11/8/2014 P ROSPECTIVE C LINICAL T RIALS IN Disclosure T RANSORAL E NDOSCOPIC H&N SURGERY FOR O ROPHARYNGEAL � I have no conflicts of interest to disclose C ANCER : ECOG3311 & RTOG1221 Chris Holsinger, MD, FACS Professor of Otolaryngology Chief, Head and Neck Surgery Stanford Cancer Center November 8, 2014 H&N Cancer, 2014: Vital Statistics Estimated new cases (USA), 2014* Deaths Oral cavity, pharynx 42,440 8,390 Larynx 12,630 3,610 Total 55,070 12,000 *CA Cancer J Clin 2014 (January) Siegel et al. ↑ 225% HPV(+)OPC 1
11/8/2014 CNXII CNX Cranial neuropathy: 48% ORN: 10% eHNS = Endoscopic T1 HPV & Transoral eHNS: Evolution of Treatment Head & Neck Surgery Transoral Endoscopic H&N Surgery is an adaptive � Clinical Equipoise has been lost. endoscopic head and neck surgical technique, providing comprehensive margin resection T2b/3 and good functional outcomes: NEJM 1987 Transoral laser microsurgery (TLM) � Transoral robotic surgery (TORS ) � � Larynx/pharynx heals by secondary intention. � No reconstruction � Why? Not efficacy. But rather, ever increasing � No disassembly of the neck toxicity and concern about long-term function � Tracheotomy not needed � Low rate <10% of G-tube following chemoRT dependency rate 2
11/8/2014 Transoral Endoscopic H&N Surgery (eHNS) eHNS: Operating through Endoscopes Robotic Scanner The Surgical Cart “Remote Manipulators” 0º vs. 30º “Virtual” Environment Real Surgery The “Vision Cart” Surgeon Console 3
11/8/2014 Transoral Resection of Pharynx Cancer The Clinical Trials Planning Meeting* November 2011 Ridge & Adelstein * R13 funded! ECOG 3311 – “HPV-positive”/ p16 + trial Observation � RTOG1221 HPV- LOW RISK : T1-T2N0-N1 negative margins Assess Eligibility: HPV (p16) + SCC Radiation Therapy � Surgical Intensification IMRT 50Gy/25 Fx oropharynx RAN (tonsil, tongue-base, DO INTERMEDIATE: GPC) Transoral Resection MIZ Clear/close margins Evaluate 2-year PFS E < 1mm ECS Local-Regional Recurrence, Functional (any approach) Outcomes/QOL Stage III-IV: cT1-2, N1- 2-4 metastatic LN with neck dissection � ECOG3311 HPV+ 2b PNI LVI Baseline Functional/ � Descalation (?) with surgery HIGH RISK : Radiation Therapy QOL Assessment IMRT 60 Gy/30 Fx Accrual goal = 377 Positive Margins > 1mm ECS or ≥ 5 metastatic LN Radiation Therapy IMRT 66 Gy/33 Fx + CDDP 40 mg/m 2 weekly 4
11/8/2014 RTOG 1221: Phase IIb Schema 3311 T Stage R Arm 1: eHNS * + Neck Dissection (Experimental Arm) 1. T1 A “Risk-based” post-operative Adjuvant Therapy, 2. T2 +/- IMRT (60 Gy) +/- Weekly cisplatin ** for high-risk patients with ≥ 5 N metastatic nodes, extracapsular extension, or positive surgical margins on final surgical pathology N stage D STRA 1. N1 O � Primary objective is to evaluate the 2-yr PFS in HPV+ SCC patients TIFY 2. N2 M treated with low-dose RT (assume 85% per arm) Arm 2: Chemoradiotherapy (Control Arm) I Zubrod Status Z 1. 0 IMRT (70 Gy) + 2. 1 E Weekly cisplatin � Secondary end points : Early/late toxicities, swallowing function, QOL, and oral/serum/tissue biomarkers in predicting clinical outcome Eligible Accrual goal = 144 - Oropharyngeal SCC: Tonsil, BOT, GPC - Stage III-IV: T1-2, N1-2b (72 vs. 72) - p16 NEGATIVE (IHC) *eHNS = TLM or TORS ** italicized text will be added at next protocol amendment (in progress) 17 Primary Objective Phase II-b Design (Control Arm) � Primary: To determine if surgical intensification � Radiotherapy w/concurrent chemotherapy � IMRT: 70 Gy over 6 weeks: 2 Gy, 35 fractions for patients with HPV-negative OPC will improve Concurrent weekly cisplatin (40 mg/m 2 IV) � progression-free survival by 10% � Unilateral neck IMRT can be used � For T1-2 lateralized tonsil tumors with < 1 cm invasion into the soft palate � Based on stage-matched patients enrolled in RTOG � No or limited lateral invasion of BOT 0129, we estimate that 2-year PFS for patients in the � N1 neck involvement � For “big T2” or N2b , bilateral IMRT allowed control arm of the proposed trial is 55%. � RadOnc PI: Wade Thorstad (Wash U.) 5
11/8/2014 Phase II-b Design: Post-Op ChemoRT Experimental (Surgical) Arm � Patients w/ positive margins or extracapsular spread (ECS) in cervical nodes (or with ≥ 5 metastatic nodes without ECS ) will receive � Transoral eHNS (TORS vs. TLM) postoperative cisplatin, 40 mg/m 2 IV on days 1, 8, 15, 22, 29, and 36, for & Neck Dissection a total of 6 weekly doses concurrent with IMRT (60 Gy at 2 Gy in 30 fractions over 6 weeks). � Patients with involved surgical margins or ECS may receive a 6 Gy boost � Risk-based post-operative adjuvant therapy will at 2 Gy per fraction to the area of the positive margin or ECS. be guided by pathological findings of the primary tumor and within cervical nodes. Post-Op RT only No PORT � Patients with “close” margins (<3mm), lymphovascular (LVI) or perineural � Indication for No Post-operative Radiation Therapy invasion (PNI), >1 metastatic lymph nodes will receive IMRT (60 Gy at 2 Gy) in 30 fractions over 6 weeks. For patients with pT1-2, pN0 OPC, negative � Subclinical regions at risk for microscopic disease (e.g. contralateral margins (>3mm), no adverse features (LVI or PNI), hemineck, when indicated) will receive 54 Gy (1.8 Gy/fraction, using integrated boost technique) � no adjuvant therapy would be given. 6
11/8/2014 Prospective Clinical Trials Credentialing: Standardizing Technique of Transoral eHNS in Endoscopic H&N Surgery? � How can we ensure and maintain quality? � IRB Approval (since we can’t operate on a phantom) � TORS vs. TLM � “Bovie” and headlight � 10 CASES: paired op/path report � Questionnaire Credentialing Update � 37 Surgeons Credentialed; 10 pending 7
11/8/2014 Online Upload of Credentials Standardizing Surgical Margins � Being Systematic is Important � Dimensions: Four (4) quadrants + Deep � Mucosal � Medial, lateral, anterior, posterior � Mucosal/superficial margin: 3mm=clear � Deep � May vary by site, tonsil vs. BOT � Intact superior constrictor without tumor on the deep margin is considered “negative” 8
11/8/2014 The Deep Margin of Superior Constrictor in transoral eHNS (TORS/TLM) Mandibular BOT BOT Mandibular MedPtyg MedPtyg T T PPS PPS Maxillary SP SP Maxillary Holsinger & Laccourreye Arch.Otolaryngol.Head.Neck.Surg 2005 Pathology Assessment Neck Dissection � Levels II-IV; 20 nodes minimum per side � Margin: submission and orientation � Defect based (submitted by surgeons) or Resection based (from specimen by pathologist � Neck Dissection Impairment Index � NDII, Taylor et al. OTOHNS 2002 � Final reporting � Intraoperative (frozen) or permanent with the rest of the specimen (post-fixation) ◦ 10-item validated PRO instrument used to specifically measure QOL-related shoulder dysfunction in patients � ECOG Path PI: Joaquin Garcia, MD (Mayo) who have undergone neck dissection � RTOG Path PI: Diana Bell, MD (MDACC) 9
11/8/2014 Stopping Rules and Q/A Functional Outcomes: Swallowing � Severe bleeding rate > 10% (defined as return ◦ To assess swallowing function, the MDADI, and PSS-HN will be administered in both arms ( TRUONG; Tufts ) to OR or "catastrophic" grade 4/5) � Defined endpoints, pre and post treatment � Post-Tx: post-op, 3-6 months, 2yrs � Positive margin rate of 2/10 consecutive cases ◦ To enhance the PRO data, objective correlates include a leads to surgeon "on hold" status with MBS performed at baseline, 6 and 24 months after reactivation after 10 off-study cases with 0-1 treatment and clinician grading (CTCAE, v.4) to compare with MDADI scores. ( LEWIN; MDACC ) positive margin Prospective baseline MBS data to predict Accrual, as of 10/31/2014 swallowing outcomes � ECOG3311: 39 pts. � 1st Pt: Jan 22, Stanford � RTOG1221: 1 pt Videofluoro Imaging � Outreach to VAMCs � International Surgeons (standard): 30 frames/sec 10
11/8/2014 FUTURE INNOVATION Single Port Surgeon Cart Ducati Sp may faciliate true “two-handed surgery” of the head & neck Not available for sale within the United States Davinci Sp Summary G ame-changing Technology for H&N Surgery � NCI-sponsored trials � Transoral eHNS � Conceptual Advance � ECOG3311: HPV+ Deintensification � Two-handed surgery in confined space � RTOG1221: HPV- Intensification � Surgeon control (from console) of H&N surgical anatomy � Standardized Path & Surgery � Technical / Engineering Advances � Credentialing � Bendable, Flexible Instrumentation � Focus on Function, QOL � Angled Endoscopy at point of service (0-45°) � Smaller scale 11
11/8/2014 Thank you bit.ly/HolsingerRobotics 46 12
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