297 [18F]FDG-PET/CT to prevent futile surgery: a blinded, randomised controlled multicentre trial 4 Introduction Thyroid nodules are common, but seldom harbour malignancy [463, 464]. Ultrasonography and fine needle aspiration cytology (FNAC) adequately differentiate benign from malignant thyroid nodules in approximately 70% of patients, but diagnostic dilemmas remain for nodules with indeterminate cytology, including atypia of undetermined significance or follicular lesion of undetermined significance (Bethesda III, AUS/FLUS) and (suspicious for a) follicular neoplasm (Bethesda IV, FN/ SFN) or Hürthle cell neoplasm (Bethesda IV, HCN/SHCN) [18, 464]. The follicular lesions of which this group largely consists, require histopathological assessment of capsular and vascular invasion to obtain a conclusive benign or malignant diagnosis [18]. Current international guidelines recommend repeat FNAC in Bethesda III nodules, and consideration of clinical and ultrasound characteristics and patient preference in both Bethesda III and IV nodules, before deciding to proceed with either active surveillance or diagnostic surgery [17, 18]. When diagnostic surgery is performed, mere one in four indeterminate thyroid nodules harbours malignancy. Thus, the surgery is futile in approximately 75% of these patients, with associated morbidity, risk of surgical complications, higher health care costs, and possible negative influence on the patients’ health-related quality of life (HRQoL) [18, 29, 465, 466]. A more accurate pre-operative differentiation is needed to avoid futile diagnostic surgeries for benign nodules. Positron emission tomography/computed tomography (PET/CT) using 2-[18F]fluoro-2-deoxy-Dglucose ([18F]FDG) visualises metabolic activity in tissues. A meta-analysis of the earlier small, non-randomised studies demonstrated that [18F]FDG-PET/CT reliably ruled out malignancy with 95% sensitivity in indeterminate thyroid nodules, increasing to 100% for nodules above 15 mm in diameter [38]. Consequently, [18F]FDG-PET/CT-driven management may cost-effectively reduce the fraction of futile surgeries from ~75% to ~40%, with an expected reduction in direct health care costs while maintaining HRQoL [29, 38]. More recent studies reported sensitivities ranging from 71% to 100%, with most trials confirming the safety of [18F]FDG-PET/CT-driven management [39, 40]. International guidelines acknowledged the potential, but stopped short of recommending the routine use of [18F]FDG-PET/CT for indeterminate thyroid nodules, as randomised-controlled trials underpinning the impact of [18F]FDG-PET/CT on improved patient outcomes are lacking [17]. Here, we report the first randomised-controlled trial evaluating the implementation of [18F]FDG-PET/ CT as a rule-out test in the diagnostic workup of indeterminate thyroid nodules. The primary objective was to accurately reduce unbeneficial patient management, i.e., avoid diagnostic surgery for benign nodules and avoid surveillance for malignant and borderline nodules requiring surgical resection. Secondary objectives were to determine the impact of [18F]FDG-PET/CT-driven management on the surgical complication rate, HRQoL, societal costs, and consequences of incidental PET/CT findings, and to assess the implementability of [18F]FDG-PET/CT.
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