Total or near-total thyroidectomy is the primary treatment for differentiated thyroid carcinoma. Postoperatively, DTC are treated with radioiodine (131I) and thyroid stimulating hormone (TSH) suppressive levothyroxine therapy.~But 5% to 20% of patients with DTC develop distant metastases; some of them become refractory to 131I therapy.~Targeted therapies have been studied in iodine refractory DTC for several years but none of these treatments has yet been approved in DTC and clinicians continue to enroll patients in clinical trials. The agents used so far in thyroid cancer are small molecules sharing the property to inhibit various tyrosine kinase receptors such as Vascular Endothelial Growth Factor Receptor (VEGFR), Epidermal Growth Factor Receptor (EGFR), RET or c-met.~The VEGF (Vascular Endothelial Growth Factor) is one of the several pro angiogenic molecules that play a pivotal role in angiogenesis, one of the mechanisms involved in tumor growth and dissemination.~VEGF expression is highly prevalent in Papillary Thyroid Carcinoma (PTCs) (79%), Follicular Thyroid Carcinoma (FTCs) (50%) or Poorly Differentiated Thyroid Carcinoma (PDTCs) (37%) and VEGFR is respectively expressed in 76%, 83% and 25% for VEGRF-1 and 68%, 56% and 37% for VEGRF-2.~Pazopanib (GW786034 - GlaxoSmithKline) is an orally administered, potent multitarget tyrosine kinase inhibitor of VEGFR in particular (but also of PDGFR-α and -β, and stem cell factor receptor c-Kit).~The results obtained in metastatic or locally advanced refractory DTC are currently available (phase II study of 39 patients with metastatic, rapidly progressive RAI-refractory DTC, treated with pazopanib 800mg daily, were published in Lancet Oncology in 2010 by KC Bible), demonstrating the efficacy of these therapies in this indication. However, no clear data is yet available indicating the optimal duration of treatment in first line therapy: patients are currently treated until progression or until drug discontinuation due to toxicity. Indeed, patients may have some difficulties to manage the chronic mild to moderate (grade 1-2) side-effects related to long-term treatment, leading some asymptomatic patients in whom tumor is controlled by TKI treatment to ask for treatment interruption.~The intermittent administration should avoid the occurrence of long-term adverse event and subsequent dose reductions or discontinuation, thus allowing a longer control of underlying disease.~All these considerations led our reflexion in the design of the present study, that is to say to determine the feasibility of pazopanib treatment interruption with reintroduction at progression in iodine refractory progressive DTC patients as compared to pazopanib continuous administration, after 6 initial cycles of pazopanib 800 mg daily for all patients included in the study, with a strong rationale for intermittent administration of pazopanib.
The objective of this study is to determine the feasibility of pazopanib treatment interruption with reintroduction at progression in iodine refractory progressive Differentiated Thyroid Cancer (DTC) patients as compared to pazopanib continuous administration.