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Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis C.Z. Li a,c, P. Zhang b,c, R.W. Li a, C.T. Wu a, X.P. Zhang a, H.C. Zhu a,* a
Oncological Surgery, Affiliate Hospital of Hebei United University, Tangshan 063000, Hebei, China b Nursing and Rehabilitation College, Hebei United University, Tangshan 063000, Hebei, China Accepted 6 May 2015 Available online - - -
Abstract Background: In early breast cancer patients with sentinel node metastasis, the effect of axillary lymph node dissection (ALND) is controversial. The purpose of this study is to compare the safety and efficacy of sentinel lymph node biopsy (SLNB) alone versus ALND in patients with early breast cancer and sentinel node metastasis. Methods: We searched PubMed, Embase, Web of Science, and Cochrane Library databases from 1965 to February 2014. All data were analyzed using Review Manager Software 5.2. Results: 12 studies, which included 130,575 patients from five randomized controlled trials and seven observational studies, met our inclusion criteria. 26,870 early breast cancer patients underwent SLNB alone and 103,705 underwent ALND. Patients underwent ALND had more paresthesia (risk ratio [RR] 0.26, 95% confidence interval [CI] 0.20e0.33; p < 0.01) and lymphedema (RR 0.28, 95% CI 0.20e0.41; p < 0.01) than those had SLNB alone. There were no significant differences in overall survival (hazard ratio [HR] 0.95, 95% CI 0.85e1.06; p ¼ 0.35), disease-free survival (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.96), and locoregional recurrence (RR 0.92, 95% CI 0.59e1.44; p ¼ 0.73). Conclusion: Current evidence indicates that axillary dissection may be omitted in early breast cancer patients with sentinel lymph metastasis. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Axillary lymph node; Breast cancer; Dissection; Sentinel lymph node
Introduction Breast cancer is the most common cancer and the second only to lung cancer as a cause of cancer death, with an estimated 232,340 new cases and 39,620 died of the disease among American women in 2013. Although about 1 in 8 American women will develop breast cancer in her lifetime,1 the mortality appears to be decreasing due to early * Corresponding author. Department of Oncological Surgery, Affiliate Hospital of Hebei United University, 73 Jianshe South Road, Tangshan 063000, Hebei, China. Tel.: þ86 0315 2308103; fax: þ86 0315 2852195. E-mail address: [email protected] (H.C. Zhu). c These authors contributed equally.
detection and more effective treatment. About 36% women diagnosed with breast cancer undergo mastectomy with axillary lymph node dissection (ALND).2 Although reliably identifies nodal metastasis and maintains regional control,3 ALND leads to a significant morbidity such as seroma, lymphedema, paresthesia, infection and pain from intercostal and intercostal-brachial nerve injury.4 If the sentinel lymph node is negative, the axillary nodes are most probably not involved and ALND should not be performed in breast cancer patients.5 Sentinel lymph node biopsy (SLNB) was introduced for breast cancer in the early 1990s as a method to predict the status of the axillary nodes.6 Compared with ALND, SLNB alone has been
http://dx.doi.org/10.1016/j.ejso.2015.05.007 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
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demonstrated to decrease unnecessary complications, shorter hospital stay and improve the quality of life of patients.7,8 The current NCCN guidelines recommend that the sentinel lymph node-negative breast cancer patients do not require ALND.9 However, the effect of ALND in sentinel lymph node-positive early breast cancer is controversial in previous studies.10e12 Moreover, due to small sample size, these studies were not adequately powered to detect whether ALND can be omitted in early breast cancer patients with positive sentinel lymph. Therefore, in order to provide the latest and most convincing evidence, we systematically reviewed the current available studies to compare the safety and efficacy of SLNB alone versus ALND in early breast cancer with sentinel node metastasis. Overall survival, disease-free survival, locoregional recurrence and adverse events were assessed with metaanalytical methods. Materials and methods Study selection We conducted a comprehensive literature search of PubMed, Embase, Web of Science, and Cochrane Library databases from 1965 to February 2014. The following MeSH search headings were used: “sentinel lymph node”, “axillary lymph node”, “metastasis”, “dissection” and “breast cancer”. The related-articles function was used to broaden the search, and all abstracts, articles, and citations were reviewed without language restriction. When the patient’s material was reported more than once, we selected the article with the most complete data in this metaanalysis. If the applicability of an article could not be determined by the title or abstract alone, the full text would be reviewed. Any disagreements were arbitrated by the corresponding author. Study inclusion and exclusion criteria These studies would be selected if they fulfilled the following inclusion criteria: (1) Design: randomized controlled trials (RCTs) and observational studies. (2) Patients: clinical T1 or T2 N0 M0 breast cancer women with sentinel lymph node metastasis. (3) Intervention: SLNB alone (4) Comparison: ALND. (5) Outcomes: overall survival, disease-free survival, locoregional recurrence and adverse events. Exclusion criteria: Studies evaluated less than 30 patients, abstracts, letters, editorials and expert opinions, reviews without original data, meta-analysis, and case reports. Data extraction and management Two authors independently extracted data from the inclusion studies. The following information was extracted
from each study: first author, year of publication, type of study, patient characteristics, tumor stage, number of positive sentinel lymph nodes, tumor grade, type of histology, follow-up, and the outcomes. Agreement regarding study inclusion was assessed using the Cohen kappa statistic. Types of outcome measures The primary outcomes evaluated in this review were overall survival, disease-free survival, and the incidence rate of locoregional recurrence, which was defined as recurrence in the axillary, supraclavicular or internal mammary nodes. The secondary outcomes were adverse events (infection, axillary seroma, paresthesia, and lymphedema). Quality assessment We used the Cochrane Risk of Bias Tool to assess the risk of bias for each RCT.13 This tool includes six specific domains: selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias. Quality assessment of the observational studies were assessed using the NewcastleeOttawa Scale.14 A star rating from 0 to 9 was allocated to each study based on the patient’s selection criteria, comparability of cases and controls on the basis of the design or analysis, and the exposure. Studies achieving more than 7 stars were considered to be of higher quality. Two reviewers independently assessed the quality of the included studies. Discrepancies were re-examined, and consensus was reached by discussion. Statistical analysis The data were analyzed by the Review Manager software 5.2 (updated by the Cochrane Library for Systematic Reviews). Hazard ratio (HR) was used as a summary statistic for censored outcomes (overall survival and disease-free survival) as described by Parmar and colleagues.15 The logHR and its standard error were required for each study in the meta-analysis. We calculated the logHR using the reported HR and confidence interval (CI). We extracted HR using the generic inverse variance method available. The risk ratio (RR) was used to analyze dichotomous variables, such as localregional recurrence and adverse events. Heterogeneity among studies was evaluated by the I-squared statistic (I2). The I2 measures the extent of inconsistency among studies and is interpreted as approximately the proportion of total variation in study estimates. I2 of less than 25% is considered as low heterogeneity, 25e50% as moderate heterogeneity, and more than 50% as high heterogeneity.16 If the p value was more than 0.1, the fixed-effects model would be reported, otherwise, the random-effects model would be used. Subgroup analysis was performed according to the type of study (RCTs versus observational studies). Sensitivity analysis (excluding 1 or more studies) was used to explore possible sources of heterogeneity
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
C.Z. Li et al. / EJSO xx (2015) 1e9
among different studies. Bgger’s test and funnel plot were performed to determine the presence of publication bias. Results Search results A total of 1856 studies were identified by the initial database search. 691 studies were removed. 1165studies were screened, among which 1116 were excluded according to the titles and abstracts for various reasons (case reports, reviews, conference abstract only and metaanalysis). The remaining 32 full-text studies were assessed for eligibility, 20 of which were excluded because of sentinel node-negative patients.5,17e35 Finally, 12 studies fulfilled the inclusion criteria and were included in this meta-analysis.36e47 The selection process was shown in Fig. 1. Study characteristics The main characteristics of included studies were shown in Table 1. The comparison of patient characteristics between SLNB alone and ALND was addressed in Table 2. The twelve studies were from 2007 to 2014. The sample size was a range from 233 to 25,346 (a total of 130,575 patients). Analysis was done on 26,870 patients underwent SLNB alone and 103,705 underwent ALND. There were five randomized controlled trials39,40,42,44,46 and seven observational studies.36e38,41,43,45,47 Although 3 of the included studies refer to the same study population (the ACOSOG Z11 trial),42,44,46 they assessed different outcomes. Giuliano et al.42 compared the overall survival and disease-free survival, Giuliano et al.44 assessed the locoregional recurrence and Lucci et al.46
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evaluated adverse event. All included studies were published in English. Seven studies reported overall survival,36e38,40,42,43 seven studies reported disease-free survival,36,38e43 five studies reported localregional recurrence,40e42,45,47 and two studies reported adverse events.46,47
Quality assessment The risk of bias assessment of the randomized controlled trials was shown in Supplementary Table. Four RCTs adequately described random components in the sequence generation process.40,42,44,46 Three RCTs provided insufficient information to permit judgment of low risk bias or high risk bias in allocation concealment, binding of participants, and binding of outcome assessment.42,44,46 We used the Newcastele Ottawa Scale to assess the quality of the observational studies. One study47 got seven stars indicating a high quality, and six studies36e38,41,43,45 were assessed 4 to 6 stars (Table 1).
The overall survival between ALND and SLNB alone Overall survival was reported in seven studies36e38,40,42,43,45 (Fig. 2A). Patients had SLNB alone were associated with lower overall survival than those had ALND, but this difference was not significant (HR 0.95, 95% CI 0.85e1.06; p ¼ 0.35), with no significant heterogeneity (c2; ¼ 3.02, I2 ¼ 0%, p ¼ 0.81). The finding was consistent with subgroup analysis for RCTs (HR 0.87, 95% CI 0.62e1.24; p ¼ 0.45) and observational studies (HR 0.96, 95% CI 0.85e1.08; p ¼ 0.47). No publication bias was detected by Begg’s test (p ¼ 0.36) in the funnel plot (Supplementary Fig. 1).
Figure 1. Flow chart of study selection process.
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
Author
Wang et al. Park et al. Yi et al.
Year Type of study
SLNB alone /ALND
T stage T1/T2
SLNB alone
ALND
SLNB alone
ALND
SLNB alone
64 (35e91) 48 (37e59) 54 (22e91) 53 (33e75) 53 (28e81)
60 (28e87) 49 (39e58) 57 (29e89) 55 (29e75) 54 (26e81)
56 (43e68) 56 (24e92) 59 (22e96) RCT 436/420 56 (24e92) Observational 20,217/77,097 58 (49e69) RCT 414/373 56 (24e92) Observational 449/210 59 (28e90)
59 (46e72) 54 (25e90) 56 (18e99) 54 (25e90) 56 (48e67) 54 (25e90) 58 (28e88)
2014 Observational 393/876 2014 Observational 197/2348 2013 Observational 188/673 121/112 467/464
Crawford 2013 Observational 135/426 et al. Giulian 2011 RCT 436/420 et al. Yi et al. 2010 Observational 4267/22,561 2010 2009 2007 2007
Number of positive SLNs (1/2/3)
Tumor grade (I/II/III/unknown)
Size of node metastasis
ALND
SLNB alone
SLNB alone
Micro Macro Micro Macro
266/127
555/321
347/46/0 607/269/0
130/67
1171/1177
187/1/9
1746/436/166 NA
NA
152/36
445/228
NA
NA
NA
NA
NA
NA
NA
22/47/40/12
322/145
316/148
450/17/0 440/23/1
44/91
90/336
NA
303/133
284/136
324/76/41 203/68/149
2987/1280 11,764/9315 NA
ALND
NA
NA
ALND
97/171/41/85 173/390/104/209 NA
Follow Outcomes Quality up (NOSa) (years)
NA
NA
NA
11.8
NA
NA
NA
NA
10.3
OS, DFS, 6 LLR OS 5
NA
136
52
158
515
5.8
DFS, OS 5
4/50/23/2
121
0
112
0
7.9
DFS
90/241/135/1 118/214/129/3
467
0
464
0
5.0
NA
NA
NA
NA
NA
10.0
OS, DFS, RCT LRR, Adverse event DFS 5
81/148/87/120 71/158/94/97
199
237
165
255
5.6
OS, DFS RCT
NA
2240 2185
4598 17,963 6.0
OS
5
NA
LLR
RCT
NA
NA
NA
NA
5.6
RCT
303/133
284/136
324/76/41 203/68/149
81/148/87/120 71/158/94/97
NA
NA
NA
NA
NA
NA
NA
3674 16,543 6585 70,512 7.9
OS
5
294/120
271/132
NA
NA
NA
NA
NA
NA
NA
NA
5.6
RCT
344/105
123/87
NA
NA
96/263/90/0
30/126/54/0
NA
NA
NA
NA
2.9
Adverse event Adverse event
7
Abbreviations: RCT: randomized controlled trial; SLNB: sentinel lymph nodes biopsy; ALND: axillary lymph node dissection; OS: overall survival; LLR: localregional recurrence; DFS: disease-free survival; NOS: NewcastleeOttawa Scale; NA: not available; Macro: macrometasis (2.0 mm). a Quality assessment of the observational studies was assessed using the NewcastleeOttawa Scale. The quality of the evidence is classified as three levels: high (more than seven stars), moderate (four to six stars), poor (less than four stars).
C.Z. Li et al. / EJSO xx (2015) 1e9
Age (year)
Sola 2013 RCT et al. Galimberti 2013 RCT et al.
Giuliano et al. Bilimoria et al. Lucci et al. Langer et al.
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Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
Table 1 Characteristic of included studies.
C.Z. Li et al. / EJSO xx (2015) 1e9 Table 2 Comparison of patient characteristics between patients who underwent SLNB alone and patients who underwent ALND in patients with sentinel lymph node metastasis. Characteristic
SLNB alone
ALND
Age (years) Tumor size (cm) Tumor grade I II III Unknown T Stage T1 T2 Number of positive SLNs 1 2 3 Size of node metastasis Micrometastasis (2.0 mm) Race White Black Other Operation type Breast conserving surgery Mastectomy
56.0 (47.3e64.6) 55.8 (49.5e62.0) 1.89 (1.14e2.64) 2.16 (0.94e3.38) 10,240 (38%) 13,795 (52%) 448 (1.7%) 2213 (8.3%)
49,206 (48%) 45,229 (44%) 638 (0.6%) 7574 (7.4%)
4548 (70%) 1984 (30%)
14,748 (56%) 11,748 (44%)
1308 (87%) 140 (9.3%) 50 (3.7%)
2996 (73%) 796 (19%) 316 (8%)
6837 (27%) 19,017 (73%)
12,082 (12%) 89,245 (88%)
20,878 (83%) 2191 (8.7%) 1966 (8.3%)
84,092 (84%) 8220 (7.8%) 8222 (8.2%)
21,154 (82%) 4910 (18%)
52,581 (51%) 50,907 (49%)
The disease-free survival between ALND and SLNB alone Pooling the data of seven studies36,38e43 that assessed the disease-free survival (Fig. 2B) showed no significant difference (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.96) between SLNB alone and ALND, with significant heterogeneity (c2; ¼ 11.35, I2 ¼ 47%, p ¼ 0.08). Subgroup analysis indicated that there was no significant difference in disease-free survival between SLNB alone and ALND, both in RCTs (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.92) and observational studies (HR 1.10, 95% CI 0.94e1.29, p ¼ 0.23). There was no publication bias by Begg’s test (p ¼ 0.22) (Supplementary Fig. 2). The localregional recurrence between ALND and SLNB alone
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by Begg’s test (p ¼ 0.94) with symmetrical funnel plot (Supplementary Fig. 3). The adverse event between ALND and SLNB alone Two studies that assessed 1190 patients reported on paresthesia.46,47The difference was statistically significant in favor of SLNB alone (RR 0.26, 95% CI 0.20e0.33; p < 0.001), with no significant between-study heterogeneity (c2; ¼ 0.85, I2 ¼ 0%, p ¼ 0.36). Additionally, Lucci and colleagues46 indicated that there was significant difference in infections (RR 0.36, 95% CI 0.18e0.70; p ¼ 0.003) and axillary seroma (RR 0.40, 95% CI 0.25e0.65; p ¼ 0.0002) between SLNB alone and ALND. Two studies46,47 that assessed 1160 patients reported on lymphedema. The difference was significant between SLNB alone and ALND (RR 0.28, 95% CI 0.20e0.41; p < 0.001), with significant heterogeneity (c2; ¼ 3.96, I2 ¼ 75%, p ¼ 0.05) (Fig. 3). Comparison the outcomes between patients with sentinel lymph nodal micrometastasis and macrometastasis The micrometastatic sentinel node was established on at least one metastatic deposit in the range of 0.2e2 mm, and macrometastatic sentinel node was defined as more than 0.2 mm according to the sixth edition of the American Joint Committee on Cancer (AJCC) staging manual.13 We performed subgroup analysis to compare the survival between SLNB alone and ALND in early breast cancer patients with sentinel node metastasis according to the size of node metastasis (micrometastasis or macrometastasis). The pooled data of four studies (2 RCTs39,40 and 2 observational studies43,45) including patients with sentinel lymph nodal micrometastasis indicated that there were no significant differences in overall survival (HR 0.94, 95% CI 0.72e1.23, p ¼ 0.65) and disease-free survival (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.99) between ALND and SLNB alone (Fig. 2D). Only one observational study45 assessed 22,187 patients with nodal macrometastasis. Its result showed that the overall survival (HR 0.91, 95% CI 0.83e1.01, p ¼ 0.06) and localregional recurrence (HR 0.85, 95% CI 0.62e1.16, p ¼ 0.30) were no statistical differences between SLNB alone and ALND. Heterogeneity analysis
Localregional recurrence was reported in five studies40e42,45,47 that investigated 6142 patients (Fig. 2C). The localregional recurrence rate was higher in SLNB alone than those in the ALND, but the difference was not statistical significant (RR 0.92, 95% CI 0.59e1.44; p ¼ 0.73), with no significant between-study heterogeneity (c2; ¼ 1.82, I2 ¼ 0%, p ¼ 0.77). Our subgroup analysis showed that the result was not substantially affected by study design. There was no evidence of publication bias
There were no significant heterogeneities in overall survival (c2; ¼ 3.02, I2 ¼ 0%, p ¼ 0.81), and locoregional recurrence (c2; ¼ 1.82, I2 ¼ 0%, p ¼ 0.77). Referring to disease free survival and lymphedema, the p value of heterogeneity test was less than 0.1, or the I2 value of heterogeneity was more than 50%, indicating significant heterogeneity. The source of heterogeneity may come from type of study. The study of Yi et al. and Langer
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
Figure 2. A: Forest plot of overall survival. B: Forest plot of disease-free survival. C: Forest plot of localregional recurrence. D: Forest plot of sentinel lymph node micrometastasis. Abbreviations: ALND: axillary lymph node dissection; SLNB: sentinel lymph node biopsy; CI: confidence interval; SE: standard error.
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
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Figure 3. Forest plot of adverse event. Abbreviations: ALND: axillary lymph node dissection; SLNB: sentinel lymph node biopsy; CI: confidence interval.
et al. involved a multicenter retrospective population, which may exist potential selection bias. After we removed these studies, the DFS (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.84) and RR (RR 0.39, 95% CI 0.24e0.65; p ¼ 0.0002) were not substantially altered. Discussion The present meta-analysis identifies five RCTs and seven observational studies comparing the safety and efficacy between ALND and SLNB alone in early breast cancer patients with sentinel node metastasis. Our analysis shows that SLNB alone and ALND are comparable in overall survival and disease-free survival, and SLNB alone do not increase localregional recurrence in patients with early breast cancer, both in RCTs and observational studies. ALND results in more paresthesia, lymphedema, infections, and axillary seroma than SLNB alone. Moreover, compared with SLNB alone, ALND does not improve the survival of early breast cancer patients with sentinel node micrometastasis or macrometastasis. Several meta-analyses have been previously performed to compare the difference between SLNB alone and ALND in early breast cancer patients with sentinel node metastasis. A meta-analysis by Wang et al.48 evaluated the effectiveness and safety of ALND in early breast cancer. The authors concluded that there were no significant
differences in overall survival, disease-free survival and regional lymph node recurrence for sentinel lymph nodepositive patients. However, the result was based on a subgroup analysis of only one RCT,42 which would lead to potential publication bias. Glechner et al.49 including one RCT and two observational studies showed that the 5year overall survival rate was higher in ALND than in SLNB alone, but the difference was not statistically significant (Odds ratio [OR] 1.18, 95% CI 0.95e1.47, P ¼ 0.14), with high heterogeneity among studies (I2 ¼ 78%, P ¼ 0.01) by random effects model. If adopting fixed effects model, the survival rate was significantly different between SLNB alone and ALND in early breast cancer patients (OR 1.20, 95% CI 1.10e1.31, P < 0.01). Therefore, the result was not robust. In another meta-analysis including three RCTs and five retrospective studies,50 Ram et al. also concluded that the overall survival and disease-free survival were not significantly different between SLNB alone and ALND. Notably, the author did not performed subgroup analysis according to the type of study, which may result in weak result. The previous meta-analysis had obvious defects that might weaken the credibility of the results. Our updated meta-analysis included 12 studies with a total of 130,575 patients, which greatly increased the amount of samples and the accuracy of results. Moreover, the qualities of observational studies were assessed by NewcastleeOttawa Scale, and the results
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
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showed that six studies had medium qualities. We performed subgroup analysis according to the type of study, and the results showed that there were no significant differences in overall survival, disease-free survival and localregional recurrence between SLNB alone and ALND, whether in RCTs or observational studies subgroup, which made our results more robust. Although the included studies are the best data analysis available, the present study has several limitations. First, seven included studies are observational studies, which may have inherent limitations, such as selection bias, performance bias, detection bias and selective reporting bias. One RCT was unclear in performance bias, and three RCTs provided insufficient information to assess the risk of detection bias (Supplementary Table). It is necessary to conduct larger sample studies using homogenous patients and wellmatched controls. Second, the adverse results are based on a small quantity of studies due to lack of original studies, two of the adverse results they report on are based on only one study, and the other two are based on two studies, this may result in publication bias. The high quality prospective trials on larger populations are needed to further confirm these results. Third, we did not perform a subgroup analysis by using number of sentinel lymph node metastasis for the insufficiency of detailed data. Therefore, future research should be done to compare the outcomes between SLNB alone and ALND for fall outside the ACOSOG Z11 trial, such as more than three sentinel nodes metastasis. Fourth, only English studies were included in this paper, which may be a source of potential publication bias. In conclusion, the current evidence indicates that the recurrence and survival sentinel lymph node biopsy alone are comparable to axilla lymph node dissection among early breast cancer patients with sentinel node micrometastasis or macrometastasis. High-quality prospective trials on larger populations are needed to further confirm these results.
Acknowledgments The authors thank Jianyong Liu, Department of Hepatobiliary Surgery, the Affiliated Tumor Hospital of Guangxi Medical University, for statistical analysis. Authors’ contributions Conceived and designed the meta-analysis: C.Z. Li and P. Zhang. Electronic search: R.W. Li and C.T. Wu. Extraction of data: C.Z. Li and P. Zhang. Statistical analyzed the data: R.W. Li and H.C. Zhu. Wrote the paper: C.Z. Li and P. Zhang. Revised the paper: C.T. Wu and X.P Zhang. All authors read and approved the final manuscript. Conflict of interest statement The authors declare no conflict of interest.
Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejso.2015.05.007. References 1. DeSantis C, Ma J, Bryan L, et al. Breast cancer statistics, 2013. CA Cancer J Clin 2014;64:52–62. 2. Cancer facts & figures 2014;. Atlanta: American Cancer Society; 2014. Accessed at: http://www.cancer.org/acs/groups/content/@ research/documents/webcontent/acspc-042151.pdf. 3. Graversen HP, Blichert-Toft M, Andersen JA, et al. Breast cancer: risk of axillary recurrence in node-negative patients following partial dissection of the axilla. Eur J Surg Oncol 1988;14:407–12. 4. Petrek JA, Pressman PI, Smith RA. Lymphedema: current issues in research and management. CA Cancer J Clin 2000;50:292–307. [quiz 308e211]. 5. Veronesi U, Viale G, Paganelli G, et al. Sentinel lymph node biopsy in breast cancer: ten-year results: of a randomized controlled study. Ann Surg 2010;251:595–600. 6. Giuliano AE, Kirgan DM, Guenther JM, et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994; 220:391–8. [discussion 398e401]. 7. Langer I, Guller U, Berclaz G, et al. Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients. Ann Surg 2007;245: 452–61. 8. Dabakuyo TS, Fraisse J, Causeret S, et al. A multicenter cohort study to compare quality of life in breast cancer patients according to sentinel lymph node biopsy or axillary lymph node dissection. Ann Oncol 2009;20:1352–61. 9. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology:breast, version 3; 2014. http://www.nccn. org/professionals/physiciangls/PDF/breast.pdf. 10. Chu KU, Turner RR, Hansen NM, et al. Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection? Ann Surg 1999;229:536–41. 11. Guenther JM, Hansen NM, DiFronzo LA, et al. Axillary dissection is not required for all patients with breast cancer and positive sentinel nodes. Arch Surg 2003;138:52–6. 12. Hwang RF, Gonzalez-Angulo AM, Yi M, et al. Low locoregional failure rates in selected breast cancer patients with tumor-positive sentinel lymph nodes who do not undergo completion axillary dissection. Cancer 2007;110:723–30. 13. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. 14. Wells GA SB OCD, Peterson J, Welch V, et al. The NewcastleOttawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_ epidemiology/oxford.asp. 15. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17:2815–34. 16. Hatala R, Keitz S, Wyer P, et al. Tips for learners of evidence-based medicine: 4. Assessing heterogeneity of primary studies in systematic reviews and whether to combine their results. CMAJ 2005;172:661–5. 17. Wernicke AG, Goodman RL, Turner BC, et al. A 10-year follow-up of treatment outcomes in patients with early stage breast cancer and clinically negative axillary nodes treated with tangential breast irradiation following sentinel lymph node dissection or axillary clearance. Breast Cancer Res Treat 2011;125:893–902.
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C.Z. Li et al. / EJSO xx (2015) 1e9 18. Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 2010;11:927–33. 19. Kim HJ, Son BH, Lim WS, et al. Impact of omission of axillary lymph node dissection after negative sentinel lymph node biopsy: 70-month follow-up. Ann Surg Oncol 2010;17:2126–31. 20. Kiluk JV, Ly QP, Santillan AA, et al. Axillary recurrence rate following negative sentinel node biopsy for invasive breast cancer: long-term follow-up (vol 17, pg 552, 2010). Ann Surg Oncol 2010; 17:552–7. 21. Degnim AC, Zakaria S, Boughey JC, et al. Axillary recurrence in breast cancer patients with isolated tumor cells in the sentinel lymph node [AJCC N0(iþ)]. Ann Surg Oncol 2010;17:2685–9. 22. Kim HA, Jo EJ, Kim MS, et al. A comparison of outcomes for the patients with pathologically node-negative breast cancer and who were treated either with sentinel lymph node biopsy only or with conventional axillary lymph node dissection. J Breast Cancer 2009;12: 265–71. 23. Canavese G, Catturich A, Vecchio C, et al. Sentinel node biopsy compared with complete axillary dissection for staging early breast cancer with clinically negative lymph nodes: results of randomized trial. Ann Oncol 2009;20:1001–7. 24. Zavagno G, De Salvo GL, Scalco G, et al. A randomized clinical trial on sentinel lymph node biopsy versus axillary lymph node dissection in breast cancer e results of the sentinella/GIVOM trial. Ann Surg 2008;247:207–13. 25. Kuijt GP, van de Poll-Franse LV, Voogd AC, et al. Survival after negative sentinel lymph node biopsy in breast cancer at least equivalent to after negative extensive axillary dissection. Eur J Surg Oncol 2007;33:832–7. 26. Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymphnode dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol 2007;8:881–8. 27. Konstantiniuk P, Schrenk P, Reitsamer R, et al. A nonrandomized follow-up comparison between standard axillary node dissection and sentinel node biopsy in breast cancer. Breast 2007;16:520–6. 28. Takei H, Suemasu K, Kurosumi M, et al. Sentinel lymph node biopsy alone has no adverse impact on the survival of patients with breast cancer. Breast J 2006;12:S157–64. 29. Schulze T, Mucke J, Markwardt J, et al. Long-term morbidity of patients with early breast cancer after sentinel lymph node biopsy compared to axillary lymph node dissection. J Surg Oncol 2006; 93:109–19. 30. Palesty JA, Foster JM, Hurd TC, et al. Axillary recurrence in women with a negative sentinel lymph node and no axillary dissection in breast cancer. J Surg Oncol 2006;93:129–32. 31. Khakpour N, Hunt KK, Kuerer HM, et al. Sentinel lymph node dissection provides axillary control equal to complete axillary node dissection in breast cancer patients with lobular histology and a negative sentinel node. Am J Surg 2005;190:598–601. 32. Cox C, Wilkie C, White LB, et al. Survival outcomes in nodenegative breast cancer patients evaluated with complete axillary node dissection (CALND) versus sentinel lymph node (SLN) biopsy. Ann Surg Oncol 2005;12:S68. 33. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349:546–53. 34. Blanchard DK, Donohue JH, Reynolds C, et al. Relapse and morbidity in patients undergoing sentinel lymph node biopsy alone or with axillary dissection for breast cancer. Arch Surg 2003;138: 482–7.
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35. Giuliano AE, Haigh PI, Brennan MB, et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2000;18:2553–9. 36. Wang J, Mittendorf EA, Sahin AA, et al. Outcomes of sentinel lymph node dissection alone vs. axillary lymph node dissection in early stage invasive lobular carcinoma: a retrospective study of the Surveillance, Epidemiology and End Results (SEER) database. PLoS One 2014;9. 37. Park HS, Chae BJ, Song BJ, et al. Effect of axillary lymph node dissection after sentinel lymph node biopsy on overall survival in patients with T1 or T2 node-positive breast cancer: report from the Korean Breast Cancer Society. Ann Surg Oncol 2014;21:1231–6. 38. Yi M, Kuerer HM, Mittendorf EA, et al. Impact of the American College of Surgeons Oncology Group Z0011 criteria applied to a contemporary patient population. J Am Coll Surg 2013;216:105–13. 39. Sola M, Alberro JA, Fraile M, et al. Complete axillary lymph node dissection versus clinical follow-up in breast cancer patients with sentinel node micrometastasis: final results from the multicenter clinical trial AATRM 048/13/2000. Ann Surg Oncol 2013;20:120–7. 40. Galimberti V, Cole BF, Zurrida S, et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 2013;14:297–305. 41. Crawford JD, Ansteth M, Barnett J, et al. Routine completion axillary lymph node dissection for positive sentinel nodes in patients undergoing mastectomy is not associated with improved local control. Am J Surg 2013;205:581–4. [discussion 584]. 42. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011;305:569–75. 43. Yi M, Giordano SH, Meric-Bernstam F, et al. Trends in and outcomes from sentinel lymph node biopsy (SLNB) alone vs. SLNB with axillary lymph node dissection for node-positive breast cancer patients: experience from the SEER database. Ann Surg Oncol 2010;17: S343–51. 44. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases. Ann Surg 2010;252: 426–33. 45. Bilimoria KY, Bentrem DJ, Hansen NM, et al. Comparison of sentinel lymph node biopsy alone and completion axillary lymph node dissection for node-positive breast cancer. J Clin Oncol 2009; 27:2946–53. 46. Lucci A, McCall LM, Beitsch PD, et al. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol 2007;25:3657–63. 47. Langer I, Guller U, Berclaz G, et al. Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery e a prospective Swiss multicenter study on 659 patients. Ann Surg 2007;245:452–61. 48. Wang Z, Wu LC, Chen JQ. Sentinel lymph node biopsy compared with axillary lymph node dissection in early breast cancer: a metaanalysis. Breast Cancer Res Treat 2011;129:675–89. 49. Glechner A, Wockel A, Gartlehner G, et al. Sentinel lymph node dissection only versus complete axillary lymph node dissection in early invasive breast cancer: a systematic review and meta-analysis. Eur J Cancer 2013;49:812–25. 50. Ram R, Singh J, McCaig E. Sentinel node biopsy alone versus completion axillary node dissection in node positive breast cancer: systematic review and meta-analysis. Int J Breast Cancer 2014; 2014:513780.
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Review
Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis C.Z. Li a,c, P. Zhang b,c, R.W. Li a, C.T. Wu a, X.P. Zhang a, H.C. Zhu a,* a
Oncological Surgery, Affiliate Hospital of Hebei United University, Tangshan 063000, Hebei, China b Nursing and Rehabilitation College, Hebei United University, Tangshan 063000, Hebei, China Accepted 6 May 2015 Available online - - -
Abstract Background: In early breast cancer patients with sentinel node metastasis, the effect of axillary lymph node dissection (ALND) is controversial. The purpose of this study is to compare the safety and efficacy of sentinel lymph node biopsy (SLNB) alone versus ALND in patients with early breast cancer and sentinel node metastasis. Methods: We searched PubMed, Embase, Web of Science, and Cochrane Library databases from 1965 to February 2014. All data were analyzed using Review Manager Software 5.2. Results: 12 studies, which included 130,575 patients from five randomized controlled trials and seven observational studies, met our inclusion criteria. 26,870 early breast cancer patients underwent SLNB alone and 103,705 underwent ALND. Patients underwent ALND had more paresthesia (risk ratio [RR] 0.26, 95% confidence interval [CI] 0.20e0.33; p < 0.01) and lymphedema (RR 0.28, 95% CI 0.20e0.41; p < 0.01) than those had SLNB alone. There were no significant differences in overall survival (hazard ratio [HR] 0.95, 95% CI 0.85e1.06; p ¼ 0.35), disease-free survival (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.96), and locoregional recurrence (RR 0.92, 95% CI 0.59e1.44; p ¼ 0.73). Conclusion: Current evidence indicates that axillary dissection may be omitted in early breast cancer patients with sentinel lymph metastasis. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Axillary lymph node; Breast cancer; Dissection; Sentinel lymph node
Introduction Breast cancer is the most common cancer and the second only to lung cancer as a cause of cancer death, with an estimated 232,340 new cases and 39,620 died of the disease among American women in 2013. Although about 1 in 8 American women will develop breast cancer in her lifetime,1 the mortality appears to be decreasing due to early * Corresponding author. Department of Oncological Surgery, Affiliate Hospital of Hebei United University, 73 Jianshe South Road, Tangshan 063000, Hebei, China. Tel.: þ86 0315 2308103; fax: þ86 0315 2852195. E-mail address: [email protected] (H.C. Zhu). c These authors contributed equally.
detection and more effective treatment. About 36% women diagnosed with breast cancer undergo mastectomy with axillary lymph node dissection (ALND).2 Although reliably identifies nodal metastasis and maintains regional control,3 ALND leads to a significant morbidity such as seroma, lymphedema, paresthesia, infection and pain from intercostal and intercostal-brachial nerve injury.4 If the sentinel lymph node is negative, the axillary nodes are most probably not involved and ALND should not be performed in breast cancer patients.5 Sentinel lymph node biopsy (SLNB) was introduced for breast cancer in the early 1990s as a method to predict the status of the axillary nodes.6 Compared with ALND, SLNB alone has been
http://dx.doi.org/10.1016/j.ejso.2015.05.007 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
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demonstrated to decrease unnecessary complications, shorter hospital stay and improve the quality of life of patients.7,8 The current NCCN guidelines recommend that the sentinel lymph node-negative breast cancer patients do not require ALND.9 However, the effect of ALND in sentinel lymph node-positive early breast cancer is controversial in previous studies.10e12 Moreover, due to small sample size, these studies were not adequately powered to detect whether ALND can be omitted in early breast cancer patients with positive sentinel lymph. Therefore, in order to provide the latest and most convincing evidence, we systematically reviewed the current available studies to compare the safety and efficacy of SLNB alone versus ALND in early breast cancer with sentinel node metastasis. Overall survival, disease-free survival, locoregional recurrence and adverse events were assessed with metaanalytical methods. Materials and methods Study selection We conducted a comprehensive literature search of PubMed, Embase, Web of Science, and Cochrane Library databases from 1965 to February 2014. The following MeSH search headings were used: “sentinel lymph node”, “axillary lymph node”, “metastasis”, “dissection” and “breast cancer”. The related-articles function was used to broaden the search, and all abstracts, articles, and citations were reviewed without language restriction. When the patient’s material was reported more than once, we selected the article with the most complete data in this metaanalysis. If the applicability of an article could not be determined by the title or abstract alone, the full text would be reviewed. Any disagreements were arbitrated by the corresponding author. Study inclusion and exclusion criteria These studies would be selected if they fulfilled the following inclusion criteria: (1) Design: randomized controlled trials (RCTs) and observational studies. (2) Patients: clinical T1 or T2 N0 M0 breast cancer women with sentinel lymph node metastasis. (3) Intervention: SLNB alone (4) Comparison: ALND. (5) Outcomes: overall survival, disease-free survival, locoregional recurrence and adverse events. Exclusion criteria: Studies evaluated less than 30 patients, abstracts, letters, editorials and expert opinions, reviews without original data, meta-analysis, and case reports. Data extraction and management Two authors independently extracted data from the inclusion studies. The following information was extracted
from each study: first author, year of publication, type of study, patient characteristics, tumor stage, number of positive sentinel lymph nodes, tumor grade, type of histology, follow-up, and the outcomes. Agreement regarding study inclusion was assessed using the Cohen kappa statistic. Types of outcome measures The primary outcomes evaluated in this review were overall survival, disease-free survival, and the incidence rate of locoregional recurrence, which was defined as recurrence in the axillary, supraclavicular or internal mammary nodes. The secondary outcomes were adverse events (infection, axillary seroma, paresthesia, and lymphedema). Quality assessment We used the Cochrane Risk of Bias Tool to assess the risk of bias for each RCT.13 This tool includes six specific domains: selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias. Quality assessment of the observational studies were assessed using the NewcastleeOttawa Scale.14 A star rating from 0 to 9 was allocated to each study based on the patient’s selection criteria, comparability of cases and controls on the basis of the design or analysis, and the exposure. Studies achieving more than 7 stars were considered to be of higher quality. Two reviewers independently assessed the quality of the included studies. Discrepancies were re-examined, and consensus was reached by discussion. Statistical analysis The data were analyzed by the Review Manager software 5.2 (updated by the Cochrane Library for Systematic Reviews). Hazard ratio (HR) was used as a summary statistic for censored outcomes (overall survival and disease-free survival) as described by Parmar and colleagues.15 The logHR and its standard error were required for each study in the meta-analysis. We calculated the logHR using the reported HR and confidence interval (CI). We extracted HR using the generic inverse variance method available. The risk ratio (RR) was used to analyze dichotomous variables, such as localregional recurrence and adverse events. Heterogeneity among studies was evaluated by the I-squared statistic (I2). The I2 measures the extent of inconsistency among studies and is interpreted as approximately the proportion of total variation in study estimates. I2 of less than 25% is considered as low heterogeneity, 25e50% as moderate heterogeneity, and more than 50% as high heterogeneity.16 If the p value was more than 0.1, the fixed-effects model would be reported, otherwise, the random-effects model would be used. Subgroup analysis was performed according to the type of study (RCTs versus observational studies). Sensitivity analysis (excluding 1 or more studies) was used to explore possible sources of heterogeneity
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
C.Z. Li et al. / EJSO xx (2015) 1e9
among different studies. Bgger’s test and funnel plot were performed to determine the presence of publication bias. Results Search results A total of 1856 studies were identified by the initial database search. 691 studies were removed. 1165studies were screened, among which 1116 were excluded according to the titles and abstracts for various reasons (case reports, reviews, conference abstract only and metaanalysis). The remaining 32 full-text studies were assessed for eligibility, 20 of which were excluded because of sentinel node-negative patients.5,17e35 Finally, 12 studies fulfilled the inclusion criteria and were included in this meta-analysis.36e47 The selection process was shown in Fig. 1. Study characteristics The main characteristics of included studies were shown in Table 1. The comparison of patient characteristics between SLNB alone and ALND was addressed in Table 2. The twelve studies were from 2007 to 2014. The sample size was a range from 233 to 25,346 (a total of 130,575 patients). Analysis was done on 26,870 patients underwent SLNB alone and 103,705 underwent ALND. There were five randomized controlled trials39,40,42,44,46 and seven observational studies.36e38,41,43,45,47 Although 3 of the included studies refer to the same study population (the ACOSOG Z11 trial),42,44,46 they assessed different outcomes. Giuliano et al.42 compared the overall survival and disease-free survival, Giuliano et al.44 assessed the locoregional recurrence and Lucci et al.46
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evaluated adverse event. All included studies were published in English. Seven studies reported overall survival,36e38,40,42,43 seven studies reported disease-free survival,36,38e43 five studies reported localregional recurrence,40e42,45,47 and two studies reported adverse events.46,47
Quality assessment The risk of bias assessment of the randomized controlled trials was shown in Supplementary Table. Four RCTs adequately described random components in the sequence generation process.40,42,44,46 Three RCTs provided insufficient information to permit judgment of low risk bias or high risk bias in allocation concealment, binding of participants, and binding of outcome assessment.42,44,46 We used the Newcastele Ottawa Scale to assess the quality of the observational studies. One study47 got seven stars indicating a high quality, and six studies36e38,41,43,45 were assessed 4 to 6 stars (Table 1).
The overall survival between ALND and SLNB alone Overall survival was reported in seven studies36e38,40,42,43,45 (Fig. 2A). Patients had SLNB alone were associated with lower overall survival than those had ALND, but this difference was not significant (HR 0.95, 95% CI 0.85e1.06; p ¼ 0.35), with no significant heterogeneity (c2; ¼ 3.02, I2 ¼ 0%, p ¼ 0.81). The finding was consistent with subgroup analysis for RCTs (HR 0.87, 95% CI 0.62e1.24; p ¼ 0.45) and observational studies (HR 0.96, 95% CI 0.85e1.08; p ¼ 0.47). No publication bias was detected by Begg’s test (p ¼ 0.36) in the funnel plot (Supplementary Fig. 1).
Figure 1. Flow chart of study selection process.
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
Author
Wang et al. Park et al. Yi et al.
Year Type of study
SLNB alone /ALND
T stage T1/T2
SLNB alone
ALND
SLNB alone
ALND
SLNB alone
64 (35e91) 48 (37e59) 54 (22e91) 53 (33e75) 53 (28e81)
60 (28e87) 49 (39e58) 57 (29e89) 55 (29e75) 54 (26e81)
56 (43e68) 56 (24e92) 59 (22e96) RCT 436/420 56 (24e92) Observational 20,217/77,097 58 (49e69) RCT 414/373 56 (24e92) Observational 449/210 59 (28e90)
59 (46e72) 54 (25e90) 56 (18e99) 54 (25e90) 56 (48e67) 54 (25e90) 58 (28e88)
2014 Observational 393/876 2014 Observational 197/2348 2013 Observational 188/673 121/112 467/464
Crawford 2013 Observational 135/426 et al. Giulian 2011 RCT 436/420 et al. Yi et al. 2010 Observational 4267/22,561 2010 2009 2007 2007
Number of positive SLNs (1/2/3)
Tumor grade (I/II/III/unknown)
Size of node metastasis
ALND
SLNB alone
SLNB alone
Micro Macro Micro Macro
266/127
555/321
347/46/0 607/269/0
130/67
1171/1177
187/1/9
1746/436/166 NA
NA
152/36
445/228
NA
NA
NA
NA
NA
NA
NA
22/47/40/12
322/145
316/148
450/17/0 440/23/1
44/91
90/336
NA
303/133
284/136
324/76/41 203/68/149
2987/1280 11,764/9315 NA
ALND
NA
NA
ALND
97/171/41/85 173/390/104/209 NA
Follow Outcomes Quality up (NOSa) (years)
NA
NA
NA
11.8
NA
NA
NA
NA
10.3
OS, DFS, 6 LLR OS 5
NA
136
52
158
515
5.8
DFS, OS 5
4/50/23/2
121
0
112
0
7.9
DFS
90/241/135/1 118/214/129/3
467
0
464
0
5.0
NA
NA
NA
NA
NA
10.0
OS, DFS, RCT LRR, Adverse event DFS 5
81/148/87/120 71/158/94/97
199
237
165
255
5.6
OS, DFS RCT
NA
2240 2185
4598 17,963 6.0
OS
5
NA
LLR
RCT
NA
NA
NA
NA
5.6
RCT
303/133
284/136
324/76/41 203/68/149
81/148/87/120 71/158/94/97
NA
NA
NA
NA
NA
NA
NA
3674 16,543 6585 70,512 7.9
OS
5
294/120
271/132
NA
NA
NA
NA
NA
NA
NA
NA
5.6
RCT
344/105
123/87
NA
NA
96/263/90/0
30/126/54/0
NA
NA
NA
NA
2.9
Adverse event Adverse event
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Abbreviations: RCT: randomized controlled trial; SLNB: sentinel lymph nodes biopsy; ALND: axillary lymph node dissection; OS: overall survival; LLR: localregional recurrence; DFS: disease-free survival; NOS: NewcastleeOttawa Scale; NA: not available; Macro: macrometasis (2.0 mm). a Quality assessment of the observational studies was assessed using the NewcastleeOttawa Scale. The quality of the evidence is classified as three levels: high (more than seven stars), moderate (four to six stars), poor (less than four stars).
C.Z. Li et al. / EJSO xx (2015) 1e9
Age (year)
Sola 2013 RCT et al. Galimberti 2013 RCT et al.
Giuliano et al. Bilimoria et al. Lucci et al. Langer et al.
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Table 1 Characteristic of included studies.
C.Z. Li et al. / EJSO xx (2015) 1e9 Table 2 Comparison of patient characteristics between patients who underwent SLNB alone and patients who underwent ALND in patients with sentinel lymph node metastasis. Characteristic
SLNB alone
ALND
Age (years) Tumor size (cm) Tumor grade I II III Unknown T Stage T1 T2 Number of positive SLNs 1 2 3 Size of node metastasis Micrometastasis (2.0 mm) Race White Black Other Operation type Breast conserving surgery Mastectomy
56.0 (47.3e64.6) 55.8 (49.5e62.0) 1.89 (1.14e2.64) 2.16 (0.94e3.38) 10,240 (38%) 13,795 (52%) 448 (1.7%) 2213 (8.3%)
49,206 (48%) 45,229 (44%) 638 (0.6%) 7574 (7.4%)
4548 (70%) 1984 (30%)
14,748 (56%) 11,748 (44%)
1308 (87%) 140 (9.3%) 50 (3.7%)
2996 (73%) 796 (19%) 316 (8%)
6837 (27%) 19,017 (73%)
12,082 (12%) 89,245 (88%)
20,878 (83%) 2191 (8.7%) 1966 (8.3%)
84,092 (84%) 8220 (7.8%) 8222 (8.2%)
21,154 (82%) 4910 (18%)
52,581 (51%) 50,907 (49%)
The disease-free survival between ALND and SLNB alone Pooling the data of seven studies36,38e43 that assessed the disease-free survival (Fig. 2B) showed no significant difference (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.96) between SLNB alone and ALND, with significant heterogeneity (c2; ¼ 11.35, I2 ¼ 47%, p ¼ 0.08). Subgroup analysis indicated that there was no significant difference in disease-free survival between SLNB alone and ALND, both in RCTs (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.92) and observational studies (HR 1.10, 95% CI 0.94e1.29, p ¼ 0.23). There was no publication bias by Begg’s test (p ¼ 0.22) (Supplementary Fig. 2). The localregional recurrence between ALND and SLNB alone
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by Begg’s test (p ¼ 0.94) with symmetrical funnel plot (Supplementary Fig. 3). The adverse event between ALND and SLNB alone Two studies that assessed 1190 patients reported on paresthesia.46,47The difference was statistically significant in favor of SLNB alone (RR 0.26, 95% CI 0.20e0.33; p < 0.001), with no significant between-study heterogeneity (c2; ¼ 0.85, I2 ¼ 0%, p ¼ 0.36). Additionally, Lucci and colleagues46 indicated that there was significant difference in infections (RR 0.36, 95% CI 0.18e0.70; p ¼ 0.003) and axillary seroma (RR 0.40, 95% CI 0.25e0.65; p ¼ 0.0002) between SLNB alone and ALND. Two studies46,47 that assessed 1160 patients reported on lymphedema. The difference was significant between SLNB alone and ALND (RR 0.28, 95% CI 0.20e0.41; p < 0.001), with significant heterogeneity (c2; ¼ 3.96, I2 ¼ 75%, p ¼ 0.05) (Fig. 3). Comparison the outcomes between patients with sentinel lymph nodal micrometastasis and macrometastasis The micrometastatic sentinel node was established on at least one metastatic deposit in the range of 0.2e2 mm, and macrometastatic sentinel node was defined as more than 0.2 mm according to the sixth edition of the American Joint Committee on Cancer (AJCC) staging manual.13 We performed subgroup analysis to compare the survival between SLNB alone and ALND in early breast cancer patients with sentinel node metastasis according to the size of node metastasis (micrometastasis or macrometastasis). The pooled data of four studies (2 RCTs39,40 and 2 observational studies43,45) including patients with sentinel lymph nodal micrometastasis indicated that there were no significant differences in overall survival (HR 0.94, 95% CI 0.72e1.23, p ¼ 0.65) and disease-free survival (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.99) between ALND and SLNB alone (Fig. 2D). Only one observational study45 assessed 22,187 patients with nodal macrometastasis. Its result showed that the overall survival (HR 0.91, 95% CI 0.83e1.01, p ¼ 0.06) and localregional recurrence (HR 0.85, 95% CI 0.62e1.16, p ¼ 0.30) were no statistical differences between SLNB alone and ALND. Heterogeneity analysis
Localregional recurrence was reported in five studies40e42,45,47 that investigated 6142 patients (Fig. 2C). The localregional recurrence rate was higher in SLNB alone than those in the ALND, but the difference was not statistical significant (RR 0.92, 95% CI 0.59e1.44; p ¼ 0.73), with no significant between-study heterogeneity (c2; ¼ 1.82, I2 ¼ 0%, p ¼ 0.77). Our subgroup analysis showed that the result was not substantially affected by study design. There was no evidence of publication bias
There were no significant heterogeneities in overall survival (c2; ¼ 3.02, I2 ¼ 0%, p ¼ 0.81), and locoregional recurrence (c2; ¼ 1.82, I2 ¼ 0%, p ¼ 0.77). Referring to disease free survival and lymphedema, the p value of heterogeneity test was less than 0.1, or the I2 value of heterogeneity was more than 50%, indicating significant heterogeneity. The source of heterogeneity may come from type of study. The study of Yi et al. and Langer
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
Figure 2. A: Forest plot of overall survival. B: Forest plot of disease-free survival. C: Forest plot of localregional recurrence. D: Forest plot of sentinel lymph node micrometastasis. Abbreviations: ALND: axillary lymph node dissection; SLNB: sentinel lymph node biopsy; CI: confidence interval; SE: standard error.
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
C.Z. Li et al. / EJSO xx (2015) 1e9
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Figure 3. Forest plot of adverse event. Abbreviations: ALND: axillary lymph node dissection; SLNB: sentinel lymph node biopsy; CI: confidence interval.
et al. involved a multicenter retrospective population, which may exist potential selection bias. After we removed these studies, the DFS (HR 1.00, 95% CI 0.98e1.02, p ¼ 0.84) and RR (RR 0.39, 95% CI 0.24e0.65; p ¼ 0.0002) were not substantially altered. Discussion The present meta-analysis identifies five RCTs and seven observational studies comparing the safety and efficacy between ALND and SLNB alone in early breast cancer patients with sentinel node metastasis. Our analysis shows that SLNB alone and ALND are comparable in overall survival and disease-free survival, and SLNB alone do not increase localregional recurrence in patients with early breast cancer, both in RCTs and observational studies. ALND results in more paresthesia, lymphedema, infections, and axillary seroma than SLNB alone. Moreover, compared with SLNB alone, ALND does not improve the survival of early breast cancer patients with sentinel node micrometastasis or macrometastasis. Several meta-analyses have been previously performed to compare the difference between SLNB alone and ALND in early breast cancer patients with sentinel node metastasis. A meta-analysis by Wang et al.48 evaluated the effectiveness and safety of ALND in early breast cancer. The authors concluded that there were no significant
differences in overall survival, disease-free survival and regional lymph node recurrence for sentinel lymph nodepositive patients. However, the result was based on a subgroup analysis of only one RCT,42 which would lead to potential publication bias. Glechner et al.49 including one RCT and two observational studies showed that the 5year overall survival rate was higher in ALND than in SLNB alone, but the difference was not statistically significant (Odds ratio [OR] 1.18, 95% CI 0.95e1.47, P ¼ 0.14), with high heterogeneity among studies (I2 ¼ 78%, P ¼ 0.01) by random effects model. If adopting fixed effects model, the survival rate was significantly different between SLNB alone and ALND in early breast cancer patients (OR 1.20, 95% CI 1.10e1.31, P < 0.01). Therefore, the result was not robust. In another meta-analysis including three RCTs and five retrospective studies,50 Ram et al. also concluded that the overall survival and disease-free survival were not significantly different between SLNB alone and ALND. Notably, the author did not performed subgroup analysis according to the type of study, which may result in weak result. The previous meta-analysis had obvious defects that might weaken the credibility of the results. Our updated meta-analysis included 12 studies with a total of 130,575 patients, which greatly increased the amount of samples and the accuracy of results. Moreover, the qualities of observational studies were assessed by NewcastleeOttawa Scale, and the results
Please cite this article in press as: Li CZ, et al., Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.007
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C.Z. Li et al. / EJSO xx (2015) 1e9
showed that six studies had medium qualities. We performed subgroup analysis according to the type of study, and the results showed that there were no significant differences in overall survival, disease-free survival and localregional recurrence between SLNB alone and ALND, whether in RCTs or observational studies subgroup, which made our results more robust. Although the included studies are the best data analysis available, the present study has several limitations. First, seven included studies are observational studies, which may have inherent limitations, such as selection bias, performance bias, detection bias and selective reporting bias. One RCT was unclear in performance bias, and three RCTs provided insufficient information to assess the risk of detection bias (Supplementary Table). It is necessary to conduct larger sample studies using homogenous patients and wellmatched controls. Second, the adverse results are based on a small quantity of studies due to lack of original studies, two of the adverse results they report on are based on only one study, and the other two are based on two studies, this may result in publication bias. The high quality prospective trials on larger populations are needed to further confirm these results. Third, we did not perform a subgroup analysis by using number of sentinel lymph node metastasis for the insufficiency of detailed data. Therefore, future research should be done to compare the outcomes between SLNB alone and ALND for fall outside the ACOSOG Z11 trial, such as more than three sentinel nodes metastasis. Fourth, only English studies were included in this paper, which may be a source of potential publication bias. In conclusion, the current evidence indicates that the recurrence and survival sentinel lymph node biopsy alone are comparable to axilla lymph node dissection among early breast cancer patients with sentinel node micrometastasis or macrometastasis. High-quality prospective trials on larger populations are needed to further confirm these results.
Acknowledgments The authors thank Jianyong Liu, Department of Hepatobiliary Surgery, the Affiliated Tumor Hospital of Guangxi Medical University, for statistical analysis. Authors’ contributions Conceived and designed the meta-analysis: C.Z. Li and P. Zhang. Electronic search: R.W. Li and C.T. Wu. Extraction of data: C.Z. Li and P. Zhang. Statistical analyzed the data: R.W. Li and H.C. Zhu. Wrote the paper: C.Z. Li and P. Zhang. Revised the paper: C.T. Wu and X.P Zhang. All authors read and approved the final manuscript. Conflict of interest statement The authors declare no conflict of interest.
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