Treatment Of Medullary Thyroid Cancer Research Articles

Putative BRAF activating fusion in a medullary thyroid cancer

Medullary thyroid cancer (MTC) is a malignancy of the calcitonin-producing parafollicular cells of the thyroid gland. Surgery is the only curative treatment for this cancer. External beam radiation therapy is reserved for adjuvant treatment of MTC with aggressive features. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overactivation of the RET oncoprotein in a large subpopulation of MTCs. However, not all patients carry oncogenic alterations of this kinase. Hence, there is still a need for comprehensive molecular characterization of MTC utilizing whole-genome and transcriptome-sequencing methodologies with the aim of identifying targetable mutations. Here, we describe the genomic profiles of two medullary thyroid cancers and report the presence of a putative oncogenic BRAF fusion in one. Such alterations, previously observed in other malignancies and known targets of available drugs, can benefit patients who currently have no treatment options.

Molecular Targeted Therapies of Aggressive Thyroid Cancer.

Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in each TC patient.

Medullary Thyroid Cancer that Stains Negative for CA 19-9 has Decreased Metastatic Potential

Presently, no clinical tools are available to diagnose the metastatic potential of medullary thyroid cancer (MTC) at disease presentation. Surveillance with calcitonin (Ct) and carcinoembryonic antigen (CEA) is currently recommended for the observation and diagnosis of metastatic disease after initial treatment of MTC. Recently, carbohydrate antigen (CA)19-9 staining has been associated with aggressive forms of MTC and metastatic spread. This pilot study explored whether positive CA19-9 staining of MTC tissue is associated with its metastatic potential. Sixteen cases of MTC were identified, and tissue specimens were immunostained for CA 19-9 and other MTC tumor markers. Clinical information about patients' MTC was collected through a retrospective chart review. Overall, 63% of the specimens stained positive for CA19-9. The median size of positively staining specimens was 2.6 cm (interquartile range [IQR] 1.2-3.2) compared to 0.7 cm (0.5-1.2) in negatively staining MTC specimens (P = .04). All specimens from patients diagnosed with stage IV MTC stained positive for CA19-9, compared to only 40% of cases that were classified as stages I to III (P = .03). Furthermore, 100% of the primary specimens that were documented to have metastatic spread stained positive for CA19-9. The sensitivity for ruling out stage IV MTC based on negative staining for CA 19-9 was 100%. Based on these results, we conclude that negative staining of MTC for CA19-9 may be associated with its decreased metastatic potential.

The importance of Src signaling in sarcoma.

Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.

Surgical management of medullary thyroid cancer: which guidelines should we follow?

Surgery is currently the only curative treatment for medullary thyroid cancer. Unfortunately, the surgical strategy that will offer patients at each disease stage the best chance of a biochemical cure remains unclear. The American Thyroid Association and British Thyroid Association guidelines offer different strategies. A retrospective analysis of the surgical management of 47 patients with medullary thyroid cancer diagnosed between 1994 and 2013 was performed. Surgical management was compared with current American Thyroid Association and British Thyroid Association guidelines. Outcome was defined as the first post-operative calcitonin measurement. All patients with stage I-III disease achieved a post-operative biochemical cure regardless of the guidelines followed. The overall biochemical cure rate for patients with stage IVa disease was significantly reduced to 10 per cent (p < 0.01), but the biochemical cure rate for stage IVa disease patients who underwent bilateral lateral lymph node dissection was 33.3 per cent. The conservative, surveillance-driven approach recommended by the American Thyroid Association is appropriate for stage I-III disease. However, the more aggressive approach advocated by the British Thyroid Association might provide stage IVa disease patients a greater chance of achieving a biochemical cure.

The cAMP analogs have potent anti-proliferative effects on medullary thyroid cancer cell lines.

The oncogenic activation of the rearranged during transfection (RET) proto-oncogene has a main role in the pathogenesis of medullary thyroid cancer (MTC). Several lines of evidence suggest that RET function could be influenced by cyclic AMP (cAMP)-dependent protein kinase A (PKA) activity. We evaluated the in vitro anti-tumor activity of 8-chloroadenosine-3',5'-cyclic monophosphate (8-Cl-cAMP) and PKA type I-selective cAMP analogs [equimolar combination of the 8-piperidinoadenosine-3',5'-cyclic monophosphate (8-PIP-cAMP) and 8-hexylaminoadenosine-3',5'-cyclic monophosphate (8-HA-cAMP) in MTC cell lines (TT and MZ-CRC-1)]. 8-Cl-cAMP and the PKA I-selective cAMP analogs showed a potent anti-proliferative effect in both cell lines. In detail, 8-Cl-cAMP blocked significantly the transition of TT cell population from G2/M to G0/G1 phase and from G0/G1 to S phase and of MZ-CRC-1 cells from G0/G1 to S phase. Moreover, 8-Cl-cAMP induced apoptosis in both cell lines, as demonstrated by FACS analysis for annexin V-FITC/propidium iodide, the activation of caspase-3 and PARP cleavage. On the other hand, the only effect induced by PKA I-selective cAMP analogs was a delay in G0/G1-S and S-G2/M progression in TT and MZ-CRC-1 cells, respectively. In conclusion, these data demonstrate that cAMP analogs, particularly 8-Cl-cAMP, significantly suppress in vitro MTC proliferation and provide rationale for a potential clinical use of cAMP analogs in the treatment of advanced MTC.

A novel multiple tyrosine-kinase targeted agent to explore the future perspectives of anti-angiogenic therapy for the treatment of multiple solid tumors: cabozantinib.

The process of angiogenesis involves the formation of new blood vessels from pre-existing vasculature by the over expression of certain factors leading to the growth and development of all solid tumor types. Hepatocyte growth factor receptor abbreviated as c-Met and vascular endothelial growth factor abbreviated as VEGF are some of the factors responsible for the induction in tumor growth and development. Recently a number of analogues associated with these receptors are under study. US FDA on November 29, 2012 approved a drug named cabozantinib formerly known as XL184 which is being marketed under the trade name of Cometriq for the treatment of Medullary Thyroid Cancer (MTC). Designing of the drug has been done in such a fashion that it can inhibit both VEGFR2 and c-Met simultaneously without over expressing any of the factors leading to the inhibition of angiogenesis. The drug is still under study for the evaluation of its efficacy in cases of many other solid tumor types including breast cancer, castration resistant prostate cancer (CRPC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastric or gastroesophageal junction cancer, melanoma, small cell lung cancer (SCLC), ovarian cancer and primary peritoneal or fallopian tube carcinoma. This review article consists of preclinical and clinical data of cabozantinib and its efficacy and safety towards various types of solid tumors.

Fewer cancer reoperations for medullary thyroid cancer after initial surgery according to ATA guidelines.

Surgery is still the only curative treatment for medullary thyroid cancer (MTC). We evaluated clinical outcome in patients with locoregional MTC with regard to adequacy of treatment following ATA guidelines and number of sessions to first intended curative surgery in different hospitals. We reviewed all records of MTC patients (n = 184) treated between 1980 and 2010 in two tertiary referral centers in the Netherlands. Symptomatic MTC (palpable tumor or suspicious lymphadenopathy) patients without distant metastasis were included (n = 86). Patients were compared with regard to adequacy of surgery according to ATA recommendations, tumor characteristics, number of local cancer reoperations, biochemical cure, clinical disease-free survival (DFS), overall survival (OS), and complications. Adherence to ATA guidelines resulted in fewer cancer-related reoperations (0.24 vs. 0.60; P = 0.027) and more biochemical cure (40.9 vs. 20 %; P = 0.038). Surgery according to ATA-guidelines on patients treated in referral centers was significantly more often adequate (59.2 vs. 26.7 %; P = 0.026). Tumor size and LN+ were the most important predictors for clinical recurrence [relative risk (RR) 4.1 (size > 40 mm) 4.1 (LN+) and death (RR 4.2 (size > 40 mm) 8.1 (LN+)]. ATA-compliant surgery resulted in fewer local reoperations and more biochemical cure. Patients in referral centers more often underwent adequate surgery according to ATA-guidelines. Size and LN+ were the most important predictors for DFS and OS.

Pharmacokinetic Evaluations of the Co-Administrations of Vandetanib and Metformin, Digoxin, Midazolam, Omeprazole or Ranitidine

Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655). Four open-label, phase I studies were conducted in healthy volunteers: n=14 (metformin), n=14 (digoxin), n=17 (midazolam), n=16 (omeprazole), n=18 (ranitidine). Three of these comprised the following regimens: metformin 1000mg±vandetanib 800mg, midazolam 7.5mg±vandetanib 800mg, or digoxin 0.25mg±vandetanib 300mg. The randomized study comprised vandetanib 300mg alone and then either (i) omeprazole 40mg (days 1-4), and omeprazole+vandetanib (day 5); or (ii) ranitidine 150mg (day 1), and ranitidine+vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. Vandetanib+metformin increased metformin area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and maximum observed plasma concentration (Cmax) by 74 and 50%, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52% versus metformin alone. Vandetanib+digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0-last) and Cmax by 23 and 29%, respectively, versus digoxin alone, with only a 9% decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug-drug interactions.

Cabozantinib for progressive metastatic medullary thyroid cancer: a review.

Medullary thyroid cancer is uncommon and patients typically present with advanced disease. Treatment options for patients with progressive, metastatic medullary thyroid cancer had been limited until recently. Tyrosine kinase inhibitors have garnered increasing interest in this subset of patients. The US Food and Drug Administration recently approved cabozantinib, a tyrosine kinase inhibitor, after promising results were shown in a large Phase III clinical trial. This review summarizes the clinical pharmacology, clinical trials, and safety data for cabozantinib and concludes with a discussion of possible future directions for the treatment of medullary thyroid cancer.

Multikinase Inhibitors for the Treatment of Progressive, Metastatic Medullary Thyroid Cancer - An Evolving Paradigm.

Medullary thyroid cancer (MTC) is an uncommon type of thyroid cancer, representing around 4 % of the all thyroid cancers, and is a challenging malignancy. So far, surgery has been the only curative treatment and until recently there have been no effective medications. Within the past 5 years, multi-targeted kinase inhibitors have emerged that have shown convincing efficacy against such tumours. These drugs have changed the landscape in MTC treatment by providing effective medication for the first time. The modes of action of these drugs differ, but most target RET, a tyrosine kinase shown to play an important role in the pathobiology of MTC, as well as other receptors including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor MET. Two agents in this class, vandetanib and cabozantinib, have demonstrated efficacy and safety in phase III trials and have consequently received regulatory approval. Other therapies for MTC treatment, including some with similar modes of action, are also in early development.

Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor.

Cabozantinib is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, FLT3, c-KIT, and RET. Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer (MTC), NSCLC, breast, ovarian, pancreatic, and prostate cancer. In MTC, gain of function mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC in up to 50% of cases RET mutations occur. Additionally, activating molecular changes in VEGFR and MET pathways have also been implicated in MTC progression. Clinical responses with cabozantinib in MTC could be observed in early clinical trials, and following confirmation of clinical benefit in a randomized phase III trial, cabozantinib gained FDA approval for first-line treatment of advanced MTC in 2012. In prostate cancer models, MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis. A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer. Therefore, randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients.

Thiocoraline alters neuroendocrine phenotype and activates the Notch pathway in MTC‐TT cell line

Medullary thyroid cancer (MTC) is an aggressive neuroendocrine tumor (NET). Previous research has shown that activation of Notch signaling has a tumor suppressor role in NETs. The potential therapeutic effect of thiocoraline on the activation of the Notch pathway in an MTC cell line (TT) was investigated. Thiocoraline was isolated from a marine bacterium Verrucosispora sp. MTT assay (3-[4, 5-dimethylthiazole-2-yl]-2, 5-diphenyltetrazolium bromide) was used to determine the IC50 value and to measure cell proliferation. Western blot revealed the expression of Notch isoforms, NET, and cell cycle markers. Cell cycle progression was validated by flow cytometry. The mRNA expression of Notch isoforms and downstream targets were measured using real-time PCR. The IC50 value for thiocoraline treatment in TT cells was determined to be 7.6 nmol/L. Thiocoraline treatment decreased cell proliferation in a dose- and time-dependent manner. The mechanism of growth inhibition was found to be cell cycle arrest in G1 phase. Thiocoraline activated the Notch pathway as demonstrated by the dose-dependent increase in mRNA and protein expression of Notch isoforms. Furthermore, treatment with thiocoraline resulted in changes in the expression of downstream targets of the Notch pathway (HES1, HES2, HES6, HEY1, and HEY2) and reduced expression of NET markers, CgA, and ASCL1. Thiocoraline is a potent Notch pathway activator and an inhibitor of MTC-TT cell proliferation at low nanomolar concentrations. These results provide exciting evidence for the use of thiocoraline as a potential treatment for intractable MTC.Thiocoraline is a potent Notch pathway activator and an inhibitor of medullary thyroid cancer cell line (MTC-TT) cell proliferation at low nanomolar concentrations. These results provide evidence for the use of thiocoraline as a potential treatment for intractable MTC.

Uptodate view on diagnostics and treatment of medullary thyroid cancer

During last 4 years leading endocrine societies of the world published clinical recommendations on diag nostics and treatment of medullary thyroid cancer. The article covers most aspects of following patients with this pathology.

Interleukin-2 and Lanreotide in the Treatment of Medullary Thyroid Cancer: In Vitro and In Vivo Studies

To date no efficacious treatments are available for advanced medullary thyroid carcinoma (MTC). We investigated in vitro and in vivo a new strategy for the therapy of MTC, combining human recombinant IL-2 with lanreotide (LAN), a somatostatin analog. The in vitro effects of LAN on the sensitivity of TT cells, a MTC cell line, to IL-2-stimulated human peripheral blood mononuclear cells were determined by a lactate dehydrogenase release assay. In addition, we evaluated the toxicity, the effects on quality of life, and the antitumor activity of sc low-dose IL-2 in combination with LAN (90 mg every 28 days) in a series of 6 patients with symptomatic and advanced MTC. The cytotoxicity of IL-2-activated peripheral blood mononuclear cells was significantly increased in TT cells treated with LAN or LAN plus IL-2 compared with that in TT cells without treatment. The therapy was well tolerated, and a statistically significant improvement of quality of life was observed in patients treated with the combination of LAN and IL-2. After 6 months of therapy, partial response and stable disease have been recorded in 2 and 3 patients, respectively, with a significant decrease in calcitonin levels in 3 patients. Both in vitro and in vivo evidence suggests that the combination of LAN and IL-2 may have a role in the management of advanced and symptomatic MTC. However, these preliminary data require further validation in larger randomized trials.

Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase

RET kinase is aberrantly activated in thyroid cancers and in rare cases of lung and colon cancer, and has been validated as a molecular target in these tumors. Vandetanib was recently approved for the treatment of medullary thyroid cancer. However, vandetanib is ineffective in vitro against RET mutants carrying bulky aminoacids at position 804, the gatekeeper residue, similarly to drug-resistant BCR–ABL mutants in chronic myeloid leukemia. Ponatinib is a multi-target kinase inhibitor that was recently approved for treatment-refractory Philadelphia-positive leukemia. We show here potent inhibition of oncogenic RET by ponatinib, including the drug-insensitive V804M/L mutants. Ponatinib inhibited the growth of RET+ and BCR–ABL+ cells with similar potency, while not affecting RET-negative cells. Both in biochemical and in cellular assays ponatinib compared favorably with known RET inhibitors, such as vandetanib, cabozantinib, sorafenib, sunitinib and motesanib, used as reference compounds. We suggest that ponatinib should be considered for the treatment of RET+ tumors, in particular those expressing vandetanib-resistant V804M/L mutations.

New developments in the diagnosis and treatment of thyroid cancer

Thyroid cancer exists in several forms. Differentiated thyroid cancers include those with papillary and follicular histologies. These tumors exist along a spectrum of differentiation, and their incidence continues to climb. A number of advances in the diagnosis and treatment of differentiated thyroid cancers now exist. These include molecular diagnostics and more advanced strategies for risk stratification. Medullary cancer arises from the parafollicular cells and not the follicular cells. Therefore, diagnosis and treatment differs from those of differentiated thyroid tumors. Genetic testing and newer adjuvant therapies have changed the diagnosis and treatment of medullary thyroid cancer. This review will focus on the epidemiology, diagnosis, workup, and treatment of both differentiated and medullary thyroid cancers, focusing specifically on newer developments in the field.

Effect of Metformin on the Medullary Thyroid Cancer Cells

Background. Medullary thyroid cancer (MTC) is associated with activation of mTOR signalingpathways. Recent studies showed that the anti-diabetic agent metformin decreases proliferation of cancer cellsthrough AMPK-dependent inhibition of mTOR.The objective of current study — assessment of the effect of metformin on MTC cells.Materials and Methods. Performed growth, viability, migration and resistance to anoikis assays using twoMTC-derived cell lines (TT and MZ-CRC-1). Expressions of molecular targets of metformin were examined inMTC cell lines and in 14 human MTCs tissue samples.Results. We found that metformin inhibited growth and decreased expression of Cyclin D1 in MTC cells. Treatmentwith metformin was associated with inhibition of mTOR/p70S6K/pS6 signaling and with down-regulation ofpERK in both TT and MZ-CRC-1 cells. Metformin had no significant effects on pAKT in the cell lines examined.Metformin inducible AMPK activation was noted only in TT cells. Treatment with AMPK inhibitor (Compound C)or AMPK silencing did not prevent growth-inhibitory effects of metformin in TT cells. Metformin had no effect on MTC cell migration, but reduced the ability of cells to form multi-cellular spheroids in non adherent conditions.Immunostaining of human MTC showed over-expression of Cyclin D1 in all tumors compared to corresponding normal tissue. Activation of mTOR/p70S6K was detected in 8/14 (57.1 %) of examined tumors.Conclusions. Together these findings indicate that growth inhibitory effects in MTC cells are associated withdown-regulation of both mTOR/6SK and pERK signaling pathways. Expression of metformin’s molecular targetsin human MTC cells suggests its potential utility for the treatment of MTC in patients.

Vandetanib: A novel targeted therapy for the treatment of metastatic or locally advanced medullary thyroid cancer

The pharmacology, pharmacokinetics, efficacy, safety and tolerability, drug and food interactions, cost, and place in therapy of vandetanib are reviewed. Vandetanib is a small-molecule inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and receptor tyrosine kinase signaling pathways, which are involved in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Vandetanib was evaluated in a randomized, placebo-controlled, double-blind Phase III study comparing vandetanib with placebo in adult patients with unresectable locally advanced or metastatic hereditary or sporadic MTC. Vandetanib demonstrated a statistically significant longer progression-free survival (predicted median of 30.5 months) compared with placebo (median of 19.3 months) (hazard ratio, 0.46; 95% confidence interval, 0.31-0.69; p = 0.0001). The most commonly observed adverse effects of vandetanib include nausea, diarrhea, headache, rash, prolongation of the Q-T interval, and hypertension. Because it can prolong the Q-T interval, vandetanib is contraindicated for use in patients with serious cardiac complications, including congenital long QT syndrome, bradyarrhythmias, uncompensated heart failure, and a history of torsades de pointes. Vandetanib has been shown to be more effective than placebo in the treatment of advanced MTC; however, it has not been compared with radiation, resection, or embolization. Vandetanib also has significant and fairly common cardiac toxicities. The cost, benefits, and risks of vandetanib for patients with MTC should be weighed, as alternative treatments remain an option for most patients.

Pharmacokinetic evaluation of cabozantinib for the treatment of thyroid cancer

Introduction: Conventional treatment modalities for thyroid cancer lead to complete remission in only one-third of patients with distant metastases. On the other hand, medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), although rare, are responsible for a significant percentage of thyroid cancer-related deaths. New treatments are needed to treat such patientsAreas covered: The aim of this review is to provide the latest information on cabozantinib (CBZ), a new tyrosine kinase inhibitor (TKI) that is currently used mainly as a treatment of MTC. The authors collated data that were retrieved from a PubMed literature search.Expert opinion: CBZ targets multiple cell-signaling pathways involved in the molecular pathogenesis of thyroid cancer. These are namely VEGF receptor-2, hepatocyte growth factor receptor and rearranged during transfection receptor. Furthermore, it is a drug which may be used in cases where conventional therapies (mainly for MTC) are proved ineffective or have shown poor results with a good outcome. CBZ may also be administered alone or in combination with other drugs of the same family.