Total Thyroidectomy With and Without Prophylactic Central Neck Lymph Node Dissection in People With Low-risk Papillary Thyroid Cancer

Background:

- Thyroid cancer is the most common endocrine malignancy and papillary thyroid cancer
(PTC) accounts for more than 80% of thyroid cancer.

- The incidence of thyroid cancer has risen over the past decades.

- Central neck lymph node metastasis (LNM) is common in PTC and preoperative imaging
studies do not identify all involved lymph nodes in the central neck.

- It remains controversial if prophylactic central neck lymph node dissection (pCND) in
patients with low-risk PTC results in lower rates of persistent/recurrent disease and
higher complication rates as there has been no randomized controlled trial addressing
these issues to date.

- Serum thyroglobulin (Tg), especially when TSH-stimulated, is a very sensitive and
specific marker for persistent/recurrent PTC, in the absence of interfering anti-Tg
antibodies.

- Retrospective studies have compared the postoperative TSH-stimulated Tg levels between
those who underwent pCND and those who did not with conflicting results. A randomized
trial is needed.

- Health-related quality of life (QOL) is a well-accepted tool to measure the outcome of
cancer treatments. SF-36 v2 questionnaire has been frequently used to evaluate the QOL
in patients with thyroid cancer. There is no study evaluating the difference in QOL in
patients with low-risk PTC undergoing total thyroidectomy (TT) with and without pCND.

Objectives:

-To determine and compare biochemical cure rates in patients with low-risk PTCs undergoing
total thyroidectomy (TT) with and without pCND as measured by postoperative TSH-stimulated
serum thyroglobulin (stim-Tg) at 3 months (prior to RAI treatment).

Eligibility:

- Patients greater than or equal to 18 years who have thyroid nodule(s) greater than or
equal to 1 cm. but less than or equal to 4 cm. in size with either:

- inconclusive thyroid cytology positive for BRAF V600E mutation or RET/PTC
rearrangement or

- cytologically suspicious for or consistent with PTC

- Absence of extrathyroidal extension or lymphadenopathy suggesting metastatic PTC on
physical examination and neck ultrasound.

Design:

- Prospective, single-blinded, randomized controlled clinical trial.

- Cytology will be reviewed by Laboratory of Pathology, NCI or a pathology laboratory at
the enrolling institution. Once patients provide written informed consent, they will
receive routine history, physical, radiographic (neck ultrasonography (USG), and/or
other indicated tests) examinations as well as blood tests. Preoperative fine needle
aspiration for cytology and BRAFV600E mutation will be performed if participant has not
had either test performed.

- Preoperative assessment of QOL using standardized questionnaire (SF-36 v2) will be
obtained within 30 days prior to surgery

- Preoperative vocal cord assessment will be done by flexible laryngoscopy.

- Participants will be randomized after clinical staging, including ultrasonography, to
receive TT and pCND or TT alone and will be blinded from the result of randomization and
treatment. Patients will remain blinded from treatment assignment for the duration of
the study except for patients assigned to TT alone but found to have lymph node
metastases as described below.

- If participants in TT alone group are found to have lymph node metastasis at the time of
the operation by frozen section analysis, a therapeutic CND will be performed.
Participants will remain in the intention to treat (TT alone) group. TT patients will be
informed if a therapeutic CND is indicated and as such the blind will be broken for
these patients prior to study completion.

- All participants will have intact parathyroid hormone (PTH), calcium and electrolytes
checked preoperatively, in the morning after surgery, 2 weeks, and 6 months
postoperatively.

- Postoperative flexible laryngoscopy will be performed on postoperative day 1 (or
postoperative day 2, if it cannot be performed on the first postoperative day) and 6
months postoperatively if vocal cord abnormality is found on postoperative day 1

- Postoperative assessment of QOL will be done on day 1, 2 weeks, 3 months and 6 months,
1, 5 and 10 years postoperatively.

- Participants with postoperative hypoparathyroidism (low PTH and hypocalcemia) will be
treated with calcium replacement with or without vitamin D analogue. Serum PTH and
electrolytes will be monitored until resolved.

- Stim-Tg will be checked at 3 months postoperatively (prior to RAI scan/ablation, if
indicated) and at 1 year postoperatively or 1 year post-remnant ablation. 1 year stim-Tg
evaluation will be performed in patients enrolled at the NIH but is optional in patients
enrolled at non-NIH site(s) Unstimulated Tg, thyroid function tests, and
anti-thyroglobulin antibodies will be checked annually for 10 years.

- Soft tissue neck ultrasonography will be performed in all patients preoperatively and
every year postoperatively for the first 10 years.

- If biochemical evidence of tumor recurrence occurs, patients will undergo appropriate
radiographic studies and/or nuclear scintigraphy. Tissue biopsy of suspicious lesion(s)
will be performed if clinically indicated.

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed at least 1 thyroid nodule
that is greater than or equal to1 cm. but less than or equal to 4 cm measured in
greatest dimension and confirmed by the Laboratory of Pathology, NCI or confirmed by
the pathology laboratory of the enrolling institution:

- Indeterminate thyroid biopsy per Bethesda System for reporting thyroid
cytopathology with BRAF V600E mutation or RET/PTC rearrangement

- Cytologically or histologically suspicious or confirmed PTC per Bethesda System
for reporting thyroid cytopathology.

- Age greater than or equal to 18 years. Because PTC occurs rarely in patients <18 years
of age, children are excluded from this study.

- Absence of radiographic evidence of extrathyroidal extension.

- Absence of abnormal lymphadenopathy suggesting metastatic PTC on physical examination
and/or imaging studies.

- ECOG performance status less than or equal to 2

- Patients must have adequate organ function to safely undergo general anesthesia and
thyroidectomy. Laboratory values obtained less than or equal to 4 weeks prior to
surgery must demonstrate adequate bone marrow function (Hb greater than or equal to
6.0 mmol/L, absolute neutrophil count greater than or equal to 1.5 x 10^9/L, platelets
greater than or equal to 80 x 10^9/L), liver function (serum bilirubin less than or
equal to 2 x ULN, serum transaminases less than or equal to 3 x ULN). Patients with
chronic kidney disease who are on chronic renal replacement therapy are allowed..
Other tests, such as pulmonary function tests, cardiac echocardiogram or stress test,
will be performed if clinically indicated.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

- Women must not become pregnant prior to surgery or during the first 3 months after
surgery. Women who can become pregnant will be asked to practice an effective form of
birth control for up to 3 months after surgery.

EXCLUSION CRITERIA:

- Patients who have had previous thyroid surgery

- Patients whose tumors are deemed unresectable by clinical/imaging criteria.

- Patients with known synchronous distant metastatic disease.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded because we do not want to expose the unborn child to the
procedures necessary to perform the surgery.