Disclosure Comprehensive Management of Thyroid Cancer

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

4/24/20211

4/24/2021

Jonathan George, MD, MPHAssociate ProfessorHead & Neck Surgical OncologyUCSF Medical Center

Comprehensive Management of Thyroid Cancer

Disclosure

Nothing to disclose


Objective

• To inform & update radiation oncology and other advanced health

care providers on management options for advanced thyroid cancer


OverviewManagement of Thyroid Cancer

Anatomy & Epidemiology

Clinical Evaluation, Imaging & FNA

Treatment

• Advanced Thyroid Cancer

Surgery

Radioiodine Ablation

External Beam RT

Systemic Therapy



4/24/20212

Thyroid Anatomy

– 10-20 g butterfly-shaped gland

• 2 lobes + isthmus

• Pyramidal lobe above isthmus (50%)

– Fibrous capsule

– Anterior to 2nd and 3rd tracheal rings


• Important nearby structures

– Trachea

– Recurrent laryngeal nerve

– Vessels (carotid, jugular)

– Esophagus

– Parathyroid glands

• Lymph node drainage

– Level VI (central compartment)

– Level II-IV (anterior deep cervical)

– Level V (posterior cervical)

– Superior mediastinum

Thyroid Anatomy


Thyroid Cancer Groupings

Histological Subtypes

• Differentiated

‒ Papillary

‒ Follicular

‒ Hürthle cell

• Poorly differentiated

‒ Insular, Columnar, etc

‒ Medullary

• Undifferentiated

‒ Anaplastic


• A ‘benign’ malignancy

• Seldom recurs

• Recurrences easily managed with

surgery or I-131

• Minimal survival impact

Misperceptions of Thyroid Cancer



4/24/20213

Papillary thyroid cancer (PTC) ‒Excellent prognosis ~ 95% 10y DSS

‒~5% have distant metastasis at diagnosis

• Poor prognosis variants

Tall Cell

Diffuse sclerosing

Columnar cell

‒Associated with early invasion, large tumor size, distant metastsis

Differentiated Thyroid Cancer


6

• Follicular thyroid cancer (FTC) • Risk of metastasis at diagnosis: 2-5%– 10-year DSS: 85%

– Hürthle cell carcinoma (3%)• Less favorable prognosis

• Large size, invasive, early nodal and distant metastasis

• 10 yr DSS ~75%



7

Ahn HS et al. Korea’s Thyroid Cancer “Epidemic” –Screening and Overdiagnosis. NEJM 371(19), Nov 6 2014.

Increasing incidence, mortality unchanged…

DTC Epidemiology


Increased incidence likely due to early capture & treatment

DTC Epidemiology



4/24/20214

DTC Epidemiology

Grogan RH, et al. AAES 34th Annual Meeting, 2013.

Excellent survival but recurrence remains a problem

• Recurrence higher mortality

Grogan et al, 2013: 30 year FU(N=2883):

• Recurrence ~30%

Thyroid Cancer


Locally recurrent disease is bad…

• Mortality: 11-17%

• 36-80% of deaths secondary to

uncontrolled local disease

Thyroid Cancer


Djalilian et al, 1974


Poorer Outcomes

\

Bilimoria KY et al. Annals of Surgery 246(3), 375-384; 2007

Larger Tumors


Multifocal disease

• ~20-60% of DTC• 2x increased risk of nodal mets, 3x distant mets

Poorer Outcomes

Tsang 1998; Kebebew 2005


4/24/20215

Extrathyroidal Extension

•36% local recurrence rate •18% death from disease

Samaan et al Head Neck 1994

Sites of Invasion• Strap muscle 53%• RLN 47%• Trachea 37%• Esophagus 21%• Larynx 12%• Other sites 30%

McCaffery et al Head and Neck 1994, N=264, 1940-1999

Poorer Outcomes


Nodal Metastasis Higher recurrence

Clinical N+ ~22% recurrence

vs 4-6% for clinical N0

Worse Survival

Cranshaw, Surg Oncol 2008; Bardet, Eur J Endo 2008; So, Surgery 2010; Wada, Ann Surg 2003.

20-year Survival (DSS)

Age N0 N1

<45 yrs 94% 100%

>45 yrs 90% 79%p = 0.04

Poorer Outcomes


BRAF V600E Oncogene (PTC)• Most common genetic alteration in PTC Present in ~20-80%

of PTC

• May indicate more aggressive phenotype

• Associated with ETE, LN metastasis, and advanced stage

• Worse outcomes in several retrospective studies

Prognostic Factors


BRAF V600E Oncogene (PTC)• Worse outcomes in several retrospective studies

‒ Xing et al. JAMA 2013 (N=1849)

Overall mortality higher in patients with BRAF mutation (5.3% vs. 1.1%)

• But not significant after accounting for other pathologic features

• Unclear if this is truly an independent risk factor

• BRAF inhibition: Vemurafenib, dabrafenib

Prognostic Factors



4/24/20216

Clinical Evaluation

Most thyroid nodules detected by either palpation or imaging (incidental)

• History

• Compressive symptoms, dysphagia, dyspnea, voice

changes/hoarseness

• Symptoms of hypo- or hyperthyroidism

• History of ionizing radiation

• Family history of thyroid cancer


Clinical EvaluationVoice Assessment

• Preop voice assessment is officially recommended

■ All patients undergoing thyroid surgery should have preoperative voice assessment

■ Voice is part of the physical exam for thyroid cancer

■ Preoperative laryngeal exam should be performed in all patients with:

‐ Preoperative voice abnormalities

‐ Known thyroid cancer with posterior ETE or extensive CNM

‐ History of cervical or upper chest surgery

‐ Postop voice & laryngeal assessment

■ Patients should have their voice assessed in the postoperative period.

■ Formal laryngeal exam should be performed if the voice is abnormal.


• In-clinic Nasolaryngoscopy

Clinical EvaluationVoice Assessment

Initial Imaging: Diagnostic US

‐ Recommendation 6: Thyroid US

■ Thyroid/neck US for all patients with known or suspected thyroid nodules

‐ Sonographic pattern & size guide need for FNA


Diagnostic ImagingUltrasound


4/24/20217


Published in Thyroid. January 2016, 26(1): 1-133.DOI: 10.1089/thy.2015.0020

© Mary Ann Liebert, Inc.FIG. 2. ATA nodule sonographic patterns and risk of malignancy.



Published in Thyroid. January 2016, 26(1): 1-133.DOI: 10.1089/thy.2015.0020

© Mary Ann Liebert, Inc.

FIG. 1. Algorithm for evaluation and management of patients with thyroid nodules based on US pattern and FNA cytology. R, recommendation in text.



Pattern of nodule sonographic features confers risk of malignancy which, when combined with nodule size, guides decision-making

FNA cutoffs modified if…

• Presence of suspicious LNs

• Patient risk factors

Diagnostic BiopsyFine Needle Aspiration Cross-sectional Imaging

• CT or MRI

‒ if concerning US or physical exam

Bulky thyroid mass

Lymph node metastasis

Recurrent disease

Vocal cord paralysis

Dysphagia

Fixation of mass

Substernal extension

Diagnostic Imaging

US + CT have improved sensitivity and comparable specificity for nodal disease in thyroid cancer patients than either exam alone.

Kim E. Thyroid 2008.



4/24/20218

• PET/CT

‒No role in initial diagnosis of DTC

Inverse relationship between FDG avidity and differentiation, iodine uptake

Poorly or De-Differentiated >FDG uptake

‒Indications:

Negative whole body I131 scans, Rising TG

‒Survival Correlation if high-volume FDG-avid disease

Diagnostic ImagingCross-sectional Imaging


Surgery

Endocrinology

Radiology• Neuroradiology & Nuclear Medicine

Pathology

Radiation Oncology

Medical Oncology

Multidisciplinary ManagementThyroid Cancer Conference

Surgery: Gross total resection

Post-operative RAI

TSH Suppression

EBRT in select cases

Systemic therapy for high-risk DM pts

Long-term surveillance with US & TG

Management Goals “Thyroid surgery is horrid butchery; no honest and sensible surgeon would ever engage in thyroid surgery”

Samuel D. Gross – 1866


4/24/20219

Theodore Kocher

(1841-1917)

First surgeon to win Nobel prize (1909)

“The extirpation of the thyroid gland typifies perhaps better than any operation the supreme triumph of the surgeon’s art.”

- William Halsted

‐ Remove primary tumor, disease extending beyond thyroid capsule, clinically evident lymph node metastases

‐ Minimize risk of recurrence

‐ Facilitate treatment with RAI

‐ Permit accurate staging and risk stratification

‐ Permit accurate surveillance

‐ Minimize treatment-related morbidity


SurgeryGoals of Surgery

• ATA Guidelines

‐ 2009 ATA

■ Total thyroidectomy for any tumor >1cm with or without evidence of locoregional or distant metastasis

‐ 2015 ATA

■ New studies Clinical outcomes are similar following unilateral and bilateral thyroid surgery




4/24/202110

ATA 2015: Three categories

‐ Thyroid cancer <1cm without extrathyroidal extension and cN0

‐ Thyroid cancer >1cm and <4cm without extrathyroidal extension and without clinical evidence of any lymph node metastasis (cN0)

‐ Thyroid cancer >4cm, or with gross ETE (cT4), or clinically apparent metastatic disease to nodes (cN1) or distant sites (cM1)



Cross-communication of intraglandular lymphatics

Extensive bilateral drainage

High incidence of regional metastasis

Multiple nodal groups at risk

Lymphatic channels parallel venous drainage

SurgeryImportance of Thyroid Lymphatics


Advanced thyroid primary: T3 or T4a

Advanced age

Node positivity

• cN+, US+, USGFNA+

Advanced histologies

• Hurthle cell, Insular, cytopath “features c/w poorly differentiated carcinoma” (“spindle cells”)

• Anaplastic (IVA)

• Medullary carcinoma

Neck Lymph Node Metastasis Surgical Management


Advanced thyroid primary: T3 or T4a

Older age

Node positivity

• cN+, US+, USGFNA+

Advanced histologies

• Poorly differentiated

Central NeckWhen to do a central neck dissection?



4/24/202111

• Significantly less controversial

‒ Therapeutic only

• Compartment-oriented en-bloc neck dissection

‒May reduce the risk of recurrence and possibly mortality

Cooper et al 2009

‒Levels IIA-VBFarrag et al 2009, Lee et al 2007; ATA Surgery Working Group

Lateral Neck Dissection


Parapharyngeal Metastasis

• Be aware on imaging

• Parapharyngeal node excision

‒ Important to do

Open vs TORS

• no comparative data


• Significantly higher risk due to more variable anatomy

• Full-compartment surgery if minimal prior dissection

• Focused surgery may be relevant

‒Preop imaging shows a localized target

Targeted dissection

Revision surgerySignificantly higher risk


Radical resection may be necessary to remove all gross disease

Incomplete resection High rates of local relapse and decreased survival

Central premise: clear disease to protect vital functions of breathing, speaking, and swallowing.

Locally Invasive Thyroid CancerTrachea, Larynx, Esophagus



4/24/202112

Locally Invasive Thyroid CancerRLN Invasion


Locally Invasive Thyroid CancerManagement of the Functional RLN

• Always reduce down to microscopic residual disease whenever feasible• Exception: Both functioning RLNs grossly

involved• Do not leave “gross disease”• For tracheal margins, seek microscopic free margins

if feasible (without laryngectomy)


TumorRLN

Nerve Preservation

RLN

Tumor

Nerve Resection

Locally Invasive Thyroid CancerManagement of the Functional RLN


Local InvasionTrachea – Sleeve Resection



4/24/202113

Local InvasionTrachea – Sleeve Resection


Invasion of TracheaSleeve Resection







4/24/202114





Independent survival predictor

Mucosal invasion is rare (6%)

Often associated with concomitant tracheal invasion, RLN compromise

May need to consider laryngopharyngectomy

• Need to be ready for reconstruction

McCaffrey et al, Nakao et al 2009

Local InvasionEsophagus


Local InvasionLarynx



4/24/202115



Local InvasionWhen to do a laryngectomy?

Insufficient data

Follow axiom of local control

Most often seen in recurrence of patient noncompliant with surveillance, rather than primary treatment

Laryngectomy for local control and functional optimization


Invasion of LarynxAnterolateral vertical hemilaryngectomy





4/24/202116

Postoperative Management in WDTC

2015 ATA Guidelines: Modified Initial Risk Stratification System (MIRS)

• Risk Stratification for recurrence after initial surgery and remnant ablation

• 2015 Guidelines use ~same system as 2009

4/24/2021Comprehensive Management of Thyroid Cancer

• Thyroxine suppression of TSH

• Radioactive iodine (RAI) therapy

• External beam radiotherapy (EBRT)

• Systemic therapy

Adjuvant Treatment for DTC


• Thyroid Hormone for TSH Suppression

• Restores normal endocrine function

• Suppresses TSH secretion

• Reduces recurrence rates

‒Eliminates trophic effect of TSH on residual thyroid cells

Adjuvant Treatment for DTCTSH Suppression


Goals of RIA

Ablate thyroid remnant to achieve undetectable TG

Eliminate suspected micrometastases

Ablate known persistent disease to decrease recurrence risk

Integral to surveillance with total body iodine scans and thyroglobulin measurements

Adjuvant Treatment for DTCRadioiodine ablation



4/24/202117

Recommended for ALL patients with

Gross extrathyroidal extension

Primary tumor size > 4 cm

Distant metastases

n Post-operative unstimulated Tg > 5-10 ng/mL

NCCN Clinical Practice Guidelines Version 2.2012. 12/19/2011

Adjuvant Treatment for DTCRAI: NCCN Guidelines


I-131 Dosing

Thyroid remnant ablation: 30 mCi

Adjuvant therapy: 30-100 mCi

Treatment of metastatic foci: 100-200 mCi

Schlumberger et al. and Mallick et al. NEJM 2012

Adjuvant Treatment for DTCRIA: NCCN Guidelines


Schlumberger, et al. NEJM May 2012

Mallick, et al. NEJM May 2012

Adjuvant Treatment for DTCRIA: Update

• Role not well-defined

• No prospective studies

• Adjuvant & palliative treatment in high-risk pts

• Multiple retrospective studies

• Improvement in LRC & DFS in high-risk patients

Adjuvant Treatment for DTCExternal Beam Radiotherapy



4/24/202118

Indications None are consistent, mutually exclusive• Older age (45 or 60 years-old) • Massive primary disease• Extensive extrathyroidal extension• Macroscopic iodine-negative components• Recurrent locoregional disease, particularly if

not iodine-avid• Resection of all gross recurrence

• Morbidity of additional surgery

Adjuvant Treatment for DTCExternal Beam Radiotherapy


Authors N % EBRT Benefit Subset benefitting

Farahati et al. 169 59 LRC pT4, >40 yo, and LN+

Brierley et al. 729 44 LRC, DSS pT4, >60 yo,

Chow et al. 842 12 LRC Gross residual

Kim et al. 91 25 LRC pT4 or N+

Philips et al. 91 25 LC ETE or +margin

Adjuvant Treatment for DTCPostop EBRT: Retrospective Data

Acute Side Effects

• Mucositis of larynx, trachea and esophagus

• Skin erythema and desquamation

• Dry mouth

• Airway edema

Adjuvant Treatment for DTCPostop EBRT: Acute Side Effects

Late Side Effects

• Dry mouth (depends on radiation technique and prior RAI)

• Fibrosis of the soft tissues of the neck

• Possible esophageal stenosis

• Possible vascular injury

Adjuvant Treatment for DTCPostop EBRT: Late Side Effects


4/24/202119

Treatment Options

• I-131• Systemic therapy (TKI)• Surgery for focal DM

Treatment of Metastatic DTC

• First targets: VEGF, VEGF• Other targets identified

• BRAF, NRAS, HRAS, RET/PTC, FGFR, PDGFR• Multitargeted TKIs developed

• Sorafenib (Nexavar)• TKI targeting VEGFR-1, -2, and -3, -PDGFR β, Raf-

1, RET, and BRAF

B

Treatment of Metastatic DTCSystemic TKI

Salajegheh A et al. Eur J Surg Oncol 2011; Ferrara N et al. Nat Med 2003; Yu XM et al. Ann Surg 2008

• Multitargeted TKIs developedLenvantinib

Schlumberger M et al. NEJM 2015. Phase 3


Bergers G et al. Nat Rev Cancer 2008. Ebos JM et al. Clin Cancer Res 2009. Boelaert K et al. J Clin Endocrinol Metab 2003. He G et al. Oncol Lett 2014. Volante M et al. J Clin EndocrinolMetab 2009.

• Multitargeted TKIs developedLenvantinib

Schlumberger M et al. NEJM 2015. Phase 3• Phase 3 multicenter study• Lenvantinib vs placebo• RAI-refractory thyroid cancer• HR (progression/death): 0.21 (0.14-0.31,

p<0.001)• PFS benefit observed in all subgroups




4/24/202120

• Multitargeted TKIs developedCarbozantinibMetastatic MTCVandetanib Unresectable or metastatic MTCDoxorubicin All metastatic TCSorafenib Recurrent, RAI-nonavid TC

• Side effects• Hand and foot skin rxn, diarrhea, alopecia, rash,

myelosuppresion, cardiotoxicity



– Neuroendocrine parafollicular C-cell origin

• Do not have TSH receptors

• Do not take up iodine

– Lymph nodes frequently involved (~50%)

– Calcitonin staining is specific

– 80% are sporadic, but some can result from MEN 2 syndrome.

• Hereditary cases/syndromes

– Germline RET mutation

– MEN2A & 2B

Medullary Thyroid Carcinoma


SynopsisSurgery

No RAI or TSH suppression

Role for EBRT Enhance locoregional control

Systemic TKI therapy Role in metastatic disease

Medullary Thyroid Carcinoma (MTC)– <5% of thyroid cancers– 15-40% of thyroid cancer deaths– Mean age of diagnosis is 65– Rapidly growing, widely invasive, may see regions

of necrosis and hemorrhage– Undifferentiated histology– Thought to be a de-differentiation of a

previously differentiated thyroid cancer.• 20-30% have concurrent papillary thyroid CA• p53 loss thought to be a major step in de-

differentiation.

Undifferentiated/Anaplastic



4/24/202121

Anaplastic Thyroid Cancer

Synopsis• <5% of thyroid cancers

• 14-40% thyroid cancer deaths

• Mean age of diagnosis is 65

• Rapidly growing, widely invasive, may see regions of necrosis and hemorrhage

• Undifferentiated histology

– Spindle Cell

– Giant Cell

– Squamoid

ATC Management

SynopsisNo effective therapy exists

• BRAF–targeted therapy may delay mortality

Disease is nearly universally fatal

• Median survival ~3-7 months

Extensive local invasion is common

DM at diagnosis ~50%

RAI not useful for treatment or imaging

Untch et al, 2006

ATC Management

Surgery

• Indicated only If complete resection is possible

• Debulking no benefit


ATC Management

ChemoradiotherapyClinical trials preferred

Improves short-term survival, local control, and palliation

• Higher RT doses associated with improved survival

• CRT following complete resection may provide prolonged survival

De Crevoisier R et al. Int J Radiat Oncol Biol Phys2004.

Wang 2006



4/24/202122

SummaryComprehensive Management of Thyroid Cancer

• Thyroid cancer can be aggressive

• Beware of clinical presentation

• Surgery front-line to remove all possible gross disease

• RAI and EBRT for residual disease

• Systemic therapy for distant metastasis

• Managing aggressive thyroid cancer is a team effort


SummaryComprehensive Management of Thyroid Cancer


Disclosure Comprehensive Management of Thyroid Cancer

Documents