[18F]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules: a blinded, randomised controlled multicentre trial

Abstract

Purpose To assess the impact of an [18F]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology. Methods In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [18F]FDG-PET/CT and were randomised to an [18F]FDG-PET/CT-driven or diagnostic surgery group. In the [18F]FDG-PET/CT-driven group, management was based on the [18F]FDG-PET/CT result: when the index nodule was visually [18F]FDG-positive, diagnostic surgery was advised; when [18F]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hürthle cell and Hürthle cell nodules. Results Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32–53%]) of patients in the [18F]FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68–93%]) in the diagnostic surgery group (p < 0.001). [18F]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28–53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33–63%]) in non-Hürthle cell and 13% (2/15 [95% CI, 2–40%]) in Hürthle cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [18F]FDG-PET/CT were 94.1% (80.3–99.3%), 39.8% (30.0–50.2%), 95.1% (83.5–99.4%), 35.2% (25.4–45.9%), and 31.1% (23.3–39.7%), respectively. Conclusion An [18F]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hürthle cell nodules. Trial registration number This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.

Quantitative classification and radiomics of [18F]FDG-PET/CT in indeterminate thyroid nodules

“…As such, [ 18 F]FDG-PET/CT-driven management resulted in an oncologically safe 40% reduction in futile diagnostic surgeries for benign nodules. With a limited 40% specificity, visual [ 18 F]FDG-PET/CT assessment increased the post-test risk of malignancy but appeared unable to fully risk-stratify the approximately two-thirds visually [ 18 F]FDG-positive nodules [4]. These results validated the findings from previously published, smaller, non-randomised studies [5][6][7][8][9][10][11][12].…”

“…Part of this limited specificity is explained by the proportion of HCN/SHCN cytology, which varied from 21 to 52% in previous PET/CT studies including 23% in our trial [4][5][6]. Hürthle cell neoplasms, defined as tumours composed of > 75% Hürthle cells, constitute an extraordinary subgroup: following the abundance of mitochondria in their oxyphilic follicular-derived cells, nearly all of these neoplasms are strongly [ 18 F]FDG-positive [4,[13][14][15].…”

“…Based on cytology, clinical characteristics, and ultrasound features, diagnostic thyroid surgery was scheduled in all patients, in accordance with current international guidelines [25]. Further inclusion and exclusion criteria of the EfFECTS trial, and its comprehensive study procedures were previously reported [4]. Patients from the original study were only eligible for inclusion in the current study if their [ 18 F]FDG-PET/CT scan was acquired with strict adherence to the EANM guidelines, including a patient fasting time of at least 4 h and an acquisition time between 55 and 75 min (Fig.…”

“…These patients remained under active surveillance and had at least a follow-up ultrasound examination after 12 months. All other patients were advised to proceed to the scheduled diagnostic surgery and were treated according to current guidelines [4,32]. This resulted in the following reference standard for the current study: benign nodules were defined either as benign on final histopathology (i.e., hyperplastic nodules, follicular adenoma or Hürthle cell adenoma) or as index nodules that remained unchanged in size and appearance on ultrasound follow-up, in accordance with definitions from the EfFECTS trial.…”

“…As such, visual [ 18 F]FDG-PET/CT assessment cannot differentiate between benign and malignant Hürthle cell nodules. We previously advocated that a visual [ 18 F]FDG-PET/CT-driven diagnostic workup should be limited to non-Hürthle cell Bethesda III/ IV nodules to optimize therapeutic yield [4].…”