2017 AACE Pre-Meeting Thyroid Symposium:

What’s New in the ATA 2015 Thyroid Cancer Guidelines

Brian W Kim, MDRush University Medical Center

Chicago, IL26th Annual AACE Meeting

Austin, Texas

Dr. Brian W Kim has no industry disclosures.

So many nodules…

INTRO

33 year-old woman in your office…

Should she be worried?

Image from WIKIMEDIA COMMONS

Benign Thyroid Nodules are “Normal”

• By age 60 ~HALF of ALL PEOPLE have at least a small thyroid nodule (ATA)

• Data from adult populations: – 2-6% of people by palpation

– 19-35% of people by ultrasound

Dean & Gharib Best Pract Res Cin Endo Metab 2008

An Epidemic of Non-fatal Thyroid Cancer

As of 2015 thyroid cancer was:

• #5 most common in women [ACS]

• #9 most common cancer overall [NCI / SEER]

• Projected to be #1 most common cancer in women by 2025

• At AUTOPSY: incidental PTCA detected 0.01% USA to 35.6% FINLAND

- Boueck J and colleagues Acta Otorh Ital 2009

• 5-year mortality still <2% in absence of distant mets

An Epidemic of Non-fatal Thyroid Cancer

As of 2015 thyroid cancer is:

• #5 most common in women [ACS]

• #9 most common cancer overall [NCI / SEER]

• Projected as #1 most common cancer in women by 2025

• At AUTOPSY: incidental PTCA detected 0.01% USA to 35.6% FINLAND

- Boueck J and colleagues Acta Otorh Ital 2009

• 5-year mortality still <2% in absence of distant mets

The Clinical Challenge: Risk Stratification

• Millions of people with nodules -- including thousands of un-aggressive cancers -- how can we RISK STRATIFY PROPERLY?

– Catch the bad ones

– Leave the rest alone

PTCA

AUS/FLUS

Benign

PTCA

Newer Data, Newer Guidelines

• Evolving understanding of the natural history of PTCA

• Increasing molecular understanding of PTCA

• Clinical trial data supporting less testing and less surgical / radio-iodine treatment

• FDA approved systemic therapy for advanced disease

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer

• The American Thyroid Association (ATA) Guidelines Taskforce

• 101 Recommendations

• 133 pages

• 1078 references

MODIFIED: ULTRASOUND GUIDED RISK STRATIFICATION OF NODULES

Part I

ATA 2009 & 2015: OK to biopsy fewer nodules

Goiter and FNA Images from Wikipedia

New* Sonographic Risk Groups

2015 Table 6: Risk vs. FNA size threshold

AACE Sonographic Risk Groups

AACE 2016: notes on translation

• 3 risk groups based on US

• FNA at:

– 5 to 10 mm: CONSIDER FNA for high risk group*

– ≥ 10 mm for high risk

– > 20 mm for intermediate risk*

– > 20 mm AND growing / +risk history for low risk

• At face value ATA 2015 suggests FNA of more lower-intermediate nodules; AACE 2016 suggests more small/high risk US FNAs

Poll on FNA:Patient with no hx risk factors, has nodule:-1.9 cm, solid, mildly hypoechoic/isoechoic

•What ATA class is this? Solid = at least “low”- How hypo is hypo?

•What AACE class? Mildly hypo = “intermed.”

•Should you consider (do) FNA?- A. Yes per both AACE 2016 and ATA 2015- B. No per either AACE 2016 or ATA 2015- C. Yes per AACE 2016, Maybe not per ATA 2015- D. Maybe Not per AACE 2016; Yes per ATA 2015

High Risk History: FNA Smaller Nodules

• ATA 2009 Rec 5 / Table 3

– FNA for nodules > 5mm if +high risk history

– e.g. symptoms of malignancy, childhood irradiation, familial thyroid cancer

• ATA 2015 Text for Rec 8

– High risk history justifies consideration of FNA of smaller nodules for any/all sonographic risk groups(no mention of >5mm)

• N.b. 2015 ATA High Risk US with <1cm nodule: defer FNA unless + high risk history

2015 Table 6: Risk vs. FNA size threshold

Poll on Re-FNA:

Patient with no hx risk fx and a nodule:

- 1.6 cm, solid, very hypoechoic, irregular margins, FNA benign 9 months ago

- Repeat ultrasound: STABLE SIZE and still HIGH RISK SONOGRAPHIC APPEARARNCE

- Do you repeat the FNA?

- A. Usually

- B. Sometimes

- C. Not if the nodule is stable on ultrasound

In Surveillance: US Pattern > Growth• Rec 23A

– HIGH SUSPICION US pattern, after BENIGN FNA, repeat the US guided FNA within 12 months

– No requirement for growth for high risk US nodules (growth still applies to low - intermediate risk US pattern nodules)

• US pattern is a better predictor of FALSE NEGATIVE FNAs than growth

– Lack of validation of growth as a risk factor

– Lack of agreement in serial measurements

• AACE 7.2.1 – repeat FNA for High Risk US or suspicious clinical features

US Surveillance: not forever

• ATA 2015 Rec 24A: repeat FNA within 12 months for high suspicion ultrasound (AACE 1016 4.3 agrees)

• ATA 2015 Rec 23D:

– after 2 BENIGN FNAs, further surveillance “is no longer indicated”

– same as AACE 7.2.1

• ATA 2015 Rec 27B:

– growing nodules that are benign after FNA should be regularly monitored

Two Specific Additions since 2009

• 2015 Rec 5:

–PET+ nodule > 1 cm = FNA

–PET diffuse uptake = no FNA

• 2015 Rec 6:

– Ultrasound of nodular thyroid should ROUTINELY include lymph nodes

– (2015 Rec 32: US should be done for LN analysis pre-operatively – also per AACE 7.2.1)

MOLECULAR GENETIC TESTS: THE KNOWN UNKNOWNS

Part 1 Special Mention

Wikipedia Jay Shendure & Hanlee JiNature Biotechnology 26, 1135 - 1145 (2008) Illumina websiteFrom www.nobelprize.org

2014 ATA Draft Text: Ideal Test…

• An ideal ‘rule-in’ test would have a positive predictive value (PPV) for histopathologically-proven malignancy similar to a malignant cytologic diagnosis (98.6%),

• An ideal ‘rule-out’ test would have a negative predictive value (NPV) similar to a benign cytologic diagnosis (96.3%)

• Some commercially available tests claim to reach these parameters, but…

Challenges regarding MGTs• Unknown institutional prevalence/Bethesda

• Small “n” in most studies

– Underpowered for subgroup analysis

• Verification bias

– Patients with negative MGT don’t go to surgery often (at least not right away)

• Long-term outcome studies needed

– ideally from different centers/populations to confirm NPV

• And many other unresolved questions:

Unresolved Issues for all MGTs• Standards for validation studies?

– e.g. blinded path?

• Minimum required test characteristics?

– Should we use MGTs in cases where they reduce risk “some” but not all the way to benign FNA level?

• Post-MGT negative surveillance plan?

• Assumptions for Cost-Benefit analysis?

– First pass or second?

• Hurthle as a special case?

• Definition of pre-test probability?

Example: Thyroseq in a B4• Mrs O, a 50 yo woman; 2 cm nodule, no Hx risk fx

• Cytology B4 FN; but she doesn’t want surgery

– Risk about 1 in 3 for cancer? (at the institution…?)

• Re-FNA B4 + ThyroSeq v2: KRAS Q61R; 182 A> G 80% risk of LOW risk PTCA / (NIFTP)???*

• What if the MGT had been Negative?– What is her residual risk?

After the Guidelines: NIFT-P

Image from Wikipedia

Non-InvasiveFollicularThyroid(neoplasm)(with)Papillary-like(nuclear)(features)

Well DEMARCATED?

What is the molecular signature?

Molecular Genetic Tests: Mother May I?

• 2009 Rec 8: markers “may be considered” for indeterminate cytology, rating C

• ATA 2015 = Permissive Language, not Directive:– R13 -- “If you consider MGTs, talk to patient” “strong rec, low

quality evidence”– R14 -- use a CLIA/CAP certified lab– R15 -- AUS/FLUS, consider all data, may use molecular testing– R16 -- Foll neoplasm, consider all data, may use molecular

testing– R17 – Susp for malig, consider all data, may use molecular

testing; BRAF or mutation panel may be used if this would change surgery

• Long-term outcome data proving clinical utility are needed

TO HALVE, OR HALVE NOT: THE LOBECTOMY ISSUE

Part II

The Past: Who only needs lobectomy?

Images from Wikipedia

2009 Rec 26: thyroid cancer >1cm,

do near-total or total thyroidectomy

• Lobectomy may be sufficient for:

– small (<1 cm), low-risk, unifocal,

intrathyroidal papillary carcinomas

– No prior head and neck irradiation

– No radiologically or clinically involved

cervical nodal metastases.

Recommendation rating: A

Poll:

Would you agree that lobectomy is reasonable for an asymptomatic 60 yo male patient with a 3.9 cm FNA-B6tumor with no other nodules, no clinically involved (imaging or exam) lymph nodes, no FHx of thyroid cancer, and no prior h/o radiation?

A – Yes, “less is more”

B – No, I want the patient to live

A New Paradigm: selective lobectomy

ATA 2015 Rec 35B

•For patients with thyroid cancer >1 cm and <4 cm without extrathyroidal extension, and without clinical evidence of any lymph node metastases (cN0*), the initial surgical procedure can be either a bilateral procedure (near-total or total thyroidectomy) or a unilateral procedure (lobectomy)… continued:

A New Paradigm: 2015 Rec 35B

• …Thyroid lobectomy alone may be sufficient initial treatment for low risk papillary and follicular carcinomas;

• … however, the treatment team may choose total thyroidectomy to enable RAI therapy or to enhance follow-up based upon disease features and/or patient preferences.

• (Strong Recommendation, Moderate-quality evidence)

Still a lot of leeway!

Data for Lobectomy: Pro

Pro lobectomy: survival equivalence

• SEER: Haigh et al (2005); Mendelsohn et al (2010); Barney et al (2011); no advantage [note some lobectomy were high risk]

• Nixon et al 2012 Surgery; MSKCC (policy: do TOTAL if contralateral nodules >0.5 cm), ave 99 mo f/u

– 9 / 382 later found to have cancer in contra lobe

– 14 lobectomy patients had later completion for “development of nodules”;

– 7 were cancer of the same kind, 2 more had cancer of another histology, and 5 were benign

– Note: Nixon survival analysis acknowledges would take a big study to show small therapeutic advantages (underpowered?)

Data Con vs. Adam et al?Advantage for Total Thyroidectomy?

• Loh et al; Mazzaferri/Jhiang: – Both excluded small PTCAs

• Bilimoria et al (National Cancer Database) – No granular evaluation of data; was lobectomy

done because low risk or other reasons?

However:

• Adam et al 2014: revision of SEER accounting for complexity/severity of illness = no survival advantage to total thyroidectomy

– But what about recurrence?

How Much Recurrence is Too Much?

PTCA often multifocal / bilateral

Still…

•Loco-regional recurrence rates of less than 1-4% and completion thyroidectomy rates of less than 10% can be achieved following thyroid lobectomy

The Argument for Rec 35B, Continued

• 2015 Section B7 supporting Rec 35B:

• “In properly selected low to intermediate risk patients…the extent of initial thyroid surgery probably has little impact on disease specific survival …since salvage therapy is quite effectivein the few patients that recur after thyroid lobectomy, a conservative management approach to completion surgery, accepting a slightly higher risk of loco-regional recurrence, is an acceptable management strategy.”

Other practical considerations re: lobectomy

• Will patient/doctor be comfortable knowing surveillance with TG no longer sensitive?

• Is a “mid-normal TSH” optimal if you’ve had low risk PTCA? Or need L-T4 anyway?

• Before diagnostic lobectomy, should we do FNA of contralateral nodules NOT meeting normal criteria? e.g. small but hypoechoic

HISTOPATHOLOGIC RISK STRATIFICATION AND I-131

- THE TIPPING POINTS

Part III

Images from Wikipedia

Who should get I-131?

Conceptually unchanged vs 2009:

•LOW risk for recurrence patients don’t need it

•INTERMEDIATE risk may benefit

•HIGH risk are expected to benefit

•(POORLY differentiated probably won’t benefit)

Previously: 2009 ATA IRS “low risk”

Papillary Thyroid Cancer (with all of the following)

•No local or distant metastases;

•All macroscopic tumor has been resected

•No tumor invasion of locoregional tissues or structures

•The tumor does not have aggressive histology (e.g., tall cell, hobnail variant, columnar cell carcinoma)

•No vascular invasion

2015 ATA low risk proposed changes*

• Papillary Thyroid Cancer (with all of the following)

– Clinical N0 or ≤ 5 pathologic N1 micrometastases (<0.2 cm in largest dimension)*

– Intrathyroidal, encapsulated follicular variant of papillary thyroid cancer* (now called NIFTP)

• Intrathyroidal, well differentiated follicular thyroid cancer with only capsular invasion*

• Intrathyroidal, well differentiated follicular thyroid with minor vascular invasion*

• Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including V600E BRAF mutated (if known)*

BRAF: not quite ready for primetime?

• 2015 Rec 48C: Since BRAF mutational status appears to add little incremental prognostic value to clinico-pathological staging systems, BRAF testing is not routinely recommended for initial post-operative risk stratification in DTC. (Weak recommendation, Moderate-quality evidence)

• +BRAF in microcarcinomas doesn’t seem to increase risk of recurrence (unless +ETE)

• 2015 Fig 4: PTCA > 1cm; BRAF+ ~10% risk; associates with more aggressive features– But table changed from DRAFT to FINAL

• Ongoing trials look at BRAF in otherwise LOW risk PTC…

2015: Intermediate Risk proposed changes• Microscopic invasion of tumor into the

perithyroidal soft tissues*• Clinical N1 or >5 pathologic N1 with all involved

lymph nodes < 3 cm in largest dimension*• RAI avid metastatic foci in the neck on the first

post-treatment whole-body RAI scan • Aggressive histology (e.g., tall cell, hobnail variant,

columnar cell carcinoma) • Papillary thyroid cancer with vascular invasion.• Intrathyroidal, papillary thyroid cancer, primary

tumor 1-4 cm, V600E BRAF mutated (if known)*• Multifocal papillary microcarcinoma with

extrathyroidal extension and V600E BRAF mutated(if known)*

Practical considerations for I-131 Decision

• Note the difference between CLINICAL, RADIOLOGIC and PATHOLOGIC nodal involvement (the latter known only post-op)

• Note “extrathyroidal extension” may be minimal/focal, vs significant?

– Table 14 for I-131: “smaller tumors with microscopic ETE may not require I-131”

– You can sometimes see if tumor is intrathyroidal on pre-op imaging(!)

I-131: Fewer Patients, Less Radiation

• ATA 2015 Table 14 (who gets I-131) looks new but the principles are the same

• The minimal conditions favoring I-131?– EXTRATHYROIDAL EXTENSION, even

microscopic (… but more research needed )(MSKCC does not RAI for minor ETE alone Oral Onc 2013)

–NODAL INVOLVEMENT, extent is arguable

Change: Recommending Lower Activities

ATA 2015 Rec 55

- (Malick et al., Schlumberger et. al – 30mCi vs 100mCi)

•If radioactive iodine remnant ablation is performed after total thyroidectomy for ATA low risk thyroid cancer or intermediate risk disease with lower risk features (i.e. low volume central neck nodal metastases with no other known gross residual disease nor any other adverse features), a low administered dose activity of approximately of 30 mCi is generally favoredover higher administered dose activities. (Strong recommendation, High-quality evidence)

Fewer Iodine Scans

• 2015 Rec 66: After the first post-treatment WBS performed following RAI remnant ablation or adjuvant therapy, low-risk and intermediate-risk patients (lower risk features) with an undetectable Tg on thyroid hormone with negative antithyroglobulin antibodies and a negative US (excellent response to therapy) do not require routine diagnostic WBS during follow-up. (Strong recommendation, Moderate-quality evidence)

Grey areas in I-131 Recs

When would “aggressive histology”matter? •What if microcarcinoma but tall cell?

– Table 14: NO I-131 for MICROCARCINOMA. – No benefit of disease specific survival OR disease-

free survival… but…

•Table 14: if tumor >1cm, histology matters;– I-131 not routinely recommended, but may be

increased disease-free survival; consider for aggressive histology or lymphovascular invasion

– i.e.“aggressive histology” can qualify patient as ATA intermediate risk (and thus possibly a candidate for I-131)

NEW DEVELOPMENTS- TKIS, REDIFFERENTIATION?

Part IV

TKIs

When to start? What to watch for?

Table 16: TKI Guidance

The Future Is … Soon?

Images from Wikipedia (left), Thyroid Cancer Genome Atlas Consortium, Cell 2014 (right)

Using Genetic Info for I-131 Planning?

2015 Rec 52 (New)

• The role of molecular testing in guiding postoperative RAI has yet to be established; therefore, no molecular testing to guide postoperative RAI use can be recommended at this time.

(NO recommendation, INSUFFICIENT evidence)

Selumitinib (Ho et. al. NEJM 2013)

I-124 PET-CT allows for QUANTITATIVE measurement of iodine uptake / area, i.e. “lesional dosimetry”

Thank You !!!