Trans-Oral Robotic Surgery What is the Benefit? Radiation Rules Mihir R. Patel Director Trans-Oral Robotic Surgery Department of Otolaryngology / Head & Neck Surgery 27 July 2017 1
Outline – Benefit of TORS Early Treatment Paradigms DE-Revolution Impact of ENE TORS for Unknown Primary TORS at EMORY Summary Winship Cancer Institute | Emory University 2
HPV-Related OPSCC Demographic Marur S, et al. Curr Opin Oncol. 2014;26(3):252-258. Winship Cancer Institute | Emory University 3
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 Winship Cancer Institute | Emory University 4
Early Data: What is the trade off? CRT TORS • Standard treatment for OPSCC • Morbidity • RT 70 Gy • 0% Orocutaneous fistula • OP & Bilateral Cervical Nodes • 2% Tongue swelling/ numbness • Early/ Late Complications • 8% Bleeding • Mucositis, Xerostomia, • 3% (5 cases to OR) Dysphagia, Tissue • 1% MI Fibrosis • Swallow Function • High dose Cisplatin added to • 9% Dysphagia RT regimen 70 Gy • 7% PEG • 29% PEG dependency @ 2yrs • 5% excluding 3 salvage • > 30% constrictor 70 Gy cases • > 50% = stricture / aspiration • Margins • late toxicity in OP • 4% positive • 56% = CRT • 30% = RT Machtay M, et al. J Clin Oncol. 2008;26(21):3582-3589. Weinstein GS, et al. Laryngoscope. 2012;122(8):1701-1707. Winship Cancer Institute | Emory University 5
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-paclitaxel 1) 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. Winship Cancer Institute | Emory University 6
TORS De-Intensification Winship Cancer Institute | Emory University 7
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 18 F-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 18 F-FMISO scans • 6 No hypoxia – 30Gy • 13 + hypoxia 12 intra-treatment 18 F-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. Winship Cancer Institute | Emory University 8
Tumor Board Discussion • 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 Winship Cancer Institute | Emory University 9
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 subtle • Matted/conglomerate appearance • Size Overall impression of rENE: yes/ no • any stranding “yes” gross Winship Cancer Institute | Emory University 10
HPV OPSCC Pre-Op CT versus Pathology 1. High inter-observer agreement • (k < .001) except subtle stranding 2. Size > 3 cm significant correlation with macro pENE but not predictive rENE Radiologist 1 13/24 3. Subtle stranding was not a Radiologist 2 12/24 predictor of macro pENE All pECS Macro pENE Pathology 8/24 5/24 Sensitivity Specificity Specificity All pENE All pENE Macro pENE Radiologist 1 100% 69% 58% Radiologist 2 100% 75% 63% Winship Cancer Institute | Emory University 11
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 Winship Cancer Institute | Emory University 12
PET in HPV-Related OPSCC 95% PPV of predicting N+ disease Winship Cancer Institute | Emory University 13
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%) 4.1 cm • 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 Zenga J, et al. Laryngoscope. 2017;127(3):597-604. Winship Cancer Institute | Emory University 15
Gross Pathology: TORS Radical Tonsillectomy Winship Cancer Institute | Emory University 16
HPV-Related Recurrences 4.1 cm Zenga J, et al. Laryngoscope. 2017;127(3):597-604. Winship Cancer Institute | Emory University 17
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 Winship Cancer Institute | Emory University 18
Morbidity of CRT Failures Winship Cancer Institute | Emory University 19
TORS HPV+ HNCUP Identification Rate 100% TORS Endoscopy 75% 50% PET / CT + Panendoscopy 25% 0% UPENN UPMC (51) OSU (11) Emory (7) Multi (21) (60) Identified Unknown Unknown Winship Cancer Institute | Emory University 20 2
2005: HNCUP Linked to HPV ① Neck mass – PE = No Primary ② + 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 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. Winship Cancer Institute | Emory University 21
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. Winship Cancer Institute | Emory University 22
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