3/27/2019 Memorial Sloan Kettering Cancer Center New York...10 yrs 5% 8% 95% 92% - - 2% 4% Japan 415 ≤ 1 cm 6.5 yrs 6% 91% 3% 1% Japan 61 1-2 cm 7 yrs 7% 93% - 3% Japan 360 ≤ 1

R Michael Tuttle, MD Memorial Sloan Kettering Cancer Center New York

3/27/2019

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Is immediate surgery always necessary for low risk differentiated thyroid cancer?

R Michael Tuttle, MD

Clinical Director, Endocrinology Service

Memorial Sloan Kettering Cancer Center

Professor of Medicine

Weill Medical College of Cornell University

Disclosures

No relevant conflicts of interest

When to operate, when to watch

Active Surveillance for Low Risk Papillary Thyroid Cancer

Minimalist Surgical Options for Low Risk Papillary Thyroid Cancer

Emphasis on Proper Patient Selection, Shared Decision Making, and Development of a Unified Management Philosophy

Overview Management Philosophies in Low Risk

Thyroid Cancer

Typical Case

82 year old man Avoided health care for more than 50 years Wife insisted on a carotid US for screening

Incidental thyroid nodule detected

Thyroid US confirms a single 5 mm thyroid nodule FNA confirms papillary thyroid cancer

What now?

Surgery Vs

Observation

Typical Case

65 year old man Diabetes, HTN, A fib

Metastatic colon cancer to lung, liver and bone


What now?

Surgery Vs

Observation


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Typical Case

25 year old female Getting married in 3 months

Does not want a scar on her neck before the wedding


What now?

Surgery Vs

Observation

After wedding wants to wait another 3 months to go on her honeymoon

After honeymoon, wants to wait another 3 months because of new job

Framing the Issue

• Active surveillance (deferred intervention) – Active observation approach

– Patients with known or highly suspected disease

– Therapeutic delay (deferred intervention) has no clinically significant impact

– Therapy, when indicated, still effective

– Not palliative care/watchful waiting (non-curative)

– Classic example

• Small volume prostate cancer

• Urethral cancer

• Some lymphomas

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.

Observational Management Approach to Papillary Microcarcinoma

Dr Akira Miyauchi

Kuma Clinic

Japan

2,153 Low Risk Papillary Microcarcinoma Patients

Active Surveillance 1,179 (55%)

Immediate Surgery 974 (45%)

Continued Observation 1,085 (92%)

Surgery, Stable Disease

61 (5.2%)

Increase Size Primary Tumor

27 (2.3%)

Novel LN Metastasis 6 (0.5%)

Median Follow-up 4 yrs (range 1-10 yrs)

Salvage therapy is very effective

A cytology diagnostic for a primary thyroid malignancy will almost always lead to thyroid surgery. However, an active surveillance management approach can be considered as an alternative to immediate surgery in:

(a) patients with very low risk tumors (e.g. papillary

microcarcinomas without clinically evident metastases or local invasion, and no convincing cytologic evidence of aggressive disease),

(b) patients at high surgical risk because of co-morbid conditions, (c) patients expected to have a relatively short life span (e.g.

serious cardiopulmonary disease, other malignancies, very advanced age), or

(d) patients with concurrent medical or surgical issues that need to be addressed prior to thyroid surgery.

2015 ATA Guidelines

Haugen, Thyroid 2016


n Tumor

size

Follow-

Up

Increase

≥ 3 mm

Stable

± 3 mm

Decrease

≥ 3 mm

LN

Mets

USA 291 ≤ 1.5 cm 2 yrs 4% 92% 4% 0%

Korea 192 ≤ 1 cm 2.5 yrs 2% 95% 3% 0.5%

Korea 370 ≤ 1 cm 2.7 yrs 4% 96% - 1%

Japan 1,23

5

≤ 1 cm 5 yrs

10 yrs

5%

8%

95%

92%

-

-

2%

4%

Japan 415 ≤ 1 cm 6.5 yrs 6% 91% 3% 1%

Japan 61 1-2 cm 7 yrs 7% 93% - 3%

Japan 360 ≤ 1 cm 7 yrs 8% 92% - 1%

Columbia 57 ≤ 1.5 cm 1 yr 4% 96% - 0%

Tumor Progression During Active Surveillance

Ito, Thyroid 2014, Sugitani JCEM 2014, Kwon JCEM 2017, Sanabria JAMA

Oto 2018, Oh Thyroid 2018, Tuttle JAMA Oto 2017, Sakai Thyroid 2019

Tumor Volume: π/6 (length x width x height)

Thyroid cancers are three dimensional structures Usually ellipsoid (not spherical)

40 yr old male, PMC 1.03 x 0.64 x 0.93 cm

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwijncOao_7OAhXDqh4KHYOvCZMQjRwIBw&url=http://www.onclive.com/web-exclusives/low-risk-thyroid-microcarcinoma-suffice-with-active-surveillance&psig=AFQjCNFZLqtoHr1QS_NH3Vg0hnBfkgCjqg&ust=1473372683004410


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Tuttle et al, JAMA Otolaryngology–Head & Neck Surgery, 2017

-200

-100

0

100

200

300

400

Percent Change in Tumor Volume

(n=291)

Individual Patients

Perc

en

t C

ha

ng

e i

n T

um

or

Volu

me

Decreased > 50%

(n=19)

7%

Increased > 50%

(n=36)

12%

Stable (± 50%)

(n=228)

79%

50

Reproducible Measurement Differences Diameter ± 3 mm Volume ± 50%

≥ 3 mm ≥ 100%


n Tumor

size

Median

Follow-

Up

Tumor

Volume

Increase

≥ 50%

Tumor

Volume

Stable

± 50%

Tumor

Volume

Decrease

≥ 50%

USA 291 ≤ 1.5 cm 2 yrs 12% 79% 7%

Korea 192 ≤ 1 cm 2.5 yrs 14% 69% 17%

Korea 370 ≤ 1 cm 2.7 yrs 23% 77% -

Japan* 169 ≤ 1 cm 10 yrs 25% 57% 17%

Japan 61 1-2 cm 7 yrs 11% 89% -

Japan 360 ≤ 1 cm 7 yrs 21% 79% -

Tumor Progression During Active Surveillance

Kwon JCEM 2017, Tuttle JAMA Otolaryngology 2017,

Oh Thyroid 2018, Sakai Thyroid 2019

*Miyauchi, Surgery 2018 (tumor volume doubling rate/year)

Active Surveillance of Low Risk Papillary Thyroid Cancer

Demonstrate remarkably consistent classic exponential growth curves


Months

Lo

g V

olu

me

r = 0.99

DT: not applicable

15 to 13 mm, 1.0 to 0.9 mL

Months

Lo

g V

olu

me

r= 0.85

DT: 4 yrs

10 to 13 mm, 0.3 to 0.5 mL

Months

Log V

olu

me

r = 0.95

DT: 2.7 yrs

6 to 9 mm, 0.05 to 0.1 mL

40 yr old female Papillary Microcarcinoma

4 yrs of active surveillance

Kuma Hospital [http://www.kuma-h.or.jp/index.php?id=293]


Date Volume (ml) 12/7/2011 0.25 6/25/2012 0.37 2/4/2013 0.33 12/27/2013 0.41 10/20/2014 0.51 11/18/2015 0.46

Tumor Volume of an Ellipse: π/6 (length x width x height)

42 yr old female Papillary Microcarcinoma

5 yrs of active surveillance

Kuma Hospital

http://www.kuma-h.or.jp/index.php?id=293

r = 0.85

100% (3 mm)


50% (1-2 mm)

Indications for Transition from Active Surveillance to Surgical Intervention

• Increase in size of primary tumor*

• ≥ 3mm increase in tumor diameter and/or

• ≥ 100% increase in tumor volume

• Identification of metastatic disease

• Direct invasion into surrounding structures

• Patient preference

• Surgical intervention can be considered with a confirmed 50% increase in tumor volume based on factors such as (i) proximity of the tumor to the thyroid capsule, (ii) patient preference, or (iii) primary tumor size > 1 cm. • Conversely, even with documented increase in the size of the primary tumor by diameter or volume, surgery may be deferred in patients without other indications for intervention if they have (i) a maximum tumor diameter of < 15 mm , and/or (ii) a tumor volume doubling time > 2 years.

Tuttle/Miyauchi 2019, in Surgery of the Thyroid and Parathyroid glands, 3rd Edition, Greg Randolph, ed


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Key Factors in Clinical Decision Making

Active Surveillance of Known or Suspected Thyroid Cancer

Tumor Size (Tumor Volume)

Doubling Time (Rate of Change)

Location Patient

Preference

Tumor/US Characteristics

Patient Characteristics

Medical Team Characteristics

Implementing Active Surveillance in the US

Requires concurrent evaluation of three inter-related domains

Appropriate

Ideal

Inappropriate

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

JP Brito, Y Ito, A Miyauchi, RM Tuttle. Thyroid 2015

• Intrathyroidal PTC • Bethesda VI • Bethesda V with highly suspicious US • US highly suspicious subcentimeter US without FNA • BRAF V600E mutated Bethesda III/IV/V/VI

• 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

Relationship of Nodule to Thyroid Capsule

Ideal: normal thyroid tissue surrounding the PMC


Inappropriate

67 yr old female, right anterior superior pole, 8x7x9mm, definite anterior extrathyroidal extension, confirmed by

histology (7mm TCV PTC, minor ETE)


Appropriate

Nodule Abuts the Thyroid Capsule But Not Invasive

Posterior Capsule

Anterior Capsule


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Isthmus Nodules Rarely Appropriate

Usually Touch the Anterior and Posterior Thyroid Capsule

Nodule: 0.5 x 0.6 cm Isthmus: 0.3 cm wide

Nodule: 0.4 x 0.3 cm Isthmus: 0.5 cm wide

American College of Surgeons Operative standards for Cancer Surgery Thyroid Cancer, 2018

Course of the Recurrent Laryngeal Nerves Relative to the Intact Thyroid Gland

Anterior view of thyroid with isthmus divided



Left Lower Medial Pole Nodule (13x10x11mm)



Posterior Right Lobe Nodule (6x8x6mm)



Posterior Right Lobe Nodule (7x6x7mm)



Anterior view of thyroid with isthmus divided


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Multidisciplinary Management Team Shared Treatment Philosophy

Quality Ultrasonography Prospective Data Collection

Tracking System

Motivated Compliant

Supportive Family/Clinicians Differences in Patient Decision Making

BOTH

How do patients perceive initial treatment options?

D’Agostino et al. Psychooncology, 27:61-68, 2018. Slide from Elizabeth Grubbs, MD Anderson

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

BOTH D’Agostino et al. Psychooncology, 27:61-68, 2018.


Slide from Elizabeth Grubbs, MD Anderson


Sense of urgency




& uncertainty with

active surveillance



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

BOTH D’Agostino et al. Psychooncology, 27:61-68, 2018.




Sense of urgency




& uncertainty with

active surveillance



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

Deep level of trust

& confidence in

physician &

cancer center

Use of physician

& internet

as 1° sources

treatment‐related

info


BOTH



Weighing the Risks and Benefits of Treatment

Medical Decision Making

Maximalists or

Minimalists


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Weighing the Risks and Benefits of Treatment


Maximalists

“be ahead of the curve” “why wait”

“more is better”

Minimalists

“less is more” “unintended consequences

outweigh potential benefits”

Development of the Medical Maximizer-Minimizer Scale. Scherer et al, Health Psychology, 2016

Cancer

Blood pressure Cholesterol

Glucose BMI

Availability Bias is the tendency to let an example that comes easily to mind affect decision-making or reasoning. This can occur when a story you can readily recall plays

too big a role in how you reach your conclusion.

Availability Bias


• My sister had thyroid surgery and gained 100 lbs • Dr Google says that thyroid hormone pills are ineffective • My thyroid support group says the sooner thyroidectomy is

done the better the outcome will be

• I had a patient with small thyroid cancer that had a brain metastasis (or lung metastasis/bone metastasis)

• Last month, one of my patients had bilateral vocal cord paralysis as a result of thyroidectomy for a 5 mm PTC







Multidisciplinary Management Team Shared Treatment Philosophy

Quality Ultrasonography Prospective Data Collection

Tracking System

Motivated Compliant

Supportive Family/Clinicians Differences in Patient Decision Making

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 size of primary tumor*

• ≥ 3mm increase in tumor diameter and/or

• ≥ 100% increase in tumor volume

• Identification of metastatic disease

• Direct invasion into surrounding structures

• Patient preference

Typical Case

36 year old female Incidental finding of asymptomatic thyroid nodule

Normal thyroid function

Thyroid US confirms a single 2.0 cm thyroid nodule Contralateral lobe is normal, no abnormal lymph nodes

FNA confirms papillary thyroid cancer

What now?

Total Thyroidectomy Vs

Thyroid Lobectomy

Wants to avoid thyroid hormone replacement

Selecting Patients for Lobectomy

Appropriate

Ideal

Inappropriate




Intra-operative Findings

Post-operative Path Report

R. Michael Tuttle, Ling Zhang and Ashok Shaha, Expert Review of Endo & Metab, 2018.


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Selecting Patients for Lobectomy

Appropriate

Ideal

Inappropriate




Intra-operative Findings

Post-operative Path Report

Nixon Surgery 2012, Vaisman Clinical Endo (Oxf) 2011, Vaisman J Thyroid Res 2013, Kluijfhout Surgery 2017, Calcatera Endo Practice 2017

Immediate Completion 6-20%

Delayed Completion

5-10%

Effective Salvage Therapy

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 < 30 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.

A Practical Approach to Follow-up After Lobectomy

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

Excellent disease specific survival Highly sensitive disease detection techniques are not necessary

Risk Stratification in Thyroid Cancer

Thyroid Surgery

Adjuvant Therapy

Follow up Suspicious Nodule

Diagnosis

A dynamic, iterative, active process

AJCC 8th Edition Risk of death

Stage I, II, III, or IV

ATA Risk Recurrent/Persistent Disease Low, Intermediate, or High

Tuttle, Alzahrani, Mini-review, JCEM expected in early 2019

Ideal

Appropriate Inappropriate

Peri-Diagnostic Risk Assessment Candidates for Minimalistic Management

Indeterminate

Excellent

Biochemical Incomplete

Structural Incomplete

Response to Therapy Management recommendations

Documents

3/27/2019 Memorial Sloan Kettering Cancer Center New York...10 yrs 5% 8% 95% 92% - - 2% 4% Japan 415 ≤ 1 cm 6.5 yrs 6% 91% 3% 1% Japan 61 1-2 cm 7 yrs 7% 93% - 3% Japan 360 ≤ 1