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

R

Radboud University Medical Center

Status

Completed

Conditions

Thyroid Nodule
Thyroid Neoplasms

Treatments

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

Study type

Interventional

Funder types

Other

Identifiers

NCT02208544
NL50166.091.14 (Registry Identifier)
KUN 2014-6514

Details and patient eligibility

About

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.

Full 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.

Enrollment

132 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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;

Trial design

Primary purpose

Diagnostic

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Triple Blind

132 participants in 2 patient groups

FDG-PET/CT-driven
Experimental group
Description:
Following treatment based on FDG-PET/CT: * negative: watchful waiting including confirmatory ultrasound * positive: diagnostic thyroid surgery as planned
Treatment:
Procedure: Diagnostic Thyroid Surgery
Radiation: FDG-PET/CT
Device: Ultrasound of the head and neck
Current Practice
Other group
Description:
diagnostic thyroid surgery despite results of FDG-PET/CT
Treatment:
Procedure: Diagnostic Thyroid Surgery
Radiation: FDG-PET/CT

Trial contacts and locations

15

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Data sourced from clinicaltrials.gov

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