American Thyroid Association Design and Feasibility of a Prospective Randomized Controlled Trial of Prophylactic Central Lymph Node Dissection for Papillary Thyroid Carcinoma

Tobias Carling,1 Sally E. Carty,2 Maria M. Ciarleglio,3 David S. Cooper,4 Gerard M. Doherty,5 Lawrence T. Kim,6 Richard T. Kloos,7 Ernest L. Mazzaferri Sr.,8 Peter N. Peduzzi,3 Sanziana A. Roman,1 Rebecca S. Sippel,9 Julie A. Sosa,1 Brendan C. Stack Jr.,10
David L. Steward,11 Ralph P. Tufano,12 R. Michael Tuttle,13 and Robert Udelsman,1
for the American Thyroid Association Surgical Affairs Committee

 Background: The role of prophylactic central lymph node dissection in papillary thyroid cancer (PTC) is controversial in patients who have no pre- or intraoperative evidence of nodal metastasis (clinically N0; cN0). The controversy relates to its unproven role in reducing recurrence rates while possibly increasing morbidity (permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury).

Methods and Results: We examined the design and feasibility of a multi-institutional prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC. Assuming a 7-year study with 4 years of enrollment, 5 years of average follow-up, a recurrence rate of 10% after 7 years, a 25% relative reduction in the rate of the primary endpoint (newly identified structural disease; i.e., persistent, recurrent, or distant metastatic disease) with central lymph node dissection and an annual dropout rate of 3%, a total of 5840 patients would have to be included in the study to achieve at least 80% statistical power. Similarly, given the low rates of morbidity, several thousands of patients would need to be included to identify a significant difference in rates of permanent hypoparathyroidism and unintentional recurrent laryngeal nerve injury.

Conclusion: Given the low rates of both newly identified structural disease and morbidity after surgery for cN0 PTC, prohibitively large sample sizes would be required for sufficient statistical power to demonstrate significant differences in outcomes. Thus, a prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC is not readily feasible.

Authors are listed in alphabetical order.

1Department of Surgery, School of Medicine, Yale University, New Haven, Connecticut.
2Department of Surgery, Division of Endocrine Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
3Yale Center for Analytical Sciences, School of Public Health, Yale University, New Haven, Connecticut.
4Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
5Department of Surgery, University of Michigan Health Systems, Ann Arbor, Michigan.
6Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
7Divisions of Endocrinology, Diabetes and Metabolism, and Nuclear Medicine; Departments of Internal Medicine and Radiology; The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
8Divisions of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Florida, Gainesville, Florida.
9Department of Surgery, University of Wisconsin, Madison, Wisconsin.
10Department of Otolaryngology—Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
11Department of Otolaryngology—Head and Neck Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
12Department of Otolaryngology—Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
13Department of Endocrinology, Memorial Sloan-Kettering Cancer Center, New York, New York.