Administrative information
Title |
ESTIMation of the ABiLity of prophylactic central compartment neck dissection to modify outcomes in low-risk differentiated thyroid cancer: A Prospective Randomized Trial
Abbreviated Title of Protocol (Acronym): ESTIMABL 3
|
Trial registration | NCT 03570021 French trial registration number 2017-A01779-44 |
Protocol version | Protocol version 2.3, October 22, 2021 (submitted to Clinical Trials.gov as version 2B on December 20, 2021) |
Funding | Funded by a grant from the French National Cancer Institute, PHRC-K15-182 |
Author details | Dana M. Hartl, MD PhD Principal Investigator Isabelle Borget, PharmD Methodologist and statistician Nathalie Bouvet Forteau Data manager Salim Laghouati, MD Pharmacovigilance Elodie Lecerf Clinical Research Assistant, Promotor Yann Godbert, Xavier Carrat, Stéphane Bardet, Audrey Lasne-Cardon, Pierre Vera, Elena Ilies, Slimane Zerdoud, Jérôme Sarini, Mohamad Zalzali, Luigi La Manna, Olivier Schneegans, Antony Kelly, Philppe Kauffmann, Patrice Rodien, Laurent Brunaud, Solange Grunenwald, Elie Housseau Trial co-investigators Livia Lamartina, MD PhD ; Julien Hadoux, MD PhD Co-investigators, co-coordinators TuThyRef network Martin Schlumberger, MD PhD Founder TuThyRef network |
Name and contact information for the trial sponsor | Gustave Roussy 114 rue Edouard Vaillant 94805 Villejuif Cedex France Contact : Dr Dana M. Hartl, MD PhD dana.hartl@gustaveroussy.fr |
Role and responsibilities of sponsor and funder | Study sponsor: Organization of data collection, management of clinical research assistants Study funder: approval of study design prior to funding The interpretation of data, writing of the report and communication and publication of the results are under the responsibility of the principal investigator and methodologist. The sponsor and funder do not have oversight of data interpretation or publication. |
Role and responsibilities of committees | Coordinating center: Gustave Roussy (also promotor), coordination of participating centers, communication with the principal investigators and research assistants of each participating center Data management committee, data management team from Gustave Roussy: oversight of correct and complete reporting |
Introduction
Background and rationale
-
The technical difficulty of performing a reintervention in the central compartment secondarily, and
-
The absence of increased permanent complications of PND (in experienced hands). [3]
Study
|
Design
|
Number of patients
|
Results concerning recurrence rates
|
Other oncologic results
|
Complication rates
|
---|---|---|---|---|---|
Sanabria A et al Ann Surg 2022 [30] | Meta-analysis of 5 randomized studies | 763 409 PND 354 TT | No difference in structural recurrence rate 2.5% vs 2.7% | No difference in biochemical recurrence rate | No difference in rate of permanent hypoPTH |
Ahn JH et al Surgery 2022 [31] | Propsective randomized single center | 101 51 PND 50 TT | No difference in structural recurrence rates or successful ablation | No difference in complication rate | |
Sippel R et al Ann Surg 2020 [32] | Propsective randomized single center | 60 30 PND 30 TT | No difference in stimulated Tg levels at 6 weeks or 1 year | ||
Lee DY et al JCEM 2015 [33] | Propsective randomized single center | 257 153 PND 104 TT | No difference in LRR 3.3% vs 3.9% | No difference in number of patients treated with RAI | Higher rates of temporary hypoPTH (p=0.043) |
Viola D et al JCEM 2015 [34] | Propsective randomized single center | 181 93 PND 88 TT | No difference in LRR (7.5% vs 8.0%) | More RAI in TT alone group (p=0.002) | Higher rate of permanent hypoPTH in PND group (p=0.02) |
Chen L et al World J Surg 2018 [26] | Meta-analysis of retrospective studies | 18,376 11,098 PND 5583 TT | Lower LRR in PND group 2.52% vs 4.59% (OR=0.65) | Higher rates of temporary (OR=2.23)and permanent hypoPTH (OR=2.22)and temporary VFP (OR=2.03) | |
Liang J et al Acta Otorhino Ital 2017 [35] | Meta-analysis of retrospective studies | 6823 3312 PND 3511 TT | Lower LRR in PND group (p<0.01) | Higher rate of temporary (p<0.01) and permanent (p<0.01) hypoPTH and temporary VFP (p=0.023) in PND group | |
Zhao W et al Ann Surg Oncol 2016 [36] | Meta- analysis of retrospective studes | 4437 1969 PND 2468 TT | Lower LRR in PND group 1.1% vs 3.4% (p=0.002) | More RAI in PND group 74.6% vs 59.9% (OR 1.20) | Higher rates of temporary (p<0.00001) and permanent (p=0.03) hypoPTH |
Wang TS et al Ann Surg Oncol 2013 [6] | Meta- analysis of retrospective studes | 1740 745 PND 995 TT | No difference in LRR | No difference in rates of permanent complcations | |
Lang BH et al Thyroid 2013 [7] | Meta-analysis of retrospective studies | 3331 1592 PND 1739 TT | Lower LRR in PND group 4.7% vs 8.6% (OR=0.65) | More RAI in PND group 71.7% vs 53.1% (OR=2.60) | Higher rate of temporary hypoPTH PND group 26% vs 10.8% (OR=2.56) |
Zetoune T et al Ann Surg Oncol 2010 [37] | Meta-analysis of retrospective studies | 1264 396 PND 868 TT | No difference in LRR (2.02% vs 3.92%) |
-
Our study includes only tumors ≥11 mm (microcarcinomas are not eligible), whereas all of the studies cited in Table 1, with the exception of the study by Sippel et al. [32], included a large proportion of microcarcinomas (in Ahn et al. [31] for example, 90% of the tumors were T1 with a mean tumor size of 1.1 +/− 0.6 cm);
-
Thyroglobulin measurements will be evaluated before and after the administration of RAI to evaluate the effect of RAI ablation and eliminate this bias found in most of these studies in which outcomes were evaluated after RAI ablation in most or all patients;
-
Finally, our study is designed with a non-inferiority margin of 5% and an alpha level set at 0.025, whereas the study by Viola et al. [34] is significant but with a non-inferiority margin of 15% and an alpha of 0.05.
Rationale: choice of comparators
Objectives
Primary objective
-
Normal whole body scan (SPECT-CT) performed after the administration of 30 mCi (1.1 GBq) of 131I administered within 2–4 months following surgery,
-
Normal neck ultrasound 8+/−2 months after the 131I
-
Unstimulated ultrasensitive thyroglobulin while on L-thyroxine treatment (usTg/LT4) ≤ 0.2 ng/mL) without anti-Tg antibodies (TgAb) 8+/−2 months after administration of 131I
Secondary objectives
-
Thyroglobulin levels after surgery alone (usTg/T4) measured while on T4 treatment, 8+/−2 weeks postoperatively, before stimulation and administration of radioactive iodine
-
Percent of patients in complete remission (excellent response) at 3 and 5 years after randomization, as defined by a normal neck ultrasound and usTg/LT4 ≤ 0.2 ng/m. The endpoint of 5 years reflects the data from a prospective multicenter study of 715 patients reporting that 81% of recurrences occurred within 5 years,[43] and from a retrospective study of 1020 patients followed for 10 years reporting that all structural recurrences occurred within 8 years, with 77% occurring within 5 years [44].
-
Percent of patients at 1, 3, and 5 years after randomization with structural incomplete response in the neck defined by a malignant lesion in the neck detected by ultrasound and confirmed by cytology (and/or Tg in the needle washout fluid >10ng/ml). Cytology will be mandatory for suspicious lesions measuring 8mm or more in the smallest diameter; lesions with suspicious features on ultrasound but measuring <8 mm may undergo cytology at the discretion of the center’s principal investigators.
-
Percent of patients at 1, 3, and 5 years after randomization with biological incomplete response defined by a normal neck ultrasound and absence of disease detected on other conventional or metabolic imaging (131I, 18FDG-TEP), if performed, associated with a serum Tg/LT4>0.2 ng/ml
-
Percent of patients at 1, 3, and 5 years after randomization with an indeterminate response defined by a suspicious lesion on neck ultrasound without cytological proof of disease and/or detection of TgAb
-
Percent of patients at 1, 3, and 5 years after randomization with diagnosis of distant metastases on metabolic imaging (131I, 18FDG-TEP) or cross-sectional imaging, and confirmed cytologically (except for metastases with 131I uptake) or with repeat imaging at 6 months (if cytology not possible)
-
Percent of patients at 1, 3, and 5 years after randomization having undergone further treatment (surgery or 2nd therapeutic administration of 131I, number of retreatments per patient and indication for each retreatment)
-
At 1 year: percent of patients with persistent hypoparathyroidism with supplementation and/or persistent vocal fold paralysis; subjective dysphonia (Voice Handicap Index)[45] and dysphagia (SWAL-QOL)[46] (questionnaires in their validated French versions) compared between groups after randomization: Quality of life SF36[47], EuroQol EQ-5D,[48] Anxiety (State-Trait Anxiety Inventory-STAI)[49]
-
Cost-utility analysis.
Trial design
-
For patients with FNAB cytology Bethesda 6 “papillary carcinoma”, inclusion and randomization will we performed preoperatively.
-
For patients with FNAB cytology Bethesda 5 “suspicious cytology”, randomization (and validation of the inclusion) will then be performed in the operating room, after confirmation of malignancy by intra-operative frozen section analysis. For these patients, randomization will be performed online or by fax with the Trial Master program.
Methods: participants, interventions, and outcomes
Study setting
Eligibility criteria
Inclusion criteria
-
AND with fine-needle aspiration biopsy (FNAB) cytology in favor of “papillary thyroid carcinoma” (Type 6 according to the Bethesda classification (Appendix 2)
-
OR with FNAB cytology “suspicious for malignancy” (Type 5 according to the Bethesda classification). In this latter case, randomization will be performed if confirmation of papillary carcinoma on intra-operative frozen section analysis
Non-inclusion criteria
Criteria for eligibility of participating centers
Who will take informed consent?
Interventions
Explanation for the choice of comparators
Intervention description
Randomization of patients
-
Pre-registration (inclusion) of eligible patients after signed informed consent.
-
Surgery must be performed within 4 months of pre-registration.
-
Quality of life (SF-36, EQ-5D, STAI) questionnaires will be completed by the patient within 1 month before the surgery.
-
Before surgery, the patients will first be pre-registered (included) to check that the thyroid nodule is classified cT1bT2N0 and the FNAB cytology is classified type 5 or 6 according Bethesda (Appendix 2).
-
-
Randomization (and validation of the inclusion)
Treatments
-
Inclusion and non-inclusion criteria and patient consent
-
Neck ultrasound
-
Laryngoscopy
-
Serum calcium
-
Group 1 (reference group): total thyroidectomy with bilateral prophylactic central compartment neck dissection
-
Group 2 (“experimental” group): total thyroidectomy alone without neck dissection.
-
Stimulated usTg (Tg/rhTSH), anti-Tg antibodies (anti-Tg Ab)
-
Neck ultrasound
-
Whole body scintiscan with SPECT performed 2–5 days after the RAI administration
-
Quality control of total thyroidectomy will be ensured by calculation of the % of 131I uptake, as an estimate of the size of thyroid remnant.
-
1 year after surgery (8 +/− 2 months after 131I) (primary endpoint): usTg on thyroxine treatment (usTg/LT4) with a standard ultrasensitive kit, anti-Tg Ab, neck ultrasound
-
Yearly for 5 years (+/− 2 months after 131I): Tg/LT4, anti-Tg Ab, neck ultrasound
-
If suspicious lesion (according to standardized criteria on ultrasound [52] > or = 8 mm (smallest dimension): indication for cytological examination by fine-needle aspiration biopsy (FNAB) and, for lymph nodes, for a determination the of level of thyroglobulin (Tg) in the needle washout fluid
-
If a suspicious lesion <8mm is visualized on ultrasound (according to standardized criteria,[52] cytology with FNAB (and Tg in the needle washout fluid) will be performed upon decision of the center’s principal investigators
-
Immediate postoperative complications (0–4 months after surgery) (hypoparathyroidism requiring supplementation, recurrent nerve paralysis visualized on systematic laryngoscopy)
-
Complications at 1 year: treatment for persistent hypoparathyroidism, recurrent nerve paralysis visualized on systematic laryngoscopy performed at 1 year
-
Complete remission at 1, 3, and 5 years after randomization
-
At 1, 3, and 5 years after randomization: Quality of life [SF-36 + EQ-5D], Anxiety (State-Trait Anxiety Inventory), all questionnaires in their validated French translation:
-
Quality of life (SF-36) [47]
-
EQ-5D 3 Levels [48]
-
Anxiety (State-Trait Anxiety Inventory) [49]
-
Subjective dysphonia (measured via the Voice Handicap Index, VHI) [45]
-
Subjective dysphagia (measured via the SWAL-QOL questionnaire) [46]
Criteria for discontinuing or modifying allocated interventions
-
Lost to follow-up
-
Withdrawal of consent
-
Death
Strategies to improve adherence to interventions
Relevant concomitant care permitted or prohibited during the trial
Provisions for post-trial care
SPIRIT Reporting guidelines
Outcomes: Primary criterion
-
Normal whole body scan (SPECT-CT) at the time of administration of 131I [SPECT-CT will be performed 2–5 days after the administration of 30 mCi (1.1 GBq) of 131I after stimulation using injected recombinant human TSH (rhTSH)],
-
Normal neck ultrasound at 8+/−2 months after 131I administration
-
Unstimultaed ultrasensitive thyroglobuline while on L-thyroxine treatment (usTg/LT4) ≤ 0.2 ng/mL without anti-Tg antibodies (TgAb) at 8+/−2 months after 131I administration
Outcomes: Secondary criteria
Oncologic secondary criteria
-
Thyroglobulin levels after surgery alone (ultrasentive thyroglobuliin, usTg/T4) measured while on T4 treatment, 8 +/−2 weeks postoperatively, before stimulation or administration of radioactive iodine
-
Percent of patients in complete remission (excellent response) at 3 and 5 years after randomization, as defined by negative imaging and either unstimultaed ultrasensitive thyroglobulin while on L-thyroxine treatment (usTg/LT4) ≤ 0.2 ng/mL) without anti-Tg antibodies (TgAb) or TSH-stimulated Tg<1ng/mL
-
Percent of patients at 1, 3, and 5 years after randomization with structural incomplete response in the neck defined by the presence of structural or functional evidence of disease, with any Tg level, with or without anti-Tg antibodies
-
Percent of patients at 1, 3, and 5 years after randomization with biological incomplete response defined by negative imaging and suppressed Tg ≥1 ng/mL or stimulated Tg≥10ng/mL or rising anti-Tg antibody levels
-
Percent of patients at 1, 3, and 5 years after randomization with an indeterminate response defined by nonspecific findings on imaging studies and/or faint uptake in thyroid bed on RAI scanning (if performed) and/or on stimulated Tg detectable but <1ng/mL and/or stable or declining TgAb in the absence of structural or functional disease
-
Percent of patients at 1, 3, and 5 years after randomization with diagnosis of distant metastases on metabolic imaging (131I, 18FDG-TEP) or cross-sectional imaging, and confirmed cytologically (except for metastases with 131I uptake) or with repeat imaging at 6 months (if cytology not possible).
-
Percent of patients at 1, 3, and 5 years after randomization having undergone further treatment (surgery or 2nd therapeutic administration of 131I, number of retreatments per patient and indication for each retreatment)
Functional secondary criteria and quality of life
-
At 1 year after randomization (8+/−2 months after 131I administration): percent of patients with persistent hypoparathyroidism and/or persistent vocal fold paralysis; subjective dysphonia (Voice Handicap Index, VHI) and dysphagia (SWAL-QOL) (questionnaires in their validated French versions) compared between groups
Outcomes: Cost-utility analysis
Data collection
-
Hospitalization for initial surgery, including the time in the operating room and for performing the surgery
-
Hospitalizations for management of complications (vocal fold paralysis, hypoparathyroidism)
-
Hospitalizations for further treatments (surgery or iodine administration)
-
Equipment, consultations, medical or paramedical acts for management of complications
-
Other direct or indirect costs that are not expected to differ between strategies will not be collected.
Cost valuation
Cost-utility analysis
Participant timeline
Determination of sample size
Recruitment
Assignment of interventions: allocation
Sequence generation
Concealment mechanism
Implementation
-
Providing the Sponsor with his/her CV as well as that of co-investigators,
-
Ensuring co-investigators and other healthcare professionals should be sufficiently qualified by education, training, and experience to perform their tasks,
-
Identifying members of his/her team participating in the trial and defining their responsibilities,
-
Recruiting patients after receiving the Sponsor’s approval.
-
Personally obtaining the informed consent form which has been dated and signed by the participant in the research prior to any specific trial selection procedure,
-
Regularly completing the case report form (CRF) for each patient included in the trial and ensuring that the Clinical Research Assistant (CRA) mandated by the Sponsor has direct access to source documents in order to validate information on the CRF,
-
Dating, correcting, and signing the corrections on the CRF for each patient included in the trial,
-
Accepting regular visits from a CRA and possibly visits from auditors mandated by the Sponsor or inspectors from the regulatory authorities.
Assignment of interventions: blinding
Data collection and management
Plans for assessment and collection of outcomes
-
Frequency and/or unexpected severity of the toxicity,
-
If any information leads to doubt as to the benefit/risk ratio of the clinical trial
-
Recruitment of patients too low,
-
Poor quality of the data collected
-
Slow recruitment
-
Poor protocol adherence / serious breach to the protocol
-
Inaccurate or incomplete data recording
-
Non-compliance with the International Conference on Harmonisation (ICH) guideline for Good Clinical Practice.
-
Poor protocol adherence / serious breach to the protocol
-
Major deviation from the protocol
-
Non-compliance with the International Conference on Harmonisation (ICH) guideline for Good Clinical Practice.
Plans to promote participant retention and complete follow-up
Data management
-
Trial management in accordance with the procedures at Gustave Roussy,
-
Quality control of data at the investigating site by the Clinical Research Assistant (CRA) in accordance with the monitoring plan,
-
Possible auditing of investigating centres.
Confidentiality
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use
Statistical methods
Statistical methods for primary and secondary outcomes
-
Unstimulated thyroglobulin levels between groups will be compared between groups using a chi-square test.
-
The rate of patients in complete remission at 3 and 5 years will be compared between groups using a chi-square test.
-
The rate of patients in with structural incomplete response, biological incomplete response, indeterminate response, distant metastases, or further treatments at 1, 3, and 5 years will be compared between the 2 groups using a chi-square test for each type of response.
-
Difference in locoregional control = 6.9% at 10 years [1]
-
Difference in rate of recurrence = 4.6% at 3 years [2]
-
Difference in rate of retreatment = 8.2% at 5 years [3]
-
Rate of structural recurrence = 1.4% at 8 years [44]
-
The rate of patients at 1 year with persistent hypoparathyroidism requiring medication and/or with persistent vocal fold paralysis will be compared between groups using a chi-square test; subjective dysphonia (Voice Handicap Index) and subjective dysphagia (SWAL-QOL) toxicities will be compared using a Student test for each time of evaluation (or a Kruskall-Wallis non-parametric test if they are not normally distributed).
-
Quality of life and anxiety: The investigator will inform the patient on the objective of QoL data collection. QoL data may be not exploitable in case of great number of missing questionnaires. Data will be analyzed according to the scoring manual of each questionnaire. A longitudinal analysis using a mixed model will be used to take into account of repeated QoL assessment and the initial value. If this analysis shows a significantly different effect between groups or an interaction between treatment and time, an analysis of the treatment effect on quality of life will be carried out at each time. Mean sub-scale scores will be compared using a Student test for each time of evaluation (or a Kruskall-Wallis non-parametric test if they are not normally distributed).
Health Economics Analysis
Data collection
-
Hospitalization for initial surgery, including the time in the operating room and for performing the surgery
-
Hospitalization for the management of complications
-
Hospitalization for further treatments (surgery, radioactive iodine)
-
Equipment, consultations, medical or paramedical acts for management of complications
-
Other direct or indirect costs that are not expected to differ between strategies will not be collected.
Cost valuation
Cost-utility analysis
Interim analyses
Methods for additional analyses (e.g., subgroup analyses)
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data
Plans to give access to the full protocol, participant-level data, and statistical code
Oversight and monitoring
Composition of the coordinating center and trial steering committee
Composition of the data monitoring committee, its role and reporting structure
Adverse event reporting and harms
-
Is fatal (results in death)
-
Is life-threatening
-
Requires or prolongs inpatient hospitalization*
-
Results in persistent or significant disability / incapacity
-
Is a congenital anomaly / birth defect
-
Is medically significant**
The following are not considered to be serious adverse events (SAE):
-
A visit to the emergency room or other hospital department for less than 24 h that does not result in admission (unless considered an “important medical event” or a life-threatening event)
-
Outpatient or same-day or ambulatory procedures
-
Observation or short-stay units
-
Hospitalization due to diagnostic procedures or standard supportive care (e.g., implant of central venous catheter)
-
A pre-planned hospitalization for a condition which existed at the start of study drug and which did not worsen during the course of study drug treatment
-
Social admission (e.g., subject has no place to sleep; hospice facilities)
-
Administrative admission (e.g., for yearly physical examinations)
-
Protocol-specified admission during a clinical trial (e.g., for a procedure required by the study protocol or for clinical research)
-
Optional admission not associated with a precipitating clinical AE (e.g., for elective cosmetic surgery)
-
A copy of the summary of hospitalization or prolongation of hospitalization
-
A copy of the post-mortem report (if applicable)
-
A copy of all laboratory examinations and the dates on which these examinations were carried out, including relevant negative results, as well as normal laboratory ranges.
-
All other document that he judges useful and relevant.