Annals of Oncology Advance Access published April 6, 2011

review

Annals of Oncology
doi:10.1093/annonc/mdr117

New treatment modalities in advanced thyroid cancer

E. Kapiteijn1*, T. C. Schneider1, H. Morreau2, H. Gelderblom1, J. W. R. Nortier1 & J. W. A. Smit3
Departments of 1Clinical Oncology; 2Pathology; 3Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands

Received 13 July 2010; revised 11 November 2010 & revised 3 February 2011; accepted 17 February 2011

(DTC), undifferentiated/anaplastic thyroid carcinoma (ATC) and medullary thyroid carcinoma. Results of conventional
treatment modalities in advanced thyroid cancer have been disappointing and therefore, new therapies are needed.
Methods: We searched PubMed, The Cochrane Library, Medline and EMBASE databases and abstracts published
in annual proceedings for new treatment modalities in advanced thyroid cancer. We also searched for ongoing trials in
www.clinicaltrials.gov
Results: Six phase I, 17 phase II and 1 phase III trials with tyrosine kinase inhibitors were carried out. We found 2 pilot
studies and 11 phase II trials with redifferentiation therapies, mainly in DTC. For antiproliferative approaches, three
phase I and four phase II trials were found. Immunomodulatory gene therapy was tested in a pilot study in ATC
patients. Two phase II trials were carried out with immunotherapy. One phase I and nine phase II trials were found with
radionucleotide therapy in patients with DTC.
Conclusion: The developments in the treatment of advanced thyroid cancer are intriguing. Future trials should aim
at combinations of targeted agents with or without other treatment modalities, and will hopefully contribute to further
improvement of outcomes.
Key words: molecular pathogenesis, new treatment modalities, thyroid cancer

introduction
Thyroid cancer is the most prevalent endocrine malignancy,
estimated to account for 94% of cancers of the endocrine system
and 66% of deaths due to cancers of the endocrine system in
2007 [1]. The incidence of thyroid cancer throughout the world
is increasing. There is a contribution of improved and more
used diagnostic imaging and related incidentalomas that
account, at least in part, for the increased incidence. However,
the number of patients who die due to this disease also increases.
The current incidence in Europe is 40/1 000 000 per year,
with a nearly three times higher incidence in women [2].
Thyroid cancer is a heterogeneous disease that is classified
into differentiated thyroid carcinoma (DTC), undifferentiated
(anaplastic) thyroid carcinoma (ATC) and medullary thyroid
carcinoma (MTC). DTC and ATC together are classified as
nonmedullary thyroid cancer (NMTC). See Table 1 for
characteristics and prognosis of these subtypes. DTCs are by
far the most common (95%), and include papillary (80%) and
follicular (10%15%) as well as subtypes like Hurthle cell
carcinomas. The majority of DTCs are slowly progressive, and,
when identified at an early stage, frequently cured with
adequate surgical management and radioactive iodine 131-I
*Correspondence to: Dr E. Kapiteijn, Department of Clinical Oncology, Leiden University
Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. Tel: +31-71-5263486; Fax: +31-71-526-6760; E-mail: h.w.kapiteijn@lumc.nl

Both authors contributed equally as senior authors.

ablation therapy (RAI). Metastatic DTC that has become

inoperable or refractory to radioactive iodine therapy, however,
is associated with a poor survival (Table 1). MTCs and
especially ATCs metastasize in up to 50% of patients, thus
giving an even worse prognosis [3]. Results of conventional
treatment modalities (radiotherapy and/or chemotherapy) have
been disappointing and therefore, new therapies are needed.
As a result of the increasing knowledge of the biological basis
for thyroid cancer development, therapeutic agents that target
involved biological abnormalities have been identified. Multiple
clinical trials have been carried out in the past decade. In this
review, we describe new treatment modalities in differentiated,
anaplastic and medullary advanced thyroid cancer.

methods
We searched PubMed, The Cochrane Library. Medline and EMBASE
database and abstracts published in annual proceedings for new treatment
modalities in advanced thyroid cancer. We also searched for ongoing trials
in www.clinicaltrials.gov.

molecular pathogenesis
Nonmedullary thyroid cancer. Studies in benign thyroid cells have shown
BRAF to be an important regulator of thyroid-specific protein expression
and proliferation [4]. Based on evidence that BRAF is involved in the
development of papillary thyroid carcinoma (PTC) and in the progression
of anaplastic carcinoma, BRAF is an attractive target in thyroid cancer [5].
BRAF is a putative downstream signal transducer for rearranged during

The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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review

Background: Thyroid cancer is a heterogeneous disease that is classified into differentiated thyroid carcinoma

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Annals of Oncology

Table 1. Thyroid cancer: tumor type, age, prevalence and survival

Tumor type

Differentiated
Papillary
Follicular
Medullary
Anaplastic

Age (years)

1060
2570
1060
>60

Prevalence (%)

80
1015
510
<5

5-year survival (%)

Nonmetastatic
disease

Metastatic
disease

10-year survival (%)

Nonmetastatic
disease

Metastatic
disease

96100
79100
78100
9

45
47
24
<5

9095
85
75
<5

510
<10
10
0

transfection (RET)/PTC. Kebebew et al. [6] reported significant

associations of BRAF V600E with recurrent and persistent disease with a
higher rate of lymph node metastasis and higher TNM (tumornode
metastasis) stage in PTC and follicular variant of PTC.
In a review of 11 studies in thyroid cancer, it was noted that up to 50% of
follicular and 12% of Hurthle cell malignancies contained RAS mutations
[7]. The RAF proteins are cytoplasmic serine/threonine protein kinases that
are downstream effector molecules of RAS. Of these, BRAF is the most
efficient at phosphorylating mitogen-activated protein kinase (MAPK) and
is important in proliferative as well as apoptotic pathways [8]. Point
mutations leading to BRAF signaling independent of binding to RAS have
been reported in 35%70% of PTCs, underlining the significance of the
RAS/RAF/MAPK pathway in thyroid cancer [9]. The AKT pathway plays an
important role in cell proliferation and survival and has been found by
others to be aberrantly activated in thyroid tumors [1013]. An important
player in this pathway is the PI3KCA subunit that in turn is also regulated
by RAS. In a study by Hou et al. [14], a progressive activation of the PI3K/
AKT pathway and associated methylation of PTEN, known to suppress this
pathway, was found in thyroid adenomas, follicular and anaplastic thyroid
cancers.
In human thyroid cancer, BRAF V600E is associated with vascular
endothelial growth factor (VEGF) overexpression, which in turn is
associated with increasing tumor stage and invasiveness [15]. In 1997, Soh
et al. observed extensive angiogenesis in thyroid cancer cells that had been
xenografted into mice. By using cell lines from human differentiated,
medullary and Hurthle cell thyroid cancers, they noted a higher expression
of VEGF messenger RNA (mRNA) and protein in thyroid cancer in
comparison with normal thyroid tissue [16].
The most common genetic abnormality in papillary thyroid cancer,
occurring in 16%25% of cases, involves the RET proto-oncogene via
rearrangements leading to the fusion of the tyrosine kinase domain to the
5# end of other genes that are constitutively active in follicular thyroid cells.
This results in the generation of chimeric oncogenes and proteins denoted
RET/PTC whose expression is under the control of promoters provided by
the fused genes, leading to ligand-independent activation of RET in
papillary thyroid cancer [17]. To date, 12 of these chimeric RET/PTC
proteins have been described.
medullary thyroid cancer. Activating RET mutations are present in >95% of
hereditary MTC cases and in 20%50% of sporadic MTC cases. Several
mutational hotspots of the RET gene have been described to be
tumorigenic. Furthermore, a common specific activating point mutation,
M918T, appears to be a strong negative prognostic indicator for metastasisfree survival and overall survival (OS). Ten-year survival was 45% in
subjects with a confirmed M918T mutation, while it is reported to be as
high as 90% in absence of the mutation [18].
In addition to RET, the VEGF receptor (VEGFR) and MET protooncogene may be implicated in the pathogenesis of MTC. Mutations in the

2 | Kapiteijn et al.

MET RTK have been detected in MTC in one report [19]. Finally,
transduction of thyroid cells with mutant RET results in up-regulation of
MET [20]. For an overview of the signaling pathways involved in thyroid
cancer, see Figure 1.

new treatment modalities in thyroid carcinoma

As a result of the increasing knowledge of the biological basis for thyroid
cancer development, therapeutic agents that target these biological
abnormalities have been identified. Multiple clinical trials have been carried
out in the past decade (Table 3).
tyrosine kinase inhibitors. monotarget kinase inhibitors: Gefitinib (ZD1839)
is an oral epidermal growth factor receptor (EGFR) tyrosine kinase
inhibitor. The EGFR is highly expressed in malignant thyroid tissue and
mutations of the EGFR gene have been described in thyroid cancer.
Moreover, EGFR contributes to RET activation, signaling and growth
stimulation and is associated with poor prognosis in DTC [21]. Pennell
et al. studied the effectiveness of gefitinib in a phase II trial with a mixed
cohort of thyroid cancer patients. Four percent of patients showed disease
reduction. However, this was not qualified as partial response (PR). Overall,
24% of patients achieved stable disease lasting at least 24 weeks. Median
progression-free survival (MPFS) was almost 16 weeks, with the exception
of MTC patients, in which the median PFS was <12 weeks [22].
AZD6244 is a potent, selective non-competitive inhibitor of MEK1/2 that
has been studied in a phase I study and has shown interesting activity in two
advanced thyroid cancer patients with stable disease for at least 5 months
[23]. A phase II trial conducted in advanced DTC patients showed a PR in
3% of patients, 66% of patients had stable disease and the median PFS was
32 weeks [24].
multikinase inhibitors: Axitinib (AG-013736) is an oral TKI that
effectively blocks all of the VEGFRs. One of five patients with thyroid
carcinoma included in a phase I trial experienced tumor shrinkage, which
however, was not qualified as a PR [25]. A phase II trial by Cohen et al. [26]
studied the efficacy of axitinib in advanced or metastatic thyroid carcinoma
of any histology (n = 60). A PR was seen in 30% of the patients. Stable
disease lasting >16 weeks was reported in 38%. Objective responses
were noted in all histological subtypes with a PR rate of 31% in patients
with DTC and 18% in patients with MTC. Median PFS was 18.1 months.
Motesanib (AMG 706) is an oral TKI targeting the VEGFR 13, RET and
c-KIT. In a phase I trial by Rosen et al. [27], a 50% overall response rate was
observed in patients with advanced thyroid carcinoma. Based on these
results, a multicenter phase II trial was initiated, testing the efficacy of
motesanib therapy in patients with progressive DTC and progressive or
symptomatic MTC. In 14% of the DTC patients, PR was confirmed, and
another 35% of these previously progressive patients maintained stable
disease for at least 24 weeks. The median response duration was 40 weeks
[28]. In a phase II trial in MTC patients by Schlumberger et al. [29] only

Annals of Oncology

Figure 1. Signaling pathways involved in thyroid cancer

2% of patients had confirmed PR, but stable disease for at least 24 weeks
was reported in 48% of patients. Median PFS was 48 weeks.
Vandetanib (ZD 6474) is an oral TKI that targets VEGFR 2 and 3, RET
and EGFR. Vandetanib effectively inhibits RET/PTC3 chromosomal
translocations found in some PTC and M918T RET mutations occurring in
MEN2B-associated and some sporadic MTC [30]. In a phase II trial, Wells
et al. studied the efficacy of vandetanib in patients with metastatic
hereditary forms of MTC. Confirmed PR was reported in 17% of patients,
where another 53% had stable disease lasting at least 24 weeks [31]. A
second phase II trial in advanced hereditary MTC by Robinson et al. [32]
showed a PR rate of 16% and stable disease 24 weeks or longer in 53% of
patients. Results of a phase III trial by Wells et al. [33] in locally advanced
or metastatic MTC showed an objective response in 43% of patients, all of
which were durable. Median PFS was not reached at 24 months of followup.
Sorafenib (BAY 43-9006) is an orally active TKI targeting BRAF, VEGFR
1 and 2 and RET, conducting proapoptotic and antiangiogenic actions. In a
phase II study, Gupta et al. [34] found a PR rate of 23% and a stable disease
rate of 53% in mainly patients with advanced DTC (n = 30). The median
PFS was 79 weeks. Kloos et al. [35] examined the effect of sorafenib mainly
in patients with metastatic PTC (n = 41). Of the PTC patients, 15%
achieved a PR, whereas 56% had stable disease for at least 24 weeks. The
median PFS was 15 months. Hoftijzer et al. [36] carried out a phase II study
investigating the efficacy and the question whether sorafenib could
reintroduce radioiodine uptake in patients with iodine refractory recurrent
or metastatic DTC. Although no reintroduction of radioiodine at metastatic
sites was observed, a PR rate was reported in 23% of patients and 39% had
stable disease. The median PFS was 58 weeks. Currently, a phase III trial of
sorafenib versus placebo is carried out with the possibility of crossover in
patients with advanced iodine refractory DTC. In a small pilot study in
patients with metastatic MTC, responses were described in 40% of the
patients [37]. Lam et al. [38] carried out a phase II trial in which the efficacy
of sorafenib in hereditary (arm A) and sporadic (arm B) metastatic MTC
patients was examined. They included 16 patients with sporadic MTC. One
patient had a PR (6.3%) and 14 patients had stable disease (87.5%). Median
PFS was 17.9 months. Arm A was prematurely terminated because of slow
accrual.
Sunitinib (SU11248) is an oral TKI of VEGFR 13, RET and RET/PTC
subtypes 1 and 3. A response rate of 8% in DTC patients and 13% in MTC
patients was reported by Ravaud et al. [39], who carried out a phase II trial
to determine the effect of sunitinib in refractory advanced thyroid
carcinoma. Furthermore, 67% of DTC patients and 87% of MTC patients

review
showed disease stabilization. In a second phase II trial, Cohen et al. [40]
reported a 13% response rate and a 68% stable disease rate in patients with
DTC. In MTC patients, responses were observed in 43%, and 83% of
patients presented stable disease. Preliminary analysis from a third phase II
trial showed PR or stable disease for at least 12 weeks in 17% of DTC and
38% in MTC patients [41].
Imatinib (STI571) is an oral TKI of BCR-ABL and c-KIT. Its function is
based on its inhibition of RET autophosphorylation and RET-mediated cell
growth. So far, two small phase II trials that studied the efficacy of imatinib
in patients with metastatic MTC have been completed. In both trials, no
response was confirmed and only a few patients achieved stable disease
[42, 43]. Furthermore, a phase I trial with MTC patients treated with
imatinib combined with dacarbazine and capecitabine did not report
objective responses [44].
Pazopanib (GW786034) is an orally bioavailable TKI that targets VEGFR
13 and c-KIT. Its antitumor activity in advanced and progressive DTC was
demonstrated in a phase II trial. PRs were confirmed in 32% of patients.
Median PFS was 12 months [45].
XL184 (Exelixis) is an oral inhibitor of RET, c-MET and VEGFR 1 and 2.
c-MET activation triggers tumor growth and angiogenesis. Moreover, in
patients with PTC and MTC, overexpression and frequent mutations of the
c-MET receptor have been reported [20]. A phase I trial examined the
efficacy of XL184 in patients with advanced malignancies, including
patients with MTC. In MTC patients with measurable disease, 29% had a
confirmed PR and 68% had either confirmed PR or prolonged stable
disease 6 months [46]. Currently, a phase III trial, comparing XL184 with
placebo in patients with advanced MTC, is ongoing.
PLX 4032 is an orally administered small molecule that specifically
inhibits only the V600E mutant BRAF kinase, without appreciable
impairment of wild-type BRAF or other RAF kinases. Three patients with
PTC and documented V600E BRAF mutations have been treated in a phase
I study, with one of the three experiencing a PR and the other two having
prolonged stable disease [47].
E7080 is also an inhibitor of multiple TK, especially VEGFRs, c-KIT,
platelet-derived growth factor receptor beta stem cell factor receptor. In
animal studies, it has been shown to have potent antitumor activity against
small cell lung cancer and breast cancer most likely through inhibition of
VEGFR-2 and VEGFR-3 [48, 49]. A phase II multicenter trial has been set
up to evaluate the safety and efficacy of oral E7080 in medullary and
refractory unresectable DTC.
Effectiveness of multitargeted kinase inhibitors can be expressed by IC50
values [the half maximal (50%) inhibitory concentration (IC) of a
substance]. Table 2 shows the IC50 values for the most important tyrosine
kinase inhibitors and different targets.
other drugs. redifferentiation: Attempts have been made to reinduce the
susceptibility to 131I with retinoids. In four publications, three from the
same group, 13-cis retinoic acid therapy increased I-131 uptake in 26%
40% of patients but failed to do so in another study [5054]. Chinese
investigators treated 11 patients with dedifferentiated thyroid cancer using
1 mg/kg/day of all-trans retinoic acid followed by radioactive iodine. They
obtained mixed responses [55]. In a study by Liu et al. [56], 12 patients
with metastases of DTC, with insufficient uptake of I-131, received 6 weeks
of treatment with bexarotene. This induced I-131 uptake in metastases in 8
of 11 patients. However, uptake was only discernable at single photon
emission computer tomography and had incomplete matching with
metastases as visualized by CT scanning. A British study failed to
demonstrate clinically significant 131I uptake after administration of oral
isotretinoin [50].
Perixosome proliferator-activated receptor (PPAR) gamma activation
leads to activation of PTEN, which inhibits PI3K. A decreased PPAR
gamma expression has been observed in DTC [57]. Therefore, compounds

doi:10.1093/annonc/mdr117 | 3

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Table 2. IC50 [the half maximal (50%) inhibitory concentration (IC) of a substance] values for the most important tyrosine kinase inhibitors and
different targets
TK inhibitors
Compound

VEGFR1 IC50 (nM)

VEGFR2

VEGFR3

RET

RET/PTC3

BRAF

Other

Axitinib
Gefitinib
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL184

1.2

2
1600

0.25

3
90
9
40
0.035

0.29

6
20
17
110

59
47
41
130
4

50
224
100

22

C-KIT
EGFR-R
C-KIT
C-KIT

1.7
33
8
8

EGFR
C-MET

500
1.8

TK, tyrosine kinase; VEGFR, vascular endothelial growth factor receptor.

agonizing PPAR gamma may be beneficial in DTC. In a small study in five

131-negative patients, rosiglitazone was able to induce radioiodine uptake
into metastases in one patient [58]. In two recent studies including more
patients, increases in radioiodine uptake after >6 weeks of pretreatment
with up to 8 mg of rosiglitazone were observed in 40% and 26% of the
patients. However, post-therapy decreases in thyroglobulin levels were only
noted in 20% and 17% of cases [59, 60].
One of the mechanisms by which cells can block the expression of certain
genes is by enzymes that methylate these genes or deacetylate the histones
that envelope a particular gene. Therefore, compounds that can reverse
methylation or inhibit histone deacetylation may lead to the reexpression of
genes that are silenced in cancer. In an in vitro study in thyroid carcinoma,
the demethylating agent 5-azacytidine led to reinduction of sodium iodide
symporter (NIS) expression, accompanied by RaI uptake in thyroid cancer
cell lines [61]. In parallel, the histone deacetylase inhibitor depsipeptide has
been reported to reinduce NIS mRNA expression and RaI uptake in thyroid
carcinoma cell lines and inhibit the growth of several poorly differentiated
and anaplastic thyroid cancer cell lines [62, 63]. Depsipeptide has been
evaluated in a phase II study with NMTC with the aim of resensitize
dedifferentiated tumors to radioiodine therapy. After 2 months, stable
disease was reported in 29% of patients. One patient showed clinically
significant restoration of RAI avidity [64]. In addition, a similar study by
Sherman et al. documented restoration of RAI avidity in 2 of 20 patients.
No RECIST major responses have been seen, but stable disease was reported
in 10 patients [65]. The orally available histone deacetylase inhibitor
vorinostat was studied in 16 DTC patients and 3 MTC patients. No
objective responses were reported and most patients discontinued therapy
because of adverse events [66].
Lithium has been reported to increase tumor dosages of RAI in DTC
[6771]. In a study by Liu et al., the clinical effects of RAI with lithium
carbonate were studied in 12 patients with proven metastatic DTC. Despite
an increased uptake of RAI in seven patients, no beneficial effect of RAI
with lithium was observed on the clinical course as assessed by Tg
measurements and radiographically [72].
statins: Statins have been shown to be potent inhibitors of the
3-hydroxy-3-methyl-glutaryl-CoA reductase. In vitro studies show an effect
of statins on growth and invasion of tumor cells [73, 74]. Both lovastatin
and troglitazone have shown redifferentiating properties, in addition to
reduction of growth and invasion of tumors. Glitazones have also been
reported to reinduce the expression of NIS [73, 75].
antiproliferative approaches: In a phase II trial, the efficacy of celecoxib, a
selective cyclo-oxygenase-2 inhibitor, was investigated in patients with
progressive metastatic DTC. No complete responses were observed. One
(3%) patient with PTC achieved a PR at 6 months, which was maintained at

4 | Kapiteijn et al.

9 months. Twenty-three of 32 patients experienced progressive disease or

stopped therapy due to toxicity, thus fulfilling the intent-to-treat study end
point for celecoxib failure [76].
Thalidomide is a glutamic acid derivate with an antiangiogenic effect,
presumably by modeling tumor necrosis factor-a and blocking VEGFR and
basic fibroblast growth factor. However, its precise action mechanism is
unknown. A phase II trial was set up to study the effectiveness of
thalidomide in patients with progressive metastatic thyroid carcinoma.
Overall, 18% achieved a PR and 32% showed stable disease. PR or durable
stable disease was seen in 38% of DTC and 15% of MTC patients [77].
Lenalidomide (CC-5103) is a thalidomide derivate with a less toxic
profile. Ain et al. [78] carried out a phase II trial with lenalidomide in
patients with rapidly progressive and iodine refractory DTC patients. They
reported a response rate in 23% of patients, and another 45% showed
disease stabilization. However, median OS was <11 months.
The mechanism of the proteasome inhibitor bortezomib is complex but
includes the inhibition of IkBa degradation, which leads to inactivation of
nuclear factor kappa-light-chain-enhancer of activated B cells. The drug has
been shown to have an effect on the growth in ATC cell lines alone and in
combination with other drugs [79, 80]. The efficacy of bortezomib is
currently being studied in DTC patients not responding to radioactive
iodine therapy.
Combrestatin A4 phosphate is a novel drug whose precise mechanism is
unknown. It is structurally similar to colchicine and causes antitumor
effects by binding tubulin and disrupting vascular supply within tumors.
When given to patients with advanced cancer in a phase I trial, a single
patient with ATC had a complete response that lasted >30 months after
treatment [81]. Preliminary data from a subsequent phase II study in 26
ATC patients failed to obtain any objective responses, but seven patients
achieved disease stabilization for 12 months [82]. A phase III of this agent
in combination with carboplatin and paclitaxel (Taxol) chemotherapy is
currently accruing.
A small molecule (JNJ-26854165) that is able to stabilize Hdm2-p53 after its
ubiquitation and save the complex from proteosomal degradation is currently in
a phase I trial and has shown significant activity not only in wild-type p53
tumors but also in mutant cell lines. Long-term stabilization has been observed
in a patient with previously progressive Hurthle cell carcinoma [83]. Currently,
several trials are ongoing with this and other compounds that are also able to
inhibit Hdm2, such as Nutilins, and planned phase II trials in specific
tumor types alone or in combination with cytostatics will be initiated in the near
future.
Currently, 17-AAG (17-allylamino-17-demethoxygeldanamycin) is studied
in patients with inoperable or metastatic thyroid carcinoma including
MTC. 17-AAG induces inhibition of heat shock protein 90 (HSP90), a
molecular chaperone needed for optimum activity of oncogenic protein

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Table 3. Results of clinical trials with tyrosine kinase inhibitors and other drugs in thyroid carcinoma
Drug
Monotarget kinase inhibitors
Gefitinib

AZD6244
Multikinase inhibitors
Axitinib

Tumor type

DTC
MTC
ATC
DTC
MTC

18
4
5
39
2

0
31
18
7
14
2

20
16
45
15b
25
23
40
6.3
8
13
13
43

0
0
32

29
33
29
0
0
3
18
23

DTC + MTC + ATC

Imatinib

DTC
MTC

Pazopanib

DTC
MTC
DTC
MTC
DTC

45
11
71
93
91

30
19
231
41b
31
30
5
16
12
31
8
7

9
15
37

22
3

DTC
DTC
MTC
DTC
DTC + MTC
DTC
MTC
ATC

14
16
3
32
28
18

26

Motesanib

Vandetanib

Sorafenib

DTC
MTC
DTC + MTC
DTC
MTC
DTC
MTC

DTC

MTC
Sunitinib

DTC
MTC

XL184
PLX4032
Other drugs
Depsipeptide
Vorinostat
Celecoxib
Thalidomide
Lenalidomide
Combrestatin
A4phosphate

RR (%)
0a

SD

PFS

Reference (first author)

24% (>24 weeks)a

Pennell [22]

66%
100% (>20 weeks)

16 weeksa
< 12 weeks
16 weeksa
32 weeks

Lucas [24]
Banerji [23]

Rugo [25]

42%
27%
49% (>12 weeks)

18 months (DTC+MTC)

Cohen [26]

34% (26 weeks)

53%
87.5%
67%
68%
87%
83%

56% (>24 weeks)

27% (>24 weeks)
65%

66%

40 weeks
48 weeks

>24 months
15 monthsb
58 weeks
79 weeks
18 months
17.9 months

6 months

12 months

> 20 weeks

Rosen [27]
Sherman [28]
Schlumberger [29]

Wells [87]
Robinson [32]
Wells [33]
Kloos [35]
Hoftijzer [36]
Gupta [34]
Kober [37]
Lam [38]
Ravaud [39]
Cohen [40]
Ravaud [39]
Cohen [40]

Frank-Raue [42]
De Groot [43]
Bible [45]

32%
45%

27%

Piekarz [64]
Woyach [66]

48% (>24 weeks)

53%
(24 weeks)
53% (24 weeks)
56% b(24 weeks)

Kurzrock [46,88]
Flaherty [47]

Mrozek [76]
Ain [77]
Ain [78]

Cooney [82]

Overall outcomes.
results in PTC
, not reported; ATC, anaplastic thyroid carcinoma; DTC, differentiated thyroid carcinoma; MTC, medullary thyroid carcinoma; PFS, progression free
survival; RR, response rate; SD, stable disease.

kinases. It has been demonstrated in vitro that inhibition of

HSP90 alters the biology of thyroid cells with rearranged RET [84].
In cell lines and in xenograft models, inhibition of farnesyl protein
transferase (FTPase) activity by manumycin, a specific inhibitor of FTPase,
has shown antineoplastic properties inhibiting RAS signal transduction
pathway and inducing apoptosis [85]. Manumycin has not reached the

clinical setting due to its significant toxicity in animal models, but several
FTPases inhibitors, such as tipifarnib and lonafarnib, are currently in
clinical development. As a single agent, FTPase inhibitors have shown little
clinical activity in human solid tumors, but in a phase I trial that is
currently evaluating the combination of tipifarnib and sorafenib, a PR in an
MTC patient was reported [86].

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Recently, a phase II trial with RAD001, an agent that inhibits mammalian

target of rapamycin (MTOR), started in our center, investigating the
efficacy of RAD001 in patients with progressive unresectable recurrent or
metastatic DTC, MTC and ATC. Results are expected beginning/medio
2012. Other agents under investigation can be found on
www.clinicaltrials.gov.
Results of clinical trials with tyrosine kinase inhibitors and other drugs in
thyroid carcinoma are shown in Table 3.

In most of the patients with progressive metastatic (or recurrent)

radioiodine-refractory DTC, uptake of radiolabeled somatostatin analogs is
evident on somatostatin-receptor scintigraphy (SRS) [93, 94]. Using SRS,
patients with sufficient uptake of radiolabeled somatostatin analogs can be
selected for high-dose peptide receptor radionucleotide therapy (PRRT) as
an alternative targeted-treatment option. PRRT with the b-particleemitting radionucleotides 90Yttrium (90Y) and 177Lutetium (177Lu) give the
best results in terms of objective tumor response [95103]. Promising,
novel radiolabeled somatostatin analogs that have a broader receptor
affinity profile and, thus, a potentially wider therapeutic range are being
tested clinically [104].

other therapies in DTC and MTC. Gene therapy can be particularly

attractive for the treatment of thyroid cancer because of the possibility of
selecting targeting of therapeutic genes to tumor cells by application of
tissue-specific promoters, such as the thyroglobulin and calcitonin
promoter. The gene therapy approaches that have been investigated in
thyroid cancer are corrective gene therapy, cytoreductive gene therapy and
immunomodulatory gene therapy. Studies in tumor models of
dedifferentiated and medullary thyroid cancer have demonstrated that
sodium iodide symporter (NIS) is a potential novel reporter and therapy
gene that can pave the way for the development of a highly promising
cytoreductive gene therapy strategy [89].
In addition, immunotherapy with dendritic cells has been successfully
evaluated in a transgenic mouse model for MTC and this approach has
occasionally been tested in humans [90]. However, a robust effect has not
been demonstrated [91, 92].

Discussion
In this review we have described new treatment modalities in
DTC, ATC and MTC advanced thyroid cancer. The large
majority of patients with DTC can be cured, and others may
survive for decades despite persistent disease. However, DTC
patients with progressive radioiodine-resistant metastatic
disease have a worse prognosis and the results of conventional
treatment modalities (radiotherapy and/or chemotherapy) have
been disappointing. These patients should nowadays be
considered for entry into clinical trials with new agents. With the
new agents currently available, also advanced MTC patients seem

Table 4. Adverse events of several tyrosine kinase inhibitors

Event
HFS
Fatigue
Asthenia
Weight loss
Anorexia
Fever
Diarrhea
Constipation
Nausea
Vomiting
Abdominal pain
Alopecia
Rash
Musculoskeletal pain
Pruritus
Mucositis/stomatitis
Dry mouth
Hypertension
Headache
Anemia
Thrombopenia
Hypocalcemia
Hypophosphatemia
Hypothyroidism
Myocardial infraction
Heart failure
Rhythm disorder
Dyspnea
Proteinuria

6 | Kapiteijn et al.

Numer of patients (percentage of total (%))

Gefitinib [22]
Axitinib [26]
Motesanib [28]
9 (15)
30 (50)

3 (11)

15 (25)
18 (30)

43
10
37
25

(46)
(11)
(40)
(27)

11 (41)

29 (48)

55 (59)

1 (5)

20 (33)
8 (13)

26 (28)
11(12)
28 (30)

14 (51)

9 (15)

15 (25)
17 (28)
13 (22)

13 (14)
52 (56)
24 (26)

Sorafenib [34]

Sorafenib [36]
21(66)

35 (63)
46 (82)

18
6
2
22
2
9

(60)
(20)
(7)
(73)
(7)
(30)

18(56)

46 (82)
23 (41)

16 (50)

42 (75)

13
24
17
4
14

(43)
(80)
(57)
(13)
(47)

15 (47)
15 (47)

9 (30)
2 (7

13 (41)

14(44)

8
9
13
9
11 (12)
1 (1)

31
10
38
43
44
50
42
9
3
24
9

(55)
(18)
(68)
(77)
(78)
(89)
(75)
(16)
(0.5)
(43)
(16)

(25)
(28)
(41)
(28)

1 (3)
1 (3)
8 (27)

11 (18)

Sorafenib [35]

28 (93)
19 (63)

7 (13)
8 (15)

review

Annals of Oncology

to have a much better perspective. For ATC patients, hopefully,

targeted therapy will be the clue for better treatment since this
devastating disease has shown to be almost therapy resistant.
The large development in the treatment of advanced
thyroid cancer is due to the unraveling of the carcinogenesis
of thyroid cancer. Aberrations in RET/PTC-RAS-RAF-MAPK
pathway are present in a high percentage of thyroid cancer,
and there are also angiogenesis switch alterations and
involvement of other receptor tyrosine kinases, such as EGFR
or c-Met. Because of the oncogenic roles of activated BRAF,
RET and RET/PTC kinases, and RET/PTC kinases, the
assumption was that specific targeting of these kinases could
block tumor growth and induce senescence [105]. As can be
shown from multiple clinical trials in thyroid cancer, these
assumptions have appeared to be correct. Several promising
agents have been found in DTC and MTC (Table 3).
However, the search for new agents in sequential or
combination therapy will still be necessary since patients
eventually become progressive on these agents or do not
tolerate them.
However, there are some issues that need attention. A
substantial proportion of patients (33%50%) have stable
disease of varying duration as best response in several studies.
Given the indolent natural history of many of these tumors, a
report of stable disease is of limited value. In this context, the
determination of the best primary endpoint stays an issue.
Objective response rates give information on progression,
stabilization or shrinkage of tumors within a certain period of
time, but do not correlate per se with OS. Progression-free
survival or OS are not always preferred primary end points in
advanced thyroid cancer because of its indolent nature.
Furthermore, the RECIST criteria may not be the best method
for tumor evaluation in this tumor type since anatomical
imaging alone may have limitations. Only patients with
documented progressive disease should be included in clinical
trials. If this is not the case, the value of achieving stable
disease is even further undermined and hereby differences in
outcomes between studies may develop. Furthermore, if there
are beneficial effects of therapy on tumor response, they must
always be weighed against the side-effects of targeted
therapies and hence its influence on quality of life. The sideeffects of several tyrosine kinase inhibitors are shown in
Table 4.
In conclusion, the developments in the treatment of
advanced thyroid cancer are intriguing. The unraveling of the
molecular pathways in thyroid cancer has played a pivotal role
in the development of targeted therapy for thyroid cancer.
Issues that need to be further addressed are which radiological
examination should be used for detection and monitoring of
advanced disease, which response evaluation criteria are most
suitable, what is the optimal timing of starting therapy and
which primary end point should be used in clinical studies.
Furthermore, to increase the accrual of patients in clinical
studies, to optimize the design of protocols, to improve the
characterization of tumor tissues and to improve the tolerance
of treatment, a multidisciplinary team of medical oncologists,
endocrinologists, specialists in nuclear medicine, radiologists,
surgeons, pathologists, molecular biologists and statisticians
is highly recommended.

disclosure
The authors declare no conflicts of interest.

references
1. American Cancer Society. Cancer Facts and Figures 2007. Atlanta: American
Cancer Society 2007.
2. Hay ID, Klee GG. Thyroid cancer diagnosis and management. Clin Lab Med
1993; 13: 725734.
3. Schlumberger M, Pacini F. Thyroid tumors. Paris, France: Editions Nucleon
2006.
4. Mitsutake N, Knauf JA, Mitsutake S et al. Conditional BRAFV600E expression
induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal
instability in thyroid PCCL3 cells. Cancer Res 2005; 65: 24652473.
5. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer 2005; 12:
245262.
6. Kebebew E, Weng J, Bauer J et al. The prevalence and prognostic value of
BRAF mutation in thyroid cancer. Ann Surg 2007; 246: 466470.
7. Segev DL, Umbricht C, Zeiger MA. Molecular pathogenesis of thyroid cancer.
Surg Oncol 2003; 12: 6990.
8. Puxeddu E, Durante C, Avenia N et al. Clinical implications of BRAF mutation in
thyroid carcinoma. Trends Endocrinol Metab 2008; 19: 138145.
9. Cohen Y, Xing M, Mambo E et al. BRAF mutation in papillary thyroid carcinoma.
J Natl Cancer Inst 2003; 95: 625627.
10. Ringel MD, Hayre N, Saito J et al. Overexpression and overactivation of Akt in
thyroid carcinoma. Cancer Res 2001; 61: 61056111.
11. Miyakawa M, Tsushima T, Murakami H et al. Increased expression of
phosphorylated p70S6 kinase and Akt in papillary thyroid cancer tissues.
Endocr J 2003; 50: 7783.
12. Vasko V, Saji M, Hardy E et al. Akt activation and localisation correlate with
tumour invasion and oncogene expression in thyroid cancer. J Med Genet
2004; 41: 161170.
13. Kada F, Saji M, Ringel MD. Akt: a potential target for thyroid cancer
therapy. Curr Drug Targets Immune Endocr Metabol Disord 2004; 4:
181185.
14. Hou P, Ji M, Xing M. Association of PTEN gene methylation with genetic
alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid
tumors. Cancer 2008; 113: 24402447.
15. Espinosa AV, Porchia L, Ringel MD. Targeting BRAF in thyroid cancer. Br
J Cancer 2007; 96: 1620.
16. Soh EY, Duh QY, Sobhi SA et al. Vascular endothelial growth factor expression
is higher in differentiated thyroid cancer than in normal or benign thyroid. J Clin
Endocrinol Metab 1997; 82: 37413747.
17. Kimura ET, Nikiforova MN, Zhu Z et al. High prevalence of BRAF mutations in thyroid
cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF
signaling pathway in papillary thyroid carcinoma. Cancer Res 2003; 63:
14541457.
18. Schilling T, Burck J, Sinn HP et al. Prognostic value of codon 918 (ATG>ACG)
RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int
J Cancer 2001; 95: 6266.
19. Wasenius VM, Hemmer S, Karjalainen-Lindsberg ML et al. MET receptor
tyrosine kinase sequence alterations in differentiated thyroid carcinoma. Am
J Surg Pathol 2005; 29: 544549.
20. Ivan M, Bond JA, Prat M et al. Activated ras and ret oncogenes induce overexpression of c-met (hepatocyte growth factor receptor) in human thyroid
epithelial cells. Oncogene 1997; 14: 24172423.
21. Kogan EA, Rozhkova EB, Seredin VP et al. [Prognostic value of the expression of
thyreoglobulin and oncomarkers (p53, EGFR, ret-oncogene) in different types of
papillary carcinoma of the thyroid: clinicomorphological and
immunohistochemical studies]. Arkh Patol 2006; 68: 811.
22. Pennell NA, Daniels GH, Haddad RI et al. A phase II study of gefitinib in patients
with advanced thyroid cancer. Thyroid 2008; 18: 317323.
23. Banerji U, Camidge DR, Verheul HM et al. The first-in-human study of the
hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244

doi:10.1093/annonc/mdr117 | 7

review
24.

25.

26.

27.

28.
29.

30.

31.

32.

33.

34.
35.
36.

37.
38.
39.
40.
41.

42.

43.

44.

45.

46.

(ARRY-142886): a phase I open-label multicenter trial in patients with

advanced cancer. Clin Cancer Res 2010; 16: 16131623.
Lucas A, Cohen EE, Cohen RB et al. Phase II study and tissue correlative
studies of AZD 6244 (ARRY-142886) in iodine-131 refractory papillary
thyroid carcinoma (IRPTC) and papillary thyroid carcinoma (PTC) with follicular
elements. J.Clin.Oncol. 2010; 28 (Suppl): 15s (Abstr 5536).
Rugo HS, Herbst RS, Liu G et al. Phase I trial of the oral antiangiogenesis agent
AG-013736 in patients with advanced solid tumors: pharmacokinetic and
clinical results. J Clin Oncol 2005; 23: 54745483.
Cohen EE, Rosen LS, Vokes EE et al. Axitinib is an active treatment for all
histologic subtypes of advanced thyroid cancer: results from a phase II study.
J Clin Oncol 2008; 26: 47084713.
Rosen LS, Kurzrock R, Mulay M et al. Safety, pharmacokinetics, and efficacy of
AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors.
J Clin Oncol 2007; 25: 23692376.
Sherman SI, Wirth LJ, Droz JP et al. Motesanib diphosphate in progressive
differentiated thyroid cancer. N Engl J Med 2008; 359: 3142.
Schlumberger M, Elisei R, Bastholt L et al. Phase II study of safety and efficacy
of motesanib (AMG 706) in patients with progressive or symptomatic, advanced
or metastatic medullary thyroid cancer. J Clin Oncol 2009; 27: 37943801.
Carlomagno F, Vitagliano D, Guida T et al. ZD6474, an orally available inhibitor
of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases.
Cancer Res 2002; 62: 72847290.
Wells SA, Jr., Gosnell JE, Gagel RF et al. Vandetanib for the treatment of
patients with locally advanced or metastatic hereditary medullary thyroid
cancer. J Clin Oncol 2010; 28: 767772.
Robinson BG, Paz-Ares L, Krebs A et al. Vandetanib (100 mg) in patients with
locally advanced or metastatic hereditary medullary thyroid cancer. J Clin
Endocrinol Metab 2010; 95: 26642671.
Wells SA, Robinson BG, Gagel R.F et al. Vandetanib (VAN) in locally
advanced or metastatic medullary thyroid cancer (MTC): a randomized,
double-blind phase III trial (ZETA). J.Clin.Oncol. 2010; 28 (Suppl): 15s (Abstr
5503).
Gupta-Abramson V, Troxel AB, Nellore A et al. Phase II trial of sorafenib in
advanced thyroid cancer. J Clin Oncol 2008; 26: 47144719.
Kloos RT, Ringel MD, Knopp MV et al. Phase II trial of sorafenib in metastatic
thyroid cancer. J Clin Oncol 2009; 27: 16751684.
Hoftijzer H, Heemstra KA, Morreau H et al. Beneficial effects of sorafenib on
tumor progression, but not on radioiodine uptake, in patients with differentiated
thyroid carcinoma. Eur J Endocrinol 2009; 161: 923931.
Kober F, Hermann M, Handler A et al. Effect of Sorafenib in symptomatic
metastatic medullary thyroid cancer. J Clin Oncol 2008; 26: (330s Abstr 6058).
Lam ET, Ringel MD, Kloos RT et al. Phase II clinical trial of sorafenib in
metastatic medullary thyroid cancer. J Clin Oncol 2010; 28: 23232330.
Ravaud A, de la Fouchardiere C, Courbon F. et al. Sunitinib in patients with
refractory advanced thyroid cancer: the THYSU phase II trial 2009.
Cohen EE, Needles B.M., Cullen K.J et al. Phase 2 study of sunitinib in
refractory thyroid cancer. J.Clin.Oncol. 2009; 26 (Suppl): 6025.
Goulart B, Carr L, Martins RG et al. Phase II study of sunitinib in iodine
refractory, well-differentiated thyroid cancer (WDTC) and metastastic medullary
thyroid carcinoma (MTC). Proc Am Soc Clin Oncol 2008; 26: 6062.
Frank-Raue K, Fabel M, Delorme S et al. Efficacy of imatinib mesylate
in advanced medullary thyroid carcinoma. Eur J Endocrinol 2007; 157:
215220.
de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ et al. A phase II trial of
imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol
Metab 2007; 92: 34663469.
Hoff PM, Hoff A.O., Phan A, et al. Phase I/II trial of capecitabine (C),
dacarbazine (D) and imatinib (I) (CDI) for patients (pts) with metastastatic
medullary thyroid carcinomas (MTC). J Clin Oncol 2006; 24 (Suppl): 13048.
Bible KC, Smallridge RC, Maples WJ et al. Phase II trial of pazopanib in
progressive, metastatic, iodine-insensitive differentiated thyroid cancers. Proc
Am Soc Clin Oncol 2009; 27: 3521.
Kurzrock R, Cohen EE, Sherman SI et al. Long-term results in a cohort of
medullary thyroid cancer (MTC) patients (pts) in a phase I study of XL-184 (BMS

8 | Kapiteijn et al.

Annals of Oncology

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

907351), an oral inhibitor of MET, VEGFR2, and RET. J Clin Oncol 2010; 28
(Suppl): 15s (Abstr 5502).
Flaherty KT, Puzanov I, Sosman J et al. Phase I study of PLX4032: Proof of
concept for V600E BRAF mutation as a therapeutic target in human cancer.
J Clin Oncol 2009; 27 (Suppl): 15s (Abstr 9000).
Matsui J, Yamamoto Y, Funahashi Y et al. E7080, a novel inhibitor that targets
multiple kinases, has potent antitumor activities against stem cell factor
producing human small cell lung cancer H146, based on angiogenesis
inhibition. Int J Cancer 2008; 122: 664671.
Matsui J, Funahashi Y, Uenaka T et al. Multi-kinase inhibitor E7080 suppresses
lymph node and lung metastases of human mammary breast tumor MDA-MB231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and
VEGF-R3 kinase. Clin Cancer Res 2008; 14: 54595465.
Short SC, Suovuori A, Cook G et al. A phase II study using retinoids as
redifferentiation agents to increase iodine uptake in metastatic thyroid cancer.
Clin Oncol (R Coll Radiol) 2004; 16: 569574.
Coelho SM, Corbo R, Buescu A et al. Retinoic acid in patients with radioiodine
non-responsive thyroid carcinoma. J Endocrinol Invest 2004; 27:
334339.
Simon D, Koehrle J, Reiners C et al. Redifferentiation therapy with retinoids:
therapeutic option for advanced follicular and papillary thyroid carcinoma.
World J Surg 1998; 22: 569574.
Simon D, Korber C, Krausch M et al. Clinical impact of retinoids in
redifferentiation therapy of advanced thyroid cancer: final results of a pilot
study. Eur J Nucl Med Mol Imaging 2002; 29: 775782.
Simon D, Kohrle J, Schmutzler C et al. Redifferentiation therapy of differentiated
thyroid carcinoma with retinoic acid: basics and first clinical results. Exp Clin
Endocrinol Diabetes 1996; 104 (Suppl 4): 1315.
Zhang Y, Jia S, Liu Y et al. A clinical study of all-trans-retinoid-induced
differentiation therapy of advanced thyroid cancer. Nucl Med Commun 2007;
28: 251255.
Liu YY, Stokkel MP, Pereira AM et al. Bexarotene increases uptake of
radioiodide in metastases of differentiated thyroid carcinoma. Eur J Endocrinol
2006; 154: 525531.
Liu YY, Morreau H, Kievit J et al. Combined immunostaining with galectin-3,
fibronectin-1, CITED-1, Hector Battifora mesothelial-1, cytokeratin-19,
peroxisome proliferator-activated receptor-{gamma}, and sodium/iodide
symporter antibodies for the differential diagnosis of non-medullary thyroid
carcinoma. Eur J Endocrinol 2008; 158: 375384.
Philips JC, Petite C, Willi JP et al. Effect of peroxisome proliferator-activated
receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers.
Nucl Med Commun 2004; 25: 11831186.
Kebebew E, Peng M, Reiff E et al. A phase II trial of rosiglitazone in patients
with thyroglobulin-positive and radioiodine-negative differentiated thyroid
cancer. Surgery 2006; 140: 960966.
Tepmongkol S, Keelawat S, Honsawek S et al. Rosiglitazone effect on
radioiodine uptake in thyroid carcinoma patients with high thyroglobulin
but negative total body scan: a correlation with the expression of
peroxisome proliferator-activated receptor-gamma. Thyroid 2008; 18:
697704.
Venkataraman GM, Yatin M, Marcinek R et al. Restoration of iodide uptake in
dedifferentiated thyroid carcinoma: relationship to human Na+/I-symporter
gene methylation status. J Clin Endocrinol Metab 1999; 84: 24492457.
Kitazono M, Robey R, Zhan Z et al. Low concentrations of the histone
deacetylase inhibitor, depsipeptide (FR901228), increase expression of the
Na(+)/I(-) symporter and iodine accumulation in poorly differentiated thyroid
carcinoma cells. J Clin Endocrinol Metab 2001; 86: 34303435.
Furuya F, Shimura H, Suzuki H et al. Histone deacetylase inhibitors restore
radioiodide uptake and retention in poorly differentiated and anaplastic thyroid
cancer cells by expression of the sodium/iodide symporter thyroperoxidase and
thyroglobulin. Endocrinology 2004; 145: 28652875.
Piekarz R, Luchenko V, Draper D et al. Phase I trial of romidepsin, a histone
deacetylase inhibitor, given on days one, three and five in patients with thyroid
and other advanced cancers. Proc Am Soc Clin Oncol 2008; 26 (20S): 3571.

Annals of Oncology

65. Sherman E, Fury MG, Tuttle RM et al. Phase II study of depsipeptide (DEP) in
radioiodine (RAI)-refractory metastatic nonmedullary thyroid carcinoma. J Clin
Oncol 2009; 27 (Suppl): 15s (Abstr 6059).
66. Woyach JA, Kloos RT, Ringel MD et al. Lack of therapeutic effect of the histone
deacetylase inhibitor vorinostat in patients with metastatic radioiodinerefractory thyroid carcinoma. J Clin Endocrinol Metab 2009; 94: 164170.
67. Briere J, Pousset G, Darsy P et al. [The advantage of lithium in association with
iodine 131 in the treatment of functioning metastasis of the thyroid cancer
(authors transl)]. Ann Endocrinol (Paris) 1974; 35: 281282.
68. Gershengorn MC, Izumi M, Robbins J. Use of lithium as an adjunct to
radioiodine therapy of thyroid carcinoma. J Clin Endocrinol Metab 1976; 42:
105111.
69. Koong SS, Reynolds JC, Movius EG et al. Lithium as a potential adjuvant to
131I therapy of metastatic, well differentiated thyroid carcinoma. J Clin
Endocrinol Metab 1999; 84: 912916.
70. Pons F, Carrio I, Estorch M et al. Lithium as an adjuvant of iodine-131 uptake
when treating patients with well-differentiated thyroid carcinoma. Clin Nucl Med
1987; 12: 644647.
71. Spaulding SW, Burrow GN, Bermudez F et al. The inhibitory effect of lithium on
thyroid hormone release in both euthyroid and thyrotoxic patients. J Clin
Endocrinol Metab 1972; 35: 905911.
72. Liu YY, van der Pluijm G, Karperien M et al. Lithium as adjuvant to radioiodine
therapy in differentiated thyroid carcinoma: clinical and in vitro studies. Clin
Endocrinol (Oxf) 2006; 64: 617624.
73. Wang CY, Zhong WB, Chang TC et al. Lovastatin, a 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor, induces apoptosis and differentiation in human
anaplastic thyroid carcinoma cells. J Clin Endocrinol Metab 2003; 88:
30213026.
74. Zhong WB, Liang YC, Wang CY et al. Lovastatin suppresses invasiveness of
anaplastic thyroid cancer cells by inhibiting Rho geranylgeranylation and RhoA/
ROCK signaling. Endocr Relat Cancer 2005; 12: 615629.
75. Frohlich E, Machicao F, Wahl R. Action of thiazolidinediones on differentiation,
proliferation and apoptosis of normal and transformed thyrocytes in culture.
Endocr Relat Cancer 2005; 12: 291303.
76. Mrozek E, Kloos RT, Ringel MD et al. Phase II study of celecoxib in metastatic
differentiated thyroid carcinoma. J Clin Endocrinol Metab 2006; 91:
22012204.
77. Ain KB, Lee C, Williams KD. Phase II trial of thalidomide for therapy of
radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid
2007; 17: 663670.
78. Ain KB, Lee C, Holbrook KM et al. Phase II study of lenalidomide in distantly
metastatic, rapidly progressive, and radioiodine-unresponsive thyroid
carcinomas: preliminary results. Proc Am Soc Clin Oncol 2008; 26: 6027.
79. Mitsiades CS, McMillin D, Kotoula V et al. Antitumor effects of the proteasome
inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro.
J Clin Endocrinol Metab 2006; 91: 40134021.
80. Conticello C, Adamo L, Giuffrida R et al. Proteasome inhibitors synergize with
tumor necrosis factor-related apoptosis-induced ligand to induce anaplastic
thyroid carcinoma cell death. J Clin Endocrinol Metab 2007; 92: 19381942.
81. Dowlati A, Robertson K, Cooney M et al. A phase I pharmacokinetic and
translational study of the novel vascular targeting agent combretastatin a-4
phosphate on a single-dose intravenous schedule in patients with advanced
cancer. Cancer Res 2002; 62: 34083416.
82. Cooney MM, Savvides P., Agarwala S et al. Phase II study of combrestatin A4
phosphate (CA4P)in patients with advanced anaplstic thyroid carcinoma (ATC).
J Clin Oncol 2006; 24: 300S.
83. Tabernero J, Schoffski P, Dirix L et al. Phase I study to determine the safety,
pharmacology, and pharmacodynamics of JNJ-26854165 insubjects with
advanced stage and/or refractory solid tumors 2008 EORTC-NCI-AACR Annual
Meeting 2008 oral abstract 1592.
84. Marsee DK, Venkateswaran A, Tao H et al. Inhibition of heat shock protein 90, a
novel RET/PTC1-associated protein, increases radioiodide accumulation in
thyroid cells. J Biol Chem 2004; 279: 4399043997.

review
85. Yeung SC, Xu G, Pan J et al. Manumycin enhances the cytotoxic effect of
paclitaxel on anaplastic thyroid carcinoma cells. Cancer Res 2000; 60:
650656.
86. Hong D., Camacho L, Ng C et al. Phase I study of tipifarnib and sorafenib in
patients with biopsiable advanced cancers. Proc Am Soc Clin Oncol 2007; 25
(18S): 3549.
87. Wells SA jr, Gosnell J.E., Gagel R.F et al. Vandetanib in metastatic hereditary
medullary thyroid cancer: follow-up results of an open-label phase II trial. J Clin
Oncol 2007; 25(18 (Suppl): 6018.
88. Kurzrock R., Sherman S.I., Hong D et al. A phase I study of XL184, a MET,
VEGFR2, and RET kinase inhibitor, administered orally to patients (pts) with
advanced malignancies, including a subgroup of patients with medullary thyroid
cancer (MTC) Proceedings of 20th EORTC-NCI-AACR Symposium on Molecular
Targets and Cancer Therapeutics, Geneva, Switzerland, 2008, Abstract 383,
p. 119.
89. Spitzweg C. Gene therapy in thyroid cancer. Horm Metab Res 2009; 41:
500509.
90. Papewalis C, Wuttke M, Seissler J et al. Dendritic cell vaccination with
xenogenic polypeptide hormone induces tumor rejection in neuroendocrine
cancer. Clin Cancer Res 2008; 14: 42984305.
91. Schott M, Feldkamp J, Klucken M et al. Calcitonin-specific antitumor immunity
in medullary thyroid carcinoma following dendritic cell vaccination. Cancer
Immunol Immunother 2002; 51: 663668.
92. Schott M, Seissler J, Lettmann M et al. Immunotherapy for medullary thyroid
carcinoma by dendritic cell vaccination. J Clin Endocrinol Metab 2001; 86:
49654969.
93. Postema PT, De Herder WW, Reubi JC et al. Somatostatin receptor scintigraphy
in non-medullary thyroid cancer. Digestion 1996; 57 (Suppl 1): 3637.
94. Krenning EP, Kwekkeboom DJ, Pauwels S et al. Somatostatin receptor
scintigraphy. In Freeman, LM (ed): Nuclear Medicine Annual. New York:
Lippincott Williams & Wilkins 1995; 150.
95. Valkema R, de JM, Bakker WH et al. Phase I study of peptide receptor
radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience.
Semin Nucl Med 2002; 32: 110122.
96. Gorges R, Kahaly G, Muller-Brand J et al. Radionuclide-labeled somatostatin
analogues for diagnostic and therapeutic purposes in nonmedullary thyroid
cancer. Thyroid 2001; 11: 647659.
97. Waldherr C, Schumacher T, Pless M et al. Radiopeptide transmitted internal
irradiation of non-iodophil thyroid cancer and conventionally untreatable
medullary thyroid cancer using. Nucl Med Commun 2001; 22: 673678.
98. Bodei L, Handkiewicz-Junak D, Grana C et al. Receptor radionuclide therapy
with 90Y-DOTATOC in patients with medullary thyroid carcinomas. Cancer
Biother Radiopharm 2004; 19: 6571.
99. Virgolini I, Britton K, Buscombe J et al. In- and Y-DOTA-lanreotide:
results and implications of the MAURITIUS trial. Semin Nucl Med 2002; 32:
148155.
100. Christian JA, Cook GJ, Harmer C. Indium-111-labelled octreotide scintigraphy
in the diagnosis and management of non-iodine avid metastatic carcinoma of
the thyroid. Br J Cancer 2003; 89: 258261.
101. Gabriel M, Froehlich F, Decristoforo C et al. 99mTc-EDDA/HYNIC-TOC and
(18)F-FDG in thyroid cancer patients with negative (131)I whole-body scans.
Eur J Nucl Med Mol Imaging 2004; 31: 330341.
102. Teunissen JJ, Kwekkeboom DJ, Kooij PP et al. Peptide receptor radionuclide
therapy for non-radioiodine-avid differentiated thyroid carcinoma. J Nucl Med
2005; 46 (Suppl 1): 107S114S.
103. Stokkel MP, Verkooijen RB, Bouwsma H et al. Six month follow-up after 111InDTPA-octreotide therapy in patients with progressive radioiodine nonresponsive thyroid cancer: a pilot study. Nucl Med Commun 2004; 25:
683690.
104. Reubi JC, Macke HR, Krenning EP. Candidates for peptide receptor
radiotherapy today and in the future. J Nucl Med 2005; 46 (Suppl 1): 67S75S.
105. Knauf JA, Fagin JA. Role of MAPK pathway oncoproteins in thyroid
cancer pathogenesis and as drug targets. Curr Opin Cell Biol 2009; 21:
296303.

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