Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma

The limited therapeutic options available for patients with metastatic papillary thyroid carcinomas (PTC) and follicular thyroid carcinomas (FTC) necessitates the development of novel therapies. Identification of somatic rearrangements of the tyrosine kinase domain of the RET gene in PTC have improved our understanding of thyroid tumorigenesis. Sunitinib is active against the RET kinase and has both antineoplastic and antiangiogenic properties. Its role in the treatment of patients with thyroid carcinoma has yet to be evaluated in clinical trials. Two patients with progressive metastatic thyroid carcinoma (case 1: PTC, and case 2: FTC) were enroled in a phase I clinical trial to evaluate positron emission tomography (PET) in the monitoring of response to sunitinib. Tumour biopsies and PET were performed at baseline and 4 weeks after the commencement of sunitinib. Activation of the RET kinase pathway was evaluated using immunohistochemistry (IHC) and western blot analysis of total phosphorylated tyrosine and downstream signalling targets of the RET pathway. Both patients demonstrated sustained clinical responses to sunitinib over a duration of 4 years. In case 1, (PTC) PET confirmed evidence of a partial metabolic response, and IHC and western blot analysis demonstrated inhibition of the RET kinase pathway posttreatment. In case 2, (FTC) PET confirmed stable disease after sunitinib. IHC staining of the tumour showed low total phosphorylated tyrosine staining at baseline which did not change after treatment. These case studies highlight potential activity of sunitinib in patients with metastatic thyroid carcinoma. Sunitinib seems to be a promising agent in the treatment of thyroid cancers and this requires validation in future clinical trials.     

Sunitinib for the treatment of thyroid cancer

Introduction: Sunitinib is an oral oxindol derivative and a potent inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor and a multitargeted tyrosine-kinase inhibitor, which has antitumor and antiangiogenic activity due to the selective inhibition that can stabilize progressive metastatic disease. The aim of this review is to expose whether the drug could be considered as a new promising therapy compared with other tyrosine-kinase inhibitors.

Areas covered: In seven open-label studies carried out with sunitinb, the drug showed its anti-tumoral activity in advanced differentiated thyroid carcinoma and in medullary thyroid carcinoma. The reported objectives in advanced differentiated thyroid carcinoma, partial response ranges 13% to 55.5%, stable disease ranges 44.4% to 68%, progressive disease ranges 10% to 21% of patients, progression free survival ranges 3 to 13.3% months. In medullary thyroid carcinoma, PR ranges 0% to 55%, SD ranges 44.4% to 87.5%, PD ranges 7% to 18.8% and progression free survivalranges seven to 21 months.

Expert opinion: Sunitinib has demonstrated a potent anti-tumoral activity in differentiated thyroid carcinoma and in medullary thyroid carcinoma, but the results of the open-label trials single arm are limited. Further investigations with this agent with randomized trials are warranted.     

Targeted therapy of thyroid cancer

Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes. Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single agent studies, but prolonged disease stabilization is more commonly seen. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. Additional agents targeting tumor vasculature, nuclear receptors, epigenetic abnormalities, and the immune response to neoplasia have also been investigated. Randomized trials for several agents are underway that may lead to eventual drug approval for thyroid cancer. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasizes clinical trial opportunities for novel agents with considerable promise. Alternative options now exist for use of tyrosine kinase inhibitors that are well tolerated and may prove worthy of regulatory approval for this disease.