**1. Introduction**

Differentiated thyroid cancer (DTC) is the most frequent endocrine malignancy comprising the papillary (PTC), follicular (FTC) and poorly differentiated (PDTC) histological subtypes [1]. Although most patients with DTC can be cured by total thyroidectomy and radioiodine treatment (RAI; 10-year survival rate >90%) [2], approximately 5–10% of patients with DTC develop an aggressive disease with distant metastases and loss of 131-iodine avidity [3,4]. Inoperable metastatic and/or radioiodine refractory DTC is associated with a less favorable prognosis, with 10-year survival rates between 25% and 40%. Distant metastases most frequently occur in the lungs (50%), bones (25%) or both (20%) and less frequently at other sites (5%) [1,3,5,6]. In these patients, therapeutic options are limited.

Tyrosine kinase inhibitors (TKIs), which inhibit VEGF (vascular endothelial growth factor) receptor signaling and tumor angiogenesis, improve progression-free survival (PFS) in patients with structurally progressive, radioiodine refractory DTC [7–10]. Lenvatinib is an oral, multitargeted TKI targeting VEGFRs 1–3, FGFRs (fibroblast growth factor receptors) 1–4, PDGFR (platelet-derived growth factor receptor) α, RET (rearranged during transfection receptor tyrosine kinase) and c-KIT (receptor for stem cell factor) signaling networks [11,12]. In the placebo-controlled phase 3 "Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT)", Lenvatinib significantly prolonged progressionfree survival (PFS), resulting in approval by the US Food and Drug Administration and European Medicines Agency in 2015 [13].

Accurate assessment of treatment response is crucial to discriminate between responders and non-responders thereby avoiding inefficient therapy and its potential adverse effects. The current standard for monitoring tumor response is measurement of change in tumor size based on anatomical imaging techniques such as computed tomography (CT); this technique has been most frequently assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) [14], which were updated (RECIST 1.1 criteria) in 2009 [15]. As newer cancer treatments are cytostatic rather than cytotoxic, functional changes are expected to precede the morphologic changes and therefore 2-deoxy-2-[18F] fluoro-Dglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) has the potential to improve diagnostic accuracy and prediction of the course of tumor development [16,17]. Wahl et al. described the Positron Emission Tomography Response Criteria In Solid Tumors (PERCIST) in 2009 to provide a structured guidance for response assessment using 18F-FDG-PET [18]. However, data on potential 18F-FDG-PET/CT applications in staging and restaging of advanced radioiodine refractory DTC is limited.

The aim of this study was to assess the role of 18F-FDG-PET in the monitoring of functional tumor response (modified PERCIST 1.0 and quantitative PET-parameters) in comparison to morphological response (RECIST 1.1) in combined 18F-FDG-PET/CT and thereby predicting both PFS and disease-specific survival (DSS) in patients with advanced radioiodine refractory DTC receiving Lenvatinib treatment.
