Download PHARMACOTHERAPY IN METASTATIC THYROID CANCER

PHARMACOTHERAPY IN
METASTATIC THYROID
CANCER
VOICHIŢA MOGOŞ
Differentiated thyroid cancers may be
among the most effectively treated
malignancies in patients present with
disease localized in the thyroid bed. In
this stage the disease may be cured or
contained indefinitely with surgery
combined with radioiodine thyroid
remnants ablation where indicated.
10 % of thyroid cancer patients either
present with advanced disease or later
have recurrences after primary therapy.
Advanced thyroid cancer is defined as:
Presence of distant metastases not including cervical lymph node
metastases
Recurrent locally invasive disease of the neck
According to American Association Joint Committee on Cancer
Classification advanced thyroid cancer includes:
• Stage IV disease
• Stage II disease (distant metastases) in patients
older than 45 years .
• Any occurrence of anaplastic thyroid cancer is also
considered a advanced disease because of its
extremely poor prognosis even after aggressive
surgical resection
70
papillary
follicular
mixeddif/anaplastic
anaplastic
medullary
60
50
40
30
20
10
0
nodule
nodule/lymph node
multinodular
multi/lymph nodes
lung meta
bone meta
Clinic of Endocrinology – Iasi: 326 cases of thyroid cancer – clinical data at
presentation
Most important sites of
metastases in DTC
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lung - 45 %** - 49 %*
bone only- 24%*- 39 %**
other single sites – 4 %**- 8%*
multiple sites – 12 %**- 19 %*
papillary cancer in 51 % of cases
follicular cancers in 49 % of cases
Clinical symptoms in patients with metastases from DTC
(differentiated thyroid cancer) may be present especially
from bone metastases: swelling, pain , fractures (80 %)
Hag M., Harmer C.: Clin.Endocrinol.(Oxf), 2005, v.63, nr.1, pp: 87-93
Samson E., Brieley J., Le LW., Rotstein L., Thang RW.Cancer 2007, v.110, nr.7, pp: 1451-1456
Prognostic factors in patients with
metastastatic DTC at the time of
diagnosis
• age 100 % survival before 45 years and 62 %
survival after 45 years
• site of metastases : bone metastases or brain
metastases are of worse prognosis
• histology: papillary – 75 %, follicular – 62 %
• iodine avidity of metastases: iodine avid – 82 %,
non iodine avid – 57 %
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3 years actuarial survival - 69 %
5 year actuarial survival - 50 %
5 year disease - free patients - 16 %
71 % of death are produced by disease progression
120
100
80
StageI
Stage II
Stage III
Stage IV
60
40
20
0
0
5 years
10 years
15 years
Treatment of advanced DTC
Patients with advanced thyroid cancer have a few therapeutic
options for effective disease control
• 131 I therapy is the mainstay of initial therapy for advanced
differentiated thyroid cancer . Unfortunetely the metastatic
disease is frequntly unresponsive either primary or secondarily
to radioiodine therapy.
•
•
•
•
Other modalities:
aggressive surgery
external beam irradiation
gamma knife radiosurgery may be useful in selected patients
especcialy in respect to symptom palliation
• chemotherapy
Morris JC., Bible KC., Smallridge RC.: Clinical trials for advanced thyroid cancer. Mayo Clinic Endocrinology
Update 2007,www.mayoclinic.org/endocrinology
Pacini F., Schlumberger M et al. Eur.J.Endocrinol. 2006, v.2, 154- 203
Samson E., Brieley J., Le LW., Rotstein L., Thang RW.Cancer 2007, v.110, nr.7, pp: 1451-1456
DTC – lung metastases
• In the case of radioiodine uptake treatment consists of 131 I
administration after prolonged suppressive T4 therapy withdrawal or
rhTSH
• 131 I activity ranges from 1.7 to 7.4 MBq or higher every 4-8 month in
the first 2 years and thereafter at longer intervals.
• WBS will be performed 2-5 days after iodine administration in order to
assess the response to treatment toghether with thyroglobulin
monitoring, thus quiding further treatment.
• WBS is not required before treatment because it does not modifie
indication for treatment and may induce stunning effect (reduction of
uptake of the subsequrnt therapeutic iodine dose).
• There is no maximum cumulative dose of radioiodine that can be
given in patints with persistent disease. However most remissions are
obtained with an activity equal or lower that 22 GBq (600 mCi
• Litium may be useful as an adjuvant therapy of metastatic DTC
increasing accumulation and retention of radioiodine in the lesion.
Pacini F., Schlumberger M et al. Eur.J.Endocrinol. 2006, v.2, 154- 203
DTC – bone metastases
• Bone metastases may be treated with a combination of
surgery and 131 I.
• When 131 I is taken in the metastases - 100-150 mCi of
131 I every 4-6 month, the effectiveness of higher doses
remaind to be demonstrated. The success of the therapy
depends of the effective half-life of radioiodine in the
tumor.
• Other therapies for bone metastases include: external
beam iradiation, bisphosphonates, embolisation and
cement injections.
• Palliative surgery for bone metastases when there are
neurological or ortopedic complications is usefull to
debulk large tumors anf may be curative in patients with
a single of a few bone metastases
Pacini F., Schlumberger M et al. Eur.J.Endocrinol. 2006, v.2, 154- 203
DTC brain matastases
Brain matastases are rare .
• When possible they will be resected and if
non iodine avid or non resecatable
external beam irradiation may provide
palliation. Usually they carry a worse
prognosis, having a mean post treatment
survival of around 12 months.
Thyrotropin suppressive therapy
Rationale and recommendations for THS suppressive
therapy:
• to inhibit THS –dependent growth of thryroid cancer cells
by decreasing TSH levels to less than 0.1 mIU/L
• TSH suppressve therapy is manditory in patients with
persistent disease including those with detectable levels
of thyroglobulin and no signs or symptoms and in high
risk patients for 3-5 years.
• Adverse events of THS suppressive therapy:
thyrotixicosis and bone loss
Human Recombinant TSH for diagnostic and
therapeutic purposes in DTC
Protocol for hr TSH adminsitration prior diagnostic or therapeutic
131 Iodine administration
• 0.9 mg hrTSH day 1 and 2
• 131 Iodine id given day 3
• TG measurements in days 1-3-5
• WBS in day 5
Adverse effects of hrTSH:
• nausea
• fatique
• headache
• No toxicity and antibodies directed against hrTSH have been seen.
hrTSH provides a stimulation of tumor cells as good as T4 withdrawal.
WBS
131 I
Duntas LH et all. Hormones 2003, 2(3), 169-174
hrTSH
• preserves quality of live of patients avoiding prologend
hypothyroidism
• decreases morbidity associated with prolonged thyroid
hormones withdrawal
• it is indicated in patients unable to rise endogenous TSH
and in those in whom prolonged withdrawal is
contraindicated
• in patients with spine metastases and spinal cord
compression a short course of high dose corticoisteroids
will avoid worsening of neurological symptoms
• hrTSH is particularly suitable in advanced reccurent or
metastatic DTC, and in patients who are intolerant to
TSH stimulation by L4 withdrawal
Stategies to enhance 131 I uptake and retainment into
DTC neoplastic cells
Litium therapy: 300 mg 3 times per day or 10 mg/kg.bw
Redifferentiation in iodide non –avid DTC
– Retionoids are derivatives of vitamin A(retinol) that increase NIS
mRNA expression and iodide uptake in thyroid cancer line cell. They
bind to RXR retinoid nuclear receptor that regulates cell growth and
differentiation. In clinical trial retionoic acids reestablish iodide transport
in 20-50 % of cases. Recommended doses are of 1-1.5 mg/ kg / day of
isotretinoin or 300 mg per day bexarothene prior to 131 I uptake
– Histone dyacethylase inhibitors indice through a unclear mechanism
cell cycle arrest and dedifferentiation. Thay reestablish NIS expression,
Tg mRNA and iodide accumulation
– Valproic acid inhibits histone dyacetylase
– Gene therapy is directed to introduce NIS code into less differentiated
thyroid carcinoma cells by using a viral vector carrying the gene
Chemotherapy
Classic chemotherapy has a little or no role in the management of
advanced differentiated thyroid cancer. I is restricted to patients with
progressive disease, uncontrolled by surgery and 131 iodine
therapy.
• Studies with chemotherapy in radioresistant DTC are limited.
• Single agent doxorubicin or a combination of doxoribicin and
cysplatin provide a 10-20 % partial and transient response without
impact on prolonged survival in patients with metastatic DTC..
Recommanded doses of doxorubicin are 60-70 mg/m2 every 3
weeks.
Cysplatin and epirubicyn is another possible chemotherapy regimen
• Combined chemotherapy using carboplatin and epirubicin under
THS endogenous or exogenous stimulation demonstrated a rate of
complete and partial response of 37 %.
• Anthracycline may be indicated in patients wit bone nonfunctioning
metastases with progressive disease.
Novel therapies and clinical
trials for DTC
Target therapy is a new generation of anticancer
treatment which planned to interfere with specific
molecular targets, tipically a protein that is believed to
play a crucial role in tumor growth and progression.
Tumor progression is associated with more aggressive
behavior, metastatoc spread, loss of iodine uptake
ability that makes tumor resistant to conventional
therapies.
1. Oncogene inhibitors
2. Angiogenesis inhibitors
3. Modulators of growth or apoptosis
Cooper DS, Doherty GM et all. Thyroid, 2006, 16, 2, pp 4-22
Coelho SM et all. Arq.Bras.Endocrinol.Metab.2007, 51, 4, 612-624
Coelho Sm et al. Arq.Bras.Endocrinol.Metab.2007, 51, 4, 612-624
Strategies to inhibit RET. The different
steps involved in RET activation,
regulation, and synthesis are
schematically depicted. Each step is
associated with a potential means of
inhibition for therapy.
1, Ligand binding and formation of
ligand-GFR complex (antagonists,
antibodies);
2, receptor dimerization (inhibitors);
3, autophosphorylation (tyrosine kinase
inhibitors)
4, recruitment of adaptor proteins
(phosphatases, inhibitors of proteinprotein interaction)
5, intracellular signaling (various
inhibitors)
Jan Willem B. de Groot, Thera P. Links, John T. M.
Plukker, Cornelis J. M. Lips and Robert M. W.
Hofstra: RET as a Diagnostic and Therapeutic Target
in Sporadic and Hereditary Endocrine Tumors
Endocrine Reviews 27 (5): 535-560
6, internalization and nuclear
translocation (antibodies, inhibitors);
and
7, biosynthesis (gene therapy, RNAi).
ONCOGENE INHIBITORS
RET tyrosine kinase inhibitors in DTC
• YD6474 – Zactima acts as antiangiogenic,
RET blocking agent and inhibits EGFR
(tested in PTC cell lines)
• Pyrazolopyridines PP1 and PP2
• indolocarbazole derivatives inhibit RET in
MTC cell lines
• Sorafenib (BAY 43-9006) multikinase
inhibitor inhibitsd RET/PTC
autophosphorilation
BRAF inhibitors
• BRAF kinase belongs to the RAF family of
serine/threonine kinases ( BRAF – MAPK
– ERK pathway) 36-69 % of PTC carry a
point BRAF mutation.
• Sorafenib was tested in advanceed PTC
and anaplastic thyroid cancer
• Antisense nucleotides designed to inhibit
C-RAF ISIS 5132 (phase I study)
RAS inhibitors
RAS is a GTP-binding protein involved in
cell proliferation and survival. Mutations of
RAS have been reported in thyroid cancer
• ISIS as first generation antisense
nucleotide
• Farnesyl transferase inhibitors inactivate
RAS
• Tipifarnib, Lonafarnib, Manumicin and
paclitaxel
Other oncogene inhibitors
MEK inhibitors
• CI – 1040
• PD 03225901
• ARRY – 142886
NTRK1 incodes for a high afinity receptor for NGF and its interraction
with NGF is blocked by CEP – 701
Akt/mTOR (Akt/ mammalian target of rapamicin) acts through IP3
pathway.
- rapamicin ( Sirolimus)
- LY 294002 inhibitor of IP3 pathway was used in MTC cell lines
Angiogenesis inhibitors
Inhibitors of VEGFR
VEGF-R is the most prominent factor involved in tumor
angiogenesis and is overexpressed in poorly
differentiated and metastatic DTC
• recombinant human monoclonal antibodies against
VEGF reduce angiogenesis
• Semaxanib , Vatalanib and Axitinib (USA clinical trial) are
VEGFR inhibitors and tyrosine kinase inhibitors
• ZD6474 inhitis VEGF, RET oncogene an MEN 2a and 2
b
• Combrestatin is a tubulin –binding protein inhibitor with
vascular targeting properties
Inhibitors of EGFR
EGF-R is overexpressed in PTC and associated with poor
prognosis It. Acts through RAS-RAF MAPK cascade and
PI3 kinase pathway
• recombinant human monoclonal antibodies agains
EGFR - Mab 4253 was testes in PTC cell lines
• AG1478 is a tyrosine kinase inhibitor taht antogonises
EGF – mediated angiogenesis and local invasion
• Geftinib is a EGFR tyrosine kinase inhibitor in phase II
clinical trial for iodine refractary DTC and advanced DTC
• Irressa (ZD1830) is a tyrosine kinase inhibitor that blocks
EGFR
Inhibitors of EGFR
• Thalidomide is an antiangiogenic factor was
used in a phase II clinical trial including follicular,
insular carcinoma refractory to radioiodine and
MTC with distant metastases. 800 mg tolerated
dose induced partial response in 18 % and
stable disease in 32 % of cases with a median
survavil of 23.8 months for responders and 11
months for non-responders
• Lenalidomide – immunomodulatory,
antiangionegesis, clinical trial in USA
Modulators of growth or apoptosis
HSP 90 is a multichaperone protein complex that mediates maturation and
stability of different proteins involved in tumorigenesis: BRAF, Akt, CRAF,
Her-2, EGFR, p53. Inhibition of HSP90 lead to degradation of these proteins
and interruption of signal transduction that is essential for tumor
progression.
HSP 90 inhibitors:
• Geldamicin and ist derivatives 17 AAG and 17 DMAG ( phase I/II clinical
trials)
• Macrolide radicicol and its derivative
• Cysplatin
• Novobiocin
Tumor necrosis factor-related apoptosis inducing ligand TRIAL activates
apoptosis by acting on its receptors TRIAL R1 and TRIAL R2 ans caspase
pathway. TRIAL-induced apoptosis is inhanced by cycloheximide and
paclitaxel
Proteazome inactivators
• Bortezomib (USA clinical trial)
Modulators of growth or apoptosis
Tiazolidindione and derivatives
PPAR is considered a tumor suppressor factor. PAX8/ PPAR
fusion oncogene was seen in follicular carcinoma and
supresses wild type PPARactivity.
• Troglitazone and rosiglitazone (USA clinical trial) inhibit tumor
cell growth and upragulate NIS mRNA.
• High afinity PPAR agonist RS5444 produces growth inhibition
in anaplastic thyroid cancer cell lines. PPAR agonists induce
reversion of epidermal/mezenchymal transition which is critical
for anaplastic transformation of differentiated thyroid cancer.
They also increase cyclin-dependent apoptosis, increase
cyclin-dependent kinase inhibitors P21 and P27, decrese BcL-x
expression and decrease caspase 3 and caspase 7 activity.
• Cyclooxigenase 2 inhibitors
• Activation of COX 2 is overexpressed in different malignancies
including thyroid carcinoma. A phase II clinical trial with
celocoxib failed to prove any rezults in advanced thyroid
cancer
Other targeting therapies
Demetilating agents. Reducing aberant metilation of gene
promoters that inhibit gene expression and is associated
with loss of NIS, failure of 131 I treatmetn and
aggressive behavior of DTC may be achieved by:
• 5 azacytidine
• 5 azo 21 deoxycytidine, decitabine (USA clinical trial)
• sodium butirate, phenylbutirate and phenyacetate that
act through unknown mecanisms to induce NIS
expression and iodine uptake
Coelho SM., Pines Carvalho D., Waisman M.: Arq. Bras. Endocrinol. Metab. 2007, v.51,nr.4, 612-624
Gene therapy
Viral vectors were used to introduce
NIS gene
• Wt (wild type) p53 gene that is critical regulator of cell
cycle progression by activation the cascade of events
that lead to apoptosis.
• Prodrug suicide gene therapy
• Thymidine kinase gene is introduced within the cells and
placed under the control of thyroglobulin gene promoter
that is expressed only in thyroid cells. Once activated
thymidine kinase is able to react with Ganclyclovir
resulting in DNA strand breaks and subsequent cell
death.
Treatment of advanced MTC
Classical chemotherpy
• Doxorubicin, bleomicin, caboplatin, cyclophosphamide,
DTIC, epirubicin, etoposide, 5 fluorouracil, methotrexate,
streptozitocin, vincrisine, vinsine.
• Combinations of drugs:
• DTIC + 5FU + epirubicin
• DTIC + cyclohosphamide+ vincristine
• Complete response: 3 %
• Partial response : 24 %, no benefit for survival.
• Embolisation of liver metastases is associated with
regression of metastases and stabilization of the
disease in 60 % of patients
• Somatostatin analoques have not proven efficacy
Immunotherapy
Principles of immunotherapy:
• Stimulation of physiological immune response to tumor antigens
• To stimulate physiologic immune response by transfering dendritic
cells able to combating , calcitonin, CEA. Dendritic cells are known to
present antigens and induce immune response.
• To transfer immunostimulatory substances
Vaccination with mature dendritic cells.
It may be used in MTC patients not curecd by surgery. 2 studies
performed with this treatment showed radiological response ( tumor
reduction by 50 % assesse by Xray) in 1/7 and 4/10 patients, and
biological response (reduction of CEA and calcitonin) in 3/7 and 7/10
patients. Hormonal and radiological stabilization of the disease was
noticed in 4/7 and 3/10 patients. Treatment has a good tolerability.
Transfer of immunostimulatory substances
• Studies on murine models were performed by introducing IL2 or IL12
into MTC cells by adenoviral vectors (murine model)
Vezzosi D., Bennet A., Caron P.: Ann.Endocrinol.(Paris), 2007, v.68, pp:147-153
Radioimmunotherapy
• Intense expression by MTC cells of CEA allowed the use of anti
CEA antibodies labeled with 131 I to target these cells. 9-30
treated patients were followed 12-121 months. Modereate
regression (less than 50 %) was noticed in 7-29 %, and stable
tumor in 35-73 %.
• Combined treatment with myelodepressant labeled anti-CEA
antibodies coupled with autologous graft of hematopietic cells
rezulted in reduction of tumor size in 10 of 12 treated patients.
Vezzosi D., Bennet A., Caron P.: Ann.Endocrinol.(Paris), 2007, v.68, pp:147-153
anti CEA
Ab
131I
or 90 Y
MTC
cell
CEA
CEA Ab
labeled
haptene
131I
CEA
In labeled
Ab
haptehe
Bivalnt
antibodies
Treatments targeting RET gene
or protein
Germ line RET mutation are found in 95 % of hereditary MTC and 40-70 of sporadic
MTC Ocogenic activity of RET may be inhibited by: dominant negative RET
mutants that will create a RET protein without oncogenic activity or thyrosine
kinase inhibitors, inhibitors of RET proteinkinase or inhibition of tumorigenic
patways upstream of tyrosine kinase
Dominant negative RET mutants
• Adenoviral vectors expressing dominant negative RET mutants have being used
in some studies. Their use results in reduced quantity of RET protein at cell
surface and reduced oncogenic capacity of RET
Thyrosine kinase inhibitors
• ST 15 71, Imatinib (Glivec) reduces tumor size in animal model but the
concentration needed to induce clinical efects in humans seems to be too high.
Recently good rezults have been reported with Imatinib 600 mg per day in 9
patients
• A phase II study combining tyrosine kinase inhibitor Imatinib with chemothrapy
(dacarbazine and capecitabine are now in trials)
• Other potential target agents: erlotinib, sorafenib, vandatinib, irinotecan (clinical
trials) , bevacizumab.
• Other combined therapies associate a RET tyrosine kinase inhibitor (Glivec)
with FGFR tyrosine kinase inhibitor
Other alternatives to inhibit RET oncogenic activity
• Use of riboyzmes (catalitic molecules) directed against mutated RET mRNA
Other treatments
Use of suicide genes
The suicide gene system involves a combination of herpex
simplex virus type thymidine kinase and ganciclovir.
Phisiologically, intracellular kinases will convert
ganciclovir monophosphate in ganciclovir triphosphate
wich in toxic for cells. In animal models the suicide gene
therapy was effective in 75 % of cells.
COX 1 and COX 2 inhibitors – indometacin could induce
inhibition of tumor growth and calcitonin secretion in
mTC cell lines.
Radioiodine therapy following iodine symporter (NIS)
gene expression induced by a viral virus.
Vezzosi D., Bennet A., Caron P.: Ann.Endocrinol.(Paris), 2007, v.68,
pp:147-153
Treatment of anaplastic thyroid
cancer
47 % of cases present with syncronous metasteses at diagnosis
Classic chemotherapy
Japanese Society of Thyroid Surgery
• Cysplatin: 40 mg/m2 + etopiside: 60 mg/m2 + etopiside: 100mg/m2 +
peplomicine 5 mg for 3 days preoperatively with GCSF (Ganulocyte
Colony Stimulating Factor to prevent a risky granulocyte decrease).
Survival: 3-11 month ofter treatment
• Ausperger 9 (1990): Vinblastine, cysplatine, doxorubicine and
mitoxantrone. Survival: 9 % after 1 year
• Schlumberger (1991): chemotherapy as sensitizer for external beam
therapy:
• Before 45 years: doxorubicine 60 mg/m2 and cysplatine 90 mg/m2
• After 45 years> mitoxantrone 14 mg. 5 complete response with 3
patients survived more than 20 month
• Tezelman (cit.Giufrida 2000): Bleomicine and flurorouracyl 2 hours
before each dose of radiotion therapy
• Kebebew E. 2005: hiperfractionated radiotherapy with 100cGy 4 times
a day to the dose of 3600 cGy associeted with doxirubicine
• Doxorubicin and paclitaxel
Treatment of anaplastic thyroid
cancer
• Proteayome inhibitors: bertozonib alone ore in
association with TRIAL
• Inhibitors of VEGFR: Semaxanib and Vatalanib (USA
clinical trial) are VEGFR inhibitors and tyrosine kinase
inhibitors
• Sorafenib (RAF kinase) USA clinical trial
• Combrestatin (angiogenesis inhibitor) USA clinical trial
Gene therapy adenoviral mediated:
• p 53 tumor suppressor gene: inhibits cell proliferation
and restors Tg gene, thyroperoxidase and TSH receptor
genes
• cr6/Gadd45 tumor suppressor gene
Conclusions
• Conventional chemotherapeutic agents have
shown not substantive activity in differentiated
thyroid cancer and MTC
• Researces directed at defining genetic and
signaling patways deffects in different cancer
types including thyroid cancer improved
understanding of the pathogenesis of thyroid
cancer and made possible to design and
develop of agents that specifically target these
deffects and pathways.
Drug/ agent
Disease
target
Primary site
Tanespimycin
(17 AAG)
DTC
HSP90
Mayo Clinic Rochster
and Mayo Clinic
Jacksonville
Decitabine
DTC
DNA methylation
MD Anderson
Centre
Bortezomib
DTC
Ubiquitinproteasome pathway
Memorial Anderson
Cancer Centre
Romidepsin
DTC
Hystone deacetylase
Memorial Sloan
Kettering Cancer
Centre
Rosiglitazone
DTC
PPAR
University of
California San
Francisco
Irinotecan
MTC
Topoisomerase
Jonh Hopkins University
Sunitinib
DTC/MTC
Multikinase
University of Chicago
Combrestatin
ATC
Angiogenesis
Case Western Reserve
University
Sorafenib
ATC
Multikinase
(RAF-kinase)
Case Western Reserve
University
Sorafenib
MTC
Multikinase
(RAF – kinase)
Ohio StateUniversity
Lenalidomide
DTC
Immunomodulatory
Angiogenesis
University of Kentuky
Imatinib
ATC
Multikinase
University of Michigan
Axitinib
DTC
VGFR inhibitor
Multicenter trial
Vandatinib
MTC
RET protooncogene
Mayo Clinic Rochester
and Mayo Clinic
Jacksonville
Cancer
www.cancer.gov/search/clinical_trials
Suggestion reading
•
•
•
•
•
Coelho SM., Pines Carvalho D., Waisman M.: New perspective in the
treatment of differentiated thyroid cancer. Arq. Bras. Endocrinol.
Metab. 2007, 51 (4), 612-624
Cooper DS, Doherty GM., haugen BR., Kloos RT., Lee SL., Mandel SJ.,
Mazzaferri EL., Melver B:; Sherman SI and the American Thyroid
Association Guidelines Taskforce: Management Guidelines for
patients with thyroid nodules and differentiated thyroid cancer
Thyroid. 2006. v. 16 (2) , 4-25
Pacini F., Schlumberger M., Dralle H., Elisei R., Smit WA., Wiersinga W.
And the European Thyroid cancer Task Force: European Consensus
for the management of patients with differentiated thyroid cancer of
the follicular epitelium Eur. J. Endocrinol. 2006, v.2, pp: 154-203
Schlumberger M. : Papillary anf follicular thyroid carcinoma, Ann.
Endocrinol. (Paris). 2007, 68, 120-128
Vezzosi D., Bennet A., Caron P.: Recent advances in treatment of
medullary carcinoma Ann.Endocrinol.(Paris), 2007, 68, 147-153