Clinical trial NCT02408887: Total Thyroidectomy With and Without Prophylactic Central Neck Lymph Node Dissection in People With Low-risk Papillary Thyroid Cancer
Official title: Randomized Controlled Trial of Total Thyroidectomy With and Without Prophylactic Central Neck Lymph Node Dissection in Patients With Low-risk Papillary Thyroid Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Low-risk Papillary Thyroid Cancer
Endocrine Malignancy
Thyroid Cancer
Keywords: Thyroidectomy
Serum Thyroglobulin
Quality of Life
Central Neck Lymph Node Metastasis
Central Neck Lymph Node Dissection
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2015-04-06
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

- Papillary thyroid cancer (PTC) often spreads to lymph nodes in the neck. This can be hard to detect. People often have lymph nodes removed anyway, and researchers want to study if this is a good idea.

Objective:

- To compare the effectiveness of removing lymph nodes in the neck that show no evidence of cancer along with the thyroid, or removing only the thyroid.

Eligibility:

- Adults age 18 and older with PTC or thyroid nodules suspicious for PTC, with no evidence that the disease has spread in the body.

Design:

* Participants will be screened with medical history, physical exam, blood tests, scans, and x-rays.
* Participants will:
* Answer questions. They may have a tumor biopsy.
* Have a flexible laryngoscopy. A small tube will pass through the nose to the vocal cords.
* Group 1: have surgery to remove the thyroid gland only. Lymph nodes in the neck will be removed if the cancer has spread.
* Group 2: have surgery to remove the thyroid and lymph nodes in the neck.
* At all post-surgery visits, participants will answer questions and have blood drawn. In addition:
* 1 day: laryngoscopy.
* 2 weeks: possible laryngoscopy.
* 3 months: ultrasound of the thyroid and neck.
* Discuss whether to try hormone treatment and/or radioactive iodine.
* Possible diagnostic whole body radioiodine scan (WBS). Participants will swallow a capsule or liquid and lie under a camera.
* 6 months: ultrasound and maybe laryngoscopy.
* 1 year: diagnostic WBS and ultrasound. Participants may get thyroid stimulating hormone.
* Participants will have annual follow-up visits for 10 years. They will have a physical exam, blood drawn, scans, and may complete a questionnaire.

Detailed description: 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 thyroid stimulating hormone (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 prophylactic central neck dissection (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. Short-form 36 (SF-36) version 2 (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 radioactive iodine treatment (RAI) treatment).

Eligibility:

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

  * inconclusive thyroid cytology positive for B-Raf Proto-oncogene Serine/Threonine Kinase (BRAF) Valine 600 Glutamic Acid (V600E) mutation or rearranged in transformation/papillary thyroid carcinomas (RET/PTC) rearrangement or
  * cytologically suspicious for or consistent with PTC
* Absence of extrathyroidal extension or lymphadenopathy suggesting metastatic PTC on physical examination and neck ultrasound.

Design:

* Prospective, single-blinded, randomized controlled clinical trial.
* Cytology will be reviewed by Laboratory of Pathology, National Cancer Institute (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 central neck dissection (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.

Eligibility criteria: * INCLUSION CRITERIA:
* Patients must have histologically or cytologically confirmed at least 1 thyroid nodule that is greater than or equal to1 cm. but less than or equal to 4 cm measured in greatest dimension and confirmed by the Laboratory of Pathology, National Cancer Institute (NCI) or confirmed by the pathology laboratory of the enrolling institution:

  * Indeterminate thyroid biopsy per Bethesda System for reporting thyroid cytopathology with B-Raf Proto-oncogene Serine/Threonine Kinase (BRAF) Valine 600 Glutamic Acid (V600E) mutation or rearranged in transformation/papillary thyroid carcinomas (RET/PTC) rearrangement
  * Cytologically or histologically suspicious or confirmed PTC per Bethesda System for reporting thyroid cytopathology.
* Age greater than or equal to 18 years. Because PTC occurs rarely in patients \<18 years of age, children are excluded from this study.
* Absence of radiographic evidence of extrathyroidal extension.
* Absence of abnormal lymphadenopathy suggesting metastatic PTC on physical examination and/or imaging studies.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Patients must have adequate organ function to safely undergo general anesthesia and thyroidectomy. Laboratory values obtained less than or equal to 4 weeks prior to surgery must demonstrate adequate bone marrow function (hemoglobin (Hb) greater than or equal to 6.0 mmol/L, absolute neutrophil count greater than or equal to 1.5 x 10\^9/L, platelets greater than or equal to 80 x 10\^9/L), liver function (serum bilirubin less than or equal to 2 x upper limit of normal (ULN), serum transaminases less than or equal to 3 x ULN). Patients with chronic kidney disease who are on chronic renal replacement therapy are allowed. Other tests, such as pulmonary function tests, cardiac echocardiogram or stress test, will be performed if clinically indicated.
* Ability of subject to understand and the willingness to sign a written informed consent document.
* Women must not become pregnant prior to surgery or during the first 3 months after surgery. Women who can become pregnant will be asked to practice an effective form of birth control for up to 3 months after surgery.

EXCLUSION CRITERIA:

* Patients who have had previous thyroid surgery
* Patients whose tumors are deemed unresectable by clinical/imaging criteria.
* Patients with known synchronous distant metastatic disease.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded because we do not want to expose the unborn child to the procedures necessary to perform the surgery.

Primary outcomes:
measure: Number of Participants That Have Biochemical Cure After Total Thyroidectomy (TT) With and Without Prophylactic Central Neck Lymph Node Dissection (pCND)
timeFrame: At 3 months (prior to radioactive iodine (RAI) treatment)
Secondary outcomes:
measure: Number of Participants That Have Biochemical Cure After Total Thyroidectomy (TT) With and Without Prophylactic Central Neck Lymph Node Dissection (pCND)
timeFrame: Up to 1 year postoperatively or 1 year post remnant ablation.
measure: Number of Participants Who Completed Quality of Life (QOL) Survey at Following Timepoints: Quality of Life After Total Thyroidectomy (TT) With and Without Prophylactic Central Neck Lymph Node Dissection (pCND)
timeFrame: pre-operation(op), post-op day 1 and 2, 2 and 3 weeks post-op, 3, 6 and 9 months post-op, 1 and 2 years post-op. Approximately 4 years.
measure: Voice Quality After Total Thyroidectomy (TT) With and Without Prophylactic Central Neck Lymph Node Dissection (pCND) at 6 Months
timeFrame: baseline - pre-op and 6 months post-op
measure: Number of Participants With Hypoparathyroidism
timeFrame: 6 months
measure: Number of Participants That Have Cervical Wound Complications
timeFrame: 3 months
measure: B-Raf Proto-oncogene Serine/Threonine Kinase (BRAF) Valine 600 Glutamic Acid (V600E) Mutation Status on Lymph Node Metastasis
timeFrame: At progression
measure: Proportion of Participants That Have Less Neck Pain.
timeFrame: 6 months
measure: Improvement in Swallowing Impairment After Total Thyroidectomy (TT) With and Without Prophylactic Central Neck Lymph Node Dissection (pCND) at 6 Months
timeFrame: baseline - pre-op and 6 months post-op
measure: Number of Participants Who Developed Disease Progression or Recurrence After Surgery
timeFrame: Completed at pre-operation (op), 3 months, 6 months, 1 year, 2 years and 3 years post-op.
Other outcomes:
measure: Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
timeFrame: Date treatment consent signed to date off study, approximately 46 months and 23 days for the first group and 48 months and 3 days for the second group.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Naris Nilubol, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lang BH, Wong KP, Wan KY, Lo CY. Significance of metastatic lymph node ratio on stimulated thyroglobulin levels in papillary thyroid carcinoma after prophylactic unilateral central neck dissection. Ann Surg Oncol. 2012 Apr;19(4):1257-63. doi: 10.1245/s10434-011-2105-5. Epub 2011 Oct 12.
citation: Iyer NG, Morris LG, Tuttle RM, Shaha AR, Ganly I. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer. 2011 Oct 1;117(19):4439-46. doi: 10.1002/cncr.26070. Epub 2011 Mar 22.
citation: Lee J, Kwon IS, Bae EH, Chung WY. Comparative analysis of oncological outcomes and quality of life after robotic versus conventional open thyroidectomy with modified radical neck dissection in patients with papillary thyroid carcinoma and lateral neck node metastases. J Clin Endocrinol Metab. 2013 Jul;98(7):2701-8. doi: 10.1210/jc.2013-1583. Epub 2013 May 15.