Medullary thyroid cancer (MTC) is a neuroendocrine malignancy derived from parafollicular cells (also known as C cells) of the thyroid gland. Mutations to the RET proto-oncogene (REarranged during Transfection) cause hereditary MTC. Vandetanib is a small molecule tyrosine kinase inhibitor that selectively targets RET, vascular endothelial growth factor receptor-2 (VEGFR-2), and epidermal growth factor receptor (EGFR) dependent signaling. In April 2011, the U.S. Food and Drug Administration (FDA) approved vandetanib as an ‘orphan drug’ for the treatment of patients with unresectable, locally advanced, or metastatic MTC. Vandetanib represents the first FDA-approved therapy for patients with MTC and has ushered in a new era of targeted therapy for this uncommon disease. In this article, we review the molecular biology, history, clinical evidence, and side-effects of vandetanib therapy for patients with advanced MTC.
MEDULLARY THYROID CANCER
MTC is an uncommon disease accounting for about 5% of all thyroid cancers. The average age of onset is 50 years old and it occurs slightly more often in women than men. MTC can occur as either a sporadic or hereditary disease. Seventy-five percent of new cases of MTC are sporadic. The remaining 25% of MTC falls into one of three autosomal-dominant inherited syndromes which differ in their clinical presentation (phenotype) and their specific mutations of the RET proto-oncogene (genotype) . Multiple endocrine neoplasia (MEN) 2A is associated with MTC, pheochromocytoma, and parathyroid hyperplasia. The penetrance of MTC in families with MEN2A approaches 100%. Patients with MEN2B also present with MTC and pheochromocytoma, but do not demonstrate parathyroid hyperplasia. Instead, these patients classically have a marfanoid habitus coupled with mucosal neuromas. MTC in patients with MEN2B typically presents at a younger age and is more aggressive than in patients with MEN2A. Familial medullary thyroid cancer (FMTC) is a variant of MEN2A, but is not associated with other tumors and is generally the least aggressive phenotype, not appearing until the second or third decade of life . Parafollicular C cells associated with both germline and somatic RET mutations have a propensity to secrete both calcitonin and carcinoembryonic antigen (CEA), which can be used as tumor markers to screen for tumor recurrence.
When diagnosed and treated at an early stage, the prognosis for MTC is generally favorable, with 10-year survival rates of 70–80% . Unfortunately, at the time of diagnosis, up to 70% of patients with MTC have cervical lymph node metastasis, 15% have symptoms of local invasion such as dysphagia or hoarseness, and 10% have distant metastatic disease [1,2,4]. Surgery is the cornerstone of therapy. For those patients in whom MTC is diagnosed clinically, total thyroidectomy with bilateral central lymph node dissection is recommended for almost all patients. Recently published guidelines from the American Thyroid Association recommend a selective approach to lymph nodes in the lateral neck compartments, in which formal dissection is reserved for patients with clinically or radiographically suspicious nodes, or those with biopsy-proven metastases [5▪]. The rate of local recurrence is as high as 27% in sporadic cases and 14% in hereditary cases. The rate of distant recurrence is estimated to be 18 and 14% for sporadic and hereditary disease, respectively, at 7 years of follow-up . Local recurrence commonly requires reoperation .
One of the largest dilemmas facing care of the patient with MTC is the lack of effective adjuvant and palliative options. MTC cells do not concentrate iodine like thyroid cancers of follicular cell origin; therefore, radioactive iodine is not efficacious. Similarly, thyroid-stimulating hormone (TSH) suppression is not recommended for patients with MTC, as parafollicular C cells are not TSH responsive. External beam radiation has been used with mixed results, and the risks of radiation toxicity to surrounding structures have to be weighed against the marginal benefits radiation provides . Cytotoxic agents have failed to demonstrate a survival benefit. When MTC is diagnosed and treated while confined to the thyroid, then 10-year survival rates approach 80%, but when distant metastatic disease is present survival rates drop to 40% at 10 years of follow-up .
MOLECULAR BIOLOGY OF MEDULLARY THYROID CANCER AND THE HISTORY OF VANDETANIB
The RET proto-oncogene encodes a tyrosine kinase receptor expressed primarily in the neuroendocrine cells (including the parafollicular cells of the thyroid). RET tyrosine kinase receptor activation leads to dimerization, autophosphorylation, and downstream intracellular signaling, including RAS–MAPK and PI3K–AKT pathways that play a key role in cell growth, differentiation, survival, and programmed cell death (Fig. 1) [7,8▪]. Mutations to the RET proto-oncogene are key to the pathogenesis of MTC. Germline mutations in the RET proto-oncogene are responsible for almost all hereditary forms of MTC, while up to half of the sporadic forms of MTC harbor somatic RET mutations (usually at codon 918) [9–11].
As with most solid tumors, angiogenesis induced by the VEGF pathway is necessary to sustain tumor growth. In the VEGF signaling pathway, VEGF-A binds to one of three receptors: VEGFR-1, VEGFR-2, and VEGFR-3. VEGF-A, VEGFR-1, and VEGFR-2 are overexpressed in greater than 90% of MTC . VEGFR-2 has been implicated in tumor growth and metastasis, as it plays a role in endothelial cell proliferation, migration, and survival as well as induction of neovascularization . Overexpression of VEGFR is more commonly seen in metastasis of MTC than in the primary tumor . EGFR is a tyrosine kinase receptor that acts downstream through the activation of several cascades, including MAPK, AKT, and JAK. Thirteen percent of primary MTC tumors overexpress EGFR, while 35% of metastasis overexpress EGFR .
Vandetanib was initially developed as a molecular inhibitor of VEGF-2 tyrosine kinase and originally was demonstrated to inhibit angiogenesis activity. Additional antitumor effects were demonstrated through the inhibition of EGFR. Initial clinical development focused on tumors that expressed both VEGFR and EGFR, such as nonsmall cell lung cancer and colorectal cancer. Eventually, further work demonstrated vandetanib's antitumor effects in medullary and papillary thyroid cancer mediated by RET inhibition.
CLINICAL EVIDENCE SUPPORTING THE USE OF VANDETANIB
Initial phase I trials of ZD6474 (vandetanib) in patients with advanced solid tumors showed daily oral administration at doses of 300 mg or less to be well tolerated, with most adverse effects managed effectively with supportive care or dose interruption/reduction as needed [12,13]. After preclinical trials demonstrating the efficacy of ZD6474 inhibiting RET and VEGF signaling [14,15], phase II trials were initiated in small numbers of patients with advanced MTC. Wells et al. published the results of a phase II trial in 2010, in which 30 patients with unresectable, locally advanced, or metastatic MTC with confirmed MEN2A, MEN2B, or FMTC and a confirmed germline RET mutation received initial therapy with vandetanib 300 mg/day. In this study, 20% (6 out of 30 patients) demonstrated a partial response lasting a median duration of 10.2 months and 53% (16 out of 30 patients) showed stable disease at or beyond 24 weeks, confirming antitumor activity of vandetanib in advanced hereditary MTC with manageable adverse effects.
Another phase II trial investigated the use of lower dose vandetanib (100 mg/day) in the same patient population. This trial confirmed its efficacy in hereditary MTC patients with 16% (3 out of 19 patients) experiencing partial responses and 53% (10 out of 19 patients) experiencing stable disease at or beyond 24 weeks . Assessing the tolerability of the lower dose, diarrhea and rash were the most common side-effects occurring in 47 and 42% of patients, respectively. In addition, two patients discontinued the study because of adverse events (muscle weakness and aspiration pneumonia thought to be unrelated to study protocol) and two experienced dose reductions for diabetes insipidus and QTc prolongation.
Phase III trials
A phase III, randomized, placebo-controlled, clinical trial was performed from December 2006 to November 2007, including 331 patients from centers in 23 countries. Patients were randomized 2 : 1 to receive vandetanib 300 mg/day or placebo [18▪]. Unlike the phase II trials, the majority of patients in this study had sporadic MTC (90%) rather than hereditary forms, which only made up 10% of this study population. The study demonstrated significant results with respect to its primary endpoint, progression-free survival (PFS), with a median PFS of 19.3 months for placebo patients and a projected median of 30.5 months for patients in the vandetanib arm based on a Weibull model [hazard ratio 0.46, 95% confidence interval (CI) 0.31–0.69]. In addition, results were significant for the secondary endpoints identified prior to data collection, including objective response rate, disease control rate, and biochemical response based on calcitonin and CEA levels. Objective responses were experienced in 45% of patients in the vandetanib arm compared to 13% in the placebo arm [odds ratio (OR) 5.48, 95% CI 2.99–10.79] based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria, with the authors noting that 12 of the 13 placebo patients with responses occurred after these patients began receiving vandetanib in the open-label phase. Calcitonin and CEA biochemical response rates were 69 and 52% in patients receiving vandetanib vs. 3 and 2% in patients receiving placebo (OR 72.9 and 52.0, respectively). Study patients continue receiving vandetanib as a part of the clinical trial. The secondary endpoint of overall survival will be reported when 50% of patients have died, although there were no differences observed with a median 24-week follow-up .
Given the large number of patients with sporadic MTC in this trial, tumor samples were analyzed from all but one of the 298 patients with nonhereditary MTC to assess RET mutational status. This was determined based on direct DNA sequencing in addition to amplification-refractory mutation system (ARMS) assay for the most common sporadic RET mutation M918T, which has been associated with a poor prognosis . There were a large number of patients for which RET mutational status was indeterminate, which the authors attributed to insufficient DNA from samples, with 52% mutation positive, 2.7% mutation negative, and 45.3% with unknown status. However, subgroup analysis did suggest increased efficacy in patients with identified M918T mutations vs. no M918T mutation, as demonstrated by prolonged PFS and objective response rate (54.5 vs. 30.9%).
On the basis of findings from this randomized controlled trial, the FDA approved the use of vandetanib for the treatment of symptomatic or progressive MTC in patients with unresectable, locally advanced, or metastatic disease in April 2011 . Clinical trials are ongoing to investigate different doses, combination, or sequential therapy with other agents and long-term effects of vandetanib in patients with advanced MTC. In the future, vandetanib may also be studied in patients with thyroid cancer of follicular cell origin.
TOXICITY OF VANDETANIB
As documented by the above phase II/III clinical trials, the most common adverse effects experienced by patients taking vandetanib included rash, diarrhea, nausea, and hypertension, which were generally categorized as grade 1 or 2 based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) [16,17,18▪]. In the phase III RCT, adverse effects experienced by the patients taking vandetanib vs. placebo included diarrhea (56 vs. 26%), rash (45 vs. 11%), nausea (33 vs. 16%), and hypertension (32 vs. 5%) [18▪]. Vandetanib dose was reduced in 35% of patients and discontinued in 12% of patients because of toxicity with a median duration of treatment of 90.1 weeks. Patients on vandetanib were also found to have increasing TSH levels with prolonged treatment, seen in 78% of vandetanib patients vs. 21% in placebo patients . This resulted in increased dosing of thyroid hormone replacement in 49.3 vs. 17.2% of patients receiving vandetanib vs. placebo. Other rare adverse events associated with vandetanib include cerebrovascular events, including one case report of reversible cerebral vasoconstriction syndrome (RCVS) associated with subarachnoid hemorrhage within days of initiating therapy, and Stevens–Johnson syndrome [21,22].
An adverse effect that has received a great deal of attention in patients treated with vandetanib is QTc prolongation. In the phase III trial, QTc prolongation was documented in 14% (33 out of 231 patients) in the vandetanib arm according to CTCAE criteria (with 8% being grade 3–4) compared to 1% (1 out of 99 patients) in the placebo arm. In addition, five patients experienced adverse events resulting in death while taking vandetanib during the randomized trial, with one sudden death and one cardiopulmonary arrest, although there was no documented torsades de pointes. On the basis of frequency of ECG changes and potential fatal complications resulting from vandetanib administration, the FDA issued a boxed warning for QTc prolongation, torsades de pointes, and sudden death and implemented a Risk Evaluation and Mitigation Strategy (REMS) to limit the prescription of vandetanib to trained and certified doctors and pharmacists [19,21,23]. Under the FDA REMS Astro Zeneca, the manufacturer of vandetanib, must insure that prescribing providers are specially certified. This certification involves physicians reviewing educational material, completing a training program, agreeing to review a medication guide with the patient, and being re-trained following substantial changes in the REMS program. Additionally, the FDA REMS requires that vandetanib only be dispensed by certified pharmacies. These pharmacies must have a system to assure that prescribers of vandetanib have been certified under the REMS, that critical personnel have been trained on the risks and requirements of vandetanib, and that the pharmacy has a mechanism to document compliance with the REMS system .
A recent meta-analysis of nine phase II/III clinical trials involving 2188 patients administered vandetanib 300 mg/day for various malignancies demonstrated all-grade and high-grade QTc prolongation in 18 and 12%, respectively, among MTC patients compared to 16.4 and 3.7%, respectively, among nonthyroid cancer patients . In addition, it showed an increased incidence of high-grade QTc prolongation in patients with MTC vs. other malignancies (relative risk 3.24, 95% CI 1.57–6.71), which the authors noted could potentially have been related to the prolonged treatment times of these patients compared to those being treated for other malignancies (median treatment period >18.8 vs. 1.8–3 months). Therefore, the results of the current data support careful patient selection and monitoring when prescribing vandetanib for patients with advanced MTC, and emphasize that patients be counseled on this potentially serious adverse event.
MTC is a rare tumor of parafollicular C cells, with well described embryology, clinical presentation, and genetic associations. When diagnosed by genetic testing, prophylactic thyroidectomy can be done prior to the development of C cell hyperplasia and the development of medullary cancer, thus curing patients. When diagnosed clinically, however, MTC can be difficult to cure biochemically and is often a systemic disease at presentation. That said, patients with persistent and recurrent disease and those with bulky and widespread metastases can live for years with reasonable symptom control. For this later cohort of patients, effective adjuvant therapy has been lacking. Vandetanib has emerged as one of the more promising small molecule tyrosinse kinase inhibitors, providing durable rates of disease stabilization, with an acceptable adverse event profile. Vandetanib's recent FDA approval has ushered in a new era in the treatment of patients with MTC. Ongoing and future studies evaluating the timing of vandetanib administration, as well as combination or sequential therapy, will be critical as we move forward in the management of this complex disease.
Conflicts of interest
The authors have nothing to disclose. Departmental funds were used for incidental expenses.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 100).
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