Randomized Controlled Trial of Total Thyroidectomy With and Without Prophylactic Central Neck Lymph Node Dissection in Patients With Low-risk Papillary Thyroid Cancer
Phase: PHASE2
Conditions: Low-risk Papillary Thyroid Cancer, Endocrine Malignancy, Thyroid Cancer
Sponsor: National Cancer Institute (NCI)

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Abbreviated Title: Prophylactic Central Neck Dissection 
Version Date: 01/15/2019 
 
Abbreviated Title: Prophylactic Central Neck Dissection 
CC Protocol: 15-C-0105 G 
Version Date: 01/15/2019 
NCT Number:  NCT02408887  
Title: Randomized Controlled Trial of Total Thyroidectomy with and without Prophylactic 
Central Neck Lymph Node Dissection in Patients with Low-risk Papillary Thyroid Cancer 
 
NCI Principal Investigator:             Naris Nilubol, M.D.  
 
 
 
 
 
Surgical Oncology Program (SOP) 
                                                            Bldg. 10-CRC Room 4-5952 
 
 
 
 
 
10 Center Drive 
 
 
 
 
 
Bethesda, MD 20892 
 
 
 
 
 
Phone: 240-760-6154 
 
 
 
 
 
Email: naris.nilubol@nih.gov   
 
 
 
 
Investigational Agents:  None 
 
Coordinating Center :  
National Cancer Institute 
 
Data Safety Monitoring Board:       NCI CCR  
 
 
 

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PRÉCIS  
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 ≥ 18 years who have thyroid nodule(s) ≥1 cm but ≤ 4 cm in size with either: 
o inconclusive thyroid cytology positive for BRAF V600E mutation or RET/PTC 
rearrangement or  
o 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. 

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• 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. 

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TABLE OF CONTENTS  
Précis ............................................................................................................................................... 2 
Table of Contents  ........................................................................................................................... 4 
1. 
INTRODUCTION .................................................................................................................. 7 
1.1 
Study Objectives .............................................................................................................. 7 
1.1.1 
Primary Objective: .................................................................................................... 7 
1.1.2 
Secondary Objectives: .............................................................................................. 7 
1.2 
Background and Rationale ............................................................................................... 8 
1.2.1 
Epidemiology ............................................................................................................ 8 
1.2.2 
Management of papillary thyroid cancer .................................................................. 8 
1.2.3 
Prognosis and outcome ........................................................................................... 18 
1.2.4 
Quality of life after treatment for thyroid cancer .................................................... 19 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 19 
2.1 
Eligibility Criteria .......................................................................................................... 19 
2.1.1 
Inclusion Criteria .................................................................................................... 19 
2.1.2 
Exclusion Criteria ................................................................................................... 22 
2.2 
Screening Evaluation...................................................................................................... 22 
2.3 
Registration Procedures.................................................................................................. 23 
2.3.1 
For Participating Site Registration .......................................................................... 23 
2.4 
Randomization (or Stratification) Procedures ................................................................ 24 
2.5 
Baseline Evaluation ........................................................................................................ 24 
2.5.1 
Preoperative evaluation ........................................................................................... 24 
3 
STUDY IMPLEMENTATION ............................................................................................ 24 
3.1 
Study Design .................................................................................................................. 24 
3.2 
Study Calendar ............................................................................................................... 27 
3.3 
Surgical Guidelines ........................................................................................................ 28 
3.3.1 
Postoperative Care .................................................................................................. 29 
d. 
Receive thyroid replacement therapy per standard of care. .................................... 29 
3.3.2 
Recurrent Disease ................................................................................................... 31 
3.3.3 
Off Study Criteria ................................................................................................... 31 
3.3.4 
Off Protocol Therapy and Off-Study Procedure ..................................................... 31 
4 
BIOSPECIMEN COLLECTION .......................................................................................... 32 

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4.1 
Correlative Studies for Research .................................................................................... 32 
5 
DATA COLLECTION AND EVALUATION ..................................................................... 32 
5.1 
Data Collection ............................................................................................................... 32 
5.1.1 
Data Quality Assurance .......................................................................................... 32 
5.2 
DATA SHARING PLANS ............................................................................................ 32 
5.2.1 
Human Data Sharing Plan ....................................................................................... 32 
5.3 
Toxicity Criteria ............................................................................................................. 33 
6 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
33 
6.1 
Definitions ...................................................................................................................... 33 
6.1.1 
Adverse Event ......................................................................................................... 33 
6.1.2 
Suspected adverse reaction ..................................................................................... 34 
6.1.3 
Unexpected adverse reaction .................................................................................. 34 
6.1.4 
Serious..................................................................................................................... 34 
6.1.5 
Serious Adverse Event ............................................................................................ 34 
6.1.6 
Disability ................................................................................................................. 34 
6.1.7 
Protocol Deviation (NIH Definition) ...................................................................... 34 
6.1.8 
Non-compliance (NIH Definition) .......................................................................... 34 
6.1.9 
Unanticipated Problem............................................................................................ 35 
6.2 
NIH Intramural IRB and Clinical Director Reporting ................................................... 35 
6.2.1 
NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems 
and Deaths ............................................................................................................................. 35 
6.2.2 
NIH Intramural IRB Requirements for PI Reporting at Continuing Review ......... 35 
6.3 
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR 
MULTI-CENTER TRIALS ...................................................................................................... 36 
6.4 
Data and Safety Monitoring Plan ................................................................................... 36 
6.4.1 
Principal Investigator/Research Team .................................................................... 36 
6.4.2 
Data Safety Monitoring Board (DSMB) ................................................................. 36 
7 
STATISTICAL CONSIDERATIONS.................................................................................. 36 
8 
COLLABORATIVE AGREEMENTS ................................................................................. 38 
8.1 
Multi-Institutional Guidelines ........................................................................................ 38 
8.1.1 
IRB Approvals ........................................................................................................ 38 
8.1.2 
Amendments and Consents ..................................................................................... 38 

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9 
HUMAN SUBJECTS PROTECTIONS ............................................................................... 38 
9.1 
Rationale For Subject Selection ..................................................................................... 38 
9.2 
Participation of Children ................................................................................................ 38 
9.3 
Participation Of Subjects Unable To Give Consent (For NCI Only) ............................. 38 
9.4 
Evaluation of Benefits and Risks/Discomforts .............................................................. 39 
9.5 
Risks/Benefits Analysis.................................................................................................. 39 
9.6 
Consent Process and Documentation ............................................................................. 39 
9.6.1 
Procedure for Reconsent via Telephone ................................................................. 40 
9.6.2 
Informed consent of non-English Speaking Subjects (NCI Only).......................... 40 
10 REFERENCES ..................................................................................................................... 41 
11 APPENCIES ......................................................................................................................... 49 
11.1 
Appendix A: Voice Handicap Index-10 ..................................................................... 49 
11.2 
Appendix B: Swallowing Impairment Scale (SIS-6) ................................................. 50 
11.3 
Appendix C: SF 36 Health Survey ............................................................................. 51 
11.4 
Appendix D: Bethesda system for reporting thyroid cytopathology .......................... 53 
11.5 
Appendix E: Revised American Thyroid Association Management Guidelines for 
Fine Needle Aspiration of Thyroid Nodule .............................................................................. 54 
11.6 
Appendix F: Algorithm for Management of Differentiated Thyroid Cancer at 1 year 
after Rairemnat Ablation 11 ....................................................................................................... 55 
11.7 
Appendix G: Performance Status Criteria .................................................................. 56 
11.8 
Appendix H: Neck Pain Scale .................................................................................... 57 
11.9 
Appendix I: CCR PROBLEM REPORT FORM ....................................................... 58 
 

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1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective: 
• To determine 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). 
1.1.2 Secondary Objectives: 
• To determine 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 1 year postoperatively in patients who will 
not receive RAI or 1 year post remnant ablation. 
• To determine the following outcome measures in patients undergoing TT with and 
without pCND: 
a. The QOL of patients with low-risk PTCs undergoing TT and pCND to those 
undergoing TT alone using the SF-36v2 standardized questionnaire (preoperative, 
postoperative day 1, 2 weeks, 3 and 6 months, 1, 5 and 10 years postoperatively). 
b. Neck pain (preoperative, postoperative day 1, 2 weeks, and 6 months 
postoperatively). 
c. Subjective voice quality, swallowing impairment (preoperative, postoperative day 1, 
2 weeks, and 6 months postoperatively) as well as objective vocal cord dysfunction 
(preoperative and postoperative day 1 and 6 months postoperatively only if 
abnormality is found on postoperative day 1) and requirement for intervention. 
d. Rate and duration of both symptomatic and asymptomatic hypoparathyroidism 
including requirement and duration of postoperative oral or IV calcium replacement 
as well as vitamin D analogue for hypoparathyroidism (preoperative PTH, 
postoperative day 1, 2 weeks and 6 months postoperatively). 
e. Rate of cervical wound complications (hematoma, seroma, and surgical site infection) 
and intervention(s) required. 
f.  The use of radioactive iodine. 
g. Oncologic outcome: 
I. 
Radiographic evidence with biopsy or pathology proven recurrent disease. 
II. 
Thyroid cancer-related death. 
h. The impact of BRAF V600E mutation status on lymph node metastasis in patients 
with low-risk PTC undergoing TT with or without pCND. In addition, we will 
compare the rate of disease recurrence in patients undergoing pCND to those who 
will not undergo pCND, by BRAF V600E mutation status. 

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1.2 
BACKGROUND AND RATIONALE 
Thyroid cancer is the most common endocrine malignancy and it accounts for 3.8% of all new 
cancer diagnoses(1). Over 90% of thyroid cancers originate from follicular cells and are 
commonly well-differentiated thyroid cancer. These cancers include variants of papillary (PTC) 
and follicular thyroid cancer (FTC) (2). PTC is the most common type and it accounts for over 
80% of thyroid malignancies, followed by FTC, Hürthle cell, medullary and anaplastic thyroid 
cancer(3). While overall prognosis of classical PTC and FTC are excellent, 10%-15% of thyroid 
cancers have histologic subtypes that have been shown to have more aggressive behavior. These 
include tall cell variant, columnar cell variant, diffuse sclerosing variant PTC as well as insular 
and Hürthle cell cancers(4). Although lymph node metastasis in FTC is rare (2%), lymph node 
metastasis (LNM) is common in PTC (~50%) and is significantly more common in aggressive 
PTC variants such as tall-cell variant PTC and diffuse sclerosing variant PTC (~70%)(5-7). LNM 
is known to be an independent risk factor for local-regional recurrence in patients with thyroid 
cancer. Despite an overall good prognosis for PTC, Mazzaferri et al. reported 40-year disease 
recurrence to be approximately 35%, two-third of which occurred within the first decade. Local 
recurrence comprised 68% of the disease recurrences in this study. Half of the patients with 
distant metastasis (32% of all recurrences) died of thyroid cancer(8). Population-based studies 
have also shown that patients with LNM have higher rate of cancer-related death and decreased 
survival. (9, 10) The effect of surgical treatment for subclinical LNM in patients with low-risk 
PTC on both recurrence and survival remains unclear. The rise in thyroid cancer incidence, and 
improved sensitivity of radiographic studies and laboratory tests to detect persistent or early 
recurrent disease present a significant clinical problem as the number of patients with recurrent 
disease is expected to grow. Unfortunately, there has been a lack of good clinical evidence to 
guide appropriate treatment for patients with low-risk PTC that reduces persistent/recurrent 
disease and thyroid cancer-associated mortality. 
1.2.1 Epidemiology 
The American Cancer Society estimates that there will be more than 63,000 new cases of thyroid 
cancer and over 2,800 cases of thyroid cancer-related death in 2014. Thyroid cancer is currently 
the fifth most common cancer diagnosed in women, following breast, lung, colorectal, and 
uterine cancers(1).  
The age and gender adjusted incidence of thyroid cancer has increased faster than any 
malignancy in the recent years(11). The American Cancer Society has reported a remarkable 
increase in the incidence of thyroid cancer since the mid-1990s. The incidence has increased 
5.6% per year in men and 7.0% per year in women since 2004, which represents the largest 
annual percentage increase of any cancer in both men and women(12). The vast majority (87%) 
of the excess thyroid cancers detected in the past 15 years are attributed to an increase in small 
cancers (less than 2 cm in diameter)(13). Unfortunately, several aspects of management in 
growing number of patients with low-risk thyroid cancer remain controversial including the 
surgical management of PTC with clinically negative lymph node. 
1.2.2 Management of papillary thyroid cancer 
The debate regarding the optimal management of differentiated thyroid cancer continues due to 
the lack of good quality data. Current recommendations are largely based on level III evidence, 
consisting predominantly of retrospective studies. However, it was estimated that a randomized 

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study to detect a 10% reduction in thyroid cancer mortality at 25 years after treatment such as 
radioiodine ablation would require 4,000 patients per arm and the results would not be ready for 
35 years, thus demonstrating the difficulty of performing such clinical trials with a primary 
endpoint of overall survival(14). Current therapeutic options for patients with PTC include total 
or near total thyroidectomy with or without lymphadenectomy, and adjuvant therapy including 
radioactive iodine ablation and thyroid stimulating hormone (TSH) suppression with thyroid 
hormone. 
The majority of patients with thyroid cancer have low-risk disease and the optimal management 
of such patients continues to be a subject of debates due to the lack of high quality data. There 
has been a growing interest in utilizing molecular diagnostic markers such as BRAFV600E 
mutation and RET/PTC rearrangement to improve preoperative diagnostic accuracy of fine 
needle aspiration and to enhance patient risk stratification. RET/PTC rearrangement can help 
identify PTC in indeterminate nodules as almost all thyroid nodules positive for clonal RET/PTC 
mutations were proved to be PTC.(15)  BRAFV600E mutation is the most common genetic 
alteration found in PTC (~50%). Although the presence of BRAFV600E mutation confers a 
100% risk of malignancy and was associated with aggressive features such as extrathyroidal 
extension, lymph node metastasis (LNM), more advanced tumor stage in some studies (16, 17), it 
remains controversial if BRAF V600E mutation can be used as an independent prognostic factor 
for thyroid cancer mortality(18-20).  A number of studies suggest the utility of BRAF V600E 
mutation testing is to select patients who may benefit from more extensive initial surgery such as 
pCND because of higher rates of LNM and recurrent/persistent disease associated with this 
mutation(21-24). On the other hand, several investigators have observed an association of BRAF 
mutation with overt and occult LNM (21, 25, 26) and in up to 80% of occult (microscopic) PTC 
which are associated with near normal life expectancy. Moreover, the superior outcome of more 
extensive surgery in patients with BRAF mutation positive PTC has never been demonstrated. 
There is still insufficient data to support pCND on the basis of BRAF mutation alone in patients 
with low-risk PTC(27). Because the use BRAF V600E mutation status to guide the extent of 
surgery, particularly pCND, has never been evaluated in a prospective study, this study will 
evaluate the impact BRAF V600E mutation status on lymph node metastasis and postoperative 
stim-Tg in patients with low-risk PTC undergoing TT with pCND. In addition, we will compare 
the rate of disease recurrence in patients undergoing pCND to those who will not undergo 
pCND, by BRAF V600E mutation status. 
1.2.2.1 Surgical therapy 
When PTCis identified preoperatively, near-total or total thyroidectomy (TT) is recommended 
for patients whose primary tumor size is larger than 1 cm or have other risk factors, such as 
contralateral thyroid nodules, regional and distant metastasis, a history of radiation exposure, a 
first-degree family history of thyroid cancer. Thyroid lobectomy alone may be sufficient 
treatment for small (<1 cm), low-risk, unifocal, intrathyroidal PTC in the absence of risk 
factors(11). A near-total or total thyroidectomy is also recommended in older patients (>45 
years) with 1-1.5cm PTC because of higher recurrence rates in this age group(11).  A population-
based study of over 50,000 patients with PTC demonstrated that TT was associated with lower 
recurrence and survival rates for tumors > 1.0 cm on multivariate analysis. Patients with small 
PTCs (1.0–2.0 cm) who underwent lobectomy, had a 24% higher risk of recurrence and a 49% 
higher risk of thyroid cancer mortality(28). Thus, the standard of care for PTC ≥ 1cm. is TT.  

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1.2.2.2 Prophylactic central neck lymph node dissection and outcome 
The central lymph node compartment, commonly referred to as level VI, is the most common 
site for LNM in patients with PTC. The boundaries of the central neck lymph node compartment 
include the hyoid bone superiorly, the common carotid arteries laterally, and sternal notch or the 
brachiocephalic artery inferiorly (Figure 1).   
Figure 1. Cervical lymph node compartments.  
 
While it is well accepted that therapeutic central neck lymph node dissection (CND) is indicated 
for PTC with clinical or radiographic evidence of metastatic lymph nodes, neither clinical 
examination nor imaging studies are reliable to detect central neck LNM. Neck ultrasound is the 
most commonly used diagnostic tool for patients with thyroid masses but the accuracy of neck 
ultrasonography (USG) in detecting metastatic central neck lymph nodes is limited because the 
paratracheal lymph nodes are often very small, located beneath the thyroid gland, and air-filled 
trachea presents an additional barrier to detect these lymph nodes preoperatively by USG. CND 
can be technically challenging as it requires a meticulous dissection to remove lymph nodes 
along recurrent laryngeal nerves while preserving parathyroid glands and their blood supply. 
 
Because reoperation of central neck in the presence of scar tissue from previous surgery is often 
difficult and can result in high rates of morbidities such as transient and permanent recurrent 
laryngeal nerve injury and hypoparathyroidism(29), pCND at the initial operation seems logical 
as a significantly higher rate of reoperation in the central compartment was observed in patients 
who did not undergo pCND(30, 31). More recently it has been shown in three retrospective 
studies that pCND can reduce the doses of 131I administered— or obviate it entirely—for low-
risk patients shown to have no LMN (pN0)(32-34). Thus, pCND may be beneficial in some 
patients (pN0) by avoiding or reducing doses of 131I and in others (pN1) by decreasing the risk of 

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reoperative surgery in the central compartment. Complications of initial pCND include increased 
risk of transient and permanent hypoparathyroidism in contrast to what is seen with TT alone 
(35), although a recent meta-analysis has shown that experienced surgeons can perform pCND 
safely with similar complication rates(36). 
Because LNM to central neck compartment (level VI) is common in PTC and the progression of 
level VI LNM to lateral neck compartment has been suggested (37), some surgeons advocate 
routine prophylactic central neck dissection (pCND) for PTC. However, there is no consensus on 
patient selection for pCND based on preoperative information. While a formal compartment-
oriented lymph node dissection is indicated in clinically suspicious or confirmed metastatic 
lymph node(s), pCND in patient with no evidence of LNM in the central neck continues to be a 
subject of great debates because of the lack of randomized controlled trials to address the 
controversy. It is inconclusive if TT with pCND would reduce the risk of locoregional recurrence 
compared to patients undergoing TT alone as a randomized clinical trial would require over 
5,000 patients to have sufficient statistical power to detect 25% reduction in clinically 
identifiable tumor recurrence(38). Most studies to date have been retrospective, relatively 
underpowered with insufficient follow-up periods. A recent meta-analysis of 14 studies 
(n=3,331) demonstrated a 35% risk reduction of locoregional recurrence in patients who 
underwent TT and pCND but this was compared to historical controls with longer follow up time 
in the TT alone. Also, it remains unclear if or how much of the risk reduction is associated with 
the increased use of radioiodine ablation in upstaged patients as a result of detecting subclinical 
LNM or patient selection bias in studies examined(39).  
Because thyroglobulin (Tg) is produced solely by thyroid follicular cells, measuring TSH-
stimulated thyroglobulin (stim-Tg) helps in the detection of persistent/recurrent metastatic 
disease. Measurement of serum Tg levels is an important modality to monitor patients with 
differentiated thyroid cancer. In the absence of anti-thyroglobulin antibody, serum Tg has a high 
sensitivity and specificity to detect differentiated thyroid cancer of follicular cell origin after total 
thyroidectomy, and especially after thyroid remnant ablation with radioiodine. Postoperative 
stim-Tg levels have been shown to predict disease remission with 95% negative predictive 
value(40), clinical recurrence in low-risk patients (41), distant metastasis (42), disease-free 
survival and death(43).   
 To assess the completeness of surgery, some studies have compared the postoperative stim-Tg 
level between those who underwent pCND and those who did not with conflicting results (34, 
44-46). Hughes et al. retrospectively compared stim-Tg levels at pre and 1-year post remnant 
ablation in143 patients with clinical node-negative PTC who underwent TT with and without 
pCND and found no significant difference(34). Retrospective studies from Hong Kong showed a 
significant lower stim-Tg before remnant ablation and higher rate of patients with undetectable 
thyroglobulin in TT and pCND group but no difference was observed at 6 months post remnant 
ablation(44). Another study reported that post-ablative stim-Tg was inversely correlated with the 
number of lymph nodes removed from pCND, suggesting pCND resulted in more complete 
eradication of (microscopic) tumor foci (45). A large retrospective study (n=447) by Sywak et al. 
demonstrated a significantly lower post-ablative stim-Tg and higher rates of athyroglobulinemia 
in patients who had TT with pCND(46). These discordant results highlight the need for 
randomized trial that is free of selection bias and all participants undergo the same treatment 

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protocol. A summary of the controversial results surrounding the effects of pCND is 
demonstrated in Table 1. 
Table 1. A summary of the controversial effects of pCND1 on the various clinical parameters in patients 
with PTC.  
Outcome 
measures 
Study 
authors 
Type of study 
Sample 
size (n) 
Results 
Remarks 
Biochemical 
cure rate 
measured by 
stim-Tg2 
Hughes et 
al. (34) 
 
Retrospective 
 
143 
No difference in stim-
Tg before or 1 year 
post-RAI(3) 
 
Sywak et 
al. (46) 
Retrospective 
447 
Lower post-RAI stim-
Tg and higher rate of 
athyroglobulinemia 
Locoregional 
recurrence 
Lang et al. 
(39) 
 
 
 
Meta-analysis 
3,331 
 
 
 
35% reduction in 
risk of locoregional 
recurrence 
 
 
 
Data from 
retrospective 
studies, 
confounded by 
selection bias 
and the use of 
RAI 
Wada et 
al.(47) 
Retrospective 
390 
No difference  
Probably 
underpowered 
The use of RAI 
Vaisman et 
al. (48) 
 
Prospective 
 
104 
 
Decrease use of RAI 
due to higher rate of 
athyroglobulinemia 
 
Hughes et 
al. (34) 
Retrospective 
143 
Increase RAI dosage 
due to upstaging 
 

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Postoperative 
complications 
Giordano et 
al. (35) 
 
 
Retrospective 
 
 
1,087 
 
 
Increase rate of 
transient and 
permanent 
hypoparathyroidism 
 
Chisholm et 
al. (36) 
Meta-analysis 
1,132 
Low rate of 
hypoparathyroidism 
and nerve injuries 
 
Postoperative 
quality of life 
Not 
available 
 
 
Unknown 
 
Voice quality 
and swallowing 
Not 
available 
 
 
Unknown 
 
 
1pCND: Prophylactic central neck lymph node dissection 
2stim-Tg: Stimulated serum thyroglobulin 
(3)RAI: Radioactive iodine ablation therapy. 

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The current American Thyroid Association (ATA) guidelines suggest that pCND can be 
performed in patients with advanced primary thyroid tumors (T3 or T4), as patients with tumors 
>4 cm in diameter have a 2–6-fold higher risk of central lymph node involvement than patients 
with tumors ≤4 cm (T1 or T2). (11) However, the rate of occult central neck LNM in PTC < 2cm 
(T1) ranged from 36% to 61% when pCND is performed46. The impact of a small-volume 
residual disease on tumor recurrence remains not fully characterized. Locoregional recurrence 
rate of 2%-5% were observed in patients with <5 subclinical, small (<0.2cm), LNM and median 
locoregional recurrence rate of 19% (range: 7%-21%) when >5 subclinical LNM(49).  
This will be the first level 1 evidence that answers an important clinical question regarding the 
extent of initial surgery in patients with low-risk PTC. Thus, a higher rate of athyroglobulinemia 
in the pCND group would convince many surgeons to perform pCND and would alter current 
treatment guidelines. Most importantly, it would preclude the need for adjuvant radioiodine 
therapy and streamline the follow up management of patients. Lastly, it would be important to 
patients who are thyroid cancer survivors (over 500,000 patients) that they are likely “cured” of 
their disease. All of these have significant ramifications to the cost of care and patient outcome 
and survivorship.  
Voice quality of patients undergoing TT and CND may be more compromised than patients who 
have TT alone despite no clinical evidence of recurrent laryngeal nerve injury (50). This may be 
caused by transient nerve conduction disorders induced by more manipulation around recurrent 
laryngeal nerves or the disturbance of venous and lymphatic drainage from CND(50). The Voice 
Handicap Index-10 (VHI-10), a self-administered questionnaire to assess patients’ voice quality, 
was validated and published by Rosen et al.(51) . The VHI-10 has been used to assess subjective 
voice quality after thyroidectomy by several groups.(52, 53)(Appendix A)  
Swallowing impairment is frequently reported following thyroidectomy and is often self-
limited(54). Because CND requires more extensive dissection and manipulation around the 
esophagus, it may result in more pronounced swallowing impairment. However, there is no study 
evaluating the impact of CND on symptoms of swallowing impairment. Swallowing Impairment 
Score (SIS-6) (Appendix B) is a self-administered questionnaire which has been validated and 
used to assess post-thyroidectomy dysphagia(53, 54). 
1.2.2.3 Radioactive iodine ablation (RAI) 
RAI is used to eliminate the postsurgical thyroid remnant which may facilitate the early detection 
of tumor recurrence by measuring serum Tg and/or RAI whole body scan. In addition, 
posttherapy scan performed at the time of remnant ablation can provide more accurate initial 
staging as undiagnosed metastases may be visualized. Furthermore, RAI may be used as 
adjuvant therapy to ablate remaining thyroid cancer cells in patients with microscopic or gross 
clinical residual disease. A selective use of RAI is recommended in patients with high-risk 
disease known metastases, gross extrathyroidal extension, primary tumor >4 cm or in patients 
whose tumors are 1-4 cm with other higher risk features such as lymph node metastases, or a 
combination of age, tumor size, lymph node status and histology that predicts intermediate to 
high risk of recurrence or death from thyroid cancer. There was no clear benefit such as 
reduction in mortality or recurrence rates observed when RAI was used in low-risk patients 
(stage I without high-risk features)(11). 

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A selective use of RAI based on postoperative stim-Tg level has been reported to reduce the rate 
of RAI use, compared to the rate of RAI use proposed by ATA. Vaisman et al. did not use a 
routine RAI in patients with stim-Tg <1 ug/L and routinely administered RAI in patients with 
stim-Tg >5ugl/L. Patients with stim-Tg 1-5 ug/L were given the option to defer RAI and only 
17% of these patients received RAI. Overall, only 15.4% of patients in this protocol received 
RAI. There was no persistent or recurrent disease in patients who did not receive RAI (mean 
follow-up=3 years)(48).  
1.2.2.4 TSH suppression therapy 
Because differentiated thyroid cancer of follicular cell origin express the TSH receptor and 
respond to TSH stimulation by increasing cell proliferation, the suppression of TSH by supra-
physiologic dose of thyroid hormone is commonly used to decrease the risk of recurrence. The 
ATA guidelines recommended an initial level of TSH suppression to below 0.1 mIU/L for high-
risk and intermediate-risk thyroid cancer patients, while maintenance of the TSH at or slightly 
below the lower limit of normal (0.1–0.5 mIU/L) is appropriate for low-risk patients. Similar 
recommendations apply to low-risk patients who have not undergone remnant ablation, i.e., 
serum TSH 0.1–0.5 mIU/L (11). 
1.2.2.5 Serum thyroglobulin and postoperative surveillance 
An undetectable stim-Tg (< 0.5 ng/mL) in the absence of anti-Tg antibody has an approximately 
98–99.5% likelihood of identifying patients completely free of tumor on follow-up(55, 56).  
Detectable Tg after RAI ablation is associated with higher rate of disease recurrence (Figure 2A) 
(57). In addition, Tg level is typically higher in patients with distant metastasis and is correlated 
with tumor burden. (58, 59) However, stim-Tg may fail to identify patients with clinically 
significant tumor burden in the presence of anti-Tg antibody or in patients with poorly 
differentiated or other aggressive thyroid cancer subtypes, due to low Tg expression. 
Approximately 20% of patients who have no clinical evidence of disease with serum Tg levels < 
1ng/mL during thyroid hormone suppression of TSH (60) will have a serum Tg level > 2ng/mL 
after rhTSH stimulation or thyroid hormone withdrawal at 12 months after initial therapy with 
surgery and RAI. In this patient population, one third will have identification of persistent or 
recurrent disease and of increasing Tg levels, and the other two thirds will remain free of clinical 
disease and will have stable or decreasing stim-Tg levels over time (61). Using a current highly 
sensitive Tg assay, undetectable unstimulated Tg (≤ 0.1 ng/ml) has a very high negative 
predictive value to identify patients without evidence of disease when stim-Tg is used as a 
benchmark(62, 63). 
Figure 2. Serum thyroglobulin and outcomes of thyroid cancer: A: detectable post-ablative Tg is 
associated with higher recurrent rate; B: Disease-free survival in patients with stim-Tg levels ≤20 pmol/L 
and >20 pmol/L, 3 months after total thyroidectomy for well-differentiated thyroid cancer (1 ng/ml of 
thyroglobulin= ~1.515 pmol/L).  

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Although several studies suggest that a Tg cutoff level above 2 ng/ml following rhTSH 
stimulation is highly sensitive in identifying patients with persistent tumor (64-69),  the clinical 
significance of minimally detectable Tg levels in the absence of clinical evidence of disease 
remains unclear. Patients with postoperative stim-Tg > 20pmol/L (~13 ng/ml) are at increased 
risk of disease recurrence (Figure 2B)(70). In these patients, the trend in serum Tg over time will 
typically identify patients with clinically significant residual or recurrent disease. A rising 
unstimulated or stim- Tg indicates disease that is likely to become clinically apparent(61, 71).  
Tg doubling time has been identified as a reliable marker for recurrent disease as well as 
prognostic indicator in patients with and without remnant ablation(72). Patients with Tg doubling 
time less than 1 year had significantly shorter thyroid cancer-specific survival, compared to those 
with Tg doubling time more than 1 year (Figure 3) (72). The ATA recommended a diagnostic 
whole body radioiodine scan (DxWBS) to detect recurrent or persistent disease for Tg >0.3 
ng/ml or stimulated Tg > 2 ng/ml (in the absence of anti-Tg antibody) at 6-12 months after 
remnant ablation. Most patients with stim-Tg >5 ng/ml have clinically identifiable disease.(64, 
73) If stim-Tg >5-10 ng/ml and whole body RAI scan is negative, cross-axial imaging studies 
and/or FDG PET/CT should be performed(11). 
 
Figure 3. Thyroglobulin doubling time less than 1 year is associated with worse survival. 

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A follow-up of patients with low-risk differentiated thyroid cancer who have undergone total or 
near-total thyroidectomy without RAI remnant ablation may be challenging because the source 
of Tg can be from a thyroid remnant. A cohort of 80 patients with papillary thyroid 
microcarcinoma who underwent a near-total or total thyroidectomy (11 had CND) without RAI 
remnant ablation demonstrated that recombinant human TSH-stim-Tg was ≤ 1ng/ml in 56% of 
patients and whole body RAI scan was not useful to identify persistent or recurrent disease. The 
detectable stim-Tg levels mainly depended on the size of thyroid remnant shown in DxWBS(74). 
For those with thyroid remnant and detectable Tg, a rising Tg can be useful to detect recurrent 
disease. 
Based on the studies cited above, stim-Tg <2 ng/ml and unstimulated Tg ≤ 0.2 ng/ml have been 
associated with biochemical cure or remission in patients with differentiated thyroid cancer and 
stim-Tg<2 ng/ml will be used in this protocol as a cut-off for biochemical cure. Stim-Tg >5 
ng/ml or unstimulated Tg >0.3 ng/ml has been associated with persistent and recurrent 
disease(11, 48, 75, 76), and therefore, will be used in this protocol as a cut-off for biochemical 
persistent/recurrent disease. 
Serum Tg is used to guide postoperative radioiodine therapy, level of TSH suppression and the 
extent of surveillance for recurrent/persistent disease(77).   

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1.2.2.6 Postoperative surveillance in patients with PTC and anti-thyroglobulin antibodies 
The frequency of anti-Tg antibodies in patients with differentiated thyroid cancer is 
approximately 20-25% depending on the study population and assay used (78-80). The 
prevalence of anti-Tg antibodies in the general population is approximately 10%(81). Although 
the presence of anti-Tg antibodies can cause inaccurate Tg measurement, thereby limiting its 
usefulness, there has been growing evidence that the antibody levels themselves may serve as a 
surrogate biochemical marker of persistent/recurrent disease. However, the kinetics of anti-Tg 
antibodies in response to treatment differ from those of Tg levels in patients without antibodies. 
For example, an initial transient rise in anti-Tg antibodies can be observed following remnant 
ablation and it takes on average of 2-3 years for anti-Tg levels to become undetectable(82). It is 
important to recognize that anti-Tg antibody levels can fluctuate and a clear trend requires 
repetition of the tests over time. Furthermore, a variability between different assays can cause 
inconsistent results for antibody levels, thus it is recommended that anti-Tg antibodies are 
measured by the same facility using the same assay(82). Patients with declining anti-Tg antibody 
levels (over 50% from pretreatment value) over 6-12 months had significant lower recurrence 
rate than those with a lower reduction or increased levels(83). In contrast, patients with rising 
anti-Tg antibodies or those who convert negative antibody levels to positive ones are more 
concerning for progressive/recurrent thyroid cancer and a more aggressive imaging is generally 
performed(82). Therefore, a conversion or a rise in anti-Tg antibodies will be used to diagnose 
biochemical persistent/recurrent disease in this protocol. 
1.2.3 Prognosis and outcome 
Postoperative staging of PTC is crucial for determining the need for adjuvant radioactive iodine 
(RAI) therapy, the degree of TSH-suppressive therapy with levothyroxine, the methods and 
intensity of follow-up, as well as prognosis. Thyroid cancer staging is based on the American 
Joint Committee on Cancer (AJCC) TNM staging system which is intended for prediction of 
thyroid cancer-related mortality, and not for recurrence. In a study by Hundahl and colleagues, 
the outcome of 42,687patients who underwent thyroidectomy for thyroid cancer between 1985 
and 1995 was determined. The majority of the patients had stage I (56.9%) or stage II disease 
(14.4%). Overall, patients with PTC had the best 10-year survival rate (93%) when compared 
with follicular (85%), Hurthle cell (76%), medullary (75%), and anaplastic (10%) cancers (3). 
Based on the 7th edition AJCC Cancer Staging system, the 5-year disease-specific survival rates 
for PTC are 100% for stages I and II, 93% for stage III, and 51% for stage IV (84). The 
incorporation of patient age into the AJCC system favors patients younger than 45 years of age. 
Even in the presence of systemic metastases, patients younger than 45 years are classified under 
stage II disease. Although the long-term survival of patients with PTC is usually excellent, the 
clinically detectable (positive imaging findings or a positive biopsy) recurrence rate is 
significant, up to 35% during 40-year follow-up(8). This may be an underestimation of the true 
rate of recurrence because patients with an elevated serum Tg level but no clinical detectable 
recurrences were excluded. Mazzaferri et al. demonstrated that approximately half of all 
recurrences occurred during the first 5 years following definitive surgical treatment and 75% 
within the first 10 years; therefore, a long-term follow-up is necessary. Two-third of the 
recurrences occurred in the neck whereas the one-third occurred in distant sites(67).  Patients at 
the extremes of age (<20 or >60 years) had higher recurrence rates. Half of thyroid cancer related 
deaths are from PTC due to its high prevalence. Approximately half of the patients with PTC die 

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within 5 years once distant metastases are detected. Younger patients with systemic metastases 
survive longer(85). Common sites of systemic metastases for thyroid cancer are lungs (50%), 
bones (20%), and multiple organ involvement (16%). Higher rates of distant metastasis were 
observed in patients with Hurthle cell cancer and FTC than PTC. Five and ten-year overall 
mortality rates after the diagnosis of metastases were 65% and 75%, respectively(85). 
1.2.4 Quality of life after treatment for thyroid cancer 
It is increasingly recognized that the diagnosis and treatment of cancer can have a major impact 
on all aspects of a patient’s quality of life (QOL). The QOL of patients with thyroid cancer can 
be affected by multiple different modalities of treatments and their complications. There have 
been only a limited number of studies addressing the QOL of patients with thyroid cancer. The 
QOL of patients with thyroid cancer can be affected by outcomes of various treatments including 
modified radical neck dissection (53), hypoparathyroidism (86), and hypothyroidism in 
preparation for radioactive iodine ablation(87). The QOL in patients undergoing thyroid surgery 
for cancer can be affected by the complications and other postoperative changes such as neck 
pain, dysphagia, and voice changes without evidence of nerve injury. Because more extensive 
surgery such as in patients undergoing TT and pCND may have more negative impact on QOL 
therefore, it should be assessed in conjunction to potential oncologic benefit to fully understand 
the risks and benefits of the procedure. Currently, there is no randomized controlled trial 
assessing the QOL in patients with PTC undergoing TT and pCND compared to TT alone. 
The Short Form 36 Health Survey version 2.0 (SF-36) (Appendix C) has been widely used to 
assess the QOL of patients with various diseases, including cancer. It is a tool that measures 
health-related QOL according to an inclusive standard and not a disease-specific standard. The 
score is expressed numerically by the provided scoring algorithm. The SF-36 is a comprehensive 
short-form instrument with 36 questions that can be self-administered to yield a health profile. It 
comprises of 8 domains: physical functioning, role limitations caused by physical problems, 
bodily pain, general health, vitality, social functioning, role limitations caused by emotional 
problems, and mental health. The SF-36 is capable of capturing the impact of treatments on 
patient’s QOL including complications from surgery, the effects of preparation for radioiodine 
treatment and its side effects, and the length of follow-up(87-89). 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histologically or cytologically confirmed at least 1 thyroid nodule that 
is ≥1 cm but ≤ 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(90) (Appendix D: Bethesda system for reporting thyroid cytopathology 
 

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• Appendix E) with BRAF V600E mutation or RET/PTC rearrangement 
• Cytologically or histologically suspicious or confirmed PTC per Bethesda System for 
reporting thyroid cytopathology(90) (Appendix D: Bethesda system for reporting thyroid 
cytopathology 
 
 
 

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• Appendix E) 
2.1.1.2 Age >18 years.  Because PTC occurs rarely in patients <18 years of age, children are 
excluded from this study. 
2.1.1.3 Absence of radiographic evidence of extrathyroidal extension. 
2.1.1.4 Absence of abnormal lymphadenopathy suggesting metastatic PTC on physical 
examination and/or imaging studies. 
2.1.1.5 ECOG performance status <2 (Karnofsky >60%, see Appendix G). 
2.1.1.6  Patients must have adequate organ function to safely undergo general anesthesia and 
thyroidectomy. Laboratory values obtained ≤ 4 weeks prior to surgery must demonstrate 
adequate bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥ 1.5 x 
109/L, platelets ≥ 80 x 109/L), liver function (serum bilirubin ≤ 2 x ULN, serum 
transaminases ≤ 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. 
2.1.1.7 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
2.1.1.8 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. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who have had previous thyroid surgery 
2.1.2.2 Patients whose tumors are deemed unresectable by clinical/imaging criteria. 
2.1.2.3 Patients with known synchronous distant metastatic disease. 
2.1.2.4 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. 
2.1.2.5 Pregnant women are excluded because we do not want to expose the unborn child to the 
procedures necessary to perform the surgery.     
2.2 
SCREENING EVALUATION 
Study candidates will undergo the following evaluations which may be performed within 4 
weeks prior to enrollment. 
a. Detailed demographic data will be collected from the medical record and patient 
interview, physical examination for each participant. Data will be securely stored in a 
computerized database.  
b. All participants with thyroid nodule(s) that have not been biopsied or non-diagnostic 
nodule(s) will undergo USG-guided preoperative fine needle aspiration following the 
ATA guidelines (Appendix E). The specimen(s) will be sent for cytology. 

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c. Cytology will be reviewed by Laboratory of Pathology, NCI or the laboratory of 
pathology at the  enrolling institution at any time prior to enrollment. 
d. Laboratory evaluation includes:  
• 
CBC with differential  
• 
Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium 
total, Ionized Calcium, Magnesium total (Mg), Inorganic Phosphorus, Alkaline 
Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total 
Protein. 
• 
PT/PTT 
• 
Thyroid Stimulating Hormone (TSH), Free T4 and T3 (only if TSH is abnormal), 
intact parathyroid hormone (PTH), anti-thyroglobulin antibodies, thyroglobulin 
e. Radiographic evaluation includes 
• 
Thyroid and soft tissue neck ultrasonography (USG)  
• 
Computerized tomography (CT scan) without contrast of neck or chest and/or 
other tests will be done if clinically indicated. 
2.3 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  
Verification of Registration will be forwarded electronically via e-mail to the research team. A 
recorder is available during non-working hours. 
2.3.1 For Participating Site Registration 
Registration will be a two-part process as patients are screened on this protocol. A protocol 
registration form will be supplied by the CCR study coordinator and updates will be provided as 
needed. Subject eligibility and demographic information is required for registration. To initially 
register a subject, after the participant has signed consent, complete the top portion of the form 
and send to CCR study coordinator.  Once eligibility is confirmed, after completion of screening 
studies, complete the remainder of the form which is the eligibility checklist, indicating that the 
patient is being registered for treatment and send to CCR study coordinator. In addition, source 
documents supporting the eligibility criteria must be sent to the CCR study coordinator. The 
CCR study coordinator will notify you either by e-mail or fax that the protocol registration form 
has been received which will include the unique patient/subject ID number. Questions about 
eligibility should be directed to the CCR study coordinator or PI.  Questions related to 
registration should be directed to the CCR study coordinator.  
Subjects that do not meet screening criteria should be removed from the study following the 
procedure in Section 3.3.4 

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2.4 
RANDOMIZATION (OR STRATIFICATION) PROCEDURES 
After confirmation of eligibility at Central Registration Office, CRO staff will provide the 
research team with the randomized treatment assignment.  Patients will be randomized to receive 
TT alone or TT+ pCND. Randomization will be conducted a 1:1 fashion using variable block 
sizes. Written confirmation of registration to the protocol and the randomization arm selected 
will be obtained from the CRO and placed on the patient’s research record. 
2.5 
BASELINE EVALUATION 
2.5.1 Preoperative evaluation 
a. Participants will fill out the following questionnaires which will be conducted within 4 
weeks prior to surgery to establish the baseline status of: 
• QOL using SF-36 v2 questionnaire (Appendix C) 
• Neck pain (scale 0 (no pain) to 10 (unimaginable, unspeakable pain)) 
• Voice quality using Voice Handicap Index-10 questionnaire (Appendix A) 
• Swallowing symptoms using Swallowing Impairment Score (SIS-6) questionnaire 
(Appendix B) 
b. All participants will undergo flexible laryngoscopy to establish baseline vocal cord 
functions. 
c. Urine or serum pregnancy test. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a prospective, randomized, single-blinded, controlled trial in patients with a suspicious or 
confirmed PTC ≤ 4 cm without clinical evidence of lymphadenopathy or extrathyroidal 
extension on imaging. Preoperative evaluation will be performed to establish the baseline status 
of participant’s QOL, neck pain (scale 1 to 10), subjective voice and objective vocal cord 
function, and swallowing status using standardized questionnaires (see below). BRAF V600E 
mutation status of the tumor will be assessed in all patients after thyroidectomy. Enrolled 
participants will be randomly assigned preoperatively to receive either TT alone or TT with 
pCND. Participants and their families will be blinded from the results of randomization. If a 
patient who is assigned to TT alone group is found to have LNM intraoperatively by frozen 
section, a CND will be performed and the patient will remain in TT alone group (intention to 
treat). Participants in both groups will receive uniform, routine postoperative care and follow-up 
evaluation per protocol (see below). Stim-Tg will be measured in all participants prior to 
remnant ablation at 3 months postoperatively (prior to remnant ablation, if indicated). Stim-Tg at  
1-year post-remnant ablation or 1 year postoperatively if participants do not receive remnant 
ablation will be performed in patients enrolled at the NIH but is optional in patients enrolled at 
non-NIH site(s).  Tg and anti-thyroglobulin antibodies will be measured annually for 10 years.   
The postoperative complications and QOL of participants will be assessed during preoperative 
evaluation, postoperative day 1, 2 weeks, 3 and 6 months, 1, 5 and 10 years postoperatively. 
Surgical outcome will be evaluated at postoperative day 1, 2 weeks, and 6 months 
postoperatively. Participants will have an evaluation for radioactive iodine ablation by the 

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endocrinology service.  The standardized protocol will be used based on histologic findings and 
patient’s risk of recurrence per NIDDK protocol. (Table 2) Similarly, participants will be 
managed using a standardized protocol for TSH suppression therapy based on the risk of 
recurrence. 
Table 2. Post-operative risk stratification:  Guideline for management of patients with clinical 
characteristics that modify initial assessment of risk1 
Clinical factor 
Postoperative 
Stim-Tg 
(ng/ml) 
131I 
ablation/preparation2 
Thyroid 
hormone goal 
T1-T2, Nx or N0 
<5 
No remnant ablation 
TSH low normal3 
T1-T2, Nx or N0 
≥5 
30 mci(91)/WD or rhTSH 
TSH low normal 
T3, Nx or N0    
<45 years old 
<5 
No remnant ablation 
TSH subnormal4 
≥5 
50-100 mCi/ WD or 
rhTSH 
TSH subnormal 
T3, Nx or N0      
≥45 years old 
<5 
No remnant ablation 
TSH subnormal 
≥5 
100 mCi/ WD or rhTSH 
TSH subnormal 
T4, Any N 
Any 
150 mCi/WD 
TSH suppressed5 
N1   <45 years old 
<5 
No remnant ablation 
TSH subnormal 
≥5 
50-100 mCi/ WD or 
rhTSH 
TSH subnormal 
         ≥45 years old 
<5 
No remnant ablation 
TSH suppressed 

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Clinical factor 
Postoperative 
Stim-Tg 
(ng/ml) 
131I 
ablation/preparation2 
Thyroid 
hormone goal 
≥5 
100 mCi/ WD or rhTSH 
TSH suppressed 
M1 
Any 
≥ 150 mCi/WD 
TSH suppressed 
Histologic variants 
Any 
≥ 150 mCi/WD 
TSH suppressed 
        Tall cell 
Diffuse Sclerosing 
        Hurthle 
        Insular 
Anaplastic/ 
Dedifferentiated 
WD: withdrawal of thyroid hormone; rhTSH; recombinant human TSH 
1The management may vary individually based on patient’s risk factors and investigator’s discretion 
2 All follow 2-week low iodine diet 
3 Low normal goal: TSH 0.5 to 1 mU/L 
4 Subnormal goal: TSH 0.1 to 0.5 mU/L 
5Suppressed goal: TSH <0.1 mU/L

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Biochemical cure or remission in this study is defined as stim-Tg < 2 ng/ml or unstimulated Tg ≤ 
0.2 ng/ml. Biochemical persistent or recurrent disease is suspected when stim-Tg ≥5 ng/ml or 
unstimulated Tg >0.3 ng/ml or a conversion or a rise in anti-Tg antibodies.   
An interim analysis will be performed after 90 who do not have anti-thyroglobulin antibody 
patients are enrolled (See Section 7), including a subgroup analysis based on BRAF V600E 
mutation status.  
3.2 
STUDY CALENDAR  
Test 
Screen 
Baseline 
(Preop) 
1 day 
postop 
2 
weeks 
postop 
3 
months 
postop 
6 
months  
postop 
1 year 
Postop 
Annually 
(M24-
M120) 
 
History/Physical 
examination 
x 
 
x 
x 
x 
x 
x 
x 
QOL 
Questionnaire 
 
x 
x 
x 
x 
x 
x 
M60 and 
M120 
Neck pain 
 
x 
x 
x 
 
x 
 
 
VHI-10 
 
x 
x 
x 
 
x 
 
 
SIS-6 
 
x 
x 
x 
 
x 
 
 
Labs1 
x 
 
x 
x 
x 
x 
x 
x 
Tg and thyroid 
antibodies 
x 
 
 
 
x 
x 
x 
x 
Neck USG 
x 
 
 
 
x 
x 
x 
x 
FNA thyroid  
 
x 
 
 
 
 
 
 
Flexible 
laryngoscopy 
 
x 
x2  
As 
needed 
 
X3 
 
 
Thyroid 
hormone 
replacement or 
suppression 
therapy 
 
 
x 
x 
x 
x 
x 
x 

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Test 
Screen 
Baseline 
(Preop) 
1 day 
postop 
2 
weeks 
postop 
3 
months 
postop 
6 
months  
postop 
1 year 
Postop 
Annually 
(M24-
M120) 
 
Thyroid 
hormone 
withdrawal or 
recombinant 
TSH for stim-
Tg 
 
 
 
 
x 
 
x6 
 
DxWBS 
 
 
 
 
x5 
 
x5 
 
Urine or Serum 
Pregnancy Test 
 
X 
 
 
 
 
 
 
Advance 
Directive (NIH 
only)4 
 
X 
 
 
 
 
 
 
1. Intact PTH, Chemistries including Calcium, albumin, ionized calcium, inorganic 
phosphorous, thyroid function tests (except on day 1 postoperatively) and other labs as 
indicated. 
2. Flexible laryngoscopy can be performed within 2 weeks after surgery, if it cannot be 
performed in the first day postoperatively 
3. Only if vocal cord abnormalities are found on postoperative day 1flexible laryngoscopy. 
4. As indicated in Section 9.3, all subjects will be offered the opportunity to complete an NIH 
advance directives form.  This should be done preferably at baseline but can be done at any 
time during the study as long as the capacity to do so is retained.  The completion of the 
form is strongly recommended, but is not required 
5. Optional for participating sites 
3.3 
SURGICAL GUIDELINES 
Patients who are randomized to receive TT and pCND will undergo standard TT.  pCND will be 
performed on the ipsilateral side to the dominant tumor by removal of lymphoid and fibrofatty 
tissue from the hyoid area to the innominate/subclavian vessels and from ipsilateral common 
carotid sheath medially, including the pretracheal and ipsilateral paraesophageal lymph nodes. If 
participant has bilateral biopsy-proven PTC, bilateral pCND will be performed in those who are 
randomized to receive TT and pCND. Care will be taken to preserve the parathyroid glands and 
their blood supply. If the parathyroid gland is devascularized, it will be autotransplanted into the 
sternocleidomastoid muscle pocket.  

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Uniform postoperative care and monitoring will be provided to participants in both groups 
equally. 
3.3.1 Postoperative Care 
3.3.1.1 Postoperative day 1, participants will be seen in-house and will: 
a. Fill out the following questionnaires. 
• QOL using SF-36 v2 questionnaire 
• Neck pain (scale 0 (no pain) to 10 (unimaginable, unspeakable pain)) 
• Voice quality using Voice Handicap Index-10 questionnaire 
• Swallowing symptoms using Swallowing Impairment Score (SIS-6) questionnaire  
b. Undergo flexible laryngoscopy to assess vocal cord functions. This can be performed 
within 2 weeks postoperatively, if it cannot be done on the first postoperative day. 
c. Receive laboratory evaluation at 6 hours postoperatively and AM of postoperative day 
1which includes Calcium total, Ionized Calcium, Magnesium total (Mg), Inorganic 
Phosphorus, and intact PTH. 
d. Receive thyroid replacement therapy per standard of care. 
3.3.1.2 Two weeks postoperatively (± 2 days), participants will be seen in clinic and will 
a. Fill out the following questionnaires. 
• QOL using SF-36 v2 questionnaire 
• Neck pain (scale 0 (no pain) to 10 (unimaginable, unspeakable pain)) 
• Voice quality using Voice Handicap Index-10 questionnaire 
• Swallowing symptoms using Swallowing Impairment Score (SIS-6) questionnaire 
b. Receive laboratory evaluation prior to a clinic visit which includes Sodium (Na), 
Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Urea 
nitrogen (BUN), Albumin, Calcium total, Ionized Calcium, Magnesium total (Mg), 
Inorganic Phosphorus, and intact PTH. 
c. Have index tumor from pathology specimen tested for BRAF V600E mutation in either 
the Clinical Center Laboratory or the laboratory of the participating site 
d. Undergo flexible laryngoscopy, if clinically indicated. 
e. Receive TSH suppression therapy, if indicated, per standardized protocol ( 
f. Table 2) 
3.3.1.3 Three months postoperatively (± 2 weeks) 
• To assess the primary endpoint of the study, all participants will be seen in clinic, and 
will either receive recombinant TSH injections or start thyroid hormone withdrawal. 
• Participants will be evaluated by endocrinology service for stim-Tg measurement and 
DxWBS per standardized protocol (optional in patients enrolled at non-NIH site):  

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a. Laboratory evaluation includes: (stimulated) Tg, anti-thyroglobulin antibodies, TSH, 
FT4, T3, Calcium total, Ionized Calcium, Magnesium total (Mg), Inorganic 
Phosphorus, and intact PTH. 
b. DxWBS or RAI with post therapy scan will be performed as needed. If DxWBS is 
indicated patients should start and maintain a low iodine diet two weeks prior to the 
scan. 
c. Baseline neck USG. 
d. QOL using SF-36 v2 questionnaire 
3.3.1.4 Six months postoperatively (± 2 weeks), participants will be seen in clinic and will 
a. Fill out the following questionnaires. 
• QOL using SF-36 v2 questionnaire 
• Neck pain (scale 0 (no pain) to 10 (unimaginable, unspeakable pain)) 
• Voice quality using Voice Handicap Index-10 questionnaire 
• Swallowing symptoms using Swallowing Impairment Score (SIS-6) questionnaire  
b. Undergo flexible laryngoscopy only if there were impaired vocal cord function(s) on 
postoperative day 1 or 2. 
c. Receive laboratory evaluation which includes CBC with differential, Sodium (Na), 
Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Urea 
nitrogen (BUN), Albumin, Calcium total, Ionized Calcium, Magnesium total (Mg), 
Inorganic Phosphorus, TSH, FT4, T3, Tg, anti-thyroglobulin antibodies, and intact 
PTH. 
d. Undergo soft tissue neck USG. Any suspicious lymph node(s) or lesion(s) will be 
biopsied for cytology and Tg wash. 
3.3.1.5 One year postoperatively (± 2 weeks) for participants who do not receive remnant 
ablation or one year post-remnant ablation, they will be seen in clinic and 
a. Participants who undergo remnant ablation will either receive recombinant TSH for 2 
consecutive days or will undergo thyroid hormone withdrawal for 4 weeks, followed 
by laboratory evaluation. Participants who do not undergo remnant ablation will 
receive only recombinant TSH for 2 consecutive days, followed by laboratory 
evaluation which includes Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Ionized Calcium, Magnesium total (Mg), Inorganic Phosphorus, TSH, FT4, T3, Tg 
(stimulated), anti-thyroglobulin antibodies. Recombinant TSH-stimulated 
thyroglobulin is optional in patients enrolled at non-NIH site. 
b. Iodine free 24hr urine collection 
c. DxWBS will be performed in all participants enrolled at NIH Clinical Center and is 
optional in patients enrolled at non-NIH site. Patients must start and maintain a low 
iodine diet two weeks prior to the scan. 

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d. All participants will undergo soft tissue neck USG. Any suspicious lymph node(s) will be 
biopsied if clinically indicated. 
e. Participant who develops elevated unstimulated or stimulated Tg with or without 
suspicious neck lesion on USG will undergo metastatic work up per 2009 ATA 
guidelines (11) (Appendix F). 
f. QOL using SF-32 v2 questionnaire. 
3.3.2 Recurrent Disease 
Surveillance for persistent or recurrence disease will be performed every year for 10 years. The 
study blind will be broken after the 10 year visit unless medically necessary for the patient’s 
continued care.  Work up includes: 
a. Detailed history and physical examination in clinic. 
b. Calcium total, Ionized Calcium, Magnesium total (Mg), Inorganic Phosphorus, TSH, Tg 
(while on levothyroxine), anti-thyroglobulin antibodies.  
c.  Soft tissue neck USG. 
d. Other radiographic imaging or nuclear scintigraphy as clinically indicated. 
e. QOL using SF-36 v2 questionnaire will be assessed at 5 and 10 years postoperatively. 
3.3.3 Off Study Criteria 
• Absence of thyroid cancer in final pathology 
• Participant requests to be withdrawn from study 
• Completion of 10-year assessment 
• Lost to follow-up 
• Investigator discretion 
• Screen failure 
• Death 
3.3.4 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office   
ncicentralregistration-l@mail.nih.gov.  
For participating sites: 
The Participant Status Updates Form will be supplied by the CCR study coordinator. Send the 
completed form to the CCR study coordinator. 

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4 
BIOSPECIMEN COLLECTION 
4.1 
CORRELATIVE STUDIES FOR RESEARCH 
Patients will be co-enrolled on protocol 09-C-0242.  Biospecimens will be collected as specified 
in protocol 09-C-0242. 
For participating sites: 
Biospecimens will not be collected at participating sites. 
5 
DATA COLLECTION AND EVALUATION  
5.1 
DATA COLLECTION 
The PI at each site will be responsible for overseeing entry of data into a password protected 
electronic system (NCI C3D) and ensuring data accuracy, consistency and timeliness. Clinical 
data will be entered into the NCI C3D at least once every two weeks when patients are enrolled 
on the trial. Protocol-specific eCRFs will be developed for this trial in C3D. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
The NCI investigators will be responsible for the collection, maintenance, and quality control of 
the study data. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
5.1.1 Data Quality Assurance 
The research team will monitor each patient’s dataset throughout the study. Source document 
review will be made against entries on the eCRF and a quality assurance check will be performed 
to ensure that the investigator is complying with the protocol and regulations. In addition, after 
the research team (data managers) completes the CRFs a research nurse or physician at the NCI 
will review and verify the data. 
5.2 
DATA SHARING PLANS 
5.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
• Coded, linked data in an NIH-funded or approved public repository.   
• Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 

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• Identified or coded, linked data with approved participating sites under appropriate 
agreements. 
How and where will the data be shared?  
Data will be shared through: 
• An NIH-funded or approved public repository, clinicaltrials.gov 
• BTRIS (automatic for activities in the Clinical Center) 
• Publication and/or public presentations. 
When will the data be shared?  
• Before publication. 
• At the time of publication or shortly thereafter. 
5.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
 
6 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
No experimental treatments or procedures are performed as a part of this protocol and therefore 
no adverse events are expected.  In the unlikely event that an adverse event occurs that is 
attributable to the research, CTCAE v. 4.0 will be used for grading such events. Patients who 
meet the standard of care criteria for resection of their disease will undergo a major operative 
procedure and may receive extensive care in the ICU.  The principal investigator or designee will 
closely monitor and document the clinical care and treatment of each patient as per standard of 
care at the NIH Clinical Center. As per NIH Clinical Center standards of practice, the 
Occurrence Reporting System will be used to report any clinical events meeting these reporting 
criteria. 
6.1 
DEFINITIONS 
6.1.1 Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.  

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6.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the research procedure caused the adverse event. For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
research procedure and the adverse event. A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused by a 
research procedure. 
6.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.  
6.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
6.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
6.1.6 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
6.1.7 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
6.1.8 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 

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6.1.9 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
6.2 
NIH INTRAMURAL IRB AND CLINICAL DIRECTOR REPORTING 
6.2.1 NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems 
and Deaths 
The Protocol PI will report in the NIH Problem Form to the NIH Intramural IRB and NCI 
Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
6.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  

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6.3 
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR 
MULTI-CENTER TRIALS 
The site PI must immediately report to the coordinating center PI any serious adverse event, 
whether or not considered treatment related, including those listed in the protocol and must 
include an assessment of whether there is a reasonable possibility that the treatment caused the 
event within 24 hours of PI awareness of the event.  The site PI will use CCR Problem report 
form (Appendix I). The Site PI must also report any protocol deviations to the coordinating 
center PI within 7 days of PI awareness. Participating centers must also submit the report to their 
IRB in accordance with their institutional policies. 
6.4 
DATA AND SAFETY MONITORING PLAN 
6.4.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
6.4.2 Data Safety Monitoring Board (DSMB)  
This protocol requires monitoring by the NCI CCR Data Safety Monitoring Board (DSMB) as 
described in Section 7. Interim outcome results will not be revealed to the investigators of the 
trial; results will be presented to the investigators prior to final accrual to the trial only if the 
DSMB recommends early termination of the trial.  
7 
STATISTICAL CONSIDERATIONS   
The primary goal of this study is to determine if there is a difference in biochemical cure rates 
based on postoperative stimulated thyroglobulin levels (stim-Tg) at 3 months, primarily focusing 
on the rates of athyroglobulinemia, in patients with clinically node negative PTC undergoing TT 
and with and without pCND. Serum Tg, especially when TSH-stimulated, is a very sensitive and 
specific marker for residual thyroid tissue, persistent or recurrent differentiated thyroid cancer of 
follicular cell origin, in the absence of anti-Tg antibodies. Because patients with differentiated 
thyroid cancer whose Tg and/or stim-Tg becomes undetectable after treatment(s) are typically 
considered free of disease in the absence of radiographic evidence of tumor, we use 
athyroglobulinemia as a surrogate for biochemical remission. We conservatively estimate that 
there should be at least a 20% higher rate of athyroglobulinemia in patients undergoing TT and 
pCND (θ2 =0.4) compared to TT alone (θ1=0.2) during early postoperative period.  With a total 
of 180 evaluable participants (approximately n=90 for each arm) who have no anti-thyroglobulin 

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antibody, the trial will have 80% power (beta=0.20) to detect the difference between 0.2 and 0.4 
using a Fisher’s exact test with two-sided significance level (alpha) of 0.05. 
The protocol will not have any stratification at the time of randomization because there are no 
known factors associated with athyroglobulinemia. Because this study only enrolls patients with 
low-risk PTC, it is unlikely that there would be many patients with advanced age and advanced 
PTC that may be unevenly distributed which may confound with the results of the study. 
This study will be monitored by the NCI/CCR Data Safety and Monitoring Board, both for 
toxicity as well as efficacy and futility with respect to the primary endpoint. 
Beginning in the first spring after twenty total patients have been randomized and treated on the 
trial, the study will be monitored by the DSMB on an annual basis to evaluate the safety of the 
two arms. The SAEs (typically grade 3 toxicities, or greater) will be reported according to type 
of toxicity, and maximal grade noted per patient, for toxicities with at least a possible attribution 
to the therapy provided on that arm. Comparisons will be made between the two arms using a 
Cochran-Armitage test for trend, or other appropriate methods, to determine if there is increased 
toxicity associated with either arm. 
In addition, at the first DSMB meeting held following the point at which half of the required total 
subjects have been enrolled and evaluated, an interim evaluation for greater than expected 
difference in fractions with athyroglobulinemia will be performed. Specifically, after 90 total 
patients who do not have anti-thyroglobulin antibody have been evaluated, using an O’Brien-
Fleming approach, if the two-tailed p-value for a comparison of the two rates is <0.0054, then 
the trial will be stopped at that time and a significant difference declared. While invoking this 
boundary at an interim point will technically require that the final p-value be 0.0492 or less for 
the overall significance level to be retained at a 0.05 level, as a practical matter, p<0.05 will still 
be required to declare a significant result. 
In addition, a single interim evaluation for futility will also take place after 90 evaluable patients 
accrued. At the same DSMB meeting as the single interim evaluation for efficacy, the study will 
be evaluated for futility as follows: if the fraction with athyroglobulinemia on the arm with TT + 
pCND is identical to or lower than that of the TT alone arm, then accrual will stop because of 
very small probability of achieving a statistically significant difference in favor of the 
combination arm if the trial were to be completed. 
Data on QOL, swallowing and pain will be collected at baseline and at several postoperative time 
points indicated using the tools described in the protocol. Changes from baseline to the 
postoperative values will be determined, normally by subtraction, and the resulting changes over 
time will be compared between the two randomized arms using appropriate non-parametric tests 
such as a Wilcoxon rank sum test. Other statistical methods may be used as appropriate for the 
data obtained. As these are secondary evaluations, the results will not be formally adjusted for 
multiple comparisons, but any results with p-values <0.05 may be interpreted as needed in the 
context of the number of such tests being performed. 
The trial will have an accrual ceiling of 225 participants in order to allow for a 20% rate of 
patients with PTC that have anti-thyroglobulin antibody, 86-88 which limits the use of 
postoperative Tg and stim-Tg and thus cannot be included in the 180 required for evaluation. It is 
anticipated that accrual time will be approximately 6 to 7 years as the investigators currently 

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perform 25-30 cases of preoperative suspicious or confirmed PTC per year and anticipate a 
higher accrual rate once the protocol is open and publicized.  
8 
COLLABORATIVE AGREEMENTS 
8.1 
MULTI-INSTITUTIONAL GUIDELINES 
8.1.1 IRB Approvals  
The PI will provide the NIH Intramural IRB with a copy of the participating institution’s 
approved yearly continuing review.  Registration will be halted at any participating institution in 
which a current continuing approval is not on file at the NIH Intramural IRB. 
8.1.2 Amendments and Consents 
The CCR PI will provide the NIH Intramural IRB with copies of all amendments, consents and 
approvals from each participating institution. 
9 
HUMAN SUBJECTS PROTECTIONS  
9.1 
RATIONALE FOR SUBJECT SELECTION 
All participants who meet the eligibility criteria will be enrolled regardless of gender, race, 
ethnicity or other socioeconomic or demographic factors. However, the cohort is expected to 
comprise predominantly female participants as the incidence of thyroid cancer is higher in 
women. 
9.2 
PARTICIPATION OF CHILDREN 
Because PTC is rare in children and presents at more advanced stage, we will exclude children 
(age <18 years) from the study to ensure that our cohort represents the majority of patients with 
PTC. 
9.3 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT (FOR NCI ONLY)  
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 9.4) all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study.  
Patients may experience personal benefit even during the follow-up period because they will be 
closely monitored and treated as needed.    
Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation as needed for the following: an independent assessment of whether an individual has 
the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate 
when indicated; and/or an assessment of the capacity to appoint a surrogate  For those subjects 
that become incapacitated and do not have pre-determined substitute decision maker, the 
procedures described in MAS Policy 87-4 and NIH HRPP SOP 14E for appointing a surrogate 

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decision maker for adult subjects who are (a) decisional impaired, and (b) who do not have a 
legal guardian or durable power of attorney, will be followed. 
9.4 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
Participants will likely experience direct benefit from the study because all will undergo total 
thyroidectomy for PTC which is considered a standard of care. Furthermore, there is the potential 
reduction in locoregional recurrence rate in those undergoing pCND. 
Risks and discomforts that participants will experience are from the surgical procedures (TT with 
or without pCND) and their complications, which are the standard of care. These include, but not 
limited to, postoperative pain, surgical site bleeding or infection, voice and/or swallowing 
impairment with or without recurrent laryngeal nerve injury or external branch of superior 
laryngeal nerve injury, symptoms of hypocalcemia and discomforts from the treatment of 
hypoparathyroidism. Participants will like require 1 week of recovery before returning to work or 
routine daily activities with minimal restriction. These benefits and risks will be discussed in 
details with all participants. In addition, participants who require thyroid hormone withdrawal in 
preparation for RAI will experience symptoms of hypothyroidism up to 4 weeks prior to 
treatment. Those with low-risk for recurrence who require rhTSH in preparation for RAI will 
experience discomfort from injection sites. All of these are related to the standard of car of any 
patients with PTC.  
9.5 
RISKS/BENEFITS ANALYSIS FOR ALL PATIENTS 
The main risk of participation is related to the risk of complications from pCND. The addition of 
pCND to thyroidectomy is still considered a safe procedure with less than 1% of major 
complications. The transient hypoparathyroidism can occur up to 25% of patients undergoing TT 
and pCND, most patients are asymptomatic once the calcium replacement therapy is optimized. 
Permanent hypoparathyroidism following pCND occurs less than 1%. The benefit of pCND in 
addition to TT may include a reduction in disease recurrence. 
Patients who receive TT and pCND may be upstaged may be more likely to receive RAI due to 
the discovery of a subclinical lymph node metastasis. The risks of RAI include temporary dry 
mouth, dry eyes, loss or change of taste, and may have increased risk of second primary cancers 
in young adults. (92) However, the benefits would outweigh the risks in participants at risk for 
recurrence.  
9.6 
CONSENT PROCESS AND DOCUMENTATION 
Each procedure/test that the patient will undergo will be explained to the patient, and the 
associated risks and benefits will be reviewed prior to the intervention.  Participants must be able 
to give informed consent.  The consent form will be kept in the participant’s permanent medical 
record.  The Principal Investigator, research nurse, or associate investigator is responsible for 
completing the consent process and a copy of the consent is offered to the patient. It will be 
stated clearly that participation in the research study is voluntary and that participants can 
withdraw from the study without losing benefits they would otherwise be entitled to. Participants 
will be enrolled after the consent document has been signed. Separate consents will be obtained 
for all surgical procedures. Because all participants will not know the results of randomization, 
initial consent would indicate a possibility of CND.  

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9.6.1 Procedure for Reconsent via Telephone 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
9.6.2 Informed consent of non-English Speaking Subjects (NCI Only) 
We anticipate the enrollment of Spanish speaking research participants into our study. The IRB 
approved full consent document will be translated into that language in accordance with the 
Clinical MAS Policy M77-2. 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OHSRP SOP 12 and 45 CFR 46.117 (b) (2).  The summary that will be used is the 
English version of the extant IRB approved consent document.  Signed copies of both the 
English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible). 
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
 

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adapted management of differentiated thyroid cancer assessed by a sensitive measurement of 

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11 APPENCIES 
11.1 APPENDIX A: VOICE HANDICAP INDEX-10 
 
 
0 
1 
2 
3 
4 
1 
My voice makes it difficult for people to hear me. 
 
 
 
 
 
2 
People have difficulty understanding me in a noisy 
room. 
 
 
 
 
 
3 
My voice difficulties restrict personal and social 
life. 
 
 
 
 
 
4 
I feel left out of conversations because of my 
voice. 
 
 
 
 
 
5 
My voice problem causes me to lose income. 
 
 
 
 
 
6 
I feel as though I have to strain to produce voice. 
 
 
 
 
 
7 
The clarity of my voice is unpredictable. 
 
 
 
 
 
8 
My voice problem upsets me. 
 
 
 
 
 
9 
My voice makes me feel handicapped. 
 
 
 
 
 
10 
   People ask, “What’s wrong with your voice?” 
 
 
 
 
 
 

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11.2 APPENDIX B: SWALLOWING IMPAIRMENT SCALE (SIS-6)  
 
 
0 
1 
2 
3 
4 
1. 
It requires great effort to swallow 
 
 
 
 
 
2. 
I feel a throat obstacle during swallowing 
 
 
 
 
 
3. 
I feel pharyngeal annoyance during bolus transit 
 
 
 
 
 
4. 
I cough during bolus transit 
 
 
 
 
 
5. 
I feel a sensation of a foreign body in my pharynx 
 
 
 
 
 
6. 
I have some difficulties swallowing fluids 
 
 
 
 
 
 

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11.3 APPENDIX C: SF 36 HEALTH SURVEY 
 

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11.4 APPENDIX D: BETHESDA SYSTEM FOR REPORTING THYROID CYTOPATHOLOGY 
 
 
 

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11.5 APPENDIX E: REVISED AMERICAN THYROID ASSOCIATION MANAGEMENT GUIDELINES 
FOR FINE NEEDLE ASPIRATION OF THYROID NODULE 
 

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11.6 APPENDIX F: ALGORITHM FOR MANAGEMENT OF DIFFERENTIATED THYROID CANCER 
AT 1 YEAR AFTER RAIREMNAT ABLATION 11 
 
 

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11.7 APPENDIX G: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

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11.8 APPENDIX H: NECK PAIN SCALE 
 

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11.9 APPENDIX I: CCR PROBLEM REPORT FORM 
 
NCI Protocol #:  
Protocol Title:  
 
 
Report version: (select one) 
____Initial Report  
____Revised Report 
____Follow-up  
Site Principal Investigator: 
 
  
Date of problem:     
Location of problem: (e.g.,  patient’s home, 
doctor’s office ) 
 
 
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, 
etc…) 
 
Brief Description of Subject (if 
applicable)  
(Do NOT include personal 
Sex:  ___ Male  ___ Female 
Age:   
 ___ Not applicable (more than subject is involved) 

59 
Abbreviated Title: Prophylactic Central Neck Dissection 
Version Date: 01/15/2019 
 
identifiers)  
 
Diagnosis under study:   
Name the problem: (select all that apply)   
[  ] Adverse drug reaction   
[  ] Abnormal lab value   
[  ] Death   
[  ] Cardiac Arrest/ code  
[  ] Anaphylaxis  
[  ] Sepsis/Infection   
[  ] Blood product reaction 
[  ] Unanticipated surgery/procedure   
[  ] Change in status (e.g. increased level of care required)    
[  ] Allergy (non-medication)  
[  ] Fall  
[  ] Injury/Accident (not fall)  
[  ] Specimen collection issue   
[  ] Informed consent issue   
[  ] Ineligible for enrollment   
[  ] Breach of PII  
[  ] Tests/procedures not performed on schedule  

60 
Abbreviated Title: Prophylactic Central Neck Dissection 
Version Date: 01/15/2019 
 
[  ]  Other, brief  1-2 word description: _________________________ 
 
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent 
history): 
 
 
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  
Please explain: 
 
 *Is this problem related or possibly related to participation in the research?  __YES __NO  
Please explain: 
 
*Does the problem suggest the research places subjects or others at a greater risk of 
harm than was previously known or recognized?    __YES __NO      Please explain: 
 
 
Is this problem? (select all that apply) 
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious  
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious 
[  ] Non-compliance 

61 
Abbreviated Title: Prophylactic Central Neck Dissection 
Version Date: 01/15/2019 
 
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP. 
Is the problem also (select one)  [  ] AE  [  ] Non-AE 
Have similar problems occurred on this protocol at your site? __YES __NO       
If “Yes”, how many? ____      Please describe: 
Describe what steps you have already taken as a result of this problem: 
 
 
In addition to the NCI IRB, this problem is also being reported to: (select all that apply) 
[  ] Local IRB 
[  ] Study Sponsor 
[  ] Manufacturer : ____________________  
[  ] Institutional Biosafety Committee  
[  ] Data Safety Monitoring Board 
[  ] Other: ____________________________________  
[  ] None of the above, not applicable 
INVESTIGATOR’S SIGNATURE:  
 
DATE: