Selecting Optimal Therapeutic Strategies for Patients With Differentiated and Medullary Thyroid Cancer

Selecting Optimal Therapeutic Strategies for

Patients With Differentiated and Medullary

Thyroid Cancer

Jochen Lorch, MD, MS

Assistant Professor of Medicine

Harvard Medical School

Disclosures

Dr. Lorch discloses the following commercial

relationships:

◼ Consultant: Eisai

◼ Research Support: Bayer, Bristol-Myers Squibb, Millennium

Learning Objectives

▶ Assess risk-adapted approaches to the

management of thyroid cancer

▶ Evaluate efficacy and safety data on novel

therapies for differentiated and medullary thyroid

cancer

▶ Apply posttreatment monitoring strategies to ensure

optimal outcomes for patients with thyroid cancer

Thyroid Cancer Scope of Problem

▶ Most common endocrine cancer◼ An estimated 56,870 cases per year in US

◼ Incidence rising: 5% increase between 2004-2013

◼ Relatively stable mortality rate at 0.5 deaths per 100,000 people

but may be rising as well

▶ Subtypes◼ Papillary ~80%

◼ Follicular ~10%

◼ Poorly differentiated 5-10%

◼ Medullary 4%

◼ Anaplastic 2%

ACS, 2017; ACS, 2016.

Traditional Approach to

Thyroid Nodules >1-1.5 cm

TSH = thyroid-stimulating hormone.

Haugen et al, 2016.

Initial AssessmentUltrasound

Check TSH

Normal or Elevated

(~95%)Suppressed

(<5%)

Fine Needle Aspiration Thyroid Scan

(Noncancerous)

Thyroid Nodule FNA:

High Rate of Indeterminate Cytology

Courtesy of Erik K. Alexander, MD.

Cooper et al, 2006.

~5%

Malignant (Papillary Carcinoma)

~65-70%

No Malignant Cells

~20-25%

Indeterminate

“Suspicious for

malignancy”

“Suspicious for a follicular

neoplasm”

“Atypical (follicular) lesion

of uncertain significance”

~5%

Nondiagnostic

The Problem: Low Specificity of

Indeterminate Cytology

US = ultrasound; UG-FNA =ultrasound-guided fine-needle aspiration.

Yassa et al, 2007.

~4,595 consecutive thyroid nodules evaluated with US and UG-FNA

Despite recommendations for surgery, >50% of patients with “abnormal”

cytology are proven to have benign disease.

FNA CytologyProportion Cancer on

Histopathology

Suspicious for papillary

carcinoma60%

Suggestive of a follicular

neoplasm28%

Atypical of an undetermined

significance24%

Gene Expression

FNA = fine-need aspiration; AUS/FLUS = atypia (or follicular lesion) of undetermined significance;

FN/SNF = follicular neoplasm/suspicious for follicular neoplasm; NPV = negative predictive value.

Alexander et al, 2012.

Afirma Gene Expression Classifier – 164 Genes

Prospective, blinded, study with nodules >1 cm

1-2 additional samples after FNA (“standard of care approach”)

Comparison with 2-expert, blinded, gold-standard histopathology

n=129

Performance on All

IndeterminateCytology AUS/FLUS Cytology FN/SNF

NPV: 95% NPV: 94%NPV: 93%

n=265 n=81

False-negative rate similar to benign cytology

High NPV prevents unnecessary surgery

95% 94%

Pre-Operative Imaging

▶ Helps avoid incomplete surgery

▶ Recurrence rates up to 35%◼ Most within 5 years

◼ Some due to inadequate surgery

▶ Ultrasound to evaluate primary tumor and nodes

recommended in all patients

▶ Cross-sectional imaging used in a minority of patients◼ Indistinct margins between tumor and major vessels, esophagus,

airway

◼ Bulky nodal disease incompletely imaged with US

◼ Nodal disease in deep structures of the neck or mediastinum

Yeh et al, 2015.

Surgery: Mainstay of Therapy

▶ Total thyroidectomy for tumors

>1 cm◼ ATA guidelines now recommend

lobectomy for low-risk cancers– <4 cm

– No clinical evidence of nodes

– No extrathyroidal extension

▶ Lobectomy for unifocal cancer

<1 cm◼ No clinical evidence of nodes

◼ No history of radiation therapy or

familial thyroid cancer

ATA = American Thyroid Association.

Haugen et al, 2016.

Postoperative Risk Stratification

▶ AJCC staging: Predicts mortality not recurrence

▶ Operative report◼ Gross extrathyroidal extension

◼ Completeness of resection

▶ Specific histology

▶ Mutational status (BRAF?, BRAF + TERT promoter,

PIK3CA, TP53, AKT1)

▶ Postoperative serum thyroglobulin testing

AJCC = American Joint Committee on Cancer.

Omry-Orbach, 2016.

Postoperative Risk Stratification (cont.)

▶ Post-op I123 or I131 scans◼ May be useful in select cases

◼ Avram and colleagues (2015):– I131 scan detected nodal or distant metastatic disease in

29.4% of cases, which lead to management changes

– Many of these also had elevated post-op Tg

▶ Post-op PET/CT◼ FDG+ predicts poorer outcome and radioiodine resistance

◼ Recommended in patients with aggressive histology and

Tg >10 ng/mL

◼ Can have false-positive rate of 0-39%

PET/CT = positron emission tomography/computed tomography;

FDG = fluorodeoxyglucose; Tg = thyroglobulin.

Nascimento et al, 2015; Avram et al, 2015.

Differentiated Thyroid Cancer:

AJCC Staging

Primary tumor (T)

TX Primary tumor cannot be assessed

TO No evidence of primary tumor is found

T1 Tumor size ≤ 2 cm in greatest dimension and is

limited to the thyroid

T1

aTumor ≤ 1 cm, limited to the thyroid

T1

b

Tumor > 1 cm but ≤ 2 cm in greatest dimension,

limited to the thyroid

T2Tumor size > 2 cm but ≤ 4 cm, limited to the thyroid.

T3Tumor size >4 cm, limited to the thyroid or any tumor

with minimal extrathyroidal extension (eg, extension

to sternothyroid muscle or perithyroid soft tissues)

T4

a

Moderately advanced disease; tumor of any size

extending beyond the thyroid capsule to invade

subcutaneous soft tissues, larynx, trachea,

esophagus, or recurrent laryngeal nerve

T4

b

Very advanced disease; tumor invades prevertebral

fascia or encases carotid artery or mediastinal

vessel

Edge et al, 2010.

Regional lymph nodes (N)

Regional lymph nodes are the central compartment, lateral

cervical, and upper mediastinal lymph nodes:

NX Regional nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis

N1a Metastases to level VI (pretracheal, paratracheal,

and prelaryngeal/Delphian lymph nodes)

N1bMetastases to unilateral, bilateral, or contralateral

cervical (levels I, II, III, IV, or V) or retropharyngeal

or superior mediastinal lymph nodes (level VII)

Distant metastasis (M)

M0Metastases to unilateral, bilateral, or contralateral

cervical (levels I, II, III, IV, or V) or retropharyngeal

or superior mediastinal lymph nodes (level VII)

M1 Distant metastasis is present

Edge et al, 2010.

Papillary and follicular thyroid cancer (age <45y):

Stage T N M

I Any T Any N M0

II Any T Any N M1

Papillary and follicular; differentiated (age > 45y):

Stage T N M

I T1 N0 M0

II T2 N0 MO

III T3 N0 M0

IVAT1-3 N1b M0

T4a N0-1b M0

IVB T4b Any N M0

IVC Any T Any N M!

Differentiated Thyroid Cancer:

AJCC Staging (cont.)

ATA 2009 Risk Stratification

Haugen et al, 2016.

Risk of Recurrence as a Continuum

Haugen et al, 2016.

DTC: Mutational Landscape

▶ 402 cases, whole exome sequencing performed

▶ Low frequency of somatic alterations

▶ Mutation density correlates with age, risk of recurrence, MACIS score

▶ BRAF V600E in 61.7%, RAS (N-, H- and KRAS) 12.9%

▶ Along PI3K axis: 20/402 (5%)

DTC = differentiated thyroid cancer.

Agrawal et al, 2014.

DTC: BRAF vs RAS

Agrawal et al, 2014.

DTC: Metastatic Disease

▶ Metastatic disease frequently affects: ◼ Lungs (49%)

◼ Bones (25%)

◼ Both (15%)

▶ RAI if significant iodine uptake is detected on scans

➔ remission ~30%

▶ May follow indolent course with slow disease

progression on TSH suppression

▶ Disease considered RAI refractory if:◼ At least one lesion with no uptake

◼ Progression within 1 year following RAI

◼ Persistent disease following dose of 600 mCi

RAI = radioactive-iodine refractory.

NCCN, 2017; Haugen et al, 2016.

RAI-Refractory DTC: Characteristics

▶ Inverse relationship between ◼ BRAF and RET mutations/rearrangements

◼ FDG and RAI avidity

Ricarte-Filho et al, 2009; Cantwell-Doris et al, 2011; Xing et al, 2013.

Modulating RAI Uptake in Refractory

Disease Through MEK Inhibition

▶ Selective MAPK pathway antagonists increase the expression of

the sodium-iodide symporter and uptake of iodine in animal models

▶ Selumetinib MAPK kinase inhibitor (MEK1 and MEK2) ◼ 20 patients with RAI-refractory thyroid cancer evaluated:

– 9 BRAF+

– 5 NRAS+

◼ 12/20 patients demonstrated increased uptake of I124

– 4/9 patients with BRAF mutations

– 5/5 patients with NRAS mutations

◼ 8 patients reached the dosimetry threshold for radioiodine therapy, including all

5 patients with NRAS mutations

◼ 5 had confirmed PR and 3 had SD; all patients had decreases in serum

thyroglobulin levels (mean reduction 89%)

◼ No toxicities grade ≥3 attributable to selumetinib observed

PR = partial response; SD = stable disease; MAPK = mitogen-activated protein kinase.

Ho et al, 2013.

Modulating RAI Uptake in

Refractory Disease: Selumetinib

Ho et al, 2013.

RAI RAI + Selumetinib RAI RAI + Selumetinib

RAI-Refractory Metastatic Disease

▶ Doxorubicin◼ Response rate 10-30%

◼ No known impact on survival

▶ Carboplatin, paclitaxel and docetaxel, bleomycin◼ Response rates approximately 10-30%, usually short lived

Until recently, RAI-refractory disease was NOT

considered treatable.

NCCN, 2017.

DECISION Phase III: Sorafenib vs Placebo

in RAI-Refractory DTC

▶ Double-blind, randomized, multicenter phase III

▶ Patients with locally advanced/metastatic RAI-refractory DTC

▶ Progression within 14 months

▶ Randomly assigned 1:1 to sorafenib 400 mg BID PO or placebo, crossover

allowed

▶ Primary end point: PFS

▶ 417 patients randomly assigned (207 to sorafenib and 210 to placebo)

BID = twice daily; PO = by mouth; PFS = progression-free survival.

Brose et al, 2014.

Treatment until progression

or unacceptable toxicity

Locally advanced

or metastatic RAI

refractory DTC

Sorafenib 800 mg

Placebo

1:1 Randomization

PR

OG

RE

SS

ION

Survival follow-up

DECISION: PFS

▶ Median PFS 10.8 mo for sorafenib vs 5.8 mo for placebo ◼ HR=0.59; 95% CI: 0.45-0.76; P<0.0001

▶ No difference in OS (crossover allowed)

Brose et al, 2014.

All Cohorts

DECISION: PFS in BRAF Mutants

WT = wild type.

Brose et al, 2014.

BRAF WT

BRAF V600E

(27% sorafenib,

31.4% placebo)

BRAF V600: 20.5 vs 9.4 mo; HR=0.46; P=0.02

BRAF WT: 8.9 vs 3.8 mo; HR=0.55; P<0.001

SELECT Phase III: Lenvatinib in DTC

▶ Design similar to DECISION study

▶ 392 patients randomly assigned (2:1), double-blind, placebo-controlled

▶ Documented disease progression within 13 months

▶ Crossover to open-label lenvatinib allowed upon progression


Schlumberger et al, 2015; Stjepanovic & Capdevila, 2013.

SELECT: PFS

▶ PFS 18.3 mo (15.1-NR) vs 3.6 mo (2.2-3.7)

▶ 4 CRs (1.5%)

▶ Benefit similar for BRAF-positive and BRAF-WT cases

▶ No difference in OS except for older (>65 years) patients

OS = overall survival; NR = not reached.

Schlumberger et al, 2015.

Schlumberger et al, 2015.

SELECT: Subgroup Analysis

Nonapproved Therapies

Targeting BRAF: Vemurafenib in

BRAF-Positive PTC

▶ 51 patients with RAI-refractory progressive PTC positive for BRAF

V600E mutation

◼ Cohort 1 (n= 26) if TKI treatment naive

◼ Cohort 2 (n= 25) if previously treated with TKIs

▶ Cohort 1 vs Cohort 2 results:

◼ PRs in 38.5% and 27.3%, no complete response

◼ Clinical benefit rate (CR + PR + SD = 6 months) was 58% and 36%

◼ Median PFS at the time of data cut-off for the analysis was 18.2 mo

(95% CI: 15.5-29.3) and 8.9 mo (95% CI: 5.5-NE)

◼ Cutaneous squamous cell cancer in 27% and 20%

▶ Other grade 3/4 toxicity: Liver 4%

▶ 2 deaths reported on study, not felt to be treatment related

PTC = papillary thyroid cancer; TKI = tyrosine kinase inhibitor; CR = complete response. NE = not estimable.

Brose et al, 2016.

Everolimus in DTC:

Key Eligibility Criteria

▶ Main cohort: ◼ RAI-refractory DTC (n=33)

▶ Disease progression within 6 months prior to

enrollment

▶ PS 0-2

PS = performance status.

Lorch et al, 2013.

Everolimus in DTC: PFS

▶ PFS 12.3 mo (95% CI: 10-NR)

▶ Disease stability for 6 mo achieved in 19/33 patients

▶ Disease stability for 12 mo or more in 11/33 patients

Lorch et al, 2016.

Progression-Free Survival

Months

Su

rviv

al

0 5 10 15 20 25

25

50

75

100

Future Directions in RAI-Refractory DTC

▶ Lenvatinib plus PD-1 inhibition◼ ITOG study opening 2017/18

▶ Second-generation mTOR inhibitors◼ MLN0128

▶ Immunotherapy with PD-1/CTLA-5 inhibitors◼ Pembrolizumab in 22 patients with RAI-refractory thyroid cancer

– 2 patients had a PR for an ORR (confirmed) of 9.1%

(95% CI:1.1-29.2)

ITOG = International Thyroid Oncology Group; ORR = overall response rate.

Mehnert et al, 2016.

Medullary Thyroid Cancer

▶ Derived from parafollicular C cells

▶ Usually presents with solid mass

▶ Frequently secretes:◼ CEA, calcitonin

◼ VIP ➔ diarrhea

◼ ACTH ➔ Cushing’s disease

▶ Metastatic disease frequently affects

mediastinum, lung, bone, and liver

▶ Growth rate ranging from indolent to

extremely aggressive

Courtesy of Justine Barletta, MD and Cheryl Adackapara, MD.


Medullary Thyroid Cancer (cont.)

▶ Sporadic MTC accounts for 75% of cases, familial MTC

25%

▶ Familial MTC occurs in association with multiple

endocrine neoplasia (MEN) type 2A and 2B syndromes,

but non-MEN familial MTC can also occur

▶ Sporadic and familial cases usually involve mutation of

RET proto-oncogene

MTC = medullary thyroid cancer.

Zbuk & Eng, 2007.

Sporadic MEN2A/B

RET mutation Somatic Germline

Age (Average years) 40-45 15-25

Associated tumors –

MEN2A: MTC, pheochromocytoma, parathyroid hyperplasiaMEN2B:

MTC, pheochromocytoma, intestinal/mucosal ganglioneuromatosis,

marfanoid habitus

MTC Therapy

▶ Aggressive surgery: Complete thyroidectomy with bilateral central

compartment node dissection and unilateral neck dissection

▶ Adjuvant radiotherapy considered largely ineffective with no impact

on survival

▶ Local recurrence treated surgically

▶ Systemic disease: ◼ Often indolent with no significant progression over long period

of time

◼ Increase in calcitonin without radiographic evidence for disease

progression does not indicate need for systemic therapy


Phase III: Vandetanib in MTC

▶ Double-blind, placebo-controlled trial◼ 331 patients with advanced MTC

◼ Measurable disease (no progression required),

calcitonin level >500 pg/mL

◼ Vandetanib 300 mg (n=231) or placebo (n=100)

◼ Crossover allowed

◼ Primary end point: PFS

Wells et al, 2012.



Locally advanced

or metastatic RAI

refractory MTC

Vandetanib 300 mg

Placebo

1:1 Randomization

PR

OG

RE

SS

ION

Survival follow-up

Vandetanib in MTC: PFS

▶ 54% reduction in the rate of progression (HR=0.46; P=0.001)

▶ PFS NR in vandetanib arm, 19.3 mo for placebo

▶ Objective response rate (ORR) 45% vs 13% (P<0.001)

Wells et al, 2012.

P=0.001

Vandetanib in MTC: OS

▶ No difference in OS

▶ Subgroup analysis showed

no association with patient

characteristics (but small n

in some categories)

Wells et al, 2012.

Overall

Male

Female

White

Other

PS 1-2

PS 0

Hereditary

Sporadic or unknown

Locally advanced

Metastatic

≥1 prior Rx

No prior therapy

Response to prior Rx

No response to prior Rx

Unknown

Phase III: Cabozantinib in MTC

▶ Randomized, placebo-controlled study

▶ 330 patients with locally advanced or metastatic MTC

▶ Documented RECIST progressive disease within

14 mo of screening

▶ No limit on prior therapy


Schöffski et al, 2012.



Locally advanced

or metastatic MTC

with documented

RECIST

progression

Cabozantinib 140 mg

Placebo

1:1 Randomization

PR

OG

RE

SS

ION

Survival

follow-upNo Cross-over

No Unblinding

Cabozantinib in MTC: PFS

Elisei et al, 2013.

PFS: 11.2 vs 4.0 mo (HR=0.28 95%; CI: 0.19-0.40; P<0.001)

Cabozantinib in MTC:

Subgroup Analysis

▶ RET M918T subgroup

greatest PFS benefit from

cabozantinib vs placebo

(HR=0.15; 95% CI: 0.08-

0.28; P<0.0001)

Elisei et al, 2013; Sherman et al, 2016.

Vandetanib vs Cabozantinib in MTC:

Adverse Events

GI = gastrointestinal.

Wells et al, 2012; Schöffski et al, 2012.

Vandetanib

N=231

Cabozantinib

N=214

Adverse EventAll

n (%)

Grade ≥3

n (%)

All

n (%)

Grade ≥3

n (%)

Hypertension 73 (32) 20 (9) 70 (33) 18 (8)

Fatigue 55 (24) 13 (6) 87 (41) 20 (9)

Diarrhea 130 (56) 25 (11) 135 (63) 34 (16)

Hemorrhage NR NR 54 (25) 7 (3)

Venous thrombosis NR NR 12 (6) 8 (4)

GI perforation NR NR 7 (3) 7(3)

Non-GI fistula NR NR 8 (4) 4 (2)

QT prolongation 33(14) 18 (8) NR NR

MTC Trials

▶ RET inhibitors: Ponatinib

▶ Regorafenib open since spring 2016

▶ Immunotherapy?

Clinicaltrials.gov, 2016; Clinicaltrials.gov, 2017a.

Anaplastic Thyroid Cancer

▶ Typically a tumor of older adults

▶ Presence of pre-existing or co-existing well-differentiated carcinoma in 23-78%

of cases, usually papillary thyroid cancer

▶ History of long-standing goiter is common

▶ Clinical presentation: Rapidly growing neck mass, hoarseness, vocal cord

paralysis, dysphagia

▶ Early hematogenous metastasis, cure rate 0-10%, median survival 4-6 mo

Images courtesy of Justine Barletta, MD & Cheryl Adackapara, MD.


Spindle Cell Pattern Pleomorphic Giant Cell PatternSquamoid Pattern

Mutational Landscape in ATC

ATC = anaplastic thyroid cancer.

Kunstman et al, 2015.

ATC Therapy

▶ Thyroidectomy or debulking thyroid surgery

with neck dissection if possible

▶ Adjuvant radiotherapy or chemoradiotherapy

▶ Metastatic disease frequent, affecting

mediastinum, lung, bone, and liver

▶ Prognosis poor with 5-yr survival 0-14%

Kebebew et al, 2005; Edge et al, 2010.

All anaplastic carcinomas are considered stage IV:

T4a Intrathyroidal anaplastic carcinoma

T4bAnaplastic carcinoma with gross

extrathyroid extension

Anaplastic carcinoma (all anaplastic

carcinomas are considered stage IV):

Stage T N M

IVA T4a Any N M0

IVB T4b Any N M0

IVC Any T Any N M1

Metastatic ATC Therapy

▶ Doxorubicin + cisplatin:◼ 7/30 (23%) response rate

◼ PFS 10 months

▶ Sorafenib:◼ 2/15 (13%) PR

◼ 4/15 (27%) SD

▶ Axitinib:◼ 1/2 PR

No generally accepted standard for

treatment of metastatic ATC.

De Crevoisier et al, 2004; Nagaiah et al, 2009; Cohen et al, 2008.

FACT Phase II/III: Fosbretabulin in ATC

OS = overall survival.

Sosa et al, 2011; Sosa et al, 2014.

Design

◼ Multicenter, open-label, 2:1 randomized trial

◼ 80/180 planned patients randomly assigned. Trial stopped early

because of slow accrual

◼ Up to 6 cycles of carboplatin and paclitaxel ± CA4P

◼ Primary end point: OS

Results

◼ 75/80 randomly assigned patients received treatment

◼ Median follow up of 4.7 (0.1-32.6) mo

◼ Median survival time for the CA4P arm was 5.2 mo vs. 4.0 mo control

(HR=0.65; 95% CI: 0.38-1.10)

◼ 1-year survival was 27% on the CA4P arm vs 9% (P=0.065)

Adverse Events◼ Grade 1/2 hypertension and grade 3-4 neutropenia were more

common on the CA4P arm

ATC Trials

▶ Clinical Trials: MLN0128

▶ Everolimus: Among 7 patients, 1 had near

complete response, 1 case with PFS of 26 mo

▶ Lenvatinib: 3/9 responses

▶ Immunotherapy?

Clinicaltrials.gov, 2017b. Takahashi et al, 2014; Wagle et al, 2014.

Exceptional Response With Everolimus

H & E = hematoxylin and eosin.

Wagle et al, 2014.

H & E at Diagnosis

▶ 57-year-old patient with ATC

▶ Response to everolimus x 18 mo

Prior 6 months Progression

Response and Resistance

▶ Sequencing shows TSC2 mutation Q1178* in all samples

▶ Resistant sample with a new mutation in mTOR conveying

resistance

Wagle et al, 2014; Takei et al, 2014.

Case Study 1

A 35-year-old man presented with a right-sided neck mass to his primary care physician

and was administered an antibiotic. The neck mass persisted, however, and a thyroid

ultrasound showed a 3-cm nodule in the right lobe of the thyroid. FNA revealed malignant

cells consistent with PTC. A complete thyroidectomy with central neck dissection was

performed, which revealed a 3.3-cm well differentiated PTC with extracapsular extension

and lymphovascular invasion. Three out of 25 lymph nodes tested positive for metastatic

thyroid cancer. A chest x-ray was negative for metastatic disease.

Which of the following treatment options would you now recommend?

a. No further treatment

b. RAI to ablate thyroid remnants and eliminate possible micrometastatic disease

c. External beam radiotherapy

d. Start sorafenib 400 mg PO twice daily

e. Bilateral neck dissection levels II-IV followed by concurrent chemoradiotherapy

Case Study 1

A 35-year-old man presented with a right-sided neck mass to his primary care physician

and was administered an antibiotic. The neck mass persisted, however, and a thyroid

ultrasound showed a 3-cm nodule in the right lobe of the thyroid. FNA revealed malignant

cells consistent with PTC. A complete thyroidectomy with central neck dissection was

performed, which revealed a 3.3-cm well differentiated PTC with extracapsular extension

and lymphovascular invasion. Three out of 25 lymph nodes tested positive for metastatic

thyroid cancer. A chest x-ray was negative for metastatic disease.



b. RAI to ablate thyroid remnants and eliminate possible micrometastatic

disease

c. External beam radiotherapy

d. Start sorafenib 400 mg PO twice daily

e. Bilateral neck dissection levels II-IV followed by concurrent chemoradiotherapy

Case Study 1:

Correct Answer Rationale

▶ Patient has locally advanced PTC. Because of the size of the

lesion and presence of involved lymph nodes, treatment with RAI is

indicated. Prognosis is excellent based on favorable histology and

young age (<45 years)

▶ External beam radiotherapy delivers less radiation to cancer cells

than RAI and carries more acute and chronic side effects.

Furthermore, it does not address potential micrometastatic distant

disease

▶ Sorafenib is an option in RAI-refractory disease, which is an

unlikely scenario in this case

▶ Further surgery is not indicated in the absence of clinically

suspicious areas of disease

Case Study 2

A 52-year-old woman noticed a lump on the left side of her thyroid area and presented to her primary

care physician. She was referred for a ultrasound and FNA, which revealed a 4.2-cm MTC in the left

lobe of the thyroid. Her calcitonin was 2,342 pg/mL. A CT scan showed 2 left level III enlarged lymph

nodes but no distant metastatic disease. She underwent a complete thyroidectomy, central neck

dissection, and left neck dissection. There was no extracapsular extension but 4/34 lymph nodes were

positive for metastatic carcinoma. Follow-up CT scans 6 months after surgery showed new lung

nodules bilaterally, up to 2.4 cm in diameter and several enlarged mediastinal lymph nodes.

Calcitonin, which dropped to 135 pg/L following surgery, rose to 547pg/L. She was asymptomatic.



b. Radioactive iodine

c. Start vandetanib 300 mg daily

d. Start doxorubicin

e. Surgical removal of lung metastases

Case Study 2

A 52-year-old woman noticed a lump on the left side of her thyroid area and presented to her primary

care physician. She was referred for a ultrasound and FNA, which revealed a 4.2-cm MTC in the left

lobe of the thyroid. Her calcitonin was 2,342 pg/mL. A CT scan showed 2 left level III enlarged lymph

nodes but no distant metastatic disease. She underwent a complete thyroidectomy, central neck

dissection, and left neck dissection. There was no extracapsular extension but 4/34 lymph nodes were

positive for metastatic carcinoma. Follow-up CT scans 6 months after surgery showed new lung

nodules bilaterally, up to 2.4 cm in diameter and several enlarged mediastinal lymph nodes.

Calcitonin, which dropped to 135 pg/L following surgery, rose to 547pg/L. She was asymptomatic.




c. Start vandetanib 300 mg daily

d. Start doxorubicin

e. Surgical removal of lung metastases

Case Study 2:


▶ Patient has widely metastatic MTC with evidence of rapid disease

progression

▶ While metastatic MTC can follow an indolent course and watchful

waiting is often appropriate, therapy should be initiated in this case

▶ Vandetanib is approved for MTC

▶ MTC is derived from parafollicular C-cells and is not RAI avid

▶ Doxorubicin has some activity and is no longer considered

appropriate first-line therapy

▶ Surgical removal of metastatic disease is a consideration for

symptom control or debulking of mass that is encroaching on vital

structures

Case Study 3

A 56-year-old woman noticed a rapidly enlarging lump at the base of her neck approximately 2 weeks

ago. She presented with hoarseness and 10-lb weight loss. Laryngoscopy revealed a paralyzed right

vocal cord. A CT scan of the neck showed a 7-cm neck mass originating from the thyroid causing

displacement and compression of the trachea. A CT scan of the chest revealed numerous pulmonary

nodules. Needle biopsy of the neck mass was consistent with anaplastic thyroid cancer.


a. Surgical debulking followed by chemoradiotherapy


c. Start sorafenib 400 mg twice daily

d. No therapy

e. Radiofrequency ablation of thyroid tumor and lung metastases

Case Study 3

A 56-year-old woman noticed a rapidly enlarging lump at the base of her neck approximately 2 weeks

ago. She presented with hoarseness and 10-lb weight loss. Laryngoscopy revealed a paralyzed right

vocal cord. A CT scan of the neck showed a 7-cm neck mass originating from the thyroid causing

displacement and compression of the trachea. A CT scan of the chest revealed numerous pulmonary

nodules. Needle biopsy of the neck mass was consistent with anaplastic thyroid cancer.


a. Surgical debulking followed by chemoradiotherapy


c. Start sorafenib 400 mg twice daily

d. No therapy

e. Radiofrequency ablation of thyroid tumor and lung metastases

Case Study 3:


▶ ATC is very aggressive with early distant metastasis and poor

prognosis. Fortunately, it is also quite rare

▶ Surgical debulking to prevent airway compromise is standard of care,

irrespective of the presence of metastatic disease. To reduce or—if

possible—eradicate regional disease and prevent or delay recurrence,

radiotherapy or concurrent chemoradiotherapy is used

▶ Sorafenib appears to have minimal activity in this disease and may be

tried in an attempt to control systemic disease but should not be used

as initial treatment

▶ ATC is not RAI avid, thus patients are not candidates for RAI treatment

▶ Radiofrequency ablation of primary or metastatic lesions is considered

experimental and should not be used if more established frontline

therapy is possible

Key Takeaways

▶ Targeted therapy has transformed the treatment of metastatic

thyroid cancer

▶ Sorafenib and lenvatinib approved for

RAI-refractory DTC

▶ Vandetanib and cabozantinib approved for MTC

▶ Thyroid cancer is an active area of investigation and treatment

options should multiply in coming years

Audience Q&As

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Education

Selecting Optimal Therapeutic Strategies for Patients With Differentiated and Medullary Thyroid Cancer