FDG-PET/CT in Evaluation of Cytological Indeterminate Thyroid Nodules to Prevent Unnecessary Surgery (EfFECTS)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Efficacy of [18F]-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (FDG-PET) in Evaluation of Cytological Indeterminate Thyroid Nodules Prior to Surgery: a Multicentre Cost-effectiveness Study

Conditions
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Thyroid Nodule, Thyroid Neoplasms

Intervention / Treatment
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* Procedure: Diagnostic Thyroid Surgery
* Device: Ultrasound of the head and neck
* Radiation: FDG-PET/CT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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; Scheduled for surgical excision (preferably) within 2 months of the inclusion date; Age ≥ 18 years; 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); 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; Willing to participate in all aspects of the study; Exclusion Criteria: 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. Proven benign disease or insufficient material for a cytological diagnosis: FNAC Bethesda category I or II during local reading or central review Performance of non-routine additional diagnostic tests that alter the patients treatment policy (e.g. mutation analysis on cytology) Inability to undergo randomization: Any patient that will receive thyroid surgery for other reasons (e.g. mechanical or cosmetic complaints). Inability to undergo treatment: Inability to undergo surgery in the opinion of the surgeon / anaesthetist. 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 General contra-indications: Inability to give informed consent; Severe psychiatric disorder;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FDG-PET/CT-driven<br>Following treatment based on FDG-PET/CT: negative: watchful waiting including confirmatory ultrasound positive: diagnostic thyroid surgery as planned | Procedure: Diagnostic Thyroid Surgery<br>* Diagnostic Thyroid Surgery<br>* Other names: Thyroidectomy;Device: Ultrasound of the head and neck<br>* Confirmatory Neck Ultrasonography in FDG-PET/CT negative patient in the experimental arm<br>Radiation: FDG-PET/CT<br>* Head and Neck FDG-PET/CT<br>* Other names: fluorodeoxyglucose positron emission tomography;|
| Other: Current Practice<br>diagnostic thyroid surgery despite results of FDG-PET/CT | Procedure: Diagnostic Thyroid Surgery<br>* Diagnostic Thyroid Surgery<br>* Other names: Thyroidectomy;Radiation: FDG-PET/CT<br>* Head and Neck FDG-PET/CT<br>* Other names: fluorodeoxyglucose positron emission tomography;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fraction of unbeneficial treatment | Unbeneficial treatment is defined as either: surgery in benign disease watchful waiting in malignant disease benign or malignant disease is defined on final histology (after surgery) or 12 month follow-up including confirmatory neck ultrasonography. This parameter is compared between both study arms based on intention-to-treat. | 12 months after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fraction Complications | SO1b: To determine the effect of incorporation of FDG-PET/CT on the complication-ratio. | 12 months after inclusion | 
| Fraction False-Negative FDG-PET/CT's | SO1c: To determine the false-negative fraction of FDG-PET/CT in this population. | 12 months after inclusion | 
| Lesion and Patient Characteristics | SO1d: To determine the influence of lesion size, pathological classification and patient characteristics on the diagnostic accuracy of FDG-PET/CT. | 12 months after inclusion | 
| Fraction Incidental FDG-PET/CT Findings | SO1e: To determine whether incorporation of FDG-PET/CT of the head and neck lead to overdiagnosis in non-thyroidal incidental findings. | 12 months after inclusion | 
| Overall and Disease Free Survival | SO1f: To determine the short-term overall and disease free survival in both study arms. | 12 months after inclusion | 
| FDG-PET/CT Implementation-hampering Factors | SO1g: To determine which factors hamper implementation of this modality for this indication (structured interviews). | 12 months after inclusion | 
| Fraction of Patients being operated despite negative FDG-PET/CT | SO1h: To determine the fraction of patients that cannot be reassured by a negative PET-scan (experimental arm only) despite careful selection of patients (implementability). | 12 months after inclusion | 
| HRQoL-scores according to SF36-II, EQ-5D-5L, SF-HLQ and ThyPRO including changes | SO2a: To determine the impact on the experienced HRQoL between the group with and without FDG-PET/CT according to 4 different questionnaires at 4 timepoints during the first 12 months after FDG-PET/CT. SO2b: To determine whether patients in the experimental arm with negative PET-findings have a different HRQoL than those who receive surgery independent of the FDG-PET/CT results. | Baseline, 2 months, 6 months and 12 months after inclusion | 
| Direct Costs | SO3a: To determine the effect of incorporation of FDG-PET/CT on the mean direct costs (=volume of care multiplied by activity based costs) per patient during the first 12 months after FDG-PET/CT. | 12 months after inclusion | 
| Number of Hospitalisation Days | SO3b: To determine the effect of incorporation of FDG-PET/CT on the average length of hospital stay for treatment of (complications of) thyroid lesions? | 12 months after inclusion | 
| Number of Sick Leave Days | SO3c: To determine the total number of sick leave days for the first three months in the patients? Do these differ between both study arms? | 3 months after inclusions | 
| incremental Net Monetary Benefit | SO3d: To determine the incremental Net Monetary Benefit of incorporation of FDG-PET/CT with respect to quality-adjusted life-years (QALYs, based on EQ-5D-5L index and overall survival) saved including sensitivity analysis. SO3e: To determine the incremental Net Monetary Benefit of incorporation of FDG-PET/CT with respect to decrease in unbeneficial treatment. Sensitivity analysis will be performed. A mere description will be given as there is no accepted value for this kind of analysis. | 12 months after inclusion | 
| Tissue Protein- and Gene-expression profile | SO4a: Are there potential protein- or gene-expression profiles, capable of determining the nature of the FNAC-indeterminate nodes (cytology) SO4b: What is the interaction/correlation between the parameters mentioned in SO4a and the results of the FDG-PET/CT scan and the final diagnosis? | 12 months after inclusion of last patient | 
| Molecular biomarkers in relation to FDG-PET/CT | SO4b: What is the interaction/correlation between the parameters mentioned in SO4a and the results of the FDG-PET/CT scan and the final diagnosis? Can these tissue molecular biomarkers help in selecting the patients that benefit most from FDG-PET, or vice versa? Can higher pre-operative diagnostic accuracy be achieved by combining FDG-PET and molecular biomarkers? Are molecular biomarkers related to false-positive or false-negative FDG-PET/CT results? | 12 months after inclusion of last patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thyroid Nodule, Indeterminate Cytology, FDG-PET/CT, Diagnostic Thyroid Surgery, Efficacy, Cost-Effectiveness, Quality-of-Life, Thyroidectomy