Indeterminate Bethesda III Thyroid Nodules Clinical Trial
Radiofrequency Ablation for Indeterminate Bethesda III Thyroid Nodules
In the United States, there is an estimated 10% lifetime probability for developing a thyroid nodule. Up to 15% of these nodules will prove to be malignant. The incidence of thyroid cancer is increasing and is the third leading cause of cancer in women; accordingly, identification of a nodule 1. cm or larger in diameter often prompts a sophisticated diagnostic evaluation comprised of sonographic pattern risk assessment combined with fine needle aspiration biopsy (FNAB), which enables the assessment of cellular morphologic features that could not be identified by means of clinical assessment or imaging. Ultrasound-guided FNAB has been shown to accurately classify 62-85% of thyroid nodules as benign, thereby avoiding diagnostic surgery8,9. Yet, 20-30% of aspirations still yield indeterminate cytologic findings: "atypia (or follicular lesion) of undetermined significance," "follicular neoplasm or suspicious for follicular neoplasm," and "suspicious for malignancy with a risk of malignancy ranging from 6-75%." Most patients with cytologically indeterminate nodules are referred for diagnostic thyroid surgery, but the majority prove to have benign disease. For these patients, thyroid surgery is unnecessary, yet it exposes them to 2-10% risk of serious surgical complications, and most would require thyroid hormone replacement therapy for life. Research in recent years has focused on the potential of molecular diagnostic approaches that could capitalize on increasing knowledge of the molecular etiology of thyroid nodules and the transcriptional and mutation landscape of thyroid cancers to augment diagnostic accuracy of FNABs. Most molecular profiling tests demonstrate a high sensitivity and negative predictive value that helps to decrease the number of benign nodules undergoing unnecessary diagnostic surgery. However, these classified benign nodules may continue to grow and ultimately may need to undergo surgery due to compressive symptoms. Although thyroid surgery has always been the mainstay of treatment for symptomatic nodular goiters, and is associated with excellent outcomes in experienced hands, thyroid surgery carries a low risk of complications that include recurrent or superior laryngeal nerve injury leading to voice changes, hypoparathyroidism, hypothyroidism with need for thyroid hormone supplementation, and unsightly scarring. Although many patients with thyroid cancers find these risks acceptable, these risks are sometimes less acceptable to patients with benign disease. In an era when the medical field is treating thyroid diseases less aggressively, there is a pressing need to identify approaches to treat indolent malignant disease less invasively. Introduced in the early 2000s, ultrasound-guided percutaneous ablation of thyroid lesions has emerged as a potential alternative to surgery in patients with benign thyroid nodules. Of the myriad ablation methods, the most commonly used technique is radiofrequency ablation (RFA). An expanding body of evidence shows that radiofrequency ablation and other percutaneous interventions are effective treatments for benign solid thyroid nodules, toxic adenomas, and thyroid cysts resulting in overall volume reduction ranges of 40-70% with durable resolution of compressive and hyperthyroid symptoms. In addition, RFA has been used as an effective alternative treatment in the management of locally recurrent thyroid cancers in patients who are not good surgical candidates. Although these percutaneous techniques have been steadily. gaining acceptance in Europe and Asia over the past 20 years, they have been slow to be adopted in the US. In 2018 Hamidi et al published the first US institutional experience of 14 patients who received RFA, reigniting interest in the procedure, however, there remains a dearth of data regarding clinical experience in the United States and no randomized clinical trials have been performed evaluating RFA vs active surveillance for micropapillary carcinomas.
Adult patients >/=18 years of age who have a thyroid nodule <4cm in size and have a fine needle aspiration biopsy demonstrating indeterminate cytology Bethesda III (AUS or FLUS) that has been molecularly profiled determined benign using Afirma GSC, ThyroSeq v3, or ThyGenEXT/Thyramir will be eligible for enrollment in the study. If clinically indicated and after thorough evaluation of each individual case, participants will be offered ultrasound guided RFA in addition to active surveillance and surgery as viable options for management, and will be included in the study if they opt for RFA. Once patients are evaluated and the best treatment option and/or course of action is determined, and explained to the patients in detail, if the patient opt for RFA then the patient will be offered to participate in the study. Study participation will be offered to current patients at the Endocrine Center who already had an RFA procedure before protocol approval. If the current patients agree to participate in the study, a consent form will be obtained. We will use Telehealth in the case of patients that cannot come physically to a clinic visit. If this option is used for consultation, study participation will be offered and explained to patients this way, and if patients agree to research participation, the research team will send patients a RedCAP Link for E-Consenting. For patients that come to the Endocrine Center and decide to proceed with the RFA procedure after their visit, or in the case that the research team cannot approach a patient for any given reason (e.g. not a good time for the patient or Telehealth is not an option), an Information Sheet (see document attached) will be used instead of written consent when necessary. In this case, study participation will be explained to the patient in detail over the phone using the Information Sheet. Patients will have ample time to ask questions and get answers. If patients decide to participate in the study, a copy of this form will be mailed to patients for their records. The research team prefers to do this instead of submitting a request to the IRB for consenting the patient the same day of the procedure as the patient might be anxious or vulnerable at the time of the procedure. Interventions: The following 2 interventions are standard of care and not done as part of this research. 1. RFA: ultrasound-guided thermoablation will be performed using STARmed internally cooled RFA electrodes (18 gauge) powered by the VIVA RF generator in accordance with the 'moving shot' technique described by Baek et al.[7, 8]. The RFA procedure uses image guidance to place an electrode through the skin into the target area. In RFA, high frequency electrical currents are passed through an electrode, creating a small region of heat to treat the lesion. 2. Follow-up ultrasounds performed at 1, 3, 6, and 12 months post procedure. - Retrospective Data Collection & Request for Waiver of Written Consent Patients who have received at least one RFA procedure on or after 1/1/2000 until 7/22/2020 will be identified through WebCIS, Eclipsys, CROWN, and EPIC the Columbia University Medical Center electronic medical record databases. Names and medical record numbers will be used to collect demographic, laboratory, surgical, and other records. Data will be transferred to The Endocrine Center database, which is maintained on a secure server, satisfying institutional requirements for the secure storage of protected health information. This database is a multi-user system, and is in compliance with the IRB Data Security policy effective 11/15/2013. No additional blood work, radiological procedures, or invasive or non-invasive studies will be ordered. Specific information to be collected will include patient demographics (personal identifiers such as name, address and telephone numbers) and medical history: primary diagnosis and any additional comorbidities; details of RFA procedure; vital status; (alive with disease, alive without disease, dead with disease, dead without disease, dead due to disease). A waiver of consent is requested for all potential subjects that have already had an RFA procedure or no longer under the ongoing care of the investigators. As only information already on file is required and no additional blood work, radiological procedures, or invasive or non- invasive studies are necessary for participation, there is no more than minimal risk to these subjects, and inclusion in the study will not adversely affect the rights and welfare of these subjects. Power analysis: RFA of thyroid nodules can decrease nodule volume up to 75-80% from baseline at 6 months. We expect that patients who opt for the observation arm will have no significant change in nodule volume. To detect this effect size, with power of 0.8 and type 1 error at 0.05, we would need to enroll 29 patients in each study arm. Variables: Primary outcome measure is volume reduction ratio (VRR) of the nodule. Secondary outcome measures include nodule recurrence, regrowth, cosmetic and symptom scores. We will describe and compare the baseline characteristics of subjects including age, sex, race, tumor size, tumor sonographic appearance including echogenicity, vascularity, presence of calcifications, and solidity, and relevant serum studies. Analysis: Continuous variable distributions will be assessed by means of histograms and tests for non-normality and skewness; the log transform will be applied where appropriate. Univariable analyses will be performed using the 2, student's t-test, and Mann-Whitney test. ;