• Lenvatinib
• Radioiodine-Refractory Thyroid Cancer
• tumor response
• [18F]FDG-PET/CT

Background. Monitoring tumor response to oncologic treatment is an integral and increasingly important function of [18F]FDG-PET/CT. The possibility to differentiate as early as possible “responders” from “non-responders” patients during oncologic therapies can maximize the effectiveness of patient care. Moreover, oncologic imaging is expected to have a major role not only in the individual patient, but also in clinical trials designed to help select which new therapies should be advanced to progressively larger and more expensive clinical trials. The metabolic response assessed by [18F]FDG-PET/CT as a leading indicator of tumor response may be even more predictive of outcome than morphologic criteria, especially in the case of new cytostatic drugs. Recently, in agreement with the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer, AIFA has approved the use of Lenvatinib, a new Multikinase Inhibitor (MKI), for the management of patients with progressive metastatic Radioiodine-Refractory Thyroid Cancer. Tumor response to MKIs in this setting is currently assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and patient symptoms, while the role of [18F]FDG-PET/CT seems under-explored. Aim. To assess the role of [18F]FDG-PET/CT in monitoring tumor response to Lenvatinib in progressive metastatic Radioiodine-Refractory Thyroid Cancer patients and to predict prognosis with respect to different quantitative parameters. Patients and Methods. From December 2014 to September 2016, 33 patients with progressive Radioiodine-Refractory Thyroid Cancer (M/F=17/16; mean age: 65 years+/- 8,7; histologic type: 21 papillary thyroid carcinoma, 8 follicular thyroid carcinoma, 3 poorly differentiated thyroid carcinoma, 1 oxyphilic cells) were enrolled at the Department of Endocrinology of the University of Pisa to be submitted to treatment with Lenvatinib (24 mg/day). All patients underwent a baseline [18F]FDG-PET/CT scan, then repeated after about 1, 2, 6 and 12 months during therapy. All scans were performed with a PET/CT Discovery 710 scanner (GE Healthcare, Milwaukee, USA), including acquisition from the cranial vertex to half thigh, about 60 minutes after the injection of [18F]FDG (3.7 MBq/Kg). Patients fasted for at least 4 hours and finger stick blood glucose levels were <200 mg/dl prior to injection. Metabolic response to therapy was assessed in each site of disease (thyroid bed, lymph node, lung, bone, and other sites) during follow-up by qualitative evaluation, PET Response Criteria in Solid Tumors (PERCIST 1.0), maximal standardized uptake value (SUVmax), and metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as measures of metabolic tumor burden. TLGwb and MTVwb were then determined by adding together the MTV and TLG of each site of disease to provide an index of the overall malignant process in the entire body. Results. All patients had high metastatic metabolic involvement disease in more than two sites, in particular at the lymph nodes (32/33 patients) and in the lung (27/33 patients). Fifteen out of 33 patients died during follow-up (median of survival 19.9 months), while 18/33 patients are still alive, though with a reduced dose of Lenvatinib because of adverse effects. During the follow-up 21/33 patients presented progression metabolic disease (PMD) by PERCIST, 14/21 after about 1 month since the onset of therapy. The lack of early metabolic response assessed by PERCIST criteria was significantly associated with mortality, although the response by PERCIST at the end of follow-up was obviously found to be more predictive of outcome. In multivariate analysis, SUVmax, MTVwb and TLGwb of the overall malignant process in the entire body at baseline were not significantly associated with overall survival (OS), although the majority of patients had decrease in total metabolic tumor burden during treatment. The reduction of both TLGwb and MTVwb was statistically significant only between the baseline PET/CT scan and the first control scan. Subsequently, tumor response, in terms of total tumor burden, showed a slight decrease, but remained essentially stable. This was also confirmed with respect to target lesions in thyroid bed, lymph nodes, and in the lungs, whose mean values of SUVmax, TLG and MTV showed an initial statistically significant decrease between the baseline PET/CT scan and the first control scan. Moreover, based on logistic regression there was a significant statistical evidence (likelihood-ratio test p <0.01) that OS depended on the persistence of TLG response (total and target ΔTLG %) at lymph node level after a median of 4.7 months of treatment. On the other hand, in bone metastases there was not a statistically significant response to therapy during follow up. Conclusion. Quantitative [18F]FDG-PET/CT can be a useful tool to evaluate tumor response during MKIs therapy in progressive metastatic Radioiodine-Refractory Thyroid Cancer patients.