Management of Advanced Medullary Thyroid Carcinoma

Melvil Šabani, Drago B Jelovac, Milan B Petrović, Miodrag Gavrić

Melvil Šabani, Drago B Jelovac, Milan B Petrović, Miodrag Gavrić, School of Dental Medicine, Clinic for Maxillofacial Surgery, University of Belgrade, Dr Subotića 4, 11000 Belgrade, Serbia.
Melvil Šabani, Department of Medicine, Clinique de Genolier, 3 Route du Muids, 1272 Genolier, Switzerland

Correspondence to: Melvil Šabani, MD, DMD, School of Dental Medicine, Clinic for Maxillofacial Surgery, University of Belgrade, Dr Subotića 4, 11000 Belgrade, Serbia
Email: melvils94 @hotmail.com
Telephone: +381-64-074-00-02
Received: April 29, 2014
Revised: July 9, 2014
Accepted: July 15, 2014
Published online: August 18, 2014


Thyroid cancer is a common endocrine tumor that is somewhat on the increase in the United States. Medullary thyroid carcinomas are relatively uncommon thyroid malignancies. Despite the fact that medullary thyroid carcinoma is considered to be a rare disease, it is the subject of prolific research activity. Approximately three-fourths of cases of medullary thyroid carcinoma are sporadic, one-fourth is hereditary and may be a part of a multiple endocrine neoplasia 2A, 2B or a familial medullary thyroid carcinoma without associated endocrinopathies. Altered molecular pathways in tumoral cells contribute to the progression of the disease. There is no curative treatment for advanced medullary thyroid carcinoma. Currently, two new multi-tyrosine kinase inhibitors have been approved by the United States Food and Drug Administration and the European Medicines Agency. Both are recommended for the systemic treatment of selected patients with MTC. Patients who cannot benefit from multi-tyrosine kinase inhibitors could be incorporated in clinical trials using other targeted therapies. The over-expression of cholecystokinin type “brain” receptors, renamed by an International Union of Pharmacology committee as cholecystokinin type 2 receptors, was found in medullary thyroid carcinoma. Because of the fact that scintigraphy or positron emission tomography scans and peptide receptor radionuclide therapy match these type of receptors, they could be used in alternative diagnostic procedures and targeted therapy.

Key words: Medullary thyroid carcinoma; Tyrosine kinase inhibitor; Peptide receptor radionuclide therapy

© 2014 The Authors. Published by ACT Group Ltd.

Šabani M, Jelovac DB, Petrović MB, Gavrić M. Management of Advanced Medullary Thyroid Carcinoma. Journal of Tumor 2014; 2(8): 202-207 Available from: URL: http://www.ghrnet.org/index.php/JT/article/view/806


Thyroid cancer is the fastest-increasing cancer in both genders in the United States. 60,220 new cases were expected in 2013[1]. Risk factors for thyroid cancer are: history of goiter, thyroid cancer in the family, exposure to radiation in childhood, being female, rare genetic syndromes and abnormal genes[1]. Medullary thyroid carcinoma was described for the first time in 1959 by John B. Hazard et al[2]. They reported the presence of 21 cases of MTCs among 600 thyroid carcinomas removed surgically between 1926 and 1957 at Cleveland Clinic in Ohio. MTC represents 3.5% of all reviewed cases of thyroid carcinomas[2], and is considered as a rare disease. The prevalence of MTC in the European Union is 1/14,300[3]. Despite this fact, MTC is today at the centre of prolific research activity.

Diagnosis of MTC

MTC is usually present as a thyroid nodule[4] or a palpable cervical lymph node. The functional status of the thyroid nodule is inactive or "cold" during radioactive iodine scanning, because MTC derives from parafollicular thyroid cells which synthetize and secrete calcitonin (Ct) taking their origin from transformed neural crest-derivating C-cells. The diagnosis of MTC can be made by fine-needle aspiration biopsy (FNAB) followed by detection of amyloid and if necessary by Ct immunohistochemical staining. Ct is considered as a tumor marker of MTC in preoperative screening and postoperative follow-up[5-7]. Routine screening of Ct should be included in the diagnostic management of a thyroid nodule[8]. Risk for MTC was estimated as extremely high when the value of basal serum calcitonin (bCt) is up to 100 pg/mL[6-7]. Approximately three-fourths of cases of MTC are sporadic, one-fourth is hereditary and may be a part of Multiple Endocrine Neoplasia (MEN) 2A, MEN 2B or Familial MTC (FMTC) without associated endocrinopathies[6]. In molecular diagnosis of MTC the presence of Rearranged during Transfection (RET) pro-oncogen germline or somatic mutation should be always investigated[9] because in hereditary MTC, RET germline mutation is found in 100% of cases and in sporadic MTC, RET somatic mutation is found in 40% of cases[9]. The behaviour of the MTC depends on its molecular profile[10]. In sporadic MTC, RET (M918T, exons 16, 10, 11) screening should be performed. If it proves negative, RAS (H-and K-RAS) somatic mutation should be also investigated[9].

Treatment of MTC

Treatment of MTC can be surgical, systemic or both. Thyroidectomy with central compartment and ipsilateral or bilateral lateral neck dissection is the appropriate surgical treatment for MTC. Dralle and Machens[11] recommended performance of an ipsilateral lateral neck dissection with a bCt level of 20-200 pg/mL and a bilateral dissection with a bCt level of up to 200 pg/mL. Before the presence of any detectable MTC is established, prophylactic thyroidectomy could be indicated after early screening by genetic testing. According to some authors, prophylactic surgery should be performed for patients with RET mutation codons 883 (at 1 month of age), 918 (at 6 months of age), 611, 618, 620, 634 (at 5 years of age), 609, 630, 768, 790, 791, 804 and 891 (at 10 years of age)[12]. The American Thyroid Association has recommended a list of RET mutations codons and, accordingly, a treatment timetable for each of them[13].

Progression of the disease and diagnosis of recurrent MTC

Among the molecular pathways that contribute to MTC tumorigenesis, heterogeneous RET mutation has been described as an important factor in the progression of the disease[14]. Tyrosine kinase receptors (TKRs) such as Epidermal Growth Factor Receptor (EGFR), Vascular Endothelial Growth Factor Receptor (VEGFR) and Hepatocyte Growth Factor Receptor (HGFR) encoded by c-MET are implicated in MTC progression[15]. Some authors have reported a frequency of 7-23% of MTC with distant metastases at first clinical presentation[13]. One to two thirds of MTC patieFnts present clinically or radiologically recurrent disease within 10 years following initial treatment[16-17]. An increase in micro-MTCs has also been described in the literature[18]. MTC metastasizes generally in the lung, liver, bones and brain. Pain, fracture or spinal cord compression could occur with bone metastases[19]. Patients with increased bCt level during postoperative follow-up are highly suspect for recurrence of the disease and should be further investigated. CEA is the other strong tumor marker used during follow-up. However, according to some authors, surgical procedures may also induce an increase in serum doubling the times of both tumor markers[20]. A combined approach with 18F-FDG PET/CT and 18F-DOPA PET/CT or using 18F-DOPA PET/CT alone are currently the most appropriate form of investigation for detecting recurrent MTC with elevated tumor markers[21-25].

Current treatments of advanced and/or symptomatic MTC

The available treatments used for distant metastatic MTC are not curative. Vandetanib, a new multi-tyrosine kinase inhibitor (multi-TKI), is currently the systemic therapy of choice in advanced MTC. Patients with a significant MTC burden and symptomatic or progressive MTC are candidates for treatment with multi-TKIs[26]. Wells et al[22] reported in their randomized double-blind phase III trial that progression-free survival (PFS) rates was 30.5 months in patients treated with Vandetanib and 19.3 months in patients treated with placebo (Table 1). RET, VEGFR-2 and 3 and EGFR are targeted by this new multi-TKI. Pathways involved in tumor growth and angiogenesis are selectively inhibited by Vandetanib. Vandetanib is generally well tolerated[27]. The most important reported side-effect of Vandetanib was a prolongation of the ECG QT interval. For this reason patients need monitoring during treatment in order to detect an ECG QT prolongation. Other targeted therapies using TKIs are evaluated in ongoing clinical trials (19, table 1). Recently, Elisei et al reported in their phase III study that PFS was 11.2 months in patients treated by Cabozantinib and 4 months in patients treated by placebo (29, table 1). Key targets of Cabozantinib are RET, MET and VEGFR-2. Others authors also reported that treatment by Cabozantinib was effective in two patients with metastatic MTC. However they found that lower doses of Cabozantinib might be needed due to side-effects in order to improve tolerability of the therapy[28]. In their phase II study, Schlumberger et al reported that median PFS was 11 months in patients treated with Motesanib (TKI); Lam et al reported that median PFS was 17.9 months in patients treated with Sorafenib (TKI); De Souza et al reported that median PFS was 7 months in patients treated with Sunitinib (TKI) (Table 1).

Research and investigational treatments of advanced MTC

Research activities are focused on other possibilities of metastatic MTC treatment of which the efficacy and toxicity have to be evaluated.


Withaferin A (WA), a natural product withanolide, showed anti-cancer activity through multiple cytotoxic mechanisms and also has potential therapeutic effects against neuro-degenerative and inflammatory diseases[34]. Some authors in their pre-clinical studies used WA to demonstrate possible therapeutic effects in MTC treatment in vitro and in vivo. According to their findings, RET inhibitor activity of WA in MTC was observed[35]. Another group reported that WA used in vitro against anaplastic and papillary thyroid carcinomas in combination therapy with Sorafenib procured synergistic efficacy and less toxicity[36]. As mentioned above, Sorafenib was also evaluated in an ongoing clinical trial for treatment of progressive metastatic MTC[19].

Anticarcinoembryonic Antigen Pre-targeted Radioimmunotherapy (pRAIT)

During pRAIT, a bispecific monoclonal antibody (BsmAb) was first administered and bound to the surface of targeted tumor cells expressing CEA. A couple of days later a radio-labeled bivalent hapten was also injected in order to attach to the BsmAb. The non-targeted radioactive hapten localized in the circulation was rapidly washed out through the kidneys. pRAIT safety and efficacy will be improved by using new-generation trivalent BsmAb (anti-CEA TF2) and histamine-succinyl-glutamine (HSG) peptides. A prospective study phase II proved efficacy of this therapy in progressive metastasized MTC. Eligible patients for pRAIT should be those with a poor prognosis because of the significant hematotoxicity of this treatment[37].

Peptide receptor radionuclide therapy (PRRT/PRRNT)

A very high incidence (92%) and density of CCK-B receptors was found in MTC[38]. CCK-B receptors were also expressed in stromal ovarian cancers (100%), astrocytomas (65%) and small cell lung cancers (57%)[39]. According to the high incidence and density of CCK-B receptors and radiosensitivity of the tumor, patients with MTC are most eligible for PRRT[40]. Béhé and Behr reported partial remission in two human volunteers and stabilization of the disease in four human volunteers with advanced and rapidly progressing MTC treated by 90-yttrium-labeled minigastrin derivative (90-Y-DTPA-MG0). In this study CCK-B receptors were targeted. However two patients developed nephropathy 1-2 years after PRRT (41, table 2). Radionuclide 111-indium which showed less toxicity to kidneys was used instead of 90-yttrium in other preclinical studies. Fast and effective tumoral uptake, low retention in normal tissues and stability represent the criteria for eligibility of CCK receptor-targeting peptides[42]. According to committee of the International Union of Pharmacology regarding receptor nomenclature and drug classification, the CCK-A receptor and the CCK-B receptor have been renamed CCK1 receptor (CCK1R) and CCK2 receptor (CCK2R), respectively. A somatostatin receptor subtype 2 (sst2) is expressed on the surface of the tumor cells in MTC and also represents a target for PRRT. Iten et al reported in their phase II clinical trial benefits in long term survival in patients with metastasized MTC treated by (90Yttrium-DOTA)-TOC. Nine patients responded to PRRT, while 22 had no response (43, table 2). Budiawan et al illustrated in their study a partial remission in a patient with inoperable progressive MTC treated by (90Yttrium-DOTA)-TOC and (177Lu-DOTA)-TOC. They also reported stabilization of the disease in four patients and progressive disease in one patient (44, table 2). Bodei et al reported in their retrospective study complete remission in two patients treated by (90Yttrium-DOTA)-TOC, the response of which to PRRT was evaluated by conventional imagery (CT, MRI, US) and in one patient with follow-up using Ct. In the patients in which response to treatment was evaluated by Ct monitoring they found partial remission in five patients, stable disease in three patients and progressive disease in 12 patients. In patients evaluated by conventional imagery, they reported stable disease in 12 patients and no response in seven patients (Table 2).


Using FNAB alone (low sensitivity of cytological evaluation alone) in preoperative diagnosis of MTC could have an impact on preoperative evaluation and initial surgery in more than 50% of patients with MTC[45]. Screening of Ct should also be investigated[8]. Ct was used as a tumor marker of MTC in preoperative screening and postoperative follow-up[5-7]. Risk of MTC was estimated as extremely high with a value of basal serum calcitonin (bCt) >100 pg/mL. Patients with increased basal serum Ct level during the postoperative follow-up are highly suspect for recurrence of the disease and should be further investigated[5,7,8]. High basal serum Ct (bCt) level is not pathognomonic for MTC (normal limit: < 10 pg/mL)[6,7]. CEA is the other strong tumor marker used during follow-up. A combined approach with 18F-FDG PET/CT and 18F-DOPA PET/CT was considered as currently the most appropriate investigation in detecting recurrent MTC with elevated tumor markers. 18F-FDG PET/CT may complement 18F-DOPA PET/CT in patients with aggressive MTC[21-25]. Patients may be selected by PET with a somatostatin analogue labelled with gallium-68 for PRRT targeting somatostatin receptors[23]. Budiawan et al[44] reported in a clinical study that 68Ga-DOTA-NOC PET/CT and 177Lu-DOTA-NOC PET/CT were used in order to evaluate the somatostatin receptor density and treatment response in patients with residual/metastatic MTC. Gotthard et al[46] reported in a clinical study that gastrine receptor scintigraphy (GRS) was more effective in detection of MTC than somatostatin receptor scintigraphy (SRS) and 18F-FDG PET/CT. In pre-clinical studies Von Guggenberg et al[47] demonstrated that cyclic DOTA-minigastrin analogs are promising candidates for gastrin receptor scintigraphy and targeted radionuclide therapy. 68Ga-DOTA-MG0 is considered as a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors, which is more effective than conventional scintigraphy[48]. Advanced MTC treatment is only palliative. The currently available therapy consists of treatment with the new multi-TKIs. Patients with a hereditary or sporadic form of MTC can both benefit from Vandetanib (TKI) whether the sporadic form of MTC is M918T positive or negative. However, PFS analyses according to the RET mutation status are still controversial, thus causing uncertainty about the degree of benefit in patients with negative or unknown RET mutation status[27]. PRRT could represent promising alternative targeted therapy for progressive MTC. PRRT targeting somatostatin receptors has been used for over 15 years as an investigational treatment of neuroendocrine tumours (NETs). Nevertheless, PRRT is still not approved by the U.S. Food and Drug Administration (FDA). Bodei et al[49] reported less favourable results in PRRT targeting somatostatin receptors in treatment of MTC and dedifferentiated thyroid carcinomas. Some authors estimated that PRRT will be approved by the European regulatory body as a treatment of NETs within three years[50]. According to the high incidence and density of CCK-B receptors (CCK2R) and radiosensitivity of the tumor, patients with MTC could be the most eligible for PRRT[40]. However, Bläker et al[51] reported that CCK2R expression was not detected in advanced T3-, T4- and Mx-tumor stages. According to their study, they reported that CCK2R were expressed only in non-metastatic T1- and T2-stage tumors. In another study, the case of a patient with metastasized MTC was reported showing negative GRS and pentagastrin test despite high serum bCT level. The authors of this study thought that in this case CCK2Rs are missing or cannot bind gastrin agonists. In the same study, they also observed that GRS had detected distant metastasis in a patient with MTC and claimed that GRS in combination with CT was more effective than SRS. According to their opinion, CCK2R seemed to be expressed even in cases of MTC dedifferentiation[46]. PRRT could lead to nephropathy because of high absorbed doses delivered to the kidneys. Co-infusion of renal-protective agents such as positively charged amino-acids is mandatory during PRRT[52]. Thanks to the work of COST action BM0607 of the European Union, three optimal peptides (PP-FM, MGD5, cyclo-MG1) have been designed for peptide receptor radionuclide targeting of CCK2/gastrin receptor-expressing tumors, because of their low renal uptake and high accumulation in the tumor[53]. In Lausanne, Switzerland, a prospective clinical study was made to prove the feasibility of 3D radiobiological dosimetry treatment planning of PRRT in order to reduce nephrotoxicity[54]. CCK2-related peptides used in targeted therapy continue to be studied. A promising phase I clinical trial using a novel CCK-2/gastrin receptor-localizing radiolabelled peptide probe for both diagnosis and treatment of metastatic MTC is ongoing (55, table 2). Conventional chemotherapy regimens with Doxorubicin, Dacarbazine, Capecitabine and Fluorouracil have demonstrated only limited efficacy in patients with MTC. Tumor response in patients treated by different protocols using cytostatic drugs was reported, but no benefit was found for survival[57].


There is no curative treatment for advanced MTC.

Conventional chemotherapy protocols have showed only limited efficacy in patients with MTC and no benefit was found for survival.

Currently, the new TKIs that received approval from the U.S. Food and Drug Administration and European Medicines Agency are considered as the first-line systemic treatment for progressive MTC. Patients with advanced MTC who cannot benefit from approved TKIs could be incorporated in clinical trials using other targeted therapies. Because of the over-expression of CCK2 receptors in MTC (incidence and density over 90%) scintigraphy or PET/CT and PRRT targeted CCK2 receptors could represent promising alternative diagnostic tools and therapy.


The authors acknowledge our patient Sofija, who gave us inspiration to compile this paper. The authors acknowledge support from the Ministry of Education, Science and Technological Development of the Republic of Serbia: Project number: 175075.


There are no conflicts of interest with regard to the present study.


1 Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11-30

2 Hazard JB, Hawk WA, Crile GJR. Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab 1959; 19: 152-161

3 Niccoli-Sire P, Conte-Devolx B. Cancer médullaire de la thyroïde. Annales d’Endocrinologie 2007; 68: 325-331

4 Gharib H, McConahey WM, Tiegs RD, Bergstralh EJ, Goellner JR, Grant CS, van Heerden JA, Sizemore GW, Hay ID. Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970. Mayo Clin Proc 1992; 67: 934-40.

5 Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di Coscio G, Miccoli P, Pinchera A. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1994; 78: 826-829

6 Elisei R. Routine serum calcitonin measurement in the evaluation of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008; 22: 941-953

7 Toledo SP, Lourenço DM Jr, Santos MA, Tavares MR, Toledo RA, Correia-Deur JE. Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma. Clinics (Sao Paulo) 2009; 64: 699-706

8 Schneider C, Kobe C, Schmidt M, Kahraman D, Malchau G, Faust M, Schicha H, Dietlein M. Calcitonin screening in patients with thyroid nodules. Diagnostic value. Nuklearmedizin 2012; 51: 228-233

9 Elisei R, Alevizaki M, Conte-Devolx B, Frank-Raue K, Leite V, Williams GR. 2012 European thyroid association guidelines for genetic testing and its clinical consequences in thyroid cancer. Eur Thyroid J 2013; 1: 216-231

10 Cakir M, Grossman AB. Medullary thyroid cancer: molecular biology and novel molecular therapies. Neuroendocrinology 2009; 90: 323-348

11 Dralle H, Machens A. Surgical management of the lateral neck compartment for metastatic thyroid cancer. Curr Opin Oncol 2013; 25: 20-26

12 Rapkin L, Pashankar FD. Management of Thyroid Carcinoma in Children and Young Adults. Journal of Pediatric Hematology/Oncology 2012; 34: S39-S46

13 Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19: 565-612

14 Eng C, Mulligan LM, Healey CS, Houghton C, Frilling A, Raue F, Thomas GA, Ponder BA. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 1996; 56: 2167 - 2170

15 Gomez K, Varghese J, Jimenez C. Medullary Thyroid Carcinoma: Molecular Signaling Pathways and Emerging Therapies. Journal of Thyroid Research 2011; 2011: Article ID 815826, 10 pages, 2011. Doi:10.4061/2011/815826

16 Van Heerden JA, CS, Gharib H, Hay ID, Ilstrup DM. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for thyroid carcinoma. Ann Surg 1990; 212: 395-400

17 Leboulleux GS, Baudin E, Bellon N, Scollo C, Travagli JP, Schlumberger M. Long-term outcome of medullary thyroid carcinoma in patients with normal postoperative medical imaging. Br J Cancer 2003; 88: 1537-1542

18 Alevizaki M, Saltiki K, Rentziou G, Papathoma A, Sarika L, Vasileiou V, Anastasiou E. Medullary thyroid carcinoma: the influence of policy changing in clinical characteristics and disease progression. Eur J Endocrinol 2012; 167: 799-808

19 Almeida MQ, Hoff AO. Recent advances in the molecular pathogenesis and targeted therapies of medullary thyroid carcinoma. Curr Opin Oncol 2012; 24: 229-234

20 Papapetrou PD, Polymeris A. Medullary thyroid carcinoma surgical cytoreduction induces an increase in serum calcitonin and carcinoembryonic antigen doubling times. Exp Clin Endocrinol Diabetes 2012; 120: 164-168

21 Luster M, Karges W, Zeich K, Pauls S, Verburg FA, Dralle H, Glatting G, Buck AK, Solbach C, Neumaier B, Reske SN, Mottaghy FM. Clinical value of 18-fluorine-fluorodihydroxyphenylalanine positron emission tomography/computed tomography in the follow-up of medullary thyroid carcinoma. Thyroid 2010; 20: 527-533

22 Kauhanen S, Schalin-Jäntti C, Seppänen M, Kajander S, Virtanen S, Schildt J, Lisinen I, Ahonen A, Heiskanen I, Väisänen M, Arola J, Korsoff P, Ebeling T, Sane T, Minn H, Välimäki MJ, Nuutila P. Complementary roles of 18F-DOPA PET/CT and 18F-FDG PET/CT in medullary thyroid cancer. J Nucl Med 2011; 52: 1855-1863

23 Treglia G, Castaldi P, Villani MF, Perotti G, de Waure C, Filice A, Ambrosini V, Cremonini N, Santimaria M, Versari A, Fanti S, Giordano A, Rufini V. Comparison of 18F-DOPA, 18F-FDG and 68Ga-somatostatin analogue PET/CT in patients with recurrent medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging 2012; 39: 569-580

24 Treglia G, Rufini V, Salvatori M, Giordano A, Giovanella L. PET Imaging in Recurrent Medullary Thyroid Carcinoma. Int J Mol Imaging, v. 2012, p. 324686, 2012. ISSN 2090-1720.

25 Verbeek HH, Plukker JT, Koopmans KP, de Groot JW, Hofstra RM, Muller Kobold AC, van der Horst-Schrivers AN, Brouwers AH, Links TP. Clinical relevance of 18F-FDG PET and 18F-DOPA PET in recurrent medullary thyroid carcinoma. J Nucl Med 2012; 53: 1863-1871

26 Kloos RT. 2012 European thyroid association guidelines for metastatic medullary thyroid cancer urge restrained use of novel kinase inhibitors. Eur Thyroid J 2012; 1: 3-4

27 Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012; 30: 134-141 Erratum in: J Clin Oncol 2013; 31: 3049

28 Kapur S, Xia H, Zakowski MF, Hameed MR, Levin MB. Metastatic Medullary Thyroid Carcinoma and Cabozantinib: Case Series and Review of Literature. World J Oncol 2014; 5: 81-89

29 Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013; 31: 3639-3646

30 Schlumberger MJ, Elisei R, Bastholt L, Wirth LJ, Martins RG, Locati LD, Jarzab B, Pacini F, Daumerie C, Droz JP, Eschenberg MJ, Sun YN, Juan T, Stepan DE, Sherman SI. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol 2009; 27: 3794-801

31 Lam ET, Ringel MD, Kloos RT, Prior TW, Knopp MV, Liang J, Sammet S, Hall NC, Wakely PE Jr, Vasko VV, Saji M, Snyder PJ, Wei L, Arbogast D, Collamore M, Wright JJ, Moley JF, Villalona-Calero MA, Shah MH. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol 2010; 28: 2323-2330

32 Capdevila J, Iglesias L, Halperin I, Segura A, Martínez-Trufero J, Vaz MÁ, Corral J, Obiols G, Grande E, Grau JJ, Tabernero J. Sorafenib in metastatic thyroid cancer. Endocr Relat Cancer 2012; 19: 209-216

33 De Souza JA, Busaidy N, Zimrin A, Seiwert TY, Villaflor VM, Poluru KB, Reddy PL, Nam J, Vokes EE, Cohen EE. Phase II trial of sunitinib in medullary thyroid cancer. J Clin Oncol 2010; 28:15s (suppl; abstr 5504)

34 Vanden Berghe W, Sabbe L, Kaileh M, Haegeman G, Heyninck K. Molecular insight in the multifunctional activities of Withaferin A. Biochem Pharmacol 2012; 84: 1282-1291

35 Samadi AK, Zhang X, Mukerji R, Donnelly AC, Blagg BS, Cohen MS. A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo. Surgery 2010; 148: 1228-1236

36 Cohen SM, Mukerji R, Timmermann BN, Samadi AK, Cohen MS. A novel combination of withaferin A and sorafenib shows synergistic efficacy against both papillary and anaplastic thyroid cancers. Am J Surg 2012; 204: 895-900

37 Salaun PY, Campion L, Bournaud C, Faivre-Chauvet A, Vuillez JP, Taieb D, Ansquer C, Rousseau C, Borson-Chazot F, Bardet S, Oudoux A, Cariou B, Mirallie E, Chang CH, Sharkey RM, Goldenberg DM, Chatal JF, Barbet J, Kraeber-Bodéré F. Phase II Trial of Anticarcinoembryonic Antigen Pretargeted Radioimmunotherapy in Progressive Metastatic Medullary Thyroid Carcinoma: Biomarker Response and Survival Improvement. J Nucl Med 2012; 53: 1185-1192

38 Reubi JC, Waser B. Unexpected high incidence of cholecystokinin-B/gastrin receptors in human medullary thyroid carcinomas. Int J Cancer 1996; 67: 644-647

39 Reubi JC, Schaer JC, Waser B. Cholecystokinin (CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res 1997; 57: 1377-1386

40 Reubi JC, Macke HR, Krenning EP. Candidates for peptide receptor radiotherapy today and in the future. J Nucl Med 2005; 46 Suppl 1: 67s-75s

41 Béhé M, Behr TM. Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies. Biopolymers 2002; 66: 399-418

42 Roosenburg S, Laverman P, van Delft FL, Boerman OC. Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor-expressing tumors. Amino Acids 2011; 41: 1049-1058

43 Iten F, Müller B, Schindler C, Rochlitz C, Oertli D, Mäcke HR, Müller-Brand J, Walter MA. Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial. Clin Cancer Res 2007; 13: 6696-6702

44 Budiawan H, Salavati A, Kulkarni HR, Baum RP. Peptide receptor radionuclide therapy of treatment-refractory metastatic thyroid cancer using (90)Yttrium and (177)Lutetium labeled somatostatin analogs: toxicity, response and survival analysis. Am J Nucl Med Mol Imaging 2013; 4: 39-52

45 Essig GF Jr, Porter K, Schneider D, Debora A, Lindsey SC, Busonero G, Fineberg D, Fruci B, Boelaert K, Smit JW, Meijer JA, Duntas L, Sharma N, Costante G, Filetti S, Sippel RS, Biondi B, Topliss DJ, Pacini F, Maciel RM, Walz PC, Kloos RT. Fine needle aspiration and medullary thyroid carcinoma: the risk of inadequate preoperative evaluation and initial surgery when relying upon FNAB cytology alone. Endocr Pract 2013; 19: 920-927

46 Gotthardt M, Béhé MP, Beuter D, Battmann A, Bauhofer A, Schurrat T, Schipper M, Pollum H, Oyen WJ, Behr TM. Improved tumour detection by gastrin receptor scintigraphy in patients with metastasised medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging 2006; 33: 1273-1279

47 Von Guggenberg E, Rangger C, Sosabowski J, Laverman P, Reubi JC, Virgolini IJ, Decristoforo C. Preclinical evaluation of radiolabeled DOTA-derivatized cyclic minigastrin analogs for targeting cholecystokinin receptor expressing malignancies. Mol Imaging Biol 2012; 14: 366-375

48 Brom M, Joosten L, Laverman P, Oyen WJ, Béhé M, Gotthardt M, Boerman OC. Preclinical evaluation of 68Ga-DOTA-minigastrin for the detection of cholecystokinin-2/gastrin receptor-positive tumors. Mol Imaging 2011; 10: 144-152

49 Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O’Dorisio MS, O’Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ, Zaknun JJ. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2013; 40: 800-816. Erratum in: Eur J Nucl Med Mol Imaging 2014; 41: 584

50 http://www.eurekalert.org/pub_releases/2013-06/sonm-rti061013.php#

51 Bläker M, de Weerth A, Tometten M, Schulz M, Hoppner W, Arlt D, Hoang-Vu C, Dralle H, Terpe H, Jonas L, von Schrenck T. Expression of the cholecystokinin 2-receptor in normal human thyroid gland and medullary thyroid carcinoma. 2002; 146: 89-96

52 Vegt E, de Jong M, Wetzels JFM, Masereeuw R, Melis M, Oyen WJG, Gotthardt M, Boerman OC. Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention. J Nucl Med 2010; 51: 1049-1058

53 Laverman P, Joosten L, Eek A, Roosenburg S, Peitl PK, Maina T, Mäcke H, Aloj L, von Guggenberg E, Sosabowski JK, de Jong M, Reubi JC, Oyen WJ, Boerman OC Comparative biodistribution of 12 ¹¹¹In-labelled gastrin/CCK2 receptor-targeting peptides. Eur J Nucl Med Mol Imaging 2011; 38: 1410-1416

54 Baechler S, Hobbs RF, Boubaker A, Buchegger F, He B, Frey EC, Sgouros G. Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy. Med Phys 2012; 39: 6118-6128

55 http://www.transcanfp7.eu/transcan/file.php/1/Calls/JTC-2011/Selected_projects/CANCER11-GRAN-T-MTC.pdf

56 Bodei L, Handkiewicz-Junak D, Grana C, Mazzetta C, Rocca P, Bartolomei M, Lopera Sierra M, Cremonesi M, Chinol M, Mäcke HR, Paganelli G. Receptor Radionuclide Therapy with 90Y-DOTATOC in Patients with Medullary Thyroid Carcinomas. Cancer Biother Radiopharm 2004; 19: 65-71

57 Orlandi F, Caraci P, Mussa A, Saggiorato E, Pancani G, Angeli A. Treatment of medullary thyroid carcinoma: an update. Endocr Relat Cancer 2001; 8:135-47

Peer reviewers: Jian Yi Li, MD, PhD, Assistant Professor and Co-Director of Neuropathology, Department of Pathology and Lab Medicine, Director of Neuropathology at the Brain Tumor Institute, North Shore-Long Island Jewish Health System, Hofstra North Shore-LIJ School of Medicine, 6 Ohio Drive, Suite 202, Lake Success, NY 11042, USA; Gianmaria Pennelli, MD, Specialist in Surgical Pathology, University of Padova, Department of Medicine DIMED, Surgical Pathology and Cytopathology Unit, via A. Gabelli 61, 35121 Padova (PD), Italy.


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