Trial Title:
Molecular Analysis for Precision Surgery in Thyroid Cancer Trial
NCT ID:
NCT06235814
Condition:
Papillary Thyroid Cancer
Conditions: Official terms:
Thyroid Neoplasms
Thyroid Cancer, Papillary
Thyroid Diseases
Conditions: Keywords:
Radioactive Iodine
Fine Needle Aspiration
Parathyroid Hormone
Thyroid Stimulating Hormone
Thyroglobulin
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Molecular Analysis for Thyroid Resection
Description:
Protocol for Operative Management based on Molecular Risk Classifier
Patients will have a televisit (i.e. video-visit) with us in 2 weeks once the ThyroSeq
molecular analysis results. In that visit, we will discuss the operation the patient will
receive, including the risks and benefits of the operation. Operative management will be
dictated by the molecular results listed below:
- Low molecular-risk: thyroid lobectomy
- High molecular-risk: total thyroidectomy
- Intermediate molecular-risk: randomization to thyroid lobectomy or total
thyroidectomy
Of note, the respective operations for the low and high molecular-risk groups are
standard of care.
Arm group label:
Thyroid Lobectomy
Arm group label:
Total Thyroidectomy
Summary:
Ideal surgical extent for differentiated thyroid cancer remains unclear. Routine use of
molecular analysis in biopsy-proven thyroid cancer could provide important prognostic
information to help guide extent of surgery - thyroid lobectomy versus total
thyroidectomy. This is a pilot feasibility study for the use of routine molecular
analysis in Bethesda V and VI thyroid cancers, with randomization of the
intermediate-molecular risk subgroup to thyroid lobectomy and total thyroidectomy. The
investigators hypothesize that patients will 1) agree to preoperative molecular analysis,
and 2) 50% of intermediate-risk patients will agree to and follow through with
randomization. This will be a pilot study for a future randomized controlled trial (RTC)
to compare between the two surgical approaches in intermediate-molecular risk thyroid
cancer.
Detailed description:
Significance
Incidence of thyroid cancer has substantially increased in the past decade. Papillary
thyroid cancers (PTC), typically follow a very indolent course. Although approximately
45,000 patients are diagnosed with thyroid cancer each year, only 2,000 patients die from
it with a 5-year survival of over 98%. Thus, there has been a movement to de-escalate
care to reduce unnecessary surgical morbidity, and current guidelines recommend
consideration of thyroid lobectomy over total thyroidectomy when appropriate. At this
time, it is unclear when thyroid lobectomy would be more beneficial than total
thyroidectomy. A systematic review of guidelines and expert consensuses from 2009 to 2019
for PTC 1-4 cm in size found that 11 studies recommended total thyroidectomy, 5
recommended thyroid lobectomy, and 3 recommended either depending on patient-centered
decision making. Thus, there is an unmet clinical need for improved preoperative risk
stratification to determine ideal surgical treatment of thyroid cancer.
Currently, molecular testing is used to determine the risk of malignancy in indeterminate
thyroid biopsies. However, these tests have not been used for prognostic purposes in
biopsy-proven thyroid cancer. Recent studies have demonstrated that molecular profiling
of thyroid cancer is predictive of recurrent disease. Certain high-risk mutations such as
TP53, BRAF, and TERT are associated with increased risk of recurrence and fatal disease.
Therefore, molecular testing can offer valuable prognostic information to guide
treatment.
The investigators propose a feasibility study of a future multicenter study to assess
routine use of preoperative molecular testing for risk stratification. The investigators
believe that future studies stemming from this proposal will show that for patients with
intermediate molecular risk PTC, thyroid lobectomy will have equivalent cancer outcomes
to total thyroidectomy. If true, this will reduce the surgical risk and improve quality
of life of the tens of thousands of thyroid cancer patients, without compromising cancer
outcomes. Ultimately, the investigators hope to reduce overtreatment and morbidity in the
treatment of this indolent disease.
Innovation
Routine use of molecular analysis in all thyroid cancer cases. The investigators propose
to perform Thyroseq molecular testing on all patients who present with biopsy proven
thyroid cancer. Routine molecular testing on a consecutive, prospective cohort will
reveal the distribution of gene mutations and rearrangements in a diverse thyroid cancer
population. Thyroseq, a DNA-RNA sequencing test of 112 thyroid cancer-associated genes,
can provide state of the art data to help guide appropriate treatment for these patients.
Risk stratification for recurrence based on molecular analysis. Using Thyroseq's
pre-determined risk of recurrence based on types of mutations present, the patients will
be stratified as low-, intermediate-, or high-molecular risk. Several studies have
demonstrated that certain combination of mutations, such as TERT/TP53, confer a
significantly higher risk of mortality and recurrence, whereas BRAF mutations have been
debated about their prognostic significance. Thus, the database generated from this risk
stratification process will provide vital data regarding pathologic outcomes associated
with these mutations.
Randomization for intermediate-risk PTC patients to thyroid lobectomy versus total
thyroidectomy. Current ATA guidelines allow thyroid lobectomy or total thyroidectomy for
PTCs 1-4 cm in size. The investigators are proposing one of the first studies to
randomize patients with intermediate risk disease. This is the most robust method to
determine whether outcomes are similar between thyroid lobectomy and total thyroidectomy.
Currently, no randomized trial data exists regarding this topic.
Background
Diagnosis of thyroid cancer. Patients with thyroid nodules that look concerning on
ultrasound undergo fine needle aspiration biopsy. These are then classified into the
Bethesda Category based on risk of malignancy. Bethesda I is non-diagnostic and repeat
biopsy is required, and Bethesda II is benign. Bethesda III and IV are indeterminate
nodules. With the new advances in molecular genetics, current guidelines endorse
utilization of next generation sequencing for these nodules to further delineate the risk
of malignancy. Bethesda V nodules have a high risk for malignancy, and Bethesda VI is
diagnostic of a malignancy, so those patients require operative resection. Genetic
analysis is not routinely performed for these nodules. This study will focus on patients
with these Bethesda V and VI nodules.
Surgical treatment of PTC. PTC is the predominant pathologic type of thyroid cancer,
accounting for 80-90% of all cases. Patients with diagnosed thyroid cancer should undergo
ultrasound of the neck to assess for sonographic evidence of extrathyroidal spread and
lymph node metastasis.6 Patients with nodules larger than 4cm, gross extrathyroidal
extension (clinical T4), or clinically apparent metastatic disease to lymph nodes
(clinical N1) or distant sites (clinical M1) should undergo total thyroidectomy and gross
removal of all primary tumor.6 For cancers < 1 cm and without clinical evidence of
disease spread, ATA recommends performing a thyroid lobectomy to reduce morbidity.
However, patients who fall in the middle with nodules between 1cm and 4cm without
evidence of disease spread, guidelines recommend either thyroid lobectomy or total
thyroidectomy based upon disease features and patient preference.
Postoperative radioactive iodine for high-risk disease on pathology. Patients who
ultimately end up with high-risk disease on pathology (extrathyroidal extension, numerous
lymph node involvement, high-risk histologic features, etc.) undergo radioactive iodine
(RAI) therapy. In order to receive RAI, patients must have a total thyroidectomy. Those
who initially had thyroid lobectomy and pathology returns with high-risk disease undergo
a completion thyroidectomy - removal of the remaining thyroid gland - prior to starting
RAI. After completion of all treatment, patients can be surveilled with routine
ultrasound and thyroglobulin levels.
Thyroseq molecular analysis. Molecular analysis models were trained with machine learning
algorithm on both pathologies that were confirmed to be benign (Bethesda II) and
malignant (Bethesda V and VI) to analyze which genes and mutations are associated with
malignancy.8 Thyroseq is a DNA- and RNA-based next generation sequencing model of 112
genes.4 It reports the analysis in six different categories that range from negative to
presence of high-risk mutation (Figure 1). Based on Thyroseq's risk stratification,
nodules with certain combinations of TERT/TP53 with BRAF mutations are considered high
risk for recurrence,3 and total thyroidectomy is recommended. Conversely, RAS-like
mutations are associated with non-invasive follicular thyroid neoplasm with
papillary-like nuclear features (NIFTP), or a very low-risk variant of papillary thyroid
cancer.9 Thus, a thyroid lobectomy is recommended for these low-risk cases. However,
there exists a gray area in the appropriate management of Hurthle cell-type mutation and
BRAF-type mutation, where thyroid lobectomy or total thyroidectomy are both considered
adequate treatments.
Aim 1. Determine feasibility of a future multi-center trial of routine preoperative
molecular testing for papillary thyroid cancers to guide extent of therapy. The
investigators will pilot a single-center trial performing preoperative molecular testing
on all biopsy confirmed thyroid cancers. Goal is to assess the feasibility of a future
multi-center trial to determine prognostic value of preoperative molecular analysis.
Study setting and population. Patients seeking initial consultation at UCLA for newly
diagnosed thyroid cancer (Bethesda V and VI nodules) with localized disease will be
recruited for the study. The UCLA Endocrine Center is a high-volume tertiary referral
center for patients with thyroid cancer, performing 300 thyroid operations annually. Of
these patients, approximately 200 patients per year have localized disease eligible for
this study. Inclusion criteria: patients aged 18 or older, English-speaking, with a new
diagnosis of thyroid cancer. Exclusion criteria: patients with extra-thyroidal spread or
with cancers >4cm in size.
Data collection. Patients enrolled in the study will have their thyroid nodule biopsy
samples sent for Thyroseq analysis. Based on the mutations reported by Thyroseq (Figure
1), patients will be stratified as low-, intermediate-, or high-risk. Intermediate-risk
patients will further be randomized to thyroid lobectomy or total thyroidectomy,
explained in Aim 2. Patient outcomes will be tracked, which will be further delineated in
Aim 3.
Feasibility study. For feasibility studies of randomized control trials, a sample size of
24 to 50 patients is recommended.10 Investigators anticipate that an obstacle to study
completion will be poor adherence rates to the study, particularly randomization of
surgical treatment in the intermediate-risk group. If investigators enroll 100 patients
with 50 patients randomized to the invention arm, investigators predict a 75% completion
rate of study assessments within a 95% confidence interval of +/- 12%. Thus, the
investigators' target enrollment will be 120 patients to allow up to a 20% dropout rate,
with 50 randomized to the intervention arm. The main endpoints of the feasibility
measures will include: 1) number of patients screened compared to patients enrolled, 2)
rate of study completion, and 3) dropout rate.
Aim 2. Determine the percent of eligible patients that undergo randomization to thyroid
lobectomy versus total thyroidectomy and complete assigned treatment. Patients with
intermediate-risk molecular analysis results will be further randomized to the above
intervention, to assess ideal extent of operative intervention in this population.
Treatment characteristics. Patients will receive the usual counseling, preoperative, and
postoperative care for the respective operations. Those who undergo total thyroidectomy
will have weight-based thyroid hormone replacement prescribed. All patients will be
followed by endocrine surgery and endocrinology for thyroid function management and
cancer surveillance.
Outcomes of interest. Outcomes of interest include proportion of patients who 1) agree to
randomization compared to those who enrolled in the study, and 2) complete the treatment
as assigned. As mentioned above, investigators predict that 50% of enrolled patients will
agree to randomization, with a dropout rate of 20%.
Aim 3. Determine whether preoperative molecular testing predicts postoperative
clinicopathologic findings. Patients enrolled in the study will have their clinical and
pathologic outcomes tracked in our database to assess the effectiveness of molecular risk
stratification in thyroid cancer.
Database creation. All postoperative data will be obtained with chart review. Pathologic
outcomes of interest include TNM staging, evidence of micro- and macroscopic
extrathyroidal spread, lymph node involvement, and high-risk pathologic features.
Clinical outcomes include rate of conversion to completion thyroidectomy in those who
initially undergo lobectomy, rates of postoperative RAI therapy, and evidence of
recurrence on imaging or laboratory values.
Effectiveness of molecular risk stratification. Ultimately, investigators will use
multivariable logistic regression analysis to assess of the low-, intermediate-, and
high-risk stratification correlate to final pathology outcomes.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients aged 18 years or older at the time of enrollment
- English-speaking
- Bethesda V or VI thyroid nodule that are 1-4cm in size
- Bethesda III or IV nodules who underwent previously underwent Thyroseq molecular
analysis that returned with intermediate molecular risk disease
Exclusion Criteria:
- Prior thyroid operation
- Extrathyroidal extension or lymph node metastases seen on ultrasound
- Distant metastatic disease
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of California Los Angeles
Address:
City:
Los Angeles
Zip:
90095
Country:
United States
Status:
Recruiting
Contact:
Last name:
Masha Livhits, MD
Email:
mlivhits@mednet.ucla.edu
Start date:
July 30, 2024
Completion date:
April 8, 2026
Lead sponsor:
Agency:
University of California, Los Angeles
Agency class:
Other
Source:
University of California, Los Angeles
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06235814
