fdg-pet/ct in evaluation of cytological indeterminate thyroid nodules to prevent unnecessary surgery (effects)

Conditions: Thyroid Nodule; Thyroid Neoplasms

Summary: the purpose of this study is to determine whether the use of molecular imaging using fdg-pet/ct could prevent unnecessary diagnostic thyroid surgery in case of indeterminate cytology during fine-needle aspiration biopsy.

rationale: only about ¼ of patients with thyroid nodules with indeterminate cytology are proven to suffer from a malignancy at diagnostic hemithyroidectomy. therefore \~¾ is operated upon unbeneficially. recent studies using fdg-pet/ct have suggested that it can decrease the fraction of unbeneficial procedures from \~73% to \~40%. thereby the direct costs per patient, the number of hospitalization and average sick leave days might decrease and the experienced hrqol might increase. a study will be undertaken to show the additional value of fdg-pet/ct after indeterminate cytology with respect to unbeneficial procedures, costs and utilities. main objective: to determine the impact of fdg-pet/ct on decreasing the fraction of patients with cytologically indeterminate thyroid nodules undergoing unbeneficial patient management. study design: a prospective, multicentre, randomized, stratified controlled blinded trial with an experimental study-arm (fdg-pet/ct-driven) and a control study-arm (diagnostic hemithyroidectomy, independent of fdg-pet/ct-result). study population: adult patients with a cytologically indeterminate thyroid nodule, without exclusion criteria, in 15 (university and regional) hospitals distributed over the netherlands. intervention: one single fdg-pet/low-dose non-contrast enhanced ct of the head and neck is performed in all patients. patient management depends on allocation and results of this fdg-pet/ct. main study parameters/endpoints: the number of unbeneficial interventions, i.e. surgery for benign disease or watchful-waiting for malignancy. secondary objectives: complication rate, consequences of incidental pet-findings, number of hospitalisation and sick leave days, volumes of healthcare consumed, experienced health-related quality-of-life (hrqol), genetic, cytological and (immuno)histopathological features of the nodules. sample size calculation/data analysis: based on above-mentioned estimated reduction in unbeneficial interventions from \~73% to \~40%, at least 90 patients with nodules\>10 mm need to be analyzed (2:1 allocation, α=0.05, power=0.90, single-sided fisher's exact test). after correction for nodule size and data-attrition, 132 patients need to be included in total. intention-to-treat analysis will be performed. incremental net monetary benefit based on the total direct costs per patients and the gain in hrqol-adjusted survival years are computed. cytological, histological and genetic parameters for fdg-avidity will be described. nature and extent of the burden and risks associated with participation, benefit and group relatedness: all patients undergo one fdg-pet/ct scan of head/neck (effective dose: \<3.5 msv) and are asked to fill in 6 questionnaires at 4 timepoints. fdg-pet/ct negative patients in the experimental arm will undergo a single confirmatory us (±fnac). an interim/posterior analysis of the control subjects is performed to ensure oncological safety. in case of an unexpected high false-negative ratio in this control arm, all patients will be advised to undergo surgery.

Eligibility criteria:
inclusion criteria: 1. documented history of a solitary thyroid nodule or a dominant nodule within multinodular disease, with (us-guided) fnac performed by a dedicated radiologist or experienced endocrinologist or pathologist, demonstrating an indeterminate cytological examination (i.e. bethesda category iii or iv) according to the local pathologist and confirmed after central review; 2. scheduled for surgical excision (preferably) within 2 months of the inclusion date; 3. age ≥ 18 years; 4. euthyroid state with a serum thyrotropin (tsh) or a free t4 level within the institutional upper and lower limits of normal, measured within 2 months of registration. in case of a suppressed tsh: a negative 123i, 131i or 99mtco4- scintigraphy must be available ("cold nodule"); 5. in patients with multinodular disease and a dominant nodule, the nuclear medicine physician responsible for fdg-pet/ct scan interpretation must determine whether the nodule is likely to be discriminated on fdg-pet/ct imaging prior to enrolment; 6. willing to participate in all aspects of the study; exclusion criteria: 1. high a priori probability of malignancy: * fnac bethesda category v or vi during local reading or central review; * prior radiation exposure / radiotherapy to the thyroid; * prior neck surgery or radiation that in the opinion of the pi has disrupted tissue architecture of the thyroid; * new unexplained hoarseness, change of voice, stridor or paralysis of a vocal cord; * in case a benign reason has been found (e.g. vocal cord edema), the patient is eligible; * thyroid nodule discovered as a fdg-pet positive incidentaloma * new cervical lymphadenopathy highly suspicious for malignancy; * in case malignancy is excluded, patient is eligible; * previous treatment for thyroid carcinoma or current diagnosis of any other malignancy that is known to metastasize to the thyroid; * known metastases of thyroid carcinoma; * known genetic predisposition for thyroid carcinoma: * familiar non-medullary thyroid cancer (nmtc) * familiar papillary thyroid cancer (fptc) * familiar adenomatoid polyposis coli syndrome (fap, gardner syndrome, apc-gene mutations on chromosome 5q21) * morbus cowden (pten mutation on chromosome 10q23.3) * ptc / nodular thyroid hyperplasia / papillary renal tumours. linked to locus 1q21. 2. proven benign disease or insufficient material for a cytological diagnosis: * fnac bethesda category i or ii during local reading or central review 3. performance of non-routine additional diagnostic tests that alter the patients treatment policy (e.g. mutation analysis on cytology) 4. inability to undergo randomization: * any patient that will receive thyroid surgery for other reasons (e.g. mechanical or cosmetic complaints). 5. inability to undergo treatment: * inability to undergo surgery in the opinion of the surgeon / anaesthetist. 6. contra-indications for fdg-pet/ct: * patient has evidence of infection localized to the neck in the 14 days prior to the fdg-pet/ct scan; * inability to tolerate lying supine for the duration of an fdg-pet/ct examination (\~10-15min); * poorly regulated diabetes mellitus (see next item); * hyperglycaemia at time of fdg injection prior to pet/ct (fasting serum glucose \>200mg/dl \[\>11.1 mmol/l\]); * the use of short-acting insulins within 4 hours of the pet scan is not allowed * if female and fertile: signs and symptoms of pregnancy or a positive pregnancy test / breast-feeding; * a formal negative pregnancy test is not obligatory * (severe) claustrophobia; * low dose benzodiazepines are allowed 7. general contra-indications: * inability to give informed consent; * severe psychiatric disorder;

Keywords: thyroid nodule indeterminate cytology fdg-pet/ct diagnostic thyroid surgery efficacy cost-effectiveness quality-of-life thyroidectomy