Minimalistic Initial Therapy Options For Low Risk Papillary Thyroid Cancer

Minimalistic Initial Therapy Options For Low Risk Papillary Thyroid Cancer An emphasis on proper patient selection R Michael Tuttle, MD Clinical Director, Endocrinology Service Memorial Sloan Kettering Cancer Center Professor of Medicine Weill Medical College of Cornell University

Minimalistic Treatment Options Active Surveillance (0bservation) Thyroid Lobectomy Not for every low risk thyroid cancer Not for every patient Not for every clinician

Observational Management Approach to Papillary Microcarcinoma 2,153 Low Risk Papillary Microcarcinoma Patients Dr Akira Miyauchi Kuma Clinic Japan Active Surveillance 1,179 (55%) Immediate Surgery 974 (45%) Median Follow-up 4 yrs (range 1-10 yrs) Continued Observation 1,085 (92%) Surgery, Stable Disease 61 (5.2%) Increase Size Primary Tumor 27 (2.3%) Novel LN Metastasis 6 (0.5%) Salvage therapy is very effective Oda et al, Thyroid 2016; 26(1): 150-155 Ito et al. World J Surg. 2010;34(1):28-35. Sugitani et al. World J Surg. 2010;34(6):1222-1231. Ito et al. Thyroid. 2013.

Active Surveillance of Low Risk Papillary Thyroid Cancer 291 MSKCC patients < 1.5 cm PTC/Suspicious PTC Median 2 yr follow up, Median age 51 yrs (20-86) Diameter increase of 3mm Volume increase of 50% Cumulative incidence 2.5% Cumulative incidence 12.1% 11.5% 24.8% Time (months) Time (months) Time 0 12 24 36 48 60 n 291 243 145 78 39 18 Time 0 12 24 36 48 60 n 291 236 138 71 34 15 Tuttle et al, JAMA Otolaryngology Head & Neck Surgery, 2017

192 PMC Patients Followed for 1 year (Median 2.5 yrs) Decrease volume Stable Volume Increase 3mm & Increase volume Increase volume without 3 mm increase Novel LN metastasis (33/192) (132/192) (4/192) (27/192) (1/192) 17% 69% 2% 14% 0.5% Asan Medical Center, Seoul, Korea JCEM June 2017

Active Surveillance of Low Risk PTC Outcomes are similar Japan, USA and Korea 10-15% increase volume over several years Young patients more likely to increase volume 1-2% have LN mets identified Salvage therapy very effective

Implementing Active Surveillance in the US Requires concurrent evaluation of three inter-related domains Tumor/US Inappropriate Ideal Medical Team Patient Appropriate A clinical framework to facilitate risk stratification when considering an active surveillance alternative to immediate biopsy and surgery in papillary microcarcinoma. JP Brito, Y Ito, A Miyauchi, RM Tuttle. Thyroid 2015

Proper Patient Selection Tumor/US Intrathyroidal PTC Bethesda VI Bethesda V with highly suspicious US (Highly suspicious US without FNA) Cytology interpretation and US examination at MSKCC Primary tumor up to 1.5 cm Acceptable Features Background thyroid abnormalities (Hashimoto s, MNG) BRAF V600E mutation (genetic testing not required) Without Documented increase in size LN metastases Extrathyroidal extension Subcapsular location adjacent to trachea/rln JP Brito, Y Ito, A Miyauchi, RM Tuttle. Thyroid 2015

Relationship of Nodule to Thyroid Capsule Ideal: normal thyroid tissue surrounding the PMC

Relationship of Nodule to Thyroid Capsule Inappropriate 67 yr old female, right anterior superior pole, 8x7x9mm, definite anterior extrathyroidal extension, confirmed by histology (7mm TCV PTC, minor ETE)

Course of the Recurrent Laryngeal Nerves Relative to the Intact Thyroid Gland Surgery of the Thyroid And Parathyroid Glands, Randolph G, editor

Biopsy Proven PTC In Worrisome Location Posterior Right Lobe Nodule (6x8x6mm)

Biopsy Proven PTC In Worrisome Location Left Mid Pole Nodule (13x10x11mm) Ara Chalian, U Penn: 3-4 mm section of RLN involved

Implementing Active Surveillance in the US Requires concurrent evaluation of three inter-related domains Tumor/US Multidisciplinary Management Team Shared Treatment Philosophy Quality Ultrasonography Prospective Data Collection Tracking System Medical Team Patient Motivated Compliant Supportive Family/Clinicians Differences in Patient Decision Making JP Brito, Y Ito, A Miyauchi, RM Tuttle. Thyroid 2015

How do patients perceive initial treatment options? SURGERY ACTIVE SURVEILLANCE Slide from Elizabeth Grubbs, MD Anderson BOTH D Agostino et al. Psychooncology, 27:61-68, 2018.

How do patients perceive initial treatment options? SURGERY ACTIVE SURVEILLANCE Sense of urgency Perception as potentially life threatening disease Fear of disease progression & uncertainty with active surveillance Surgery as a means of control and potential cure Slide from Elizabeth Grubbs, MD Anderson BOTH D Agostino et al. Psychooncology, 27:61-68, 2018.

How do patients perceive initial treatment options? SURGERY ACTIVE SURVEILLANCE Sense of urgency Perception as potentially life threatening disease Fear of disease progression & uncertainty with active surveillance Surgery as a means of control and potential cure View as a common, indolent, low risk disease Concerns about adjusting to life without a thyroid/ reliance on hormone replacement Openness to reconsidering surgery over the long run Slide from Elizabeth Grubbs, MD Anderson BOTH D Agostino et al. Psychooncology, 27:61-68, 2018.

How do patients perceive initial treatment options? SURGERY ACTIVE SURVEILLANCE Sense of urgency Perception as potentially life threatening disease Fear of disease progression & uncertainty with active surveillance Surgery as a means of control and potential cure Deep level of trust & confidence in physician & cancer center Use of physician & internet as 1 sources treatment related info View as a common, indolent, low risk disease Concerns about adjusting to life without a thyroid/ reliance on hormone replacement Openness to reconsidering surgery over the long run Slide from Elizabeth Grubbs, MD Anderson BOTH

Weighing the Risks and Benefits of Treatment Medical Decision Making Maximalists or Minimalists Believers Or Doubters Technology Orientation Or Naturalistic Orientation

Weighing the Risks and Benefits of Treatment Medical Decision Making Maximalists Cancer Blood pressure Cholesterol Glucose BMI Availability Bias Minimalists Cancer Blood pressure Cholesterol Glucose BMI be ahead of the curve why wait more is better Believers Technology Orientation less is more unintended consequences outweigh potential benefits Doubters Naturalistic Orientation Development of the Medical Maximizer-Minimizer Scale. Scherer et al, Health Psychology, 2016

Implementing Active Surveillance in the US Applicable to primary tumor, LN mets, and distant metastases Tumor/US Ideal Tumor Volume Follow-up Strategy Patient Appropriate Rate of Change (Doubling Time) Intervention Indications Medical Team Inappropriate Tumor Location Proper Selection Active Surveillance Management Decisions

Observational Management Strategy Serial US evaluations of the thyroid and neck Q 6 months for 2 years Then less frequently TSH suppression is not recommended Goal TSH 0.5-3 miu/l Thyroid function tests Yearly Indications for surgical intervention Increase in tumor volume (doubling time) Identification of metastatic disease Development of extrathyroidal extension Other worrisome ultrasonographic changes Patient preference JP Brito, Y Ito, A Miyauchi, RM Tuttle. Thyroid 2015

Selecting Patients for Lobectomy Intra-operative Findings Post-operative Path Report Tumor/US Medical Team Ideal Inappropriate Patient Appropriate R. Michael Tuttle, Ling Zhang and Ashok Shaha, Expert Review of Endo & Metab, 2018.

Selecting Patients for Lobectomy Intra-operative Findings Post-operative Path Report Tumor/US Medical Team Immediate Completion 6-20% Delayed Completion 5-10% Ideal Inappropriate Patient Effective Salvage Therapy Appropriate Nixon Surgery 2012, Vaisman Clinical Endo (Oxf) 2011, Vaisman J Thyroid Res 2013, Kluijfhout Surgery 2017, Calcatera Endo Practice 2017

A Clinical Framework for Decision Making with Regard to Extent of Initial Surgery Pre-operative/Intra-operative Decision Making Tumor/Imaging characteristics Ideal Solitary nodule Intrathyroidal 1 cm Clinical N0 neck Patient characteristics Minimalist mentality Motivated patient Willingness to accept possibility of small volume disease in contralateral lobe Desire to preserve thyroid function Desire to minimize surgical complications Open to intra-operative decision making Medical Team Experienced MDT Experienced US Shared treatment philosophy Uses RAI very selectively for ablation/adjuvant therapy and follow up Frozen section available R. Michael Tuttle, Ling Zhang and Ashok Shaha, Expert Review of Endo & Metab, 2018.

A Clinical Framework for Decision Making with Regard to Extent of Initial Surgery Pre-operative/Intra-operative Decision Making Tumor/Imaging characteristics Appropriate 1-4 cm Benign appearing changes on US (Hashimoto s, benign nodules) Benign appearing LN s Clinical N0 Patient characteristics Minimalist/Maximalist Desire to keep normal thyroid (or avoidance of surgical complications) outweighs concern for disease in the contralateral lobe or the desire for RAI Medical Team Surgeon and endocrinologist agree on post-op management plan Unlikely to include need for RAI Comfortable that follow-up US is adequate for low risk patient R. Michael Tuttle, Ling Zhang and Ashok Shaha, Expert Review of Endo & Metab, 2018.

A Clinical Framework for Decision Making with Regard to Extent of Initial Surgery Pre-operative/Intra-operative Decision Making Tumor/Imaging characteristics Inappropriate >4 cm Extrathyroidal extension Metastatic cervical LN s Distant metastases Multifocal, macroscopic PTC High risk molecular profile Patient characteristics Maximalist mentality Patient desires total thyroidectomy and/or RAI Indications for RAI ablation/adjuvant therapy/staging Medical Team Treatment team desires RAI for scanning/therapy or optimized serum Tg for staging and follow-up R. Michael Tuttle, Ling Zhang and Ashok Shaha, Expert Review of Endo & Metab, 2018.

Post-operative Decision Making Features Ideal Intrathyroidal classical PTC FV-PTC without vascular invasion NIFT-P Minimally invasive FTC (capsular invasion only) Pathology N0/Nx Non-stimulated Tg < 5 ng/ml Appropriate Minor extrathyroidal extension Clinical N0 but pn1 LN mets Multifocality Lymphovascular invasion Minor vascular invasion 1-2 cm potentially aggressive tumors (tall cell, hobnail, columnar cell) Non-stimulated Tg 5-30 ng/ml Inappropriate Extensive vascular invasion (FTC or HCC) Gross extrathyroidal extension Clinical N1 histologically confirmed LN mets Non-stimulated Tg > 30 ng/ml R. Michael Tuttle, Ling Zhang and Ashok Shaha, Expert Review of Endo & Metab, 2018.

Proper Patient Selection for Lobectomy Ongoing dynamic risk stratification Tumor/US Patient Ideal Appropriate Intra-Op Findings Ideal Appropriate Medical Team Inappropriate Post-Op Findings Inappropriate Pre-Op Evaluation Pre-Op Classification Additional Information Post-Op Classification R. Michael Tuttle, Ling Zhang and Ashok Shaha, Expert Review of Endo & Metab, 2018.

A Practical Approach to Follow-up After Lobectomy Excellent disease specific survival Highly sensitive disease detection techniques are not necessary Tumor/Imaging characteristics TSH goal 0.5-2.5 miu/ml With or without levothyroxine Clinic visits Post-op (to review path, check TSH, Tg) Then 6-12 month follow-up Yearly for 2-3 years with exam TSH, Free T4, Tg, TgAb with each clinic visit Imaging Neck US 6-12 months, 3 yrs, and 5 yrs Then very rarely Late completion thyroidectomy Physical exam findings Neck US findings Need for RAI Sustained, serial rise in Tg over time

Minimalistic Treatment Options Active Surveillance (0bservation) Thyroid Lobectomy Not for every low risk thyroid cancer Not for every patient Not for every clinician