364 chapter 6 Material and methods Trial design, patients and treatment The Efficacy of [18F]FDG PET in Evaluation of Cytological indeterminate Thyroid nodules prior to Surgery (EfFECTS) trial was a prospective, triple-blinded, randomised controlled multicentre trial performed in 15 hospitals in the Netherlands (ClinicalTrials.gov: NCT02208544). The trial, including the current study, was approved by the Medical Research Ethics Committee on Research Involving Human Subjects region Arnhem-Nijmegen, Nijmegen, the Netherlands. Written informed consent was obtained from each of the participants prior to any study activity. Comprehensive descriptions regarding patient eligibility, selection, randomisation, blinding, [18F]FDG-PET/CT procedures, and sample size calculation are reported in our previous work [501]. In summary, patients with a Bethesda III or IV thyroid nodule (confirmed on central review; Bethesda III on repeat FNAC) and scheduled diagnostic surgery were eligible for inclusion (Table 1). There was one index nodule per patient. Patients were randomly assigned to an [18F]FDG-PET/CT-driven group or diagnostic surgery group in a 2:1 ratio (Figure 1). Randomisation was stratified for patient sex, age, thyroid nodule size, Bethesda classification (III or IV), and inclusion site. A partial-body [18F]FDG-PET/CT of the neck was acquired in all patients, and centrally assessed by two experienced nuclear medicine physicians for any focal [18F]FDG-uptake in the thyroid that was visually higher than the background uptake of the surrounding thyroid tissue and that corresponded to the index nodule in size and location. Patient allocation and the result of the [18F]FDG-PET/CT scan were not disclosed to the patient nor his/her local physician. Subsequently, the recommended patient management in the [18F]FDG-PET/CT-driven group was based on the result of the scan. When the index nodule was [18F]FDG-positive, patients were advised to proceed to the scheduled diagnostic surgery. When the index nodule was [18F]FDG-negative, active surveillance was recommended, with at least a follow-up ultrasound after one year. Any additional follow-up visits during the trial were permitted at the discretion of the local physician. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, in accordance with current (inter)national guidelines [17, 467]. In all patients in both groups, postoperative management was based on the local histopathological diagnosis and adhered to the Dutch national guidelines [467]. The current study adhered to this local histopathological diagnosis as a reference standard, as this diagnosis likely best reflects the patient’s illness perception and estimated costs. Consequently, minor differences exist between the current study and the trial’s main report, for which all histopathology was centrally reviewed [501]. Index nodules diagnosed as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) or follicular tumour of uncertain malignant potential (FT-UMP) are considered borderline tumours: they were postoperatively treated as benign nodules, but diagnostic surgery for these potentially premalignant nodules is considered justified [19, 20]. The study-related follow-up for all patients was one year.
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