Design

 The study would be a multi-institutional, prospective, randomized, blinded (until total thyroidectomy has been performed) study (Table 1). All adult patients (≥18 years of age) with fine-needle aspiration (FNA) proven PTC and cN0 would be eligible for inclusion in the study. Informed consent would be obtained for all participants, and approval from the institutional review boards would be sought from participating institutions.

TABLE 1. SUMMARY OF CLINICAL TRIAL KEY POINTS

• Multi-institutional prospective randomized controlled trial
• Patients (≥18 years of age) with FNA proven PTC are candidates for enrollment.
• Patients with pre- and intra-operative stage T (1–4), cN0, cM0 are randomized in the operating room after total thyroidectomy has been performed.
• Randomization to group A (central neck dissection) or group B (no central neck dissection).
• The primary endpoint is newly identified structural disease, which may include persistent, recurrent, or distant metastatic disease.
• Postoperative RAI ablation therapy is standardized to 50 mCi in all patients.
• Surveillance and TSH suppression is performed in accordance with ATA guidelines.

ATA, American Thyroid Association; FNA, fine-needle aspiration; PTC, papillary thyroid carcinoma; RAI, radioactive iodine; TSH, thyrotropin.

As part of the initial assessment, demographic information (age, sex, history of radiation exposure, history of thyroid disease, past and current use of thyroid hormone treatment, known or suspected familial PTC) and the baseline characteristics outlined in Table 2 would be obtained.

TABLE 2. TIME POINTS OF SCHEDULED SURVEILLANCE

  Pre-op POD 1 1–2 wk 1 mo 3 mo 6 mo 9 mo Annually thereafter
Physical examination X           X X
Ultrasound X           X X
Chest X ray X              
TSH X              
Calcium X X       X    
Creatinine X              
PTH X X       X    
Pathology reporta     X          
I 131 therapy (50 mCi)         X      
Stimulated Tgb         X   X X
I 131 WBS         X      
Laryngoscopy X         X    
Quality of Life Survey       X   X    
Adverse events monitoring   X X       X X

aPathology report includes TNM stage, size, multifocality, margins, extrathyroidal extension number of lymph nodes removed, number of positive lymph nodes, presence of parathyroid tissue; POD, postoperative day; TSH, thyrotropin; PTH, parathyroid hormone; Tg, thyroglobulin; WBS, whole-body scan.

bAll measurements of Tg would include measurement of thyroglobulin antibodies.

All patients would need to have documentation of normal vocal cord mobility by preoperative laryngoscopy. A preoperative comprehensive neck ultrasound (US) of the thyroid and central and lateral neck compartments would be required as part of the routine preoperative planning for diagnosed PTC (13). US-guided FNA would be performed of the primary tumor and selected lymph nodes suspicious for metastatic disease in the central and/or lateral neck as part of the routine preoperative planning for PTC. The slides of patients with a cytological diagnosis of PTC at an outside hospital/institution would be reviewed by a cytopathologist at the participating institution. For cases in which there is disagreement between the findings at the outside institution and at the participating institution, the preoperative diagnosis would be based on the findings at the participating institution after review at a cytopathology consensus conference and/or referral to a third consulting cytopathologist. The use of molecular diagnostic tools (e.g., BRAF V600E mutational status) as an aid to the cytopathological diagnosis would not change the eligibility to participate in the study but would be tracked (e.g., a patient with indeterminate FNA results and BRAF mutation positivity, which indicates a preoperative diagnosis of PTC, would be eligible for enrollment).

Exclusion criteria

Only patients with pre- and intraoperatively diagnosed T (1–4), cN0, cM0 PTC would be randomized (Fig. 1). We estimate that approximately 15% of patients with PTC would present with metastatic disease or be found to have lateral and/or central node metastasis during the initial evaluation (14–20). These patients would be excluded from the study and would undergo standard management. Furthermore, we estimate that approximately 10% of patients with PTC would have intraoperative findings of central lymph node metastasis based on surgeon suspicion or intraoperative frozen section analysis (12,14–20). Intraoperative frozen section analysis of lymph nodes would be obtained at the discretion of the operating surgeon. Patients with intraoperative positive central lymph node metastasis would be excluded from the study and undergo standard surgical management. Similarly, the rare cases with lateral lymph node metastasis diagnosed intraoperatively would not be included. In addition, we estimate that approximately 2% of patients with PTC would have concomitant primary hyperparathyroidism (21). These patients would be excluded from the study and undergo standard surgical management, since concomitant parathyroidectomy likely would affect the incidence of postoperative hypoparathyroidism. Other exclusion criteria would be previous central cervical operation and inability to give informed consent or meet follow-up requirements.

Intraoperative randomization process
 
After a total thyroidectomy and central neck evaluation by the surgeon and when no suspicious lymphadenopathy has been detected, patients would be randomized to either prophylactic central lymph node dissection or to no central lymph node dissection using equal allocation. The individual surgeon would be blinded to the randomization process until after total thyroidectomy. A web-based intraoperative randomization procedure would be developed, accessible to participating investigators.
 

Central neck dissection

In patients randomized to the treatment arm, an ipsilateral prophylactic central lymph node dissection would be performed for unilateral PTC. For clinically apparent bilateral PTC, a bilateral central lymph node dissection would be performed. The goal of a prophylactic central lymph node dissection is to remove all lymphatic tissue en bloc. The superior margin is at the level of the hyoid bone, the inferior margin is at the level of the brachiocephalic vessels, the lateral margin at the medial aspect of the common carotid artery, and the contralateral margin is past the midline of the trachea but not encompassing the contralateral inferior parathyroid gland (22). The dissection includes lymph nodes posterior (deep) to the recurrent laryngeal nerve. The number of removed lymph nodes would be recorded on the pathology report, thus mandating collaboration with the pathology departments at the participating institutions.

Parathyroid autotransplantation of one or more normal parathyroid glands would be performed at the discretion of the operating surgeon after frozen section confirmation.

  

 

FIG. 1. Study design. Prospective randomized controlled trial of prophylactic central node dissection for papillary thyroid carcinoma.

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