N2a/b non-smokers with high likelihood of needing

postoperative CRT (ie suspicion of extracapsular (ENE) spread on scan / or > 4 nodes)

SELECTION RELIES ON IMAGING

Tumor Board Discussion


HPV OPSCC Pre-Op CT ENE Characteristics

• Lymph node characteristics:• Necrosis (small versus > 75% “cystic”)• Lobular contours• Perinodal stranding (subtle vs gross) • Gross invasion of adjacent structures• Matted/conglomerate appearance• Size

Overall impression of rENE: yes/ no• any stranding “yes”

subtle

gross


HPV OPSCC Pre-Op CT versus Pathology

rENE

Radiologist 1 13/24

Radiologist 2 12/24

All pECS Macro pENE

Pathology 8/24 5/24

Sensitivity All pENE

Specificity All pENE

Specificity Macro pENE

Radiologist 1 100% 69% 58%

Radiologist 2 100% 75% 63%

1. High inter-observer agreement • (k < .001) except subtle stranding

2. Size > 3 cm significant correlation with macro pENE but not predictive

3. Subtle stranding was not a predictor of macro pENE


HPV Pre-OP CT Results: False Positives

• High sensitivity (100%) for detecting pENE in OP SCC than previously reported

• Low specificity, especially for macroscopic pENE (53%-64%)

• FP rate is unacceptably high to base treatment decisions when compared to previously published criteria for rENE in non-HPV SCC


PET in HPV-Related OPSCC

95% PPV of predicting N+ disease

Gold Standard for ENE: Gross Pathology


HPV-Related Nodal Pathology• Stage 1: Level I – IV

• < 10 % Occult Met• n = 181

• cN1 = 56 (31%)• pN1 = 28 (15%)• cN2a = 42 (23%)• pN2a = 48 (27%)• cN2b < 5 nodes = 83 (46%)• pN2b < 5 nodes = 105 (58%)

• Hazard Ratio• ENE (30%) = 1.17• Adjuvant RT = 0.59• 5 or > nodes = 3.08• 96% LRC vs. 92% with CRT

alone

4.1 cm

Zenga J, et al. Laryngoscope.2017;127(3):597-604.


Gross Pathology: TORS Radical Tonsillectomy


4.1 cm

HPV-Related Recurrences

Zenga J, et al. Laryngoscope.2017;127(3):597-604.


To TORS or Not to TORS• 61yF T1N0M0 Tonsil• former smoker > 10 pk year• Radiation Treatment Summary

2015• GTV70

• involved tonsil, right soft palate, right base of tongue, right retromolar trigone, and glossotonsillar sulcus to create a CTV 70.

• CTV54 • bilateral neck nodes levels II-IV • retropharyngeal nodes • The CTVs were expanded 3 mm

to create PTVs• PTV70 treated to 70 Gy 35

fractions • PTV54 treated to 53.9 Gy 35

fractions


Morbidity of CRT Failures

20Winship Cancer Institute | Emory University2

0%

25%

50%

75%

100%

UPENN(60)

UPMC (51) OSU (11) Emory (7) Multi (21)

Identified Unknown Unknown

PET / CT + Panendoscopy

TORS Endoscopy

TORS HPV+ HNCUP Identification Rate


①Neck mass – PE = No Primary②+ Neck FNA – SCCa p16

• El-Naggar & Westra. 2011• P16 → Surrogate Marker for HPV+ in the

setting of HNCUP ③− PET/CT ④− MicroDL w/ biopsies

OP HNCUP• HPV → Surrogate Marker for OP Primary in

HNCUP • El-Mofty et al. 2008• Vent et al. 2013

2005: HNCUP Linked to HPV

El-Naggar AK, et al. Head Neck. 2012;34(4):459-461. El-Mofty SK, et al. Head Neck Pathol. 2008;2(3):163-168. Vent J, et al. Head Neck. 2013;35(11):1521-1526.


Is it necessary to identify HPV+ HNCUP?• HPV patients have favorable OS

• Projected HNCUP• 2 – 5 %• 200 – 500 est. / year• Emory

• 93% p16+ OPSCC• 7 HPV+ HNCUP

• 5 identified (71%)

• No unified treatment strategy• RT Neck + Surgery• RT Neck + Surgery + Tongue Base• C + RT Neck + Tongue Base + Tonsil + RPN• C + RT to Neck + Pharynx (all sites)

Chaturvedi AK, et al. J Clin Oncol. 2011;29(32):4294-4301.


TORS Approach to HPV+ OPSCC HNCUP• PET / CT

• No Definitive Primary

• Telescopic Panendoscopy• Directed Biopsies

• Ipsilateral to Neck Mass• Nasopoharynx

• Robotic-assisted Panendoscopy (TORS)

• Palatine Tonsillectomy• Effective method for identifying unknown tonsil

primary• Ipsilateral to adenopathy

• Lingual Tonsillectomy

2

7.3 cm


TORS Approach to HPV+ OPSCC HNCUP• PET / CT

• No Definitive Primary

• Telescopic Panendoscopy• Directed Biopsies

• Ipsilateral to Neck Mass• Nasopoharynx

• Robotic-assisted Panendoscopy (TORS)

• Palatine Tonsillectomy• Effective method for identifying unknown tonsil

primary• Ipsilateral to adenopathy

• Lingual Tonsillectomy

2

1.3 mm


Pre-TORS ERA Treatment (2013-2014)


TORS ERA Treatment (2015-2016)


Pre-TORS vs. TORS Treatment


TORS

• Tumor Characteristics (n = 51)• Tonsil = 26 (51 %) • BOT = 25 (49 %)

• T1 = 23 (45 %) • T2 = 25 (49 %) • T3 = 2 ( 4 %)• T4a = 1 ( 2 %)• Neck

• N0 = 7 (14 %)• N1 = 6 (12 %) • N2a = 21 (41 %) • N2b = 15 (29 %) • N2c = 1 ( 2 %)• N3 = 1 ( 2 %)

• Pre-Operative Imaging• 5 of 51 (10 %) Unknown• 13 of 51 (25 %) + Nodes on

PET• 3 cases PET noted rN+ but pN-• 10 cases N2b vs. N2a on Path

• ENE• 22 of 51 (43 %)

• 9 micro (< 1.0 mm)

• Margins• 1 of 51 (2 %) positive

Emory Experience (2015-2016)

Control (n = 14)• DHT 3 weeks post TORS + SND Ib - IV• MBSS

Fiberoptic Endoscopic Evaluation of Swallow (FEES) (n = 8)

• 3-5 days post-TORS + SND Ib – IV• Personalized therapeutic program

Decline on MBSimp• base of tongue retraction• pharyngeal residue• anterior hyoid excursion

Penetration-Aspiration Score• Control = 4 (p = 0.001)• FEES = 2.5 (p = 0.086)

Early FEES post-TORS


0

1

2

3

4

5

6

7

Pre-Op MBSS 3-5 Days Post-Op FEES 3 Week Post-Op MBSS

Intervention Control

Swallow Function after TORS

• FOIS (Functional Oral Intake Score)7 = PO diet, no restriction6 = PO diet, specific food limits5 = PO diet, multiple consistency & special preparation / compensation4 = PO diet, one consistency3 = tube dependent, consistent PO2 = tube dependent, min PO1 = NPO


CRT

• NRG - HN002• ARM 1

• 60 Gy in 6 wks + cisplatin• ARM 2

• 60 Gy in 5 wks

TORS

• ECOG 3311 – Phase II• ARM 1

• T1/T2 N0 /1 – observation• ARM 2

• T1/T2; N2a / 2b; < 2 mm ENE• 50 Gy adjuvant RT• 60 Gy adjuvant RT

• ARM 3• > 2 mm ENE; > 4 nodes; +

margin• 66 Gy + weekly

cisplatin

Quality of Life & Swallow Outcomes

HHPV OPSCC Re-Defining the Standard


Summary – Still looking for answers• Low-Risk Disease – Are we still treating to 70 Gy + cisplatin?

• How much more can we de-escalate• Recommend patients for clinical trials

• cure • quality of life• ECOG-ACRIN 1308

• Phase 2 selecting for low risk• IC w/ cis / paclitaxel/ cetuximab followed by 54 Gy• significantly improved swallow outcomes

• TORS may aid de-escalation• TORS + 36Gy 20 fractions BID 1-12 days + docetaxel

• Intermediate / High Risk• Does ENE matter• patients amenable to TORS where path data is needed based on newer markers• Facilitate development of new drugs


Acknowledgement

Kelly Summers, PAMartha Ryan, NPTraci Switzer, NPNabil Saba, MDDong Shin, MD

Conor Steuer, MDMark El-Deiry, MD

Amy Chen, MDArturo Solares, MD

Kelly Magliocca, DDSH. Michael Baddour, MD

Danielle Gainor, MD

Jonathan Beitler, MDKristen Higgins, MDMark McDonald, MD

Pat Hudgins, MDAshley Aiken, MD

Kristen Baugnon, MDChristopher Griffith, MD

Georgia Chen, PhDRafi Ahmed, PhD

Meryl Kaufman, SLPBeth Seelinger, SLP

Lauren Ottenstein, SLP

Documents

Trans-Oral Robotic Surgery What is the Benefit? · Director Trans-Oral Robotic Surgery. Department of Otolaryngology / Head & Neck Surgery. 27 July 2017. Winship Cancer Institute