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

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ClinicalTrials.gov Identifier: NCT02208544
Recruitment Status : Active, not recruiting
First Posted : August 5, 2014
Last Update Posted : April 5, 2019
Sponsor:
Collaborator:
Dutch Cancer Society
Information provided by (Responsible Party):
Radboud University

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.

Condition or disease Intervention/treatment Phase
Thyroid Nodule Thyroid Neoplasms Procedure: Diagnostic Thyroid Surgery Device: Ultrasound of the head and neck Radiation: FDG-PET/CT Not Applicable

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 96 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Diagnostic
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
Actual Study Start Date : July 16, 2015
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Thyroid Diseases
Drug Information available for: Thyroid

Arm Intervention/treatment
Experimental: FDG-PET/CT-driven

Following treatment based on FDG-PET/CT:

  • negative: watchful waiting including confirmatory ultrasound
  • positive: diagnostic thyroid surgery as planned
Procedure: Diagnostic Thyroid Surgery
Diagnostic Thyroid Surgery
Other Names:
  • Thyroid Lobectomy
  • Hemithyroidectomy
  • Thyroidectomy

Device: Ultrasound of the head and neck
Confirmatory Neck Ultrasonography in FDG-PET/CT negative patient in the experimental arm

Radiation: FDG-PET/CT
Head and Neck FDG-PET/CT
Other Name: fluorodeoxyglucose positron emission tomography

Current Practice
diagnostic thyroid surgery despite results of FDG-PET/CT
Procedure: Diagnostic Thyroid Surgery
Diagnostic Thyroid Surgery
Other Names:
  • Thyroid Lobectomy
  • Hemithyroidectomy
  • Thyroidectomy

Radiation: FDG-PET/CT
Head and Neck FDG-PET/CT
Other Name: fluorodeoxyglucose positron emission tomography




Primary Outcome Measures :
  1. Fraction of unbeneficial treatment [ Time Frame: 12 months after inclusion ]

    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.



Secondary Outcome Measures :
  1. Fraction Complications [ Time Frame: 12 months after inclusion ]
    SO1b: To determine the effect of incorporation of FDG-PET/CT on the complication-ratio.

  2. Fraction False-Negative FDG-PET/CT's [ Time Frame: 12 months after inclusion ]
    SO1c: To determine the false-negative fraction of FDG-PET/CT in this population.

  3. Lesion and Patient Characteristics [ Time Frame: 12 months after inclusion ]
    SO1d: To determine the influence of lesion size, pathological classification and patient characteristics on the diagnostic accuracy of FDG-PET/CT.

  4. Fraction Incidental FDG-PET/CT Findings [ Time Frame: 12 months after inclusion ]
    SO1e: To determine whether incorporation of FDG-PET/CT of the head and neck lead to overdiagnosis in non-thyroidal incidental findings.

  5. Overall and Disease Free Survival [ Time Frame: 12 months after inclusion ]
    SO1f: To determine the short-term overall and disease free survival in both study arms.

  6. FDG-PET/CT Implementation-hampering Factors [ Time Frame: 12 months after inclusion ]
    SO1g: To determine which factors hamper implementation of this modality for this indication (structured interviews).

  7. Fraction of Patients being operated despite negative FDG-PET/CT [ Time Frame: 12 months after inclusion ]
    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).

  8. HRQoL-scores according to SF36-II, EQ-5D-5L, SF-HLQ and ThyPRO including changes [ Time Frame: Baseline, 2 months, 6 months and 12 months after inclusion ]

    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.


  9. Direct Costs [ Time Frame: 12 months after inclusion ]
    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.

  10. Number of Hospitalisation Days [ Time Frame: 12 months after inclusion ]
    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?

  11. Number of Sick Leave Days [ Time Frame: 3 months after inclusions ]
    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?

  12. incremental Net Monetary Benefit [ Time Frame: 12 months after inclusion ]

    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.


  13. Tissue Protein- and Gene-expression profile [ Time Frame: 12 months after inclusion of last patient ]
    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?

  14. Molecular biomarkers in relation to FDG-PET/CT [ Time Frame: 12 months after inclusion of last patient ]

    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?



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02208544


Locations
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Netherlands
Radboudumc
Nijmegen, Gelderland, Netherlands
MUMC
Maastricht, Limburg, Netherlands
AMC
Amsterdam, Noord-Holland, Netherlands
VUmc
Amsterdam, Noord-Holland, Netherlands
MeanderMC
Amersfoort, Utrecht, Netherlands
LUMC
Leiden, Zuid-Holland, Netherlands
ErasmusMC
Rotterdam, Zuid-Holland, Netherlands
Onze Lieve Vrouwe Gasthuis
Amsterdam, Netherlands, 1091AC
Rijnstate
Arnhem, Netherlands, 6800TA
Reinier de Graaf Ziekenhuis
Delft, Netherlands, 2625 AD
UMCG
Groningen, Netherlands
St. Antonius
Nieuwegein, Netherlands, 3430EM
HagaZiekenhuis
The Hague, Netherlands, 2566MJ
UMCU
Utrecht, Netherlands
Isala Klinieken
Zwolle, Netherlands, 8025AB
Sponsors and Collaborators
Radboud University
Dutch Cancer Society
Investigators
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Study Chair: Lioe-Fee de Geus-Oei, MD, PhD Leiden University Medical Center, Leiden, the Netherlands
Study Director: Dennis Vriens, MD, PhD Leiden University Medical Center, Leiden, the Netherlands
Principal Investigator: Lisanne de Koster, MD Radboud University Medical Centre, Nijmegen, the Netherlands

Additional Information:
Publications:
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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT02208544     History of Changes
Other Study ID Numbers: KUN 2014-6514
NL50166.091.14 ( Registry Identifier: ToetsingOnline )
First Posted: August 5, 2014    Key Record Dates
Last Update Posted: April 5, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Radboud University:
Thyroid Nodule
Indeterminate Cytology
FDG-PET/CT
Diagnostic Thyroid Surgery
Efficacy
Cost-Effectiveness
Quality-of-Life
Thyroidectomy
Additional relevant MeSH terms:
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Thyroid Nodule
Thyroid Neoplasms
Thyroid Diseases
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Deoxyglucose
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents