New Treatment Options for
Metastatic Thyroid Cancer
Rajesh Kunadharaju, MBBS; Gaurav Goyal, MBBS; Avantika Rudraraju, MBBS;
and Peter T. Silberstein, MD
Newer multitargeted kinase inhibitors show prolonged overall and progression-free survival in
patients with metastatic differentiated and medullary thyroid cancers.
T
hyroid cancer is the ninth most common malig-
nancy in the U.S. At the time of diagnosis, thyroid
cancer is mostly confined to the thyroid gland and
regional lymph nodes. However, around 4% of patients
with thyroid cancer present with metastatic disease.
When compared with localized and regional thyroid
cancer, 5-year survival rates for metastatic thyroid can-
cer are significantly worse (99.9%, 97.6%, and 54.7%,
respectively).1 Treatment options for metastatic thyroid
cancer are limited and largely depend on the pathology
and the type of thyroid cancer.
Thyroid cancer can be divided into differentiated,
medullary, and anaplastic subtypes based on pathol-
ogy. The treatment for metastatic differentiated thyroid
cancer (DTC) consists of radioactive iodine therapy,
thyroid-stimulating hormone (TSH) suppression (thyrox-
ine hormone) therapy, and external beam radiotherapy.
Systemic therapy is considered in patients with metastatic
DTC who progress despite the above treatment modali-
ties. In the case of metastatic medullary thyroid cancer
(MTC), patients who are not candidates for surgery or ra-
diation are considered for systemic therapy, because MTC
does not respond to radioactive iodine or TSH suppres-
sive therapy. On the other hand, metastatic anaplastic
thyroid cancer is a very aggressive subtype with no effec-
tive therapy available to date. Palliation of symptoms is
the main goal for these patients, which can be achieved
Dr. Kunadharaju and Dr. Goyal are house officers in the Department of
Internal Medicine, and Dr. Silberstein is a professor and chief of hematol-
ogy/oncology, all at CHI Creighton University Medical Center in Omaha,
Nebraska. Dr. Rudraraju is a house officer at MacNeal Hospital in Berwyn,
Illinois. Dr. Silberstein is also chief of oncology at the VA Nebraska-Western
Iowa Healthcare System in Omaha.
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021_0815ONC_Kunad_V8jf.indd 21
by loco-regional resection and palliative irradiation.2,3
This review focuses on the newer treatment options
for metastatic DTC and MTC that are based on inhibition
of cellular kinases.
DIFFERENTIATED THYROID CANCER
Differentiated thyroid cancer is the most common his-
tologic type of thyroid cancer, accounting for 95% of
all thyroid cancers and consists of papillary, follicular,
and poorly differentiated thyroid cancer.2,3 Surgery is the
treatment of choice for DTC. Based on tumor size and
its local extension in the neck, treatment options include
unilateral lobectomy and isthmectomy, total thyroidec-
tomy, central neck dissection, and more extensive resec-
tion.2,3 After surgery, radioactive iodine is recommended
in patients with known metastatic disease; locally inva-
sive tumor, regardless of size; or primary tumor > 4 cm,
in the absence of other high-risk features.2 This should be
followed by TSH suppressive hormone therapy.2
About 7% to 23% of patients with DTC develop dis-
tant metastases.4 Two-thirds of these patients become re-
fractory to radioactive iodine.5 Prognosis remains poor in
these patients, with a 10-year survival rate from the time
of detection of metastasis of only 10%.5-7 Treatment op-
tions are limited. However, recently the understanding of
cell biology in terms of key signaling pathways called ki-
nases has been elucidated. The kinases that can stabilize
progressive metastatic disease seem to be attractive thera-
peutic targets in treating patients whose disease no longer
responds to radioiodine and TSH suppressive hormone
therapy.
Papillary thyroid cancers frequently carry gene mu-
tations and rearrangements that lead to activation of the
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 Metastatic Thyroid Cancer
Table 1. Progression-Free Survival for
Sorafenib vs Placebo in Subgroup Analysis
of Different Mutations
Subtype Sorafenib, Mo Placebo, Mo P valuea
BRAF mutated 20.5 9.4 = .02
BRAF wild-type 8.9 3.8 < .001
RAS mutated 5.5 3.5 = .045
RAS wild-type 10.8 5.8 = .004
a
P value < .05 significant.
mitogen-activated protein kinase (MAPK), which pro-
motes cell division. The sequential components leading to
activation of MAPK include rearrangements of RET and
NTRK1 tyrosine kinases, activating mutations of BRAF,
and activating mutations of RAS.8,9 Similarly, overexpres-
sion of normal c-myc and c-fos genes, as well as mutations
of HRAS, NRAS, and KRAS genes, is found in follicular
adenomas, follicular cancers, and occasionally papillary
cancers.10-14 Increased expression of vascular endothelial
growth factor (VEGF) and its receptors (VEGFRs) might
have a role in thyroid carcinoma as well.15
These kinases (the serine kinase BRAF and tyrosine
kinases RET and RAS, and the contributory roles of ty-
rosine kinases in growth factor receptors such as the
VEGFR) stimulate tumor proliferation, angiogenesis, in-
vasion, metastasis, and inhibit tumor cell apoptosis. Ki-
nase inhibitors target these signaling kinases, affecting
tumor cell biology and its microenvironment.16,17
A wide variety of multitargeted kinase inhibitors (MKIs)
have entered clinical trials for patients with advanced or
progressive metastatic thyroid cancers. Two such agents,
sorafenib and lenvatinib, are approved by the FDA for
use in selected patients with refractory metastatic DTC,
whereas many other drugs remain investigational for this
disease. In phase 2 and 3 trials, most of the treatment re-
sponses for MKIs were partial. Complete responses were
rare, and no study has reported a complete analysis of over-
all survival (OS) outcomes. Results from some new ran-
domized trials indicate an improvement in progression-free
survival (PFS) compared with placebo, and additional tri-
als are underway.
Sorafenib
Sorafenib was approved by the FDA in 2013 for the treat-
ment of locally recurrent or metastatic, progressive DTC
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021_0815ONC_Kunad_V8jf.indd 22
that no longer responds to radioactive iodine treatment.18
Sorafenib is an oral, small molecule MKI. It works on
VEGFRs 1, 2, and 3; platelet-derived growth factor re-
ceptor (PDGFR); common RET/PTC subtypes; KIT; and
less potently, BRAF.19 The recommended dose is 400 mg
orally twice a day.
In April 2014, Brose and colleagues published the
phase 3 DECISION study on sorafenib.20 It was a multi-
center, randomized, double-blinded, placebo-controlled
trial of 417 patients with radioactive iodine-refractory lo-
cally advanced or metastatic DTC that had progressed
within the previous 14 months.20 The results of the trial
were promising. The median PFS was 5 months longer in
the sorafenib group (10.8 mo) than in the placebo group
(5.8 mo; hazard ratio [HR], 0.59; 95% conidence inter-
val [CI], 0.45-0.76; P < .0001). The primary endpoint of
the trial was PFS, and crossover from placebo to sorafenib
was permitted upon progression. Overall survival did not
differ significantly between the treatment groups (pla-
cebo vs sorafenib) at the time of the primary analysis data
cutoff. However, OS results may have been confounded
by postprogression crossover from placebo to open-label
sorafenib by the majority of placebo patients.
In subgroup analysis, patients with BRAF and RAS mu-
tations and wild-type BRAF and RAS subgroups had a sig-
nificant increase in median PFS in the sorafenib treatment
group compared with the placebo group (Table 1).20
Adverse events (AEs) occurred in 98.6% of patients
receiving sorafenib during the double-blind period and
in 87.6% of patients receiving placebo. Most AEs were
grade 1 or 2. The most common AEs were hand-foot-skin
reactions (76.3%), diarrhea (68.6%), alopecia (67.1%),
and rash or desquamation (50.2%). Toxicities led to dose
modification in 78% of patients and permanent discontin-
uation of therapy in 19%.20 Like other BRAF inhibitors,
sorafenib has been associated with an increased incidence
of cutaneous squamous cell carcinomas (5%), keratoac-
anthomas, and other premalignant actinic lesions.21
Lenvatinib
In February 2015, lenvatinib was approved for the treat-
ment of locally recurrent or metastatic, progressive DTC
that no longer responds to radioactive iodine treat-
ment.22 Lenvatinib is a MKI of VEGFRs 1, 2, and 3; fi-
broblast growth factor receptors 1 through 4; PDGFR-α;
RET, and KIT.23,24 The recommended dose is 24 mg
orally once daily.
Schlumberger and colleagues published results
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7/30/15 3:49 PM

from the SELECT trial, a randomized, double-blinded,
multicenter phase 3 study involving 392 patients
with progressive thyroid cancer that was refractory to
iodine-131.25 A total of 261 patients received lenvatinib,
and 131 patients received a placebo. Upon disease pro-
gression, patients in the placebo group were allowed
to receive open-label lenvatinib. The study’s primary
endpoint was PFS. Secondary endpoints were the re-
sponse rate (RR), OS, and safety. The median PFS was
18.3 months in the lenvatinib group and 3.6 months
in the placebo group (HR, 0.21; 99% CI, 0.14-0.31;
P < .001). The RR was 64.8% in the lenvatinib group
(4 complete and 165 partial responses) and 1.5% in the
placebo group (P < .001). There was no significant dif-
ference in OS between the 2 groups (HR for death, 0.73;
95% CI, 0.50-1.07; P = .10). This difference became
larger when a potential crossover bias was considered
(rank-preserving structural failure time model; HR, 0.62;
95% CI, 0.40-1.00; P = .05).25
In a subgroup analysis, median PFS was about
14 months in the absence of prior anti-VEGFR ther-
apy and 11 months of prior therapy. The treatment-
related AEs were 97.3% in the lenvatinib group, and
75.9% were grade 3 or higher. Common treatment-
related AEs of any grade in the lenvatinib group in-
cluded hypertension (67.8%), diarrhea (59.4%), fa-
tigue or asthenia (59.0%), decreased appetite (50.2%),
decreased weight (46.4%), and nausea (41.0%). The
study drug had to be discontinued because of AEs in
14% of patients who received lenvatinib and 2% of pa-
tients who received placebo. In the lenvatinib group,
2.3% patients had treatment-related fatal events (6 pa-
tients).25
Summary
Patients with DTC who progress after radioactive iodine
therapy, TSH suppressive therapy, and external beam
radiotherapy should be considered for systemic ther-
apy. Systemic therapy consists of MKIs, which can sta-
bilize progressive metastatic disease. These newer drugs
have significant toxicities. Therefore, it is important to
limit the use of systemic treatments to patients at signif-
icant risk for morbidity or mortality due to progressive
metastatic disease. Patients treated with systemic agents
should have a good baseline performance status, such as
being ambulatory at least 50% (Eastern Cooperative On-
cology Group performance score of 2) of the day to toler-
ate these treatments.
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021_0815ONC_Kunad_V8jf.indd 23
Metastatic Thyroid Cancer
Patients who have disease progression or are unable to
tolerate sorafenib and lenvatinib can choose to participate
in clinical trials with investigational multitarget inhibi-
tors. Other alternatives include vandetinib, pazopanib,
and sunitinib, which finished phase 2 trials and showed
some partial responses.26-30 If the patients are unable to
tolerate MKIs, they can try doxorubicin-based conven-
tional chemotherapy regimens.31
Medullary thyroid cancer
Medullary thyroid cancer is a neuroendocrine tumor
arising from the thyroid parafollicular cells, accounting
for about 4% of thyroid carcinomas, most of which are
sporadic. However, some are familial as part of the mul-
tiple endocrine neoplasia type 2 (MEN 2) syndromes,
which are transmitted in an autosomal dominant fash-
ion.32,33 Similar to DTC, the primary treatment option
is surgery. Medullary thyroid cancer can be cured only
by complete resection of the thyroid tumor and any
local and regional metastases. Compared with DTC,
metastatic MTC is unresponsive to radioiodine or TSH
suppressive treatment, because this cancer neither con-
centrates iodine nor is TSH dependent.34,35
The 10-year OS rate in MTC is ≤ 40% in patients with
locally advanced or metastatic disease.32,36,37 In hereditary
MTC, germline mutations in the c-ret proto-oncogene
occur in virtually all patients. In sporadic MTC, 85% of
patients have the M918T mutation, and somatic c-ret
mutations are seen in about 50% of patients.38-42
Similar to DTC, due to the presence of mutations in-
volving RET receptor tyrosine kinase, molecular targeted
therapeutics with activity against RET demonstrate a
potential therapeutic target in MTC.43-45 Other signal-
ing pathways likely to contribute to the growth and in-
vasiveness of MTC include VEGFR-dependent tumor
angiogenesis and epidermal growth factor receptor
(EGFR)-dependent tumor cell proliferation.46
In 2011 and 2012, the FDA approved tyrosine kinase
inhibitors (TKIs) vandetanib and cabozantinib for meta-
static MTC. Similar to treatment for DTC, systemic ther-
apy is mainly based on targeted therapies. Patients with
progressive or symptomatic metastatic disease who are
not candidates for surgery or radiotherapy should be con-
sidered for TKI therapy.
Vandetanib
Vandetanib is approved for unresectable, locally advanced
or metastatic sporadic or hereditary MTC.47 The daily
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 Metastatic Thyroid Cancer

Table 2. Summary of Trials for DTC and MTC

Type of Patients, PFS, Mo (drug P value 95% CI,
Cancer Drug Clinical Trial No. vs placebo) for PFS OS HR for OS

DTC Sorafenib DECISION trial 417 10.8 vs 5.8 HR, 0.59; 95% No significant 95% CI,
(Phase 3) CI, 0.45-0.76; difference 0.54-1.19; P = .14;
P < .0001 HR, 0.80

DTC Lenvatinib SELECT trial 392 18.3 vs 3.6 HR, 0.21; 99% No significant At 18 mo,
(Phase 3) CI, 0.14-0.31; difference 72.3 (65.7-77.9) vs
P < .001 63.0 (44.3-76.9);
HR, 0.62a

MTC Vandetanib ZETA trial 331 30.5 vs 19.3 HR, 0.46; 95% Immature 95% CI, 0.48-1.65;
(Phase 3) CI, 0.31-0.69a HR, 0.89a

MTC Cabozantinib EXAM trial 330 11.2 vs 4.0 HR, 0.28; 95% Unavailable Unavailable
(Phase 3) CI, 0.19-0.40a

Abbreviations: CI, confidence interval; DTC, differentiated thyroid cancer; HR, hazard ratio; MTC, medullary thyroid cancer; OS, overall survival; PFS,
progression-free survival.
a
P value unavailable.

recommended dose is 300 mg/d. It is an oral MKI that
targets VEGFR, RET/PTC, and the EGFR.48
The ZETA trial was an international randomized phase
3 trial involving patients with unresectable locally ad-
vanced or metastatic sporadic or hereditary MTC.48 In a
ZETA trial study by Wells Jr and colleagues, patients with
advanced MTC were randomly assigned in a 2:1 ratio to
receive vandetanib 300 mg/d or placebo. After objective
disease progression, patients could elect to receive open-
label vandetanib. The primary endpoint was PFS, de-
termined by independent central Response Evaluation
Criteria in Solid Tumors assessments.
A total of 331 patients were randomly assigned to
receive vandetanib (231 patients) or placebo (100 pa-
tients). At data cutoff, with median follow-up of
24 months, PFS was significantly prolonged in patients
randomly assigned to vandetanib vs placebo (30.5 mo vs
19.3 mo; HR, 0.46; 95% CI, 0.31-0.69). The objective RR
was significantly higher in the vandetanib group (45% vs
13%). The presence of a somatic RET M918T mutation
predicted an improved PFS.
Common AEs (any grade) noted with vande-
tanib vs placebo include diarrhea (56% vs 26%), rash
(45% vs 11%), nausea (33% vs 16%), hypertension
(32% vs 5%), and headache (26% vs 9%). Torsades de
pointes and sudden death were reported in patients re-
ceiving vandetanib. Data on OS were immature at data
cutoff (HR, 0.89; 95% CI, 0.48-1.65). A final survival anal-
ysis will take place when 50% of the patients have died.48
Vandetanib is currently approved with a Risk Eval-
uation and Mitigation Strategy to inform health care
professionals about serious heart-related risks. Elec-
trocardiograms and serum potassium, calcium, mag-
nesium, and TSH should be taken at 2 to 4 weeks and
8 to 12 weeks after starting treatment and every 3 months
after that. Patients with diarrhea may require more fre-
quent monitoring.
Cabozantinib
In 2012, the FDA approved cabozantinib for the treat-
ment of progressive, metastatic MTC.49 It is an oral, small
molecule TKI that targets VEGFRs 1 and 2, MET, and
RET. The inhibitory activity against MET, the cognate
receptor for the hepatocyte growth factor, may provide
additional synergistic benefit in MTC.50 The daily rec-
ommended dose is 140 mg/d. A phase 3 randomized
EXAM trial in patients with progressive, metastatic, or
unresectable locally advanced MTC.51 Three hundred
thirty patients were randomly assigned to receive either
cabozantinib 140 mg or placebo once daily. Progression-
free survival was improved with cabozantinib compared
with that of placebo (11.2 vs 4.0 mo; HR, 0.28; 95% CI,
0.19-0.40). Partial responses were observed in 27% vs
0% in placebo. A planned interim analysis of OS was

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conducted, including 96 (44%) of the 217 patient deaths
required for the final analysis, with no statistically signifi-
cant difference observed between the treatment arms (HR,
0.98; 95% CI, 0.63-1.52). Survival follow-up is planned to
continue until at least 217 deaths have been observed.
There was markedly improved PFS in the subset of
patients treated with cabozantinib compared with pla-
cebo whose tumors contained RET M918T mutations
(61 vs 17 wk; HR, 0.15; 95% CI, 0.08-0.28) or RAS muta-
tions (47 vs 8 wk; HR, 0.15; 95% CI, 0.02-1.10).51
The most common AEs, occurring in ≥ 25% of pa-
tients, were diarrhea, stomatitis, hand and foot syndrome,
hypertension, and abdominal pain. Although uncom-
mon, clinically significant AEs also included fistula for-
mation and osteonecrosis of the jaw.
Summary
Patients with progressive or symptomatic metastatic dis-
ease who are not candidates for surgery or radiotherapy
should be considered for TKI therapy. Though not cura-
tive, TKIs can only stabilize disease progression. Initia-
tion of TKIs should be considered in rapidly progressive
disease, because these drugs are associated with consider-
able AEs affecting the quality of life (QOL).
Patients who progressed or were unable to tolerate
vandetanib or cabozantinib can choose to participate
in clinical trials with investigational multitarget inhibi-
tors. Other alternatives include pazopanib, sunitinib, and
sorafenib, which finished phase 2 trials and showed some
partial responses.29,52-57 If patients are unable to tolerate
MKIs, they can try conventional chemotherapy consist-
ing of dacarbazine with other agents or doxorubin.58-60
ConclusionS
Molecular targeted therapy is an emerging treatment op-
tion for patients with metastatic thyroid cancer (Table 2).
The authors suggest that such patients participate in clin-
ical trials in the hope of developing more effective and
tolerable drugs and recommend oral TKIs for patients
with rapidly progressive disease who cannot participate
in a clinical trial. For patients who cannot tolerate or fail
one TKI, the authors recommend trying other TKIs be-
fore initiating cytotoxic chemotherapy.
Before initiation of treatment for metastatic disease,
an important factor to consider is the pace of disease
progression. Patients who are asymptomatic and have
the very indolent disease may postpone kinase inhib-
itor therapy until they become rapidly progressive or
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021_0815ONC_Kunad_V8jf.indd 25
Metastatic Thyroid Cancer
symptomatic, because the AEs of treatment will adversely
affect the patient’s QOL. In patients with symptomatic
and rapidly progressive disease, initiation of treatment
with kinase inhibitor therapy can lead to stabilization of
disease, although at the cost of some AEs. More struc-
tured clinical trials are needed, along with an evaluation
of newer molecular targets for the management of this
progressive metastatic disease with a dismal prognosis. ●
Author disclosures
The authors report no actual or potential conflicts of interest
with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and
do not necessarily reflect those of Federal Practitioner,
Frontline Medical Communications Inc., the U.S. Govern-
ment, or any of its agencies. This article may discuss unla-
beled or investigational use of certain drugs. Please review
complete prescribing information for specific drugs or drug
combinations—including indications, contraindications,
warnings, and adverse effects—before administering phar-
macologic therapy to patients.
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