Ann Surg Oncol (2017) 24:2189–2198
DOI 10.1245/s10434-016-5691-4
ORIGINAL ARTICLE – ENDOCRINE TUMORS
The Effect of Prophylactic Central Neck Dissection
on Locoregional Recurrence in Papillary Thyroid Cancer After
Total Thyroidectomy: A Systematic Review and Meta-Analysis
pCND for the Locoregional Recurrence of Papillary Thyroid Cancer
Wenjing Zhao, MD, Lei You, MD, Xianming Hou, MD, Shaobo Chen, MD, Xiaoxia Ren, PhD, Ge Chen, MD, and
Yupei Zhao, MD
Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking
Union Medical College, Beijing, China
ABSTRACT
Background. The use of prophylactic central neck dissection (pCND) for papillary thyroid cancer (PTC) without
clinical evidence of nodal metastasis (cN0) remains controversial. This study was designed to examine whether
pCND for PTC affected locoregional recurrence (LRR).
Methods. A systematic review was performed to compare
the LRR between patients with PTC who underwent total
thyroidectomy (TT) and pCND and those who underwent
TT alone. The primary outcome was LRR. Other outcomes,
including postoperative radioiodine (RAI) ablation and
surgically related complications, were evaluated. A metaanalysis was performed using the random-effects model.
Results. We included 17 studies, which comprised 4437
patients. Patients in the TT?pCND group had a significantly reduced risk of LRR (risk ratio [RR] = 0.66; 95%
confidence interval [CI]: 0.49–0.90; P = 0.008). The LRR
in the central neck compartment (RR = 0.35; 95% CI
0.18–0.68; P = 0.002) was significantly lower in the
Wenjing Zhao and Lei You contributed equally to this article.
Electronic supplementary material The online version of this
article (doi:10.1245/s10434-016-5691-4) contains supplementary
material, which is available to authorized users.
Ó Society of Surgical Oncology 2016
First Received: 28 June 2016;
Published Online: 2 December 2016
G. Chen, MD
e-mail: pumchchenge@163.com
Y. Zhao, MD
e-mail: zhao8028@263.net
TT?pCND group, whereas the LRR in the lateral neck
compartment was similar between the two groups. Compared with the TT alone group, patients in the TT?pCND
group tended to receive higher RAI (74.6% vs. 59.9%) and
experience temporary hypocalcemia (odds ratio
[OR] = 2.37; 95% CI 1.89–2.96; P \ 0.00001), permanent
hypocalcemia (OR = 1.93; 95% CI 1.05–3.57; P = 0.03),
and increased overall morbidity (OR = 2.56; 95% CI
1.75–3.74; P \ 0.00001).
Conclusions. This meta-analysis suggested that although
pCND reduced the LRR in PTC—specifically in the central
neck compartment—it was accompanied by an increased
rate of postoperative hypocalcemia. However, the evidence
is limited and randomized, controlled trials are needed to
clarify this role further.
Thyroid cancer, the most common endocrine malignancy, continues to be the most rapidly increasing cancer
([5% per year in both men and women) with an estimated
64,300 new cases diagnosed in the United States in 2016.1
Papillary thyroid cancer (PTC) comprises the majority
(80–85%) of these cases, and the prognosis for treated PTC
patients is excellent with 10-year survival rates exceeding
90%. Despite having an excellent prognosis, PTC patients
commonly experience lymph node metastases (20–50%),
mostly in the central compartment of the neck (level VI)
comprising the prelaryngeal (Delphian), pretracheal, and
paratracheal nodal basins.2
Lymph node metastases are associated with an increased
rate of locoregional recurrence (LRR).3,4 Although therapeutic central neck dissection (CND) is indicated in PTC
patients with clinically nodal-positive disease (cN1), it
2190
remains controversial whether prophylactic central neck
dissection (pCND) should be performed in patients with no
clinical evidence of nodal metastasis (cN0).5,6
Currently, there was insufficient evidence to draw a
conclusion about the effect of combining total thyroidectomy (TT) with pCND on the LRR compared with TT
alone. Some studies favored pCND, because it could prevent regional recurrence and may be associated with lower
postsurgical thyroglobulin (Tg) levels, a higher dose of
radioactive iodine (RAI) due to pathologic upstaging, and a
lower complication rate after the first operation.7–9 However, other studies reported that although pCND decreased
postoperative Tg levels, it is not helpful in decreasing
short-term LRR in patients (cN0).9–12 Furthermore, this
procedure increases the risk of morbidity regarding injury
to the parathyroid glands and recurrent laryngeal
nerves.7,13–15 Therefore, we should weigh the potential
advantages of pCND against the risk of complications.
This controversy is partly due to a lack of high quality
evidence demonstrating any legitimate benefits of pCND in
reducing LRR. Given the low rates of recurrence and
morbidity after thyroidectomy, a recent study estimated
that 5840 patients in a prospective, randomized, controlled
trial would be necessary to have sufficient statistical power
to detect a 25% reduction in the recurrence risk.16
Although five relevant meta-analyses were conducted
through 2013, three were not strictly consistent with our
research subject; two included patients who either had
benign disease or experienced therapeutic CND, and one
excluded patients with papillary microcarcinoma.13,17–20
The remaining two studies showed different conclusions.13,19 Zetoune et al. found that pCND does not greatly
reduce LRR, whereas Lang et al. showed that pCND may
create a 35% reduction in the risk of LRR.13,19
Because the literature has been updated in the past
3 years, we performed a systematic review and metaanalysis to investigate the effect of pCND on the LRR with
the current largest sample size.
METHODS
Search Strategy
This systematic review was performed in accordance
with the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses statement.21 Studies were identified
using a literature search of English articles in the PubMed,
EMBASE, and Cochrane Library databases published
through November 27, 2015. The search parameters were
as follows: (papillary thyroid carcinoma) AND thyroidectomy AND [(lymph node dissection) OR (neck dissection)
OR (central neck dissection) OR (level VI neck dissection)
OR (level 6 neck dissection)]. The reference lists of
W. Zhao et al.
previous meta-analyses also were reviewed to identify
additional potentially relevant articles. Two authors searched articles and independently reviewed all retrieved
studies. Disagreements between the two investigators were
resolved by consensus with a third investigator.
Study Selection
The inclusion criteria were as follows: (1) a prospective
or retrospective study design; (2) a PTC diagnosis with
cN0 as determined by preoperative imaging and intraoperative examination; (3) two-arm studies comparing TT
with pCND (without lateral compartment dissection) to TT
alone; (4) sample size per arm [10 patients; (5) reporting
of the number of LRR and the mean follow-up period (in
months) in each study arm; and (6) patient age C18 years.
Accordingly, the following exclusion criteria were also
used: (1) clinical evidence of lymph node metastases by
preoperative imaging and intraoperative examination; (2)
patient history of hemithyroidectomy with pCND or
simultaneous pCND and prophylactic lateral neck dissection; (3) lack of recurrence data; or (4) the article was
published as a case report, review article, letter to the
editor, editorial, or conference abstract.
Data Extraction
Two researchers independently extracted the following
data from the selected studies: the first author’s last name,
year of publication, country of origin, study design, preoperative nodal assessment, method of selection for pCND,
tumor characteristics, number of patients who underwent
TT?pCND or TT, extent of pCND (unilateral vs. bilateral),
number of harvested normal and metastatic central LNs,
upgrade rate from stage 1/2 to stage 3 because of nodal
status, number of patients receiving RAI treatment, number
of LRRs, site of locoregional recurrence, and postoperative
complications. The quality of each study was evaluated
based on the Recommendation of the Cochrane Handbook
for Systematic Reviews of Inventions [Higgins JPT, Green
S, eds. Cochrane Handbook for Systematic Reviews of
Interventions Version 5.1.0 (updated March 2011)].
Statistical Analysis
Review Manager 5.2 software was used to analyze the
outcomes. The Q test was performed to assess the heterogeneity among studies with the I2 index as an indicator of
true heterogeneity. Statistical heterogeneity was considered
high when I2 [ 50%. All results were aggregated and
analyzed using a random-effects model. The LRR was
assessed by the risk ratio (RR), whereas the odds ratio (OR)
was examined for all other outcomes. R 3.2.3 software was
pCND for the Locoregional Recurrence of Papillary Thyroid Cancer
2191
used to conduct sensitivity analysis to investigate potential
studies that influence the reliability of results. P value
B0.05 was considered to be statistically significant, and the
95% CI was set to measure the effects.
Kingdom together.7–9,11,12,14,15,22–31 All studies featured
ultrasonography as the standard imaging procedure for
preoperative nodal assessment. With respect to the extent
of pCND, 6 of the 17 studies used bilateral pCND, 5 used
unilateral or bilateral, 1 used unilateral, and 5 studies did
not classify the pCND.7–9,11,12,14,15,22–31 Fifteen of 17
studies compared age, sex ratio, tumor size, extrathyroidal
extension, and multifocality between the two groups. For
bilateral pCND, the mean number of central LNM harvested ranged from 5.6 to 8.8, with the incidence of central
LNM ranging from 33.3 to 82.4% for the TT?pCND
group. With the high incidence of central LNM, the percentage of patients older than 45 years of age undergoing
tumor upstaging ranged from 3.2 to 34.7%.
RESULTS
Literatures Search
Our search strategy yielded 1231 abstracts from the
three databases. After excluding duplicate articles, two
reviewers independently reviewed 986 abstracts, of which
46 articles were reviewed in full text. By monitoring the
reference lists, we identified 4 additional articles.11,12,22,23
Of the 50 articles, 33 were subsequently excluded from the
meta-analysis for various reasons, and 17 articles (3
prospective studies and 16 retrospective studies) involving
4437 thyroid papillary cancer cases (2468 in the TT group
and 1969 in the TT?pCND group) were included.7–9,11,12,14,15,22–31 The description of our literature
search is illustrated in Fig. 1.
The characteristics of these studies are presented in
Table 1. The publication years ranged from 2007 to 2015;
five studies were conducted in the United States, five in
Italy, four in Korea, one in China, one in Poland, and one
study in Australia, the United States, and the United
Radioiodine (RAI) therapy was reported in 14 studies
(Table 1).7–9,11,22,23,25–30 The mean postoperative RAI rate
was 74.6% in the TT?pCND group and 59.9% in the TT
group, indicating a higher RAI ablation therapy rate for
TT?pCND (OR = 1.20, 95% CI 1.04–1.39). Seven of the
14 studies reported the dose for RAI, 3 administered a
greater I131 ablation dose to those with nodal involvement,
and the remaining 4 studies gave the same dose to both
groups.7,9,14,15,25,29,30
Locoregional Recurrence
Literature search in databases; n=1231
Pubmed: n=663
Embase: n=557
Cochrane Library: n=11
Duplicates: n=245
Titles and abstracts reviewed: n=986
Non-relevent: n=940
Articles for further review: n=46
Radioiodine Ablation Therapy
Articles from reference
list: n=4
Articles reviewed in full text: n=50
Data not available: n=16
Therapeutic neck lymph node
dissection: n=7
Not tatal thyroidectomy: n=5
Reviews: 5
Articles included for meta-analysis:
n=17
FIG. 1 Search strategy and study selection
The results of the meta-analysis showed a significantly
reduced locoregional recurrence (LRR) rate for the
TT?pCND group compared with the TT group (4.6% vs.
6.9%, RR = 0.66; 95% CI 0.49–0.90; P = 0.008;
I2 = 19%; Table 2). We evaluated the central and lateral
site of lymph node recurrence in 12 studies (Fig. 2), which
included 3396 patients (1446 received TT?pCND; 1950
received TT). A total of 7572 (2.2%) patients showed
recurrence in the central lymph node region and 105
(3.1%) patients in the lateral lymph node region. Patients in
the TT?pCND group experienced a reduced risk of
recurrence to the central lymph node region than that in the
TT group (1.1% vs. 3.4%, RR = 0.35; 95% CI 0.18–0.68;
P = 0.002; I2 = 13%). However, the rate of recurrence in
the lateral lymph node region was similar between both
groups (3.3% vs. 3.2%, respectively).
Operative Outcomes
As shown in Fig. 3, patients in the TT?pCND group
had a significantly increased risk of postoperative
hypocalcemia rate, including temporary hypocalcemia
(28.7% vs. 17.5%, OR = 2.37, 95% CI 1.89–2.96;
P \ 0.00001, I2 = 27%) and permanent hypocalcemia
USA
Italy
USA
USA
Australia,USA
and UK
Zuniga,23
2009
Costa,28 2009
Moo,29 2010
Hughes,30
2010
Popadich,31
2011
Retro
Retro
Retro
Retro
Retro
Retro
Korea
Poland
Barczynski,7
2013
Italy
So,9 2012
Raffaelli,
2012
24
China
Retro
Retro
Pro
Retro
Italy
Perrino,12
2009
Retro
Lang,8 2012
Korea
Choi,11 2008
Retro
Retro
Korea
Roh,27 2007
Study
design
Wang,22 2012 USA
Country
Study
Bi
Bi
Uni and
Bi
Uni
NA
Uni and
Bi
Bi
Bi
Uni and
Bi
NA
Uni and
Bi
NA
Bi
640
232
186
185
86
606
143
81
244
266
251
101
113
Extent of Patients
pCND
(N)
TABLE 1 Clinical characteristics of the included studies
41.5
43.2
49.8
TT alone
NA
TT alone
282
NA
TT?pCND 358
113
49.2
TT?pCND 119
62
TT alone
50
42.7
103
TT alone
52
NA
TT?pCND 124
82
37
TT alone
TT?pCND
49
NA
48
TT?pCND
20.4
NA
60/
NA
222
75/
NA
283
16/97 6.2
21/98 6.6
13/49 12.1
24/
12.9
100
22/81 10
NA
6.7
NA
NA
1.5
9.6
0
5
NA
6a
0.35
6.8
0a
6.0a
1.7
8.8
NA
NA
NA
NA
NA
NA
NA
NA
NA
5.6
NA
NA
NA
37.0
9.7
35.5
4.9
54.9
NA
40.8
6.0
49.0
9.2
61.5
16.7
33.3
5.9
46.8
NA
82.4
NA
NA
NA
37.5
NA
62.2
NA
NA
NA
NA
NA
NA
NA
17.1
NA
34.7
1.0
10.0
NA
28.6
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Mean no. of central Incidence of
Upstaged to
LNS excised
central LNM (%) stage III (%)
14a
18/64 15
NA
NA
81/
22.3
266
52/
22.7
205
16/49 20a
4/32
10/35 14.2
24/94 15
26/
17
100
13/
NA
117
41.2a
TT alone
347
NA
NA
10/
NA
126
NA
NA
17/61 19a
44
65
TT alone
6.8
22
NA
11/42 7.3
6/42
9/64
NA
46.8a
49.2
TT?pCND 259
78
36
TT
TT?pCND
45
TT?pCND
45.7
52
TT alone
118
46
TT?pCND 126
130
TT alone
NA
42.9
159
TT alone
NA
48
52
48.5
NA
Mean age Sex
Mean tumor
(years)
(M:F) size (mm)
TT?pCND 136
92
53
TT?pCND
TT alone
73
48
TT alone
TT?pCND
40
Patients
(N)
TT?pCND
Group
79
231
92
101
NA
NA
63
62
12
35
NA
NA
56
72
26
31
62
87
55
79
NA
NA
53
48
73
40
No. of RAI
ablation
2192
W. Zhao et al.
2193
(4.1% vs. 2.3%, OR = 1.93; 95% CI 1.05–3.57; P = 0.03,
I2 = 30%) than patients in the TT group. However, the
definition of permanent hypocalcemia varied among the
studies. Nine studies defined permanent hypocalcemia as
hypocalcemia and/or the need for continued calcium supplementation for longer than 6 months, whereas longer
than 12 months was the definition in two studies.8,9,11,14,15,22,25,26,29–31 When including the nine studies
for a consistent definition, the TT?pCND group had significantly higher temporary (27.4% vs. 19.6%, OR = 2.44,
95% CI 1.75–3.38; P \ 0.00001, I2 = 40%) and permanent hypocalcemia rates (6.3% vs. 2.6%, OR = 2.36; 95%
CI 1.10–5.06; P = 0.03; I2 = 35%) compared with those
of the TT group.
Regarding other operative outcomes, the results showed
that patients in both groups had a similar risk for developing temporary (OR = 1.22, 95% CI 0.85–1.75;
P = 0.27, I2 = 0) and permanent RLN injury (OR = 1.17,
95% CI 0.56–2.44; P = 0.68, I2 = 20%), hematomas
(OR = 1.19, 95% CI 0.54–2.16; P = 0.67, I2 = 0%), and
wound infection/seroma (OR = 0.85, 95% CI 0.37–1.92;
P = 0.69, I2 = 0%). Furthermore, only two studies compared the operating times; therefore, we did not pool these
data.24,26 Regarding overall complications, the result of
meta-analysis indicates that the TT?pCND group has a
significantly increased overall morbidity rate (OR = 2.56;
95% CI 1.75–3.74; P \ 0.00001; I2 = 79%; Supplementary Fig. S1) but was similar after excluding temporary
hypocalcemia (OR = 1.14; 95% CI 0.84–1.55; P = 0.40;
I2 = 27%; Supplementary Fig. S2).
Sensitivity Analyses
Sensitivity analyses performed demonstrated that the
findings of all the available studies were robust (Supplementary Table S1).
Medians were provided
DISCUSSION
a
Retro retrospective study, Pro prospective study, pCND prophylactic central neck dissection, TT total thyroidectomy, Uni unilateral, Bi bilateral, LN lymph node, LNM lymph node metastasis,
RAI radioactive iodine, NA not available
74
NA
NA
NA
51.6
TT alone
104
16/88 16
112
NA
NA
NA
52.3
Korea
Lee,26 2015
Pro
NA
257
TT?pCND 153
30/
17
123
93
88
NA
3.2
46.2
6.8
NA
NA
25/93 16
21/88 16
45.7
43.5
93
88
TT?pCND
181
NA
Italy
Viola,25 2015
Pro
580
Uni and
Bi
Retro
USA
De
Carvalho,14
2015
TT alone
212
NA
NA
NA
45.2
478
TT alone
55/
10.2
423
58
NA
NA
6.8
41.2
TT?pCND 102
15/87 14.8
194
65
NA
NA
NA
NA
7.5
NA
48/
16.13
172
53.07
12/53 17.27
46.36
65
220
TT?pCND
TT alone
285
Bi
Italy
Calò,15 2014
Retro
Country
Study
TABLE 1 continued
Study
design
Extent of Patients
pCND
(N)
Group
Patients
(N)
Mean age Sex
Mean tumor
(years)
(M:F) size (mm)
Mean no. of central Incidence of
Upstaged to
LNS excised
central LNM (%) stage III (%)
No. of RAI
ablation
pCND for the Locoregional Recurrence of Papillary Thyroid Cancer
One of the most controversial issues in the treatment of
papillary thyroid cancer is the management of CND.
Although therapeutic CND is recommended for patients
with cN1 PTC, the necessity of pCND in clinically nodenegative PTC is controversial.32,33 Many studies have
investigated the potential advantages of TT?pCND compared with TT in decreasing postoperative Tg, elevating
the tumor stage, and reducing the LRR. However, it
remains unclear whether extended TT is beneficial in
decreasing the LRR. Furthermore, we should weight the
potential accompanying disadvantages of postoperative
complications and overuse of adjuvant radioactive iodine
therapy due to upstaging the tumor with no effect in
reducing the LRR.34
2194
W. Zhao et al.
TABLE 2 Details for locoregional recurrence of included studies
Study
Group
Roh,27 2007
TT?pCND
51
0 (0)
0
0
TT alone
53
3 (4.1)
3
2
TT?pCND
24.4
1 (2.1)
0
1
TT alone
24.4
2 (3.8)
0
2
TT?pCND
82.8
19 (14.0)
NA
NA
TT alone
82.8
26 (20.0)
NA
NA
NA
Choi,11 2008
Zuniga,23 2009b
Perrino,12 2009b
Mean follow-up (months)
LRR, n (%)
CNR
LNR
TT?pCND
69.2
5 (5.4)
NA
TT alone
69.2
22 (13.8)
NA
NA
Costa,28 2009
TT?pCND
47
8 (6.3)
4
5
TT alone
64
9 (7.7)
4
5
Moo,29 2010
TT?pCND
TT alone group
37.2
37.2
2 (4.4)
6 (16.7)
0
2
1
4
Hughes,30 2010
TT?pCND
19.1a
4 (5.1)
2
2
TT alone
27.5a
2 (3.1)
2
0
31
Popadich,
2011
So,9 2012
Raffaelli,24 2012
Lang,8 2012
Wang,22 2012
TT?pCND
32
13 (5.0)
4
11
TT alone
50
29 (8.4)
22
21
TT?pCND
44.7
2 (1.7)
1
2
TT alone
45.4
4 (3.5)
3
1
TT?pCND
25
1 (0.8)
1
0
TT alone
25.5
0 (0)
0
0
TT?pCND
25.5a
3 (3.7)
0
3
TT alone
27.1a
3 (2.9)
0
3
TT?pCND
21a
0 (0)
0
0
TT alone
21a
0 (0)
0
0
Barczynski,7 2013
TT?pCND
126.4
15 (4.2)
2
13
128.8
37 (13.1)
22
15
Calò,15 2014
TT?pCND
TT alone
2 (3.1)
4 (1.8)
0
1
2
4
Viola,25 2015b
TT?pCND
59.4
7 (7.5)
NA
NA
TT alone
59.4
7 (8.0)
NA
NA
TT alone
Lee,26 2015b
De Carvalho,14 2015
100a
100a
TT?pCND
55.2
5 (3.3)
NA
NA
TT alone
49.2
4 (3.9)
NA
NA
TT?pCND
80.2
4 (3.9)
0
4
TT alone
67.4
7 (1.5)
2
4
pCND prophylactic central neck dissection, TT total thyroidectomy, LRR locoregional recurrence, CNR central neck recurrence, LNR lateral neck
recurrence, NA not available
a
Medians were provided
b
Studies that did not mention site of locoregional recurrence, so the number of patients for recurrence site was not available
The results of the meta-analysis showed that patients
who underwent TT?pCND have a significantly lower
incidence of LRR than those underwent TT, which was
similar to a previous meta-analysis in 2013.19 We evaluated the central and lateral sites of lymph node recurrences,
and PTC recurrence in the central site was lower than that
in the lateral region (2.1% vs. 3.1%, respectively). Contrary
to the similar recurrence rate at the lateral site, the recurrence at the central site was significantly lower in the
TT?pCND group than that in the lateral group
(RR = 0.35; P = 0.002), which was not reported in previous meta-analyses.13,18,19
With regards to the extended approach, patients in the
TT?pCND group tended to present with recurrence in the
lateral region than central region (3.3% vs. 1.1%, respectively); however, patients in the TT group had a similar rate
of central and lateral neck recurrence (3.4% vs. 3.3%). As
most recurrences in the TT?pCND group occurred in the
lateral neck, this indicated that lateral neck recurrence
would not have been prevented by CND.
pCND for the Locoregional Recurrence of Papillary Thyroid Cancer
A
2195
TT=pCND
Study or Subgroup
Roh, 2007
Choi, 2008
Zuniga, 2009
Perrino, 2009
Costa, 2009
Moo, 2010
Hughes, 2010
Popadich, 2011
So, 2012
Raffaelli, 2012
Lang, 2012
Wang, 2012
Barczynski, 2013
Calo, 2014
Viola, 2015
Lee, 2015
De Carvalho, 2015
Risk Ratio
TT
Events Total Events Total Weight M-H,Random, 95%CI Year
0.26 [0.01, 4.87] 2007
1.0%
0
3
73
40
48
1.6%
1
2
53
0.55 [0.05, 5.90] 2008
0.70 [0.41, 1.20] 2009
136
19
26 130 16.8%
8.2%
0.39 [0.15, 1.00] 2009
92
5
22 159
8.4%
126
8
9 118
0.83 [0.33, 2.09] 2009
3.5%
45
0.27 [0.06, 1.24] 2010
36
2
6
3.1%
1.67 [0.32, 8.81] 2010
65
78
4
2
0.60 [0.32, 1.13] 2011
259
13
29 347 14.0%
3.0%
119
0.47 [0.09, 2.54] 2012
2
4 113
0.9%
1.51 [0.06, 36.59] 2012
62
124
1
0
1.26 [0.26, 6.06] 2012
82
3
3 103
3.4%
49
0
0
Not estimable 2012
37
0.32 [0.18, 0.57] 2013
358
15
37 282 15.6%
3.0%
65
2
4 220
1.69 [0.32, 9.03] 2014
7
93
0.95 [0.35, 2.59] 2015
7.3%
88
7
153
4 104
4.8%
0.85 [0.23, 3.09] 2015
5
102
4
7 478
2.68 [0.80, 8.98] 2015
5.4%
1969
2468 100.0%
Total (95% Cl)
Total events
91
165
Heterogeneity: Tau2 = 0.07; Chi2 = 18.53, df = 15 (P =0.24); I2 = 19%
Test for overall effect: Z = 2.64 (P = 0.008)
B
Study or Subgroup
Barczynski, 2013
Calo, 2015
Costa, 2009
De Carvalho, 2015
Hughes, 2010
Moo, 2010
Popadich, 2011
Raffaelli, 2012
Roh, 2007
So, 2012
0.66 [0.49, 0.90]
0.01
TT
Risk Ratio
TT+pCND
Events Total Events Total Weight M-H, Random, 95%CI
0.07 [0.02, 0.30]
2
22 282 16.5%
358
0
1 220
65
4.0%
1.12 [0.05, 27.08]
0.94 [0.24, 3.66]
4
4 118 17.9%
126
0.93 [0.04, 19.23]
0
2 478
102
4.5%
2
2
65 10.1%
78
0.83 [0.12, 5.75]
45
0.16 [0.01, 3.25]
0
2
36
4.5%
0.24 [0.08, 0.70]
4
22 347 26.0%
259
1.51 [0.06, 36.59]
1
0
62
124
4.0%
40
0.26 [0.01, 4.87]
0
3
73
4.7%
0.32 [0.03, 3.00]
1
3 113
119
7.7%
Total (95% Cl)
1316
1794 100.0%
Total events
14
61
Heterogeneity: Tau2 = 0.15; Chi2 = 10.35, df = 9 (P =0.32); I2 = 13%
Test for overall effect: Z = 3.12 (P = 0.002)
C
Study or Subgroup
Barczynski, 2013
Calo, 2015
Choi, 2008
Costa, 2009
De Carvalho, 2015
Hughes, 2010
Lang, 2012
Moo, 2010
Popadich, 2011
Roh, 2007
So, 2012
Risk Ratio
M-H, Random, 95%CI
TT
TT+pCND
Events Total Events
2
0
40
2
1
48
5
5
126
4
1
45
0
2
78
259
21
11
1
2
119
3
1
82
358
15
13
4
4
102
2
65
4
Total
73
53
118
36
65
347
113
103
282
478
220
0.1
1
TT=pCND TT
10
100
Risk Ratio
M-H, Random, 95%CI
0.35 [0.18, 0.68]
0.01
0.1
1
TT=pCND TT
Risk Ratio
Weight M-H, Random, 95%CI
0.36 [0.02, 7.34]
2.0%
0.55 [0.05, 5.90]
3.2%
0.94 [0.28, 3.15]
11.2%
0.20 [0.02, 1.71]
3.9%
4.18 [0.20, 85.49]
2.0%
0.70 [0.34, 1.43]
26.4%
1.90 [0.17, 20.66]
3.2%
1.26 [0.26, 6.06]
7.0%
0.68 [0.33, 1.41]
25.6%
4.69 [1.19, 18.43]
9.1%
1.69 [0.32, 9.03]
6.3%
1322
1888 100.0%
Total (95% Cl)
Total events
44
61
Heterogeneity: Tau2 = 0.05; Chi2 = 11.12, df = 10 (P =0.35); I2 = 10%
Test for overall effect: Z = 0.28 (P = 0.78)
10
100
Risk Ratio
M-H, Random, 95%CI
0.94 [0.61, 1.45]
0.01
0.1
1
TT=pCND TT
10
100
FIG. 2 Forest plot showing a meta-analysis of locoregional recurrence (LRR) for included studies, a overall LRR; b central compartment
recurrence; c lateral compartment recurrence
In terms of RAI, the TT?pCND group showed a higher
rate of RAI ablation therapy (OR = 1.20, 95% CI
1.04–1.39), likely because of upstaging for the higher
incidence of central LNM from pCND. Regarding postoperative complications, patients in the TT?pCND group
had a significantly higher rate of hypocalcemia and overall
2196
FIG. 3 Forest plot showing a
meta-analysis of hypocalcemia
for included studies,
a temporary hypocalcemia;
b permanent hypocalcemia;
c temporary hypocalcemia for
6 months as the dividing value;
d permanent hypocalcemia for
6 months as the dividing value
W. Zhao et al.
A
TT+pCND
TT
Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H,Random,95%CI
4.54 [1.63, 12.62]
40
7
73
4.1%
Roh, 2007
13
1.57 [0.50, 4.90]
6
53
8
48
3.4%
Choi, 2008
1.28 [0.50, 3.31]
4.7%
Perrino, 2009
92
11 159
8
4.0%
21
5
65
4.42 [1.56, 12.51]
Hughes, 2010
78
7.68 [1.61, 36.52]
45
1.9%
14
Moo, 2010
2
36
2.54 [1.29, 4.99]
25 259
14 347
7.9%
Popadich, 2011
1.38 [0.81, 2.36]
49 119
38 113 10.9%
So, 2012
53 124
3.46 [1.65, 7.27]
6.9%
Raffaelli, 2012
62
11
15
2.34 [0.97, 5.66]
82
Lang, 2012
9 103
5.2%
37
21
6.19 [1.90, 20.17]
Wang, 2012
49
3.2%
4
2.90 [1.92, 4.38]
37 282 14.5%
Barczynski, 2013
109 358
1.80 [1.16, 2.77]
47 102
De Carvalho, 2015
154 478 13.8%
56 153
2.28 [1.28, 4.08]
9.8%
Lee, 2015
21 104
25
65
1.88 [1.04, 3.37]
9.7%
Calo, 2014
55 220
1614
2132 100.0%
2.37 [1.89, 2.96]
Total (95% Cl)
Total events
464
374
2
2
2
Heterogeneity: Tau = 0.05; Chi = 17.82, df = 13 (P =0.16); I = 27%
Test for overall effect: Z = 7.54 (P < 0.00001)
B
0.01
TT+pCND
TT
Study or Subgroup Events Total Events
48
1
0
Choi, 2008
6
1
92
Perrino, 2009
1
0
45
Moo, 2010
0
78
Hughes, 2010
2
2
Popadich, 2011
2 259
7 119
2
So, 2012
0
1 124
Raffaelli, 2012
2
Lang, 2012
1
82
0
49
3
Wang, 2012
8 358
2
Barczynski, 2013
11
12 102
De Carvalho, 2015
2
Lee, 2015
5 153
10
65
7
Calo, 2015
7
Viola, 2015
18
0
Odds Ratio
Total Weight M-H,Random,95%CI
0.36 [0.01, 9.07]
53
3.2%
0.28 [0.03, 2.36]
6.4%
159
0.26 [0.01, 6.58]
36
3.2%
4.28 [0.20, 90.78]
65
3.5%
1.34 [0.19, 9.59]
7.3%
347
3.47 [0.71, 17.07]
9.8%
113
1.52 [0.06, 37.81]
62
3.2%
2.55 [0.23, 28.63]
103
5.3%
0.10 [0.00, 1.99]
37
3.7%
3.20 [0.67, 15.19]
282 10.1%
5.66 [2.42, 13.23]
478 18.7%
1.72 [0.33, 9.05]
104
9.3%
2.53 [0.92, 6.95]
220 16.3%
Not estimable
0
Total (95% Cl)
2059
1571
100.0%
13
21
14
25
21
15
49
47
25
40
78
45
259
49
82
119
102
65
7
5
2
14
4
9
38
154
55
73
65
36
347
37
103
113
478
220
7.7%
7.5%
3.9%
13.3%
6.1%
9.5%
16.8%
19.8%
15.4%
0.01
4.54 [1.63, 12.62]
4.42 [1.56, 12.51]
7.68 [1.61, 36.52]
2.54 [1.29, 4.99]
6.19 [1.90, 20.17]
2.34 [0.97, 5.66]
1.38 [0.81, 2.36]
1.80 [1.16, 2.77]
1.88 [1.04, 3.37]
TT+pCND
TT
Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H,Random,95%CI
4.28 [0.20, 90.78]
Hughes, 2010
65
5.4%
2
0
78
Moo, 2010
0
36
4.9%
0.26 [0.01, 6.58]
1
45
2 259
Popadich, 2011
1.34 [0.19, 9.59]
2 347 10.9%
3
49
0
37
Wang, 2012
0.10 [0.00, 1.99]
5.6%
2
8.0%
82
Lang, 2012
1 103
2.55 [0.23, 28.63]
3.47 [0.71, 17.07]
7 119
So, 2012
2 113 14.6%
5.66 [2.42, 13.23]
De Carvalho, 2015
12 102
11 478 27.0%
18
Viola, 2015
Not estimable
7
0
0
7
65
10 220 23.7%
Calo, 2015
2.53 [0.92, 6.95]
Total (95% Cl)
799
1399 100.0%
2.36[1.10, 5.06]
Total events
50
37
2
2
2
Heterogeneity: Tau = 0.37; Chi = 10.71, df = 7 (P =0.15); I = 35%
Test for overall effect: Z = 2.22 (P = 0.03)
0.1
1
10
TT+pCND TT
100
Odds Ratio
M-H, Random,95%CI
2007
2010
2010
2011
2012
2012
2012
2015
2015
839
1472 100.0%
2.44[1.75, 3.38]
Total (95% Cl)
Total events
230
288
Heterogeneity: Tau2 = 0.09; Chi2 = 13.35, df = 8 (P =0.10); I2 = 40%
Test for overall effect: Z = 5.32 (P < 0.00001)
D
100
1.93 [1.05, 3.57]
TT+pCND
TT
Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H,Random,95%CI Year
Roh, 2007
Hughes, 2010
Moo, 2010
Popadich, 2011
Wang, 2012
Lang, 2012
So, 2012
De Carvalho, 2015
Calo, 2015
0.1
1
10
TT+pCND TT
Odds Ratio
M-H, Random,95%CI
Year
2008
2009
2010
2010
2011
2012
2012
2012
2012
2013
2015
2015
2015
2015
Total events
65
48
Heterogeneity: Tau2 = 0.33; Chi2 = 17.07, df = 12 (P =0.15); I2 = 30%
Test for overall effect: Z = 2.11 (P = 0.03)
C
Odds Ratio
M-H, Random,95%CI
Year
2007
2008
2009
2010
2010
2011
2012
2012
2012
2012
2013
2015
2015
2015
0.01
0.1
1
10
TT+pCND TT
100
Odds Ratio
M-H, Random,95%CI
Year
2010
2010
2011
2012
2012
2012
2015
2015
2015
0.01
0.1
1
10
TT+pCND TT
100
pCND for the Locoregional Recurrence of Papillary Thyroid Cancer
2197
morbidity than those in the TT group, which was similar to
previous meta-analyses.5,13,18,19 There were no differences
in the rate of RLN, wound infection or hematoma formation between the two groups. However, the overall
morbidity rate (excluding hypocalcemia) was similar,
indicating that complications associated with pCND were
actually related to hypocalcemia rather than other surgically related complications.
We acknowledge that our meta-analysis has several
limitations. First, regarding RAI therapy, only 7 of 17
studies mentioned the RAI therapeutic dose, which can
influence the LRR.7,9,14,15,25,29,30 Additionally, the RAI
strategies based on the indications for RAI therapy were
different among these studies, which can limit the ability to
analyze the mechanism of recurrence. Second, the extent of
pCND differed among the studies. Unilateral or bilateral
pCND may have different effect on outcomes. Third, the
follow-up period was relative short, and only 5 of 17 studies
reported an overall mean follow-up period of more than
5 years. Therefore, an extended follow-up period would be
necessary to detect LRR and distinguish real recurrence and
persistent disease. Fourth, the surveillance strategy was not
standardized among these studies. Although 14 studies used
a combination of serum Tg and neck ultrasonography during the follow-up visit as the fundamental physical
examination, the frequency and duration of these visits
differed greatly.7–9,12–15,24,26–28,30–33 Additionally, two
studies did not mention the clinical examination approaches, and one study used serum Tg alone.11,25,29
Furthermore, the definitions of recurrence were not routinely defined in the studies. Those differences in
surveillance also influenced the definition of recurrence and
the monitoring of precise time of recurrence. Finally,
because of high percentage of the studies were of retrospective design (14/17) with existing selection bias, the
quality of included studies was rated as low. Baseline
characteristics, such as age, tumor size, extrathyroidal
extension, and multifocality, showed significant differences
between both groups; thus, any of these risk factors could
potentially influence the incidence of recurrence. Moreover,
regarding the selection criteria for pCND, 9 of 17 studies
were based on the surgeon’s preference, whereas the
remaining 8 studies did not mention their methods.8,11,14,15,22–24,30,31 Therefore, we should be cautious
with our results regarding these limitations of the previously
published data.
In conclusion, this meta-analysis showed that pCND
significantly reduced the LRR for patients with PTC,
specifically in the central region. However, there are some
important limitations to pCND, including a higher rate of
postoperative RAI ablation and hypocalcemia. Furthermore, the reduction in LRR may be partially related to the
increased rate of RAI. We suggest that pCND should not be
routinely recommended for treating patients with PTC,
even by experienced surgeons. However, more evidence
from prospective, multicenter, randomized, controlled trials is needed to address further the true role of pCND in
PTC patients, not only for the actual LRR benefits but also
for safety reasons.
ACKNOWLEDGEMENT This work is supported by the grants
from the CAMS Innovation Fund for Medical Sciences (CIFMS,
2016-I2M-3-005). The authors thank Dr. Lin Ma (Department of
General Surgery, Peking Union Medical College Hospital) for furnishing data.
DISCLOSURE
interest.
The authors declare no conflict of any commercial
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