Results
Calculations of study sample size scenarios are presented in Table 3. For instance, assuming a 7year study (4 years enrollment, 3 years minimum followup, 7 years maximum followup, 5 years average followup) with a newly identified structural disease cumulative event rate of 35% after 7 years and an annual dropout rate of 3%, a total of 1568 patients (355 primary outcome events) would be required to detect a 25% reduction in the hazard rate for the newly identified structural disease with central lymph node dissection with 80% power (Scenario 1, Table 3) at a type I error of 5% (twosided). However, given that patients would all be cN0 (by preoperative US and intraoperative inspection), and thus represent lowrisk PTC, the estimated newly identified structural disease rate would likely be significantly lower. PTC without pre or intraoperative central neck nodal disease (i.e., cN0) has a low newly identified structural disease rate, even in the setting of histopathological presence of lymph node metastasis, with rates ranging from 2% to 9 % (12,14–20). Thus, a more realistic sample size scenario is presented in Table 3 as Scenario 2. Given the same assumptions as for Scenario 1, but with a cumulative 10% newly identified structural disease rate after 7 years, a total of 5840 patients (377 primary outcome events) would be required to achieve satisfactory statistical power. The key determinates of the study sample size scenarios are the reduction in hazard rate and the newly identified structural disease cumulative event rate as depicted in Fig. 2
In addition, detecting an increased complication rate in patients undergoing central neck dissection would require large sample sizes as well. For example, assuming rates of permanent hypoparathyroidism of 5% and 2.5% in those with and without central neck dissection (6), respectively, would require approximately 2000 patients to detect this difference with 80% power. Similarly, to detect differences in rates of unintentional permanent recurrent laryngeal nerve injury of 2% versus 1% with 80% power would require more than 5000 total patients (6). In contrast, postoperative levels of serum calcium and intact parathyroid hormone at postoperative day 1, prior to starting postoperative prophylaxis with calcium carbonate and/or calcitriol, could be measured with more modest sample sizes (25). However, the significance of detecting differences in serum calcium and intact parathyroid hormone on postoperative day 1 is of limited clinical value.
Annual dropout rate




1%

2%

3%

4%

5%


Reduction in hazard^{a} 
N

Events

N

Events

N

Events

N

Events

N

Events

Scenario 1^{b}  
20%  2441  586  2481  586  2522  586  2653  586  2605  586 
25%  1517  355  1542  355  1568  355  1593  355  1620  355 
33%  829  186  843  186  857  186  871  186  885  186 
40%  539  116  548  116  558  116  567  116  576  116 
Scenario 2^{c}  
20%  9043  623  9215  623  9389  623  9566  623  9746  623 
25%  5624  377  5731  377  5840  377  5950  377  6062  377 
33%  3078  197  3136  197  3196  197  3256  197  3318  197 
40%  2005  123  2044  123  2082  123  2122  123  2162  123 
^{a}Prophylactic central lymph node dissection compared with no prophylactic central lymph node dissection. For both scenarios, assuming a 7year study (4 years enrollment, 3 years minimum followup, 7 years maximum followup, 5 years average followup); 5% Type I error (twosided); 80% power. ^{b}Assuming the following newly identified structural disease (i.e., persistent, recurrent or distant metastatic disease) cumulative rates over the study period: Year 1=10%, Year 2=20%, Year 3=25%, Year 4=27.5%, Year 5=30%, Year 6=32.5%, Year 7=35% ^{c}Assuming the following newly identified structural disease (i.e., persistent, recurrent or distant metastatic disease) cumulative rates over the study period: Year 1=3%, Year 2=5%, Year 3=6%, Year 4=7%, Year 5=8%, Year 6=9%, Year 7=10%. 
Total required sample size required in a prospective randomized controlled trial of prophylactic central lymph node dissection in cN0 PTC as a function of the cumulative event rate (newly identified structural disease) and reduction in hazard rate of 20%, 25%, 33%, and 40%. All scenarios assume a fixed annual dropout rate of 3%.