Endocrine Oncology Thyroid Carcinoma

Current and Future Perspectives in Thyroid Carcinoma Treatment

Jos Manuel Gmez-Sez

Chief Clinician, Endocrinology and Nutrition Service, Bellvitge University Hospital, Barcelona and Professor, University of Barcelona.

Abstract
Thyroid nodules are a common clinical problem and evaluation with neck and thyroid ultrasound and fine-needle aspiration biopsy are the
most accurate methods for evaluating and identifying those that require surgical resection. The surgical treatment of differentiated thyroid
carcinoma is the most common and recommended approach. Post-operative 131I remnant ablation is used to eliminate the post-surgical
thyroid remnant and may facilitate the early detection of recurrence. The conclusion of two important recent studies is that the use of
recombinant human thyrotropin and low 131I dose, 30 mCi, for post-operative ablation may be sufficient for the management of low-risk
thyroid cancer. Recently, multi-targeted kinase inhibitors have emerged as promising treatments for metastatic differentiated thyroid cancers
based on mutation detection in samples from thyroid cancer. Motesanib, sorafenib, vandetanib, sunitinib, lenvatinib, imatinib and cabozantinib
are multi-kinase inhibitors that have the ability of inhibiting the rearranged during transection (RET) and vascular endothelial growth factor
receptor (VEGFR), and other kinases, and have been used in advanced differentiated thyroid carcinoma. By contrast, axitinib and pazopanib
seem to act only as anti-angiogenic agents. Anaplastic thyroid carinoma is often advanced and metastatic at diagnosis. Patients with localised
disease not amenable to surgical resection can be treated with adjuvant chemoradiotherapy.

Keywords
Thyroid nodules, differentiated thyroid carcinoma, anaplastic thyroid carcinoma, thyroid surgery, radioiodine, motesanib, sorafenib, vandetanib,
sunitinib, lenvatinib, imatinib, cabozantinib

Disclosure: The author has no conflicts of interest to declare.

Received: 7 January 2013 Accepted: 30 January 2013 Citation: European Endocrinology, 2013;9(1):227 DOI:10.17925/EE.2013.09.01.22
Correspondence: Jos Manuel Gmez-Sez, c/Sabino de Arana 40,3,2 08028 Barcelona, Spain. E: [email protected]

Thyroid nodules are a common clinical problem and with the growing cancer syndromes, multiple endocrine neoplasia type 2A, multiple
use of diagnostic imaging, the number of thyroid nodules identified endocrine neoplasia type 2B and familial MTC and is the most common
and undergoing further diagnostic evaluation by fine-needle aspiration cause of death in patients with these syndromes.7
biopsy (FNA) is steadily growing. Only 5 % of all thyroid nodules
harbour malignancy and thyroid cancer constitutes only 1 % of all Anaplastic thyroid carcinoma (ATC) is by far the most deadly of thyroid-
epithelial malignancies worldwide and represents 95% of all endocrine derived tumours, but fortunately accounts for but a small percentage.
malignancies. Thyroid cancer incidence has more than doubled in In the US, ATC is responsible for 1.7 % of all thyroid cancers, while
the past decade, with an associated rise in mortality.1,2 It is currently geographically the prevalence ranges from 1.3 to 9.8 %. In several
unknown whether the increase in papillary thyroid cancer (PTC) is countries, the prevalence of ATC has decreased dramatically, due in part
real or is an artefact of improved diagnostic techniques and other to increased dietary iodine and better management of DTC.8
procedures, or of increased screening for small nodules. Differentiated
thyroid carcinoma (DTC), which includes PTC, follicular and poorly Recently, the American Thyroid Association endorsed a guideline for
differentiated carcinomas, accounts for approximately 95 % of all management of patients with recommendations for patients with ATC.8
thyroid cancer cases1 and most patients with DTC have an excellent While all thyroid cancer patients require a multi-disciplinary team of
prognosis;3,4 however, recurrence is observed in 1015 % of patients specialists for optimal care, the coordinating physician is frequently
following surgery.1 an endocrinologist who has established a long-standing relationship
with the patient who has DTC or MTC. By contrast, the sudden onset
Following the spirit of concrete cultural and scientific integration among and explosive course of ATC necessitates immediate involvement by
the countries participating in the new reality of the EU, the European surgeons, radiation and medical oncologists, and palliative care teams.
Thyroid Association and also the American Thyroid Association have
endorsed the implementation of a consensus and guidelines for the Diagnostic Approach to and Treatment of
management of thyroid nodules and thyroid cancer.5,6 Thyroid Nodules
Thyroid nodules are the clinical manifestation of a wide spectrum
Medullary thyroid cancer (MTC) is a malignancy of the parafollicular C of thyroid diseases. In a normal gland or a diffuse goiter, thyroid nodules
cells of the thyroid and accounts for up to 5 % of all thyroid cancer may be solitary or multiple. Among multi-nodular goiters, one nodule may
cases, but causes a disproportionate number of thyroid cancer-related become clinically dominant in terms of growth, dimension and functional
deaths. MTC occurs in both sporadic and hereditary settings, the latter characteristic. The aim of the diagnostic approach to thyroid nodules is a
accounting for approximately 25% of MTC cases. The hereditary form differential diagnosis between benign and malignant nodules and, in the
of MTC occurs as a component of the autosomal, dominantly inherited event of malignancy, the selection of an appropriate surgical procedure.57

22 TOUCH ME D ICA L ME D IA 2013

 Current and Future Perspectives in Thyroid Carcinoma Treatment

Figure 1: Flow Chart for Follow-Up after Initial Treatment Surgery and Radioiodine Ablation in
Differentiate Thyroid Carcinoma 5

Patient with thyroid nodule(s)

Clinical history
Physical examination of the thyroid and the neck

Neck ultrasound FT3, FT4, TSH,

(solid/mixed) (ABTg-AbTPO)
Calcitonin

Diameter Diameter >1 cm Normal TSH Low TSH

1 cm or or
No suspicion 1 cm suspicion multi-nodular
goiter

Thyroid scan

Cold
nodule(s)

FOLLOW-UP FNAC

Benign nodule Malignant, suspicious

Surgery
or follicular neoplasm

ABTg = autoantibodies to thyroglobulin, AbTPO = antithyroidperoxidase antibody, FNAC = fine-needle aspiration cytology, FT3 = free triiodothyronine, FT4 = free thyroxine,
TSH = thyroid-stimulating hormone.

When a thyroid nodule is detected in a patient by physical examination diagnostic test that measures the expression of 167 genes in the
or incidentally during some other test, the diagnostic steps to follow cytological sample has shown promise in improving pre-operative
are: 1. A complete history and physical examination focusing on the risk assessment; of the 265 indeterminate nodules, 85 of those were
thyroid gland and adjacent cervical lymph nodes should be performed. malignant. The gene-expression classifier correctly identified 78 of the
It is important to consider history of familial thyroid cancer, of exposure 85 nodules as suspicious, with a sensitivity of 92% and with a specificity
to radiation during childhood, of rapid growth, hoarseness, hard and of 52%. The negative predictive values for atypia (or follicular lesion)
irregular consistency, ipsilateral cervical lymphadenopathy and fixation of of undetermined clinical significance, follicular neoplasm or lesion
the nodule to extrathyroidal tissues in a physical exam of the thyroid and suspicious for follicular neoplasm or suspicious cytologic findings
neck. 2. Neck and thyroid ultrasound. 3. Thyroid function analysis: thyroid were 95%, 94% and 85%, respectively. The data of the study suggest
stimulating hormone (TSH), T4 and anti-thyroid antibodies. 4. FNA cytology: consideration of a more conservative approach for most patients with
when nodule is bigger than 1 cm and/or echographic signs of suspect thyroid nodules that are cytologically indeterminate on FNA and benign
are present. FNA is the procedure of choice in the evaluation of thyroid according to gene-expression classifier results.9
nodules. Echographic guidance for FNA is recommended for those nodules
that are non-palpable, predominantly cystic or located posteriorly in the Surgical Treatment
thyroid lobe. If FNA or biopsy of a thyroid mass is positive to malignancy The surgical treatment of DTC approach can be as follows: 1. Total
and no distance extension is documented, surgical treatment is the first or subtotal thyroidectomy. The most common and recommended
option. If the serum TSH is subnormal, a radionuclide thyroid scan should approach, especially in the presence of poor prognostic factors (size
be performed using either technetium 99mTc pertechnetate or 123I.5,6 larger than 4 cm, extrathyroidal extension, bilaterality, age older
than 45 years, presence of lymph node metastases). 2. Lobectomy
Approximately 15 to 30 % of thyroid nodules evaluated by means of or isthmusectomy. This can be considered in unilateral lesions in the
FNA are not clearly benign or malignant. In a recent study, a novel absence of adverse prognostic factors. In case of margin involvement,

EUROPEA N EN DOCR IN O LO G Y 23
Endocrine Oncology Thyroid Carcinoma

thyroidectomy should be completed later. Lobectomy may be are: to destroy the residual thyroid tissue and/or any remaining residual
associated with a higher rate of local recurrence. tumour; to discover occult disease and be able to establish initial stage;
to decrease the risk of recurrence and disease-specific mortality by
Indication of lymph node dissections can be considered in case of destroying suspected, but unproven metastatic disease (as an adjuvant
palpable cervical nodes or positive biopsy. It will be radical or functional therapy); and to treat known persistent disease.13,14
according to tumour extension. In cases of non-palpable lymph nodes,
the usefulness of prophylactic lymphadenectomy is unclear, as its value In low-risk patients, some questions remain unresolved: What is the
has not been proven. Therapeutic central-compartment (level VI) neck optimal protocol for post-operative 131I administration? In which low-
dissection for patients with clinically involved central or lateral neck risk patients should 131I be administered? To answer these questions,
lymph nodes should be included to provide clearance of disease from two prospective randomised trials (ESTIMAL and HILO) on large series
the central neck. Prophylactic central-compartment neck dissection of patients who have been treated with total thyroidectomy have
(ipsilateral or bilateral) may be performed in patients with papillary been performed.
thyroid carcinoma with clinically involved central neck lymph nodes
or in advanced primary tumours (T3 or T4 stages). Near-total or total In the first (ESTIMAL), a randomised, phase III trial, two thyrotropin-
thyroidectomy without prophylactic central neck dissection may be stimulation methods (thyroid-hormone withdrawal and use of
appropriate for small (T1 or T2), non-invasive, clinically node-negative recombinant human thyrotropin) were compared and two 131I doses
papillary thyroid carcinoma and most follicular cancer.57,10 (1.1GBq and 3.7GBq) in a two-by-two design. Inclusion criteria were
an age of 18 years or older; total thyroidectomy for DTC; PTNM stage,
There are several widely used thyroid cancer stages. Application of ascertained on pathological examination of a surgical specimen, of pT1
the American Joint Committee on Cancer/International Union Against (with tumour diameter 1cm) and N1 or Nx, pT1 (with tumour diameter
Cancer (AJCC/UICC) classification system based on pathological >1 to 2cm) and any N stage or pT2N0 and absence of distant metastasis.
tumournodemetastasis (pTNM) parameters and age is recommended Thyroid ablation was assessed eight months after 131I administration
for tumours of all types. This classification is currently used and is based by neck ultrasonography and measurement of recombinant human
on the TNM system, taking into account the variables primary tumour thyrotropin-stimulated thyroglobulin. There were 752 patients enrolled
size (T), presence of node metastasis (N) and distance metastases (M). between 2007 and 2010 92% had PTC. In the 684 patients with data
that could be evaluated, ultrasonography of the neck was normal in
Tumour Node Metastasis (PTNM) 652 (95%) after 131I treatment the stimulated thyroglobulin level was
Tumour 1 ng/ml or less in 621 of the 652 patients (95 %) without detectable
T0 no evidence of primary tumour; T1a tumour 1 cm or less, thyroglobulin antibodies. Thus, thyroid ablation was complete in the
T1b tumour more than 1 cm, but not more than 2 cm; T2 tumour 92% of patients and the ablation rate was equivalent between following
more than 2cm, but not more than 4cm, in greatest dimension limited either 30mCi (1.1GBq) or 100mCi (3.7GBq) of 131I and similar in the
to the thyroid; T3 tumour more than 4 cm in greatest dimension patients treated with recombinant human thyrotropin alpha group
limited to the thyroid or any tumour with minimal extrathyroid extension; versus in the group undergoing thyroid-hormone withdrawal.15
T4a tumour of any size extending beyond the thyroid capsule to invade
subcutaneous soft tissues, larynx, trachea, oesophagus or recurrent In the second study (HILO), at 29 centres in the UK, a randomised
laryngeal nerve; T4b tumour invades prevertebral fascia or encases trial comparing low-and high-dose 131I also was conducted, each
carotid artery or mediastinal vessels. All ATC are considered T4 tumours. in combination with either thyrotropin alpha or thyroid-hormone
T4a intrathyroidal ATC surgically resectable. T4b extrathyroidal withdrawal before ablation. Patients (age range 1680 years) had tumour
ATC surgically unresectable. stage T1 to T3, with possible spread to nearby lymph nodes but without
metastasis. Endpoints were the rate of success of ablation at 69
Node metastasis months, adverse events, quality of life and length of hospital stay. A total
NX regional lymph nodes cannot be assessed; N0 no regional of 438 patients underwent randomisation; success rates were 85 % in
lymph node metastasis; N1 regional lymph node metastasis; N1a the group receiving low-dose 131I versus 88.9% in the group receiving
metastasis in ipsilateral cervical lymph node(s) metastasis to level VI the high dose and 87.1% in the patients treated with TSH alpha group
(pre-tracheal, paratracheal and pre-laryngeal/Delphian lymph nodes); versus 86.7% in the group undergoing thyroid-hormone withdrawal. The
N1b metastasis to unilateral, bilateral or contralateral cervical or conclusion of both studies is that the use of recombinant human TSH
superior mediastinal lymph nodes. and low 131I dose (1.1 GBq) for post-operative ablation may be sufficient
for the management of low-risk thyroid cancer.15,16
Distant metastasis
MX distant metastasis cannot be assessed; M0 no distant metastasis; 131I use is increasing in the US, with concern over who should receive
M1 distant metastasis.11,12 it, particularly among patients with low-risk tumours. Therefore, reducing
the radiation exposure is a major step forwards. The use of recombinant
Post-operative Treatment human thyrotropin and low-dose (1.1 GBq) post-operative 131I ablation
Post-operative 131I remnant ablation is used to eliminate the post-surgical instead of thyroid-hormone withdrawal will decrease the retention time of
remnant/post-operative residual thyroid tissue. It may facilitate the early 131I and thus the body radiation dose by 60% for any administered dose
detection of recurrence based on serum thyroglobulin measurement and maintains the quality of life of these patients. It will also reduce the
and/or 131I whole body scan uptake. Additionally, the post-therapy scan length of the stay in a radioprotection ward and sick leave and this will in
obtained at the time of remnant ablation may facilitate initial staging turn reduce the global cost of treatment.15,16 The question about whether
by identifying previously undiagnosed disease, especially in the lateral 131I ablation can be safely avoided in low-risk patients is currently being
neck. The primary goals of the first dose of 131I after total thyroidectomy addressed in a randomised trial in the UK.16

24 EUR OPE A N E ND OCRINOLOG Y

 Current and Future Perspectives in Thyroid Carcinoma Treatment

Distant metastasis are detected in 10% of patients at diagnosis and are and ipsilateral levels IIV lymphadenectomy are also indicated. If any of
the major cause of mortality. They are located in the lungs (50%), bones these nodes are involved or the basal levels of calcitonin are greater than
(25 %), lungs and bones (20 %) or at other sites (5 %). The treatment 400pg/ml, contralateral dissection should be considered. Post-operative
of persistent, recurrent and metastatic disease, for which surgery is radiotherapy may be considered in T4 tumours or those with positive
not an option, consists of 131I therapy and levothyroxine therapy to margins. In case of relapse after initial treatment, if disease is localised
suppress thyroid-stimulating hormone secretion. These treatments or it is a solitary metastasis, the treatment of choice is surgery followed
provide complete remission in a third of all metastatic patients. Poorly or not by radiotherapy. In case of relapse with unresectable localised
differentiated carcinoma is associated with a higher risk of recurrence disease, two options can be addressed: 1. Palliative radiotherapy. 2.
and distant metastasis. Furthermore, it has have a low response rate to Radiofrequency ablation or embolisation. When the disease is no longer
131I and, frequently, a rapid rate of progression. a candidate for local treatment, or in case of distant metastases, two
treatment options can be considered: 1. Chemotherapy: The approved
There are currently no effective therapies for DTC patients who fail cytotoxic drug for its use is doxorubicin, which gives response rates
to respond to 131I treatment, with conventional chemotherapy so far between 15 and 25 % in uncontrolled studies with few patients and
proving relatively ineffective.1719 These findings led to the definition of unreliable data. In this tumour type, responses to treatment with
refractory thyroid carcinoma that is observed in patients with: 1. At dacarbazine and 5-fluouracil, doxorubicin-streptozocin and dacarbazine-
least one target lesion with no detectable 131I intake. 2. Progression doxorubicin-cyclophosphamide have also been described.2427
during the 12 months following a 131I treatment. 3. Persistent disease
after the administration of 600mCi (22GBq) of 131I.20 Treatment of Unresectable or Distant
Metastatic Relapse
In the case of advanced tumours refractory to 131I therapy, there are Recently, multi-targeted kinase inhibitors have emerged as promising
four treatment options: 1. Radiotherapy can be used with radical or treatments for differentiated thyroid cancers. Striking and durable
palliative aims in both primary tumour or metastatic sites. 2. Treatment disease regression has been induced in many patients treated with
with chemotherapy. The only approved cytotoxic drug for use in thyroid these drugs based on mutation detection in samples from thyroid
cancer is doxorubicin, which results in response rates between 17 and cancer with the addition of BRAF mutation, and also the detection of
25% in uncontrolled studies with few patients and unreliable data. In one RAS, RET/PTC and PAX8/PPAR mutations, which may also contribute
of them, in combination with cisplatin, an increase in response rate was to cancer diagnosis. On the other hand, the mitogen-activated protein
obtained without impacting survival. 3. Surgery of metastasis may also kinase/extracellular signal-regulated kinase signalling pathway (MAPK/
be useful in exceptional cases such as single brain metastasis or acute ERK) and lipid kinase phosphoinositide-3-kinase signalling pathway
complications such as spinal cord compression. 4. TSH suppression (PI3K/Akt) play an important role in the transmission of cell signals.
can be useful in keeping serum TSH levels below 0.1 U/ml. In any The genes, coding the signalling cascade proteins (RET, RAS, BRAF,
case, responses to these four approaches are partial and transient PI3K, PTEN, AKT), are mutated or aberrantly expressed in thyroid
with no prolongation of survival. So, molecular-targeted therapies, cancer derived from follicular thyroid cells. Genetic and epigenetic
anti-angiogenic agents and other treatments are being studied.20,22 alternations, concerning MAPK/ERK and PI3K/Akt signalling pathways,
In a recent study pretreatment with selumetinib increases 131I uptake contribute to their activation and interaction as a consequence of
and retention in patients with thyroid cancer that are refractory to malignant follicular cell transformation. The understanding of this
131I; consequently the effect may be greater in patients with RAS molecular mechanism provides access to novel molecular prognostic
mutant cancer.21 and therapeutic strategies for inhibiting the oncogenic activity of
the signalling pathways.22,28 This ability to investigate tumour biology
Thyroid-stimulating Hormone Suppression would allow for the selection of different drugs. Several potential
The use of thyroxine following surgery is performed for two purposes: targets for therapy have been defined in DTC and MTC and represent
1. Replacement purposes of thyroxine in order to preserve thyroid new therapies for advanced thyroid carcinoma; on the other hand,
function. 2. Reducing TSH secretion, to avoid its effect as a growth- experimental cell lines are a novel and invaluable tool that can be used
and proliferation-stimulating factor of tumour cells. The effectiveness to develop innovative therapeutic approaches to poorly differentiated
of this treatment in preventing recurrence after surgery has been carcinomas in a pathophysiological context.2830 After little progress in
controversial; however, a recent meta-analysis showed a preventive this field, clinical trials are now studying molecular targeting treatment
effect on avoiding clinical adverse effects. The purpose of TSH options for patients who have thyroid cancer metastases that progress
suppression is to obtain serum TSH levels between 0.1 and 0.5U/ml despite 131I therapy. There are several aspects or reasons for including
in tumour stages II and III, and less than 0.1U/ml in high-risk tumours patients in these trials: to better define the correct patient population
for at least five years.23 for enrolment in clinical trials; to determine the best therapeutic targets
for progressive metastatic thyroid cancer; and to optimise the design
Treatment of Medullary Thyroid Carcinoma so that the appropriate endpoints are measured to best identify the
When a FNA or biopsy of a thyroid mass is positive to MTC and no activity that results in the greatest clinical benefit.31
distance extension is documented, surgical treatment is the first option.
It is important to determine the rearranged during transection (RET) Motesanib,32,33 sorafenib,34 vandetanib,35,36 sunitinib,37 lenvatinib, imatinib
proto-oncogene mutation in order to distinguish whether it is a sporadic and cabozantinib (XL-184)38 are multi-kinase inhibitors that have the
case or a family syndrome. In the presence of a genetic mutation it is ability of inhibiting RET and vascular endothelial growth factor receptor
necessary to exclude the presence of pheochromocytoma or parathyroid (VEGFR), and other kinases, and have been used in DTC. By contrast,
hyperplasia, in order to treat them appropriately also. In cases of known axitinib39 and pazopanib40 seem to act only as anti-angiogenic agents.
mutations in RET in early childhood, prophylactic thyroidectomy can be Nowadays, the most relevant are treatments directed to tyrosine kinase
recommended.7 The initial surgery is mainly total thyroidectomy. Level VI receptors that bind for a wide variety of ligands. Several specific targeted

EUROPEA N EN DOCR IN O LO G Y 25
Endocrine Oncology Thyroid Carcinoma

molecules on DTC and MTC are in development, with demonstrated but this kind of presentation is very unusual for this cancer. For patients
activity in phase II trials. with ATC, the prognosis is very poor, with an overall survival of about
36 months. Patients with localised disease not amenable to surgical
The proportion of patients achieving partial responses approaches resection can be treated with neoadjuvant chemoradiotherapy, but the
50 %. However, toxicities from these targeted drugs are substantial, role of this treatment modality is still debated.
and outcome data available up to this point have all come from single-
arm studies. Consequently, important questions about the effects of There are few active compounds against ATC; the combination of
these treatments on overall disease trajectory and mortality remain doxorubicin and cisplatin has been the standard for many years. At the
unknown. Among these, the only one that has been evaluated in a present time, paclitaxel plus a platinum compound (often carboplatin)
phase II (DTC) and III (MTC) randomised, placebo trial with demonstrated also appears to have efficacy. With regard to biological drugs, axitinib,
utility is vandetanib, so this will be the drug of choice when it becomes combretastatin A4, sorafenib and imatinib have been tested in clinical
available.35,36 A phase III trial of cabozantinib (XL184) versus placebo trials, with encouraging activity. The results from several ongoing
is also finished in MTC and is also available in the US. However, in the clinical trials on ATC will hopefully expand the limited therapeutic
absence of approved drugs, off-label use of commercially available armamentarium for this deadly disease. A number of thyroid trials have
drugs, such as sorafenib or sunitinib, is fully justified.41 been conducted: combretastatin, sorafenib, pazopanib and AG-013736
(phase II), and PPAR-g agonist (CS-7017) paclitaxel (phase I/II). Four
The results bolster the already substantial body of clinical-response clinical trials were open in Europe (sunitinib, pemetrexed, paclitaxel
data attained from single-arm trials of kinase inhibitors that suggests and bevacizumab doxorubicin), without preliminary data. The tyrosine
progress is being made towards improving outcomes in 131I resistant kinase inhibitor axitinib also yielded no responses in two treated ATC
DTC. Treatment with kinase inhibitors confers risks and potential patients. Gefitinib, an epidermal growth factor receptortargeted kinase
benefits that, at a minimum, require careful selection of patients. inhibitor similarly produced no responses in five treated ATC patients
Nevertheless, evidence continues to accumulate to suggest an apparent although one had stable disease for 12 months. However, in a trial of
beneficial role for the use of kinase inhibitors in selected patients who the kinase inhibitor imatinib, two of eight evaluable patients attained a
have progressive 131I resistant DTC or in MTC. Although more work partial response.8
is needed to better clarify which patients with differentiated thyroid
cancer might have the greatest net benefits from kinase inhibitors.42 The success of treating ATC will probably require approaches that
may involve a comprehensive molecular analysis combining genome-
Treatment of Anaplastic Thyroid Carcinoma wide screening with high throughput screens for druggable targets.
Patients with ATC who present with a rapidly expanding neck mass Individualised combination therapies that maximally inhibit major
require rapid histopathologic confirmation of the diagnosis. There are pathways and signalling nodes at multiple genetic and epigenetic
numerous genetic and epigenetic abnormalities detected by mutations levels, possibly incorporating developing delivery systems such as
and methylation analyses, array comparative genomic hybridisation gene and virus therapies, and nanoparticles, will hopefully improve the
(array CGH), microarray, microRNA and protein expression, providing outcome for patients with ATC.4547
ample opportunities for drug discoveries. If ATC is diagnosed, the
patients overall clinical status and TNM stage of the tumour should be Conclusions
determined. Treatment goals (aggressive versus supportive care), should In the last few years, the management of thyroid nodules and thyroid
be established by disclosing the status and risks/benefits, discussing the cancer has changed with new perspectives for the future. First, with the
patients values and preferences, and then having the patient make an implementation of a consensus and a guideline for the management of
informed decision. Patients with stage T4a resectable disease have the thyroid nodules and thyroid cancer. Second, with the consideration of
best long-term survival, particularly if a multi-modal approach (surgery, a more conservative approach for most patients with thyroid nodules
intensity-modulated radiotherapy for locoregional control and systemic that are cytologically indeterminate on FNA and benign according to
therapy) is used.43,44 Patients with unresectable stage T4b disease may gene-expression classifier results. Third, with the results of two studies
also respond to aggressive multi-modal therapy. Patients with distant that propose the use of recombinant human TSH and low 131I dose,
metastases only rarely have responded to traditional therapies, and if an 30 mCi (1.1 GBq) for post-operative ablation that may be sufficient for
aggressive approach is desired by the patient, a clinical trial should be the management of low-risk thyroid cancer. Four, with the knowledge
considered. Hospice or palliative care is also an important component of genes, coding the signalling cascade proteins that are mutated or
of managing patients with distant metastasis. Healthy patients with aberrantly expressed in thyroid cancer. This ability to investigate tumour
localised disease who tolerate full- dose irradiation can potentially biology would allow for the selection of different drugs. As consequence,
benefit from prolonged survival. Current therapeutic options for ATC are several potential targets for therapy have been defined in DTC, MTC and
unsatisfactory. Surgery followed by chemoradiotherapy can significantly even in ATC, and these drugs represent new therapies for advanced
prolong the survival of patients carrying small, intra-thyroidal tumours, thyroid carcinoma. n

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