Clinical trial NCT02208544: FDG-PET/CT in Evaluation of Cytological Indeterminate Thyroid Nodules to Prevent Unnecessary Surgery (EfFECTS)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Thyroid Nodule
Thyroid Neoplasms
Keywords: Thyroid Nodule
Indeterminate Cytology
FDG-PET/CT
Diagnostic Thyroid Surgery
Efficacy
Cost-Effectiveness
Quality-of-Life
Thyroidectomy
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Dutch Cancer Society
First posted: 2014-08-05
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief 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.

Detailed description: 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;

Primary outcomes:
measure: Fraction of unbeneficial treatment
timeFrame: 12 months after inclusion
Secondary outcomes:
measure: Fraction Complications
timeFrame: 12 months after inclusion
measure: Fraction False-Negative FDG-PET/CT's
timeFrame: 12 months after inclusion
measure: Lesion and Patient Characteristics
timeFrame: 12 months after inclusion
measure: Fraction Incidental FDG-PET/CT Findings
timeFrame: 12 months after inclusion
measure: Overall and Disease Free Survival
timeFrame: 12 months after inclusion
measure: FDG-PET/CT Implementation-hampering Factors
timeFrame: 12 months after inclusion
measure: Fraction of Patients being operated despite negative FDG-PET/CT
timeFrame: 12 months after inclusion
measure: HRQoL-scores according to SF36-II, EQ-5D-5L, SF-HLQ and ThyPRO including changes
timeFrame: Baseline, 2 months, 6 months and 12 months after inclusion
measure: Direct Costs
timeFrame: 12 months after inclusion
measure: Number of Hospitalisation Days
timeFrame: 12 months after inclusion
measure: Number of Sick Leave Days
timeFrame: 3 months after inclusions
measure: incremental Net Monetary Benefit
timeFrame: 12 months after inclusion
measure: Tissue Protein- and Gene-expression profile
timeFrame: 12 months after inclusion of last patient
measure: Molecular biomarkers in relation to FDG-PET/CT
timeFrame: 12 months after inclusion of last patient
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc
state: Gelderland
city: Maastricht
country: Netherlands
facility: MUMC
state: Limburg
city: Amsterdam
country: Netherlands
facility: AMC
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: VUmc
state: Noord-Holland
city: Amersfoort
country: Netherlands
facility: MeanderMC
state: Utrecht
city: Leiden
country: Netherlands
facility: LUMC
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: ErasmusMC
state: Zuid-Holland
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Arnhem
country: Netherlands
facility: Rijnstate
city: Delft
country: Netherlands
facility: Reinier de Graaf Ziekenhuis
city: Groningen
country: Netherlands
facility: UMCG
city: Nieuwegein
country: Netherlands
facility: St. Antonius
city: The Hague
country: Netherlands
facility: HagaZiekenhuis
city: Utrecht
country: Netherlands
facility: UMCU
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: Leiden University Medical Center, Leiden, the Netherlands
name: Lioe-Fee de Geus-Oei, MD, PhD
role: STUDY_CHAIR
affiliation: Leiden University Medical Center, Leiden, the Netherlands
name: Dennis Vriens, MD, PhD
role: STUDY_DIRECTOR
affiliation: Radboud University Medical Centre, Nijmegen, the Netherlands
name: Lisanne de Koster, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Geus-Oei LF, Pieters GF, Bonenkamp JJ, Mudde AH, Bleeker-Rovers CP, Corstens FH, Oyen WJ. 18F-FDG PET reduces unnecessary hemithyroidectomies for thyroid nodules with inconclusive cytologic results. J Nucl Med. 2006 May;47(5):770-5.
citation: Vriens D, de Wilt JH, van der Wilt GJ, Netea-Maier RT, Oyen WJ, de Geus-Oei LF. The role of [18F]-2-fluoro-2-deoxy-d-glucose-positron emission tomography in thyroid nodules with indeterminate fine-needle aspiration biopsy: systematic review and meta-analysis of the literature. Cancer. 2011 Oct 15;117(20):4582-94. doi: 10.1002/cncr.26085. Epub 2011 Mar 22.
citation: Vriens D, Adang EM, Netea-Maier RT, Smit JW, de Wilt JH, Oyen WJ, de Geus-Oei LF. Cost-effectiveness of FDG-PET/CT for cytologically indeterminate thyroid nodules: a decision analytic approach. J Clin Endocrinol Metab. 2014 Sep;99(9):3263-74. doi: 10.1210/jc.2013-3483. Epub 2014 May 29.
citation: de Koster EJ, de Geus-Oei LF, Dekkers OM, van Engen-van Grunsven I, Hamming J, Corssmit EPM, Morreau H, Schepers A, Smit J, Oyen WJG, Vriens D. Diagnostic Utility of Molecular and Imaging Biomarkers in Cytological Indeterminate Thyroid Nodules. Endocr Rev. 2018 Apr 1;39(2):154-191. doi: 10.1210/er.2017-00133.
citation: de Koster EJ, de Geus-Oei LF, Brouwers AH, van Dam EWCM, Dijkhorst-Oei LT, van Engen-van Grunsven ACH, van den Hout WB, Klooker TK, Netea-Maier RT, Snel M, Oyen WJG, Vriens D; EfFECTS trial study group. [18F]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules: a blinded, randomised controlled multicentre trial. Eur J Nucl Med Mol Imaging. 2022 May;49(6):1970-1984. doi: 10.1007/s00259-021-05627-2. Epub 2022 Jan 4.
citation: de Koster EJ, Noortman WA, Mostert JM, Booij J, Brouwer CB, de Keizer B, de Klerk JMH, Oyen WJG, van Velden FHP, de Geus-Oei LF, Vriens D; EfFECTS trial study group. Quantitative classification and radiomics of [18F]FDG-PET/CT in indeterminate thyroid nodules. Eur J Nucl Med Mol Imaging. 2022 Jun;49(7):2174-2188. doi: 10.1007/s00259-022-05712-0. Epub 2022 Feb 9.
citation: de Koster EJ, Vriens D, van Aken MO, Dijkhorst-Oei LT, Oyen WJG, Peeters RP, Schepers A, de Geus-Oei LF, van den Hout WB; EfFECTS trial study group. FDG-PET/CT in indeterminate thyroid nodules: cost-utility analysis alongside a randomised controlled trial. Eur J Nucl Med Mol Imaging. 2022 Aug;49(10):3452-3469. doi: 10.1007/s00259-022-05794-w. Epub 2022 Apr 18.