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Sentinel lymph node dissection only versus complete axillary lymph node dissection in early invasive breast cancer: A systematic review and meta-analysis
European Journal of Cancer (2013) 49, 812– 825
Available at www.sciencedirect.com
journal homepage: www.ejcancer.info
Review
Sentinel lymph node dissection only versus complete axillary lymph node dissection in early invasive breast cancer: A systematic review and meta-analysis Anna Glechner a,⇑, Achim Wo¨ckel c, Gerald Gartlehner a,b, Kylie Thaler a, Michaela Strobelberger a, Ursula Griebler a, Rolf Kreienberg c a
Danube University, Department for Evidence-Based Medicine and Clinical Epidemiology, Austria Research Triangle Institute (RTI) International, United States c University Hospital Ulm, Germany b
Available online 17 October 2012
KEYWORDS Systematic review Meta-analysis Breast neoplasms Disease-free survival Lymph node excision Sentinel lymph node biopsy Lymphatic metastasis Neoplasm recurrence Axilla/surgery Survival analysis
Abstract Background: The Z0011-study, a landmark randomised controlled trial (RCT) challenged the benefits of complete axillary lymph node dissection (ALND) compared with sentinel lymph node dissection only (SLND) in breast cancer patients with positive sentinel nodes. The study, however, has been criticised for lack of power and low applicability. The aim of this review was to systematically assess the evidence on the comparative benefits and harms of ALND versus SLND for sentinel node positive breast cancer patients. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and reference lists of pertinent review articles from January 2006 to August 2011. We dually reviewed the literature and rated the risk of bias of each study. For effectiveness, we included RCTs and observational studies of at least 1 year follow-up. In addition, we considered studies conducted in sentinel node-negative women to assess the risk of harms. If data were sufficient, we conducted random effects meta-analysis of outcomes of interest. Results: Meta-analysis of three studies with 50,120 patients indicated similar 5-year survival and regional recurrence rates between patients treated with ALND or SLND, although prognostic tumour characteristics varied among the 3 study-populations. Results from 6 studies on more than 11,500 patients reported a higher risk for harms for ALND than SLND. Long-term evidence on pertinent health outcomes is missing. Conclusion: The available evidence indicates that for some women with early invasive breast cancer SLND appears to be a justifiable alternative to ALND. Surgeons need to discuss advantages and disadvantages of both approaches with their patients. Ó 2012 Elsevier Ltd. All rights reserved.
⇑ Corresponding author: Address: Danube University, Dr.-Karl Dorrek-Straße 30, 3500 Krems, Austria. Tel.: +43 2732 893 2920; fax: +43 2732 893 4910. E-mail address: [email protected] (A. Glechner).
0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.09.010
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
1. Introduction Breast cancer is the most common malignancy in women, comprising 16% of all female cancers.1 In 2008, approximately 332,800 cases of breast cancer occurred in the European Union and almost 90,000 women died of the disease.2 Ecologic studies in Europe have demonstrated a rise in the incidence of breast cancer over the past decades, probably attributable to an increase in breast cancer screening.3,4 Despite the increase in the number of breast cancer sufferers, mortality from the disease has substantially decreased. This has been attributed to both breast cancer screening programmes (which enable detection of cancers at an earlier stage) and improved therapeutic possibilities.5 Axillary surgery is a crucial part of the treatment regimen for early invasive breast cancer. The surgical approach is determined by the staging and the involvement of axillary nodes.6,7 In patients with positive axillary nodes, breast cancer-specific mortality rises markedly.8 Most guidelines recommend sentinel lymph node dissection (SLND) for the staging of the disease in women with clinically negative lymph nodes.6,7 In SLND the surgeon injects dye, traces and selectively resects lymph nodes draining the primary tumour. When SLND is performed according to a standardised and quality-assured technique, accurate staging of the number of positive lymph nodes or the ratio of involved to examined lymph nodes can be used to determine further treatment strategies.6,7,9–13 In women with early invasive breast cancer without metastases in sentinel lymph nodes no further dissection of nodes in the local lymph drainage region is recommended. Most clinical practice guidelines suggest complete axillary lymph node dissection (ALND) in women with early invasive breast cancer and micro- or macro-metastatic disease.13,15 The National Institute for Health and Clinical Excellence differentiates micrometastasis and isolated tumour cells and regards patients found to have isolated tumour cells as lymph node negative with no recommendation for any further axillary surgery. A recent randomised controlled trial (RCT) conducted by the American College of Surgeons Oncology Group (ASOG Z0011 study) challenges the utility of ALND in women with early invasive breast cancer and positive sentinel nodes.16–18 Results indicated that ALND does not lead to a survival benefit compared with SLND only. The ASOG concluded that in patients with clinically-negative axillary lymph nodes, the use of ALND is not justified.16–18 This finding has been controversial, particularly because the Z0011 study failed to enrol the estimated sample size to meet the primary objective.19–23 Some authors argue that the waning utility of ALND has to be recognised and treatment guidelines need to be changed accordingly.21–23 Others claim
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that the Z0011 study results are not applicable to larger populations because it enrolled a greater proportion of oestrogen-receptor positive tumours compared with the current US-population and details about the initiation and intensity of adjuvant chemotherapy are not provided.19,20 To date, no systematic review has assessed the comparative benefits and harms of SLND and ALND in women with T1 or T2 breast cancer and positive sentinel nodes. Our objective was to review systematically the available evidence from RCTs and observational studies to determine the comparative benefits and risks of these two surgical approaches. 2. Methods 2.1. Data sources We searched PubMed, Embase, and the Cochrane Library, from 2006 to August 2011. We restricted our search dates because SLND is a relatively new technique and we did not expect to find comparative studies of ALND and SLND in sentinel positive patients before 2006. We used Medical Subject Headings as search terms when available or key words when appropriate and combined specific terms for breast cancer, sentinel lymph node biopsy, and axillary node dissection. We limited electronic searches to ‘adult 19+ years,’ and ‘human’. We did not apply language restrictions. The complete search strategy is presented in the supplementary file 1. To minimise retrieval bias, we also used semi-automatic manual searches of reference lists of pertinent review articles and letters to the editor employing the ScopusTM citation database (www. scopus.com).24 2.2. Study selection Two persons independently reviewed abstracts and full-text articles. Eligibility criteria for studies were defined a priori and are presented in Table 1. To assess the comparative effectiveness we included RCTs and observational studies that compared the two surgical approaches in sentinel node-positive women. Outcomes of interest were patient-relevant health outcomes (e.g. 5year survival, quality of life, breast cancer recurrence and surgery-associated harms). To assess quality-of-life and harms, we also examined data from studies conducted in sentinel-negative women because the risk of harms of surgical procedures is unlikely to be affected by the lymph node status. We included systematic reviews with meta-analyses where these met our inclusion criteria and were of methodologically good quality. We dually reviewed all citations and resolved disagreements about inclusion or exclusion by consensus or by involving a third reviewer.
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A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
2.3. Data extraction and quality assessment We used standardised data abstraction forms into which trained reviewers abstracted data from each study and assigned an initial rating of the risk of bias. A senior reviewer evaluated the forms. To assess the risk of bias of RCTs, we used predefined criteria based on the Cochrane Risk of Bias tool (ratings: low – unclear – high risk of bias).25 To assess the risk of bias of observational studies, we employed criteria outlined by Deeks et al.,26 for systematic reviews we used the AMSTAR (Assessment of Multiple Systematic Reviews) tool.27 2.4. Data synthesis and analyses Because data on most outcomes of interest were insufficient to conduct meta-analyses, we synthesised the evidence on the majority of outcomes qualitatively. To retrieve data not reported in publications, we contacted authors of the respective papers. When data on a particular outcome of interest were sufficient we conducted meta-analyses of the odds ratio of experiencing an event. For each meta-analysis, we conducted a test of heterogeneity (I2 statistic) and applied both a random and a fixed effects model. If high heterogeneity was present (I2 statistic P 60%) we explored the reasons for heterogeneity. Because of substantial heterogeneity and the combination of RCTs and observational studies, we report random effects model results. We assessed publication bias using funnel plots. Given the small number of component studies in our meta-analyses, however, results must be viewed cautiously. All statistical analyses were conducted using Comprehensive Meta-Analysis, version 2.2.050. 2.5. Grading strength of evidence We evaluated the strength of evidence for critical outcomes using an approach proposed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) working group.28 We dually evaluated the overall strength of evidence for each major outcome. We reconciled all disagreements in grades through consensus discussion. 3. Results Our literature searches identified 254 relevant abstracts. We retrieved 82 full-text articles for more detailed examination. Fig. 1 depicts results of the search and the study selection process. Three studies, one RCT16–18 and two observational studies29,30 met our eligibility criteria for the assessments of the comparative effectiveness. We identified 5 additional studies to determine the comparative risk of harms31–35 Table 2 and Table 3 summarise the population characteristics,
duration of follow-up and endpoints of studies included for the comparative effectiveness and risk of harms. 3.1. The comparative effectiveness of SLND only versus ALND Overall, one RCT16–18 and two cohort studies,29,30 all of unclear risk of bias, provided data on more than 25,000 patients with SLND only and more than 100,000 patients with complete ALND. The study with the lowest risk of bias was the Z0011 study, an open-label RCT that enrolled 891 patients with invasive early stage breast cancer and histologically verifiable positive sentinel lymph nodes.16–18 The study was funded by the United States (US) National Cancer Institute. Patients were randomised to either SLND only with no further axillary treatment or complete ALND. The primary outcome measure of the Z0011-study was the 5-year overall survival rate. Authors pre-specified a non-inferiority margin for SLND only treatment compared with complete ALND as a hazard ratio (HR) for overall-mortality of less than 1.3. Based on this margin, the initial recruitment plan intended to enrol 1900 patients in order to have sufficient statistical power. The target sample size could not be achieved and, consequently, the Z0011 study was underpowered. In addition, the drop-out rate was almost 20%, further reducing the statistical power. In addition to the Z0011 study, we located two retrospective cohort studies: one with data from more than 97,000 patients of the US National Cancer Database29 from the years 1998 to 2005, and one with data of more than 26,000 patients of the SEER (Surveillance, Epidemiology and End Results) database.30 We restricted the results of the two cohort-studies to a population of approximately 49,000 patients to enable a comparison to the current practice of lymph node removal. The US National Cancer Database-study defined performance of SLND as 5 or fewer lymph nodes removed, and ALND as 9 or more lymph nodes removed. The populations of the three studies differed. The cohort-studies included women with stage T3-tumours and patients who had undergone mastectomy, a population who was not eligible for the Z0011 study. In general, women in the cohort studies had more advanced disease than women in the Z0011 trial. Population characteristics are presented in Table 2. In the following sections we present findings with respect to included outcomes. 3.2. 5-year-overall-survival We pooled data of more than 50,000 patients from the three studies described above. Despite the difference in prognosis of populations in the individual studies, all three studies reported similar 5-year survival rates between SLND and ALND-treated patients. Results
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
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Table 1 Eligibility criteria of included studies. Population
For effectiveness: women with invasive breast cancer and sentinel-positive lymph node biopsy undergoing breast conserving therapy or mastectomy For quality of life and harms: women with invasive breast cancer and sentinel-positive or – negative lymph node biopsy undergoing breast conserving surgery or mastectomy
Intervention
Breast conserving surgery/mastectomy with sentinel node biopsy plus complete axillary lymph node dissection
Control
Breast conserving surgery/mastectomy with sentinel node biopsy without complete axillary lymph node dissection
Outcomes
5-year survival rate Disease-free survival Local breast cancer recurrence Regional breast cancer recurrence Quality of life Surgery-associated harms (e.g. wound infection, lymphedema)
Timing
For effectiveness: study duration at least 1 year For harms and quality of life: no restrictions on study duration
Study design
RCTs, comparative observational studies, systematic reviews with meta-analysis
RCTs, randomised controlled trials.
291 abstracts identified through systematic database-research
18 additional abstracts identified from other sources (hand search, clinical experts)
254 abstracts after exclusion of duplicates
254 abstracts reviewed
82 articles included for review
172 abstracts excluded
72 articles excluded 8– 22 – 35 – 5– 1– 1–
Incorrect publication type Incorrect population Incorrect intervention or control Incorrect endpoints Incorrect study design Incorrect year of publication
Comparative effectiveness: 5 articles (3 studies) Comparative safety: 5 articles
Fig. 1. Disposition of the literature.
for populations with micro- and macroscopic diseases from the individual studies are presented separately in Table 4. Likewise the pooled odds ratio indicates similar survival rates (over 50–60 months follow up) for women treated with SLND only and complete ALND, favouring SLND (Fig. 2: odds ratio [OR] 0.85, 95% confidence interval [CI] 0.68–1.06). This result should be interpreted cautiously because confounding by indication (i.e. a
form of selection bias where the choice of treatment is determined by prognostic factors) is likely to play a role in the observational studies. The numerically higher (albeit not statistically significant) 5-year survival rates of women treated with SLND only might be a result of confounding factors. Confounding by indication could also explain the high statistical heterogeneity (I2 77%) in our meta-analysis. In addition, prognostic
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Table 2 Main characteristics of the included studies and their populations, Studies for comparative effectiveness. Study design Sample size
Follow-up Risk of bias
Population average age
Z0011 Giuliano et al. (2010, 2011)16,17
RCT Recruitment 1999–2004
Follow-Up: 6.3 years
Patients with positive sentinel lymph nodes
SLND: n = 436 SLND + ALND: n = 420
Risk of Bias unclear
55 years
Retrospective cohort study Recruitment 1998–2005
Median Follow-Up: 63 months
Patients with positive sentinel lymph nodes.
SLND: n = 20,217 SLND + ALND: n = 77,097 SLND (6 5 LN r.): n = 1988 SLND + ALND (P 9 LN r.): n = 20,290
Risk of Bias unclear
56 years
Retrospective cohort study Diagnosis between 1998 – 2004
Follow-Up: 50 months
Patients with positive sentinel lymph nodes
SLND: n = 4425 SLND + ALND: n = 22,561
Risk of Bias unclear
57 years
National Cancer Database Bilimoria et al. (2009)29
SEER Database Yi et al. (2010)30
Intervention
SLND: SLND+ALND:
SLND: SLND + ALND:
SLND: SLND+ALND:
Population characteristics Clinical tumour stage (%)
Histologic tumour grade (%)
Hormon receptor+ (%)
Nodal metastases (%)
BCT/ mastectomy (%)
T1
T2
I
II
III
ER+ PgR+
ER+ PgR-
Micro
Macro
BCT
ME
70.6 67.9
29.4 32.1
25.6 22
46.8 48.9
27.5 29.1
68.9 66.8
13.8 15.9
44.8 37.5
55.2 62.5
100 100
0 0
Micro
Macro
BCT
ME
T1
T2
T3
Low/ intermediate
High
62.9 49.1
34.4 43.7
2.6 7.2
58.8 53.1
32.5 39.2
n.r n.r
n.r n.r
18.2 8.5
81.8 91.5
81.4 49.6
18.6 50.4
T1
T2
T3
Low/ intermediate
high
ER+
PgR+
Micro
Macro
BCT
ME
68.6 50.4
28.2 43.0
3.2 6.7
23 13.1
77 86.9
87.5 80.8
75.0 69.4
54.5 17.2
45.5 82.8
78.7 53.9
21.3 46.1
ALND, axillary lymph node dissection; BCT, breast conserving therapy; ER, oestrogen receptor; LN r., lymph nodes removed (number for nodal evaluation with lymph node count threshold), ME, Mastectomy, n.r., not reported, PgR, progesterone receptor, SEER, Surveillance, Epidemiology, and End Results; RCT, randomised controlled trial; SNLD, sentinel lymph node dissection.
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
Author Year
Table 3 Main characteristics of the included studies and their populations, Studies for harms only. Study Design Sample Size
Follow-Up Risk of Bias
Population Average Age
Intervention
Lucci et al., Z0011-Study (2007)16,18
RCT Recruitment 1999 – 2004 SLND: n = 446 SLND + ALND: n = 445 Meta-Analysis: 7 RCTs Recruitment: 1998–2005
Follow-Up: up to 12 months Risk of Bias unclear
Patients with positive sentinel lymph nodes, 55 years
SLND: SLND + ALND:
Follow-Up: up to 6 months Risk of Bias unclear
Patients with negative and positive sentinel lymph nodes 56 years
5 RCTs comparing SLND versus ALND
Follow-Up: up to 18 months Risk of Bias unclear Follow-up: up to 12 months Risk of Bias unclear
Patients with negative and positive sentinel lymph nodes 57 years
SLND: ALND:
Patients with negative and positive sentinel lymph nodes 48–49 years
SLND: ALND:
Follow-up: up to 12 months Risk of Bias unclear Follow-up: up to 24 months Risk of Bias unclear
Sentinel lymph node status not specified 59 years
SLND: SLND + ALND: ALND:
Patients with negative sentinel and positive sentinel lymph nodes 53–58 years
SLND: SLND + ALND: ALND:
Kell et al. (2010)31 (including Z001118 and the ALMANAC-trial36)
Fleissig et al., ALMANACtrial (2006)35
SLND: n = 636 SLND + ALND: n = 3828 ALND: n = 4389 RCT SLND: n = 424 ALND: n = 405
Chen et al. (2009)33
prospective cohort study SLND: n = 140 ALND: n = 81
Dabakuyo et al. (2009)32
Prospective cohort study SLND: n = 222 SLND + ALND: n = 61 ALND: n = 235 Prospective cohort study SLND: n = 61 SLND + ALND: n = 59 ALND: n = 75 Follow-Up: up to 24 months
Kootstra et al. (2008)34
Population Characteristics Number of nodes removed:
BCT
Mastectomy
Median: 2, interquartile range: 1.4 Median: 17, interquartile range: 1.22 n.r.
100%
0%
n.r.
n.r.
n.r.
93% 90%
7% 10%
median : 2, interquartile range 1–8 median : 13, interquartile range 5– 32 n.r.
32.5% 19.5%
30.8% 17.2%
} 73%
} 27%
69% 71% 40%
31% 29% 60%
n.r.
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
Author Year
ALND, axillary lymph node dissection; RCT, randomised controlled trial; n.r., not reported; BCT, Breast conserving therapy; SNLD, sentinel lymph node dissection.
817
818
Table 4 Comparative effectiveness and safety: findings and strength of evidence. Author, Year
Follow-Up
Intervention
Estimate of effect
Direction of effect
5-Year overall survival
Favours SLND 5 years
SLND SNLD + ALND
National Cancer Database Bilimoria et al. (2009)29 Seer Database Yi et al. (2010)30
5-years
SLND SNLD + ALND
50 months
SLND SNLD + ALND
92.5% (403a/436) 91.8% (386a/420) HR 0.87; 90% CI: 0.62–1.23 mac. nodal metastases: 81.3% (1185a/1458) 81.8% (15,229a/18,617) HR 0.89, 95% CI 0.76–1.04 93.4% (4132b/4425) 91.1% (20,561b/22,561) HR 1.0, 95% CI 0.9–1.2
X
mic. nodal metastases: 88.6% (470a/530) 90.9% (1,521a/1673) HR 0.84, 95% CI 0.6–1.19
SLND SNLD + ALND
Yi et al. (2010)30
50 months
SLND SNLD + ALND
1.6% (7a/436) 3.1% (13a/420) OR 0.51, 95% CI 0.2–1.29a 0.95% (42b/4425) 0.63% (142b/22,561) OR 1.51 (95%CI 1.07–2.14)b
SLND SNLD + ALND
Bilimoria et al. (2009)29
5 years
SLND SNLD + ALND
Yi et al. (2010)30
50 months
SLND SLND + ALND
0.9% (4/436) 0.5% (2/420) OR 1.94, 95% CI 0.35–10.62a mac. nodal metastases: 1.2% (18a/1458) 1.0% (186a/18,617) HR 0.58, 95% CI 0.32–1.06 mac. nodal metastases: 0.2% (4b/2185) 0.08% (14b/17,963) HR 0.3, p = 0.02
Disease-free survival Giuliano et al. (2010, 2011)16,17 Quality of life
SLND SNLD + ALND
Evidence LOW
Similar
Favours ALND
X
Evidence LOW
X
mic. nodal metastases: 0.6% (3a/530) 0.2% (3a/1673) OR 3.01(95% CI 0.65–14)a mic. nodal metastases: 0.13 % (3b/2240) 0.087% (4b/4598) OR 1.54 (95% CI 0.34–6.9)b Favours SLND
5 years
Favours ALND
X
Favours SLND 5 years
Similar X
Regional recurrence Giuliano et al. (2010, 2011)16,17
LOW
X
Favours SLND 5 years
Evidence
X
Local recurrence Giuliano et al. (2010, 2011)16,17
Favours ALND
83.9% (366a/436) 82.2% (345a/420) HR 0.88, 95% CI 0.62–1.25
X (mic.)
X (mac.)
Similar
Favours ALND
X
Favours SLND
Similar
Evidence LOW
Favours ALND
Evidence
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
Giuliano et al. (2011)17
Similar
Strength of Evidence
12 months
Koostra et al. (2008)34
2 years
Chen et al. (2009)33
12 months
Fleissig et al. ALMANAC-trial (2006)35
18 months
SLND SLND + ALND ALND
Mean Difference GHS + BRAS-Score: GHS: 4.94, p = 0.0185 BRAS: -6.28, p = 0.0013 GHS: 0 (reference) BRAS: 0 (reference) GHS: 2.96, p = 0.1562 BRAS: -0.34, p = 0.8615 (5-point difference = minimum clinically significant difference, GHS: 0 = worse, 100 = best; BRAS 0 = best, 100 = worst) EORTC-questionaire: No significant difference between SNLD and ALND in Quality of life Physical well-being: SLND + BCT > ALND + BCT, p = 0.037 TOI-Score: Significant differences between the treatment groups favouring SLND group at all time points (1 month p < 0.001, 3– 18 months p = 0.001)
Lymphedema Kell et al. (2010)31 (including Z001118 and the ALMANACtrial)36 Chen et al. (2009)33
6 months
Meta-analysis: 5 RCTs (n = 2154 patients) SLND versus ALND: OR 0.3, 95% CI = 0.14–0.66, p = 0.0028
6 months
ALND versus SLND: OR 7.153, 95% CI 1.9–26.8, p = 0.004
Movement restrictions Chen et al. (2009)33:
12 months
Fleissig et al. ALMANAC-trial (2006)35
18 months
Paraesthesia
SLND ALND SLND ALND
Significant differences 1 month postoperative in favour of the SNLD-group (flexion, extension, adduction, abduction, internal and external rotation: p < 0.001–0.038) 1 month postoperative: 6.7% (29a/ 424) 22.1% (90a/405), p < 0.001 OR: 0.26, 95% CI 0.16–0.4a 3 months postoperative: 3.3% (14a/424) 6.6% (27a/405), p = 0.035 OR: 0.48, 95% CI 0.25–0.93a Differences between the groups were no longer significant at later follow-ups (6 months: p = 0.167, 12 months: p = 0.142, 18 months: p = 0,27)
X
MODERATE
X X X
Favours SLND X
Similar
Favours ALND
Evidence MODERATE
X Favours SLND X
Similar
Favours ALND
Evidence MODERATE
X
Favours SLND
Similar
Favours ALND
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
Dubakuyo et al. (2009)32
Evidence (continued on next page)
819
820
Table 4 (continued) Author, Year
Follow-Up 31
Kell et al. (2010) (including Z001118 and the ALMANACtrial)36 Fleissig et al. ALMANAC-trial (2006)35
Intervention
6 months
18 months
SLND ALND SLND ALND
Direction of effect
Strength of Evidence
Meta-analysis: 5 RCTs (n = 3265 patients) SLND versus ALND: OR 0.25, 95% CI = 0.10–0.59, p = 0.0018
X
MODERATE
1 month postoperative: 9.3% (40a/ 424) 29.7% (121a/405), p < 0.001 OR: 0.24, 95% CI 0.17–0.36a 18 months postoperative: 8.7% (37a/424) 19% (77a/405), p = 0.001 OR: 0.28, 95% CI 0.19–0.43a Significant differences between the groups at all time points (p < 0.001 at 1, 3, 6, 12 and 18 months) favouring SLND
X
Wound-infections + seroma Kell et al. (2010)31 (including Z001118 and the ALMANACtrial)36
Koostra et al. (2008)34
30 days
SLND SLND + ALND ALND SLND SLND + ALND ALND
Meta-analysis: 3 RCTs (n = 2781 patients) Wound infections: SLND versus ALND: OR 0.58, 95% CI = 0.42–0.80, p = 0.0011 Meta-Analysis: 3 RCTs (n = 2125 patients) Seroma: SLND versus ALND: OR 0.4, 95% CI = 0.31–0.51, p = 0.0071 Wound infections: 6% (3a/54) 21% (12a/56) 12% (8a/65) SNLD versus SLND + ALND: OR 0.22, 95% CI 0.06–0.81a Seroma: 4% (2a/54) 11% (6a/56) 16% (10a/65) SNLD versus SLND + ALND: OR 0.32, 95% CI 0.06–1.66a
Favours SLND X
Similar
Favours ALND
Evidence MODERATE
X
ALND, axillary lymph node dissection; BCT, breast conserving therapy; OR, odds ratio; BRAS, arms symptoms scale; CI, confidence interval; RCT, randomised controlled trial; EORTC QLQ C-30, cancer specific health-related questionnaire (global quality of life score, five functional scales: physical, role, cognitive, emotional and social); FACT-B + 4 questionnaire, physical well-being, social wellbeing, emotional well-being, functional well-being, concerns specific to patients with breast cancer; SD, Standard Deviation; GHS, Global Health Status, EORTC QLQ-C30 plus breast cancer module, tool to assess quality of life in cancer and more specifically breast cancer; SNLD, sentinel lymph node dissection; HR, hazard ratio; TOI, Trial Outcome Index score, physical well-being, functional wellbeing, breast cancer subscales of the FACT-B + 4; Mac., macroscopic; Mic., microscopic. a Internal calculations based on the available data. b Internal calculations based on the available data and additional information supplied by the authors.
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
Estimate of effect
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
821
5-year survival Study name
Statistics for each study Upper limit
5-year survival / Total
Odds ratio
Lower limit
Z0011, 2011
0.93
0.56
1.53
Bilimora et al., 2009
0.95
0.84
1.08
16749 / 20290 1655 / 1988
Yi et al., 2010
0.73
0.64
0.83
20561 / 22561 4132 / 4425
0.85
0.68
1.06
ALND
SLND
386 / 420
403 / 436
Odds ratio and 95% CI
0.5
1
Favors SLND
2
Favors ALND
Random Effects Meta Analysis; I-squared 77%
Fig. 2. Meta-analysis of odds ratios of 5-year survival between sentinel lymph node dissection (SLND) only and complete axillary lymph node dissection (ALND).
tumour characteristics substantially varied among the analysed populations.
Out of more than 50,000 patients, only 241 experienced regional recurrences. Results of the individual studies and of macroscopic recurrence are presented in Table 4.
3.3. Local recurrence 3.5. Disease-free-survival Two studies reported on local recurrence, defined as ipsilateral breast cancer recurrence. Both studies had low event rates, decreasing the confidence in the comparisons. In the Z0011 study, the 5-year-localrecurrence-rates were not statistically significantly different between the treatment-groups.16,17 Overall, 20 of 856 patients experienced a local recurrence after 5 years, 1.6% (95% CI 0.7–3.3%) of the SLND only group compared with 3.1% (95% CI 1.7–5.2%) of the complete ALND group (OR 0.51; 95% CI 0.2–1.29). In the SEER Database-study 184 of 22,986 women experienced a local recurrence, and in this case significantly more in the SLND group compared with the ALND group (SLND: 0.95% [42/4425] versus ALND 0.63% [142/ 22,561]; OR 1.51; 95% CI 1.07–2.14).30 The National Cancer Database-study did not report local recurrence rates. 3.4. Regional recurrence Studies defined regional recurrences as recurrence in the axillary, supraclavicular or intramammary nodes. Pooled data of the three included studies presented an inconclusive, non-statistically significant result regarding the comparative risk for regional recurrence (Fig. 3, OR 1.47; 95% CI 0.96–2.24), numerically favouring women treated with complete ALND over those with SLND only. Findings have to be interpreted cautiously though because the number of events are low.
Results for disease-free survival were available only from the Z0011 RCT. Women who underwent SLND only had similar disease-free-survival rates compared with complete ALND (83.9% versus 82.2% respectively; HR 0.88; 95% CI 0.62–1.25 adjusted for adjuvant therapy and age).17 Additional adjustments for tumour-size, oestrogen-receptor-status, modified Bloom-Richardson Score and tumour-type did not affect the result. 3.6. Quality of life For the assessment of quality of life we included four additional studies which enrolled more than 1500 women with sentinel-negative lymph nodes, one RCT35 and three observational studies32–35 The Z0011 study and the two cohort studies did not report on quality of life outcomes. In all included studies, quality of life (physical, emotional and social well-being, and cognitive function) was assessed with validated, partially breast-cancer-specific quality of life-scales. Three out of four included studies, a randomised controlled study and two observational studies, reported that women who underwent SLND only had a better quality of life than women who underwent complete ALND.32,33,35 For example, a cohort study with 222 patients in the SLND-treatment arm and 61 patients in the SLND + ALND-arm, found better Global Health Status scores in the SLND only than
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Regional Recurrence Study name
Statistics for each study
Odds ratio and 95% CI
Odds ratio
Lower limit
Upper limit
SLND
ALND
Z0011, 2011
1.94
0.35
10.62
4 / 436
2 / 420
Bilimora et al., 2009
1.30
0.78
2.14
17 / 1458
168 / 18617
7 / 4425
18 / 22561
Yi et al., 2010
1.98
0.83
4.75
1.47
0.96
2.24
0.1
0.2
0.5
Favours SLND
1
2
5
10
Favours ALND
Random Effects Meta Analysis; I-squared 0 %
Fig. 3. Meta-analysis of odds ratios of regional recurrence between sentinel lymph node dissection (SLND) only and complete axillary lymph node dissection (ALND).
in the ALND group.32 The mean difference in scores was 4.94 (p = 0.018), a 5 point difference was considered to be clinically relevant. This finding was confirmed in two other studies.33,35 One study with 195 patients did not find significant differences between SNLD and ALND in quality of life.34 3.7. Comparative risk of harms of SLND only versus ALND To assess the comparative risk of harms, we included four additional studies and a meta-analysis of seven RCTs with sentinel-positive and -negative populations.31–35 Depending on the presented outcome, the meta-analysis provided data from up to five RCTs.31 The characteristics of the included studies, including the populations, are presented in Table 3. Overall, the risk of harms such as lymphedema, restricted motion, paraesthesia or wound infections was associated with the extent of the surgical intervention and occurred more frequently in patients who underwent complete ALND than SLND only. 3.8. Lymphedema A meta-analysis of five RCTs (including the Z0011study and the ALMANAC [Axillary Lymphatic Mapping Against Nodal Axillary Clearance] – trial36) with data on 2154 patients indicated that the risk of lymphedema after 6 months is 70% lower in patients with SLND only than in those treated with complete ALND (OR 0.3; 95% CI 0.14–0.66, p = 0.0028).31 This result is consistent with a more recent prospective cohort-study not included in the meta-analysis.33
3.9. Restricted motion Two studies with data on more than 1000 patients, the ALMANAC- trial and a prospective cohort study, determined the risk of postoperatively restricted arm motion.33,35 The ALMANAC-trial (n = 829), showed a 74% lower risk of limited range of motion in patients with SLND only than in patients with complete ALND (OR 0.26, 95% CI 0.16–0.4), 1 month after the intervention.35 The difference decreased over time but was still statistically significant after 3 months favouring SLND only over complete ALND (3.3% versus 6.6%; p = 0.035). After 6 and 12 months, no statistically significant differences could be detected between treatment groups. Likewise, results of the cohort study showed significant differences 1 month postoperative in favour of the SNLD-group (flexion, extension, adduction, abduction, internal and external rotation: p < 0.001–0.038).33 These differences had a tendency to decrease over time.
3.10. Paraesthesia The risk of a postoperative paraesthesia was also statistically significantly lower in patients with SLND only than with complete ALND. A meta-analysis of five RCTs with almost 3300 patients determined a 75% lower risk of upper limb-paraesthesia for SLND only than complete ALND after 6 months (OR 0.25, 95% CI 0.10–0.59, p = 0.0018).31 The ALMANAC-trial (n = 829) showed a 72% lower risk of numbness for SLND (OR: 0.28, 95% CI 0.19–0.43*), up to 18 months after the intervention.35 Inadvertent division of the intercostobrachial nerve occurred in 22.6% of complete
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
ALND procedures and in 5.3% of operations using SLND only.35 3.11. Wound-infections The risk for wound-infections was lower for women treated with SLND only than complete ALND. A meta-analysis of 3 RCTs with almost 2800 patients, determined a 42% lower risk for wound-infections with SLND only than complete ALND (OR 0.58, 95% CI 0.42–0.8; p = 00011).31 4. Discussion In this systematic review of data on more than 50,000 patients, results indicate similar 5-year survival and local- regional recurrence rates between women with positive sentinel nodes treated with SLND only or complete ALND. Furthermore, women treated with SLND only reported statistically significantly higher scores of quality of life than women undergoing complete ALND which is probably related to the lower rates of harms such as lymphedema, restricted motion, paraesthesia and wound infections. The strength of the evidence is low for some outcomes and moderate for others. Our confidence in some results is reduced because the estimates often have wide confidence intervals which include values for which a clinically important difference between the approaches exists. Issues with applicability also reduce our ability to transpose these results on the wider breast cancer population. Methodological restrictions, for example the lack of information concerning allocation concealment in the Z0011 study and susceptibility of observational studies to selection bias, may also have distorted our findings. The large sample sizes in metaanalyses of observational studies can lead to seemingly precise estimates that can be spurious due to residual confounding. Despite populations with varying prognosis in included studies, results consistently showed similar effectiveness between SLND only and complete ALND, and a higher risk for harm associated with ALND. Our results indicate that surgeons should discuss the option of performing SLND instead of complete ALND with sentinel node-positive patients. This option could be applicable to women with T1 or T2 disease, who have no clinically palpable lymph nodes, and who undergo breast conserving surgery followed by tangential irradiation and systemic therapy. The current state of evidence, however, is not yet sufficient to exactly define the group of patients for whom ALND is never necessary. Considerable uncertainties exist, particularly with respect to long-term recurrences, and in hormonereceptor positive patients. According to a cross-sectional study of the U.S. population, breast cancer patients with hormone-receptor negative tumors have a much greater risk of recurrence during the initial 7 years following
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breast cancer diagnosis than those with hormone-receptor positive tumors, who have a greater risk of recurrence after that period.19,37 In addition, new chemotherapeutic regimens, endocrine therapies and HER2-antibody directed therapies may further tip the balance of benefits and tradeoffs towards a less invasive surgical approach. Criteria to be weighed in the decision-making process for or against ALND may include prognostic factors, isolated tumour cells or micrometastases in the sentinel lymph nodes, or the ratio of involved to the total number of labelled or examined negative lymph nodes. The use of nomograms may be helpful in this process.38 Our review has several limitations. Most important are issues of applicability. Adjuvant opposing tangential field irradiation of the breast nearly always entails unintentional irradiation of the lower portions of the axillary lymph drainage regions, exposing them to a tumoureffective dose.39 No axillary-specific irradiation was performed in the Z0011-population, but it is likely, that a significant portion of the axilla was treated.16 It remains unclear whether modifications should be made to the way adjuvant radiation therapy of the breast is performed to include lymph node sites located inferior to the brachial plexus and axillary vein in cases where ALND is not performed. Furthermore, questions remain regarding the timing and intensity of adjuvant chemotherapy. The proportion of women included in these studies whose cancer was detected by screening is also unclear. A mammographic screening trial with 42,283 women indicated that women who are treated following breast cancer screening may not have developed clinically relevant breast cancer.40 Such women have a good prognosis and would dilute the beneficial effect of one surgical approach over the other. Women whose cancer was detected clinically could possibly benefit from a more invasive approach. Meta-analysis of observational studies has serious limitations and can lead to spurious, overly precise findings. We decided to statistically combine data of the Z0011 study and two observational studies because a major criticism of the Z0011 study was that it was underpowered. Despite the clinical heterogeneity of the study populations, results of all three studies indicated similar effectiveness of SLND and ALND. The uncertainty of these findings, however, is reflected by the low grading of the strength of evidence which indicates that future studies might have a substantial impact on the estimates of the effects. Finally, publication bias is a concern for all systematic reviews. The small number of studies in our metaanalyses limits the validity of statistical approaches to test for publication bias. Although we have searched for unpublished literature, there is no way for us to assess the completeness of the body of evidence.
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In light of the existing uncertainty of the evidence, only further prospective studies with appropriately delineated subgroups will define patient cohorts in whom the need for ALND can be eliminated with certainty. Given the current level of evidence, the effects of irradiation and systemic therapy should be considered and documented, and patients with higher tumour stages included.
6. 7.
Funding source 8.
German Guideline programme in Oncology: Association of the Scientific Medical Societies in Germany, German Cancer Society, German Cancer Aid. The funding sources had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
9.
10.
Authors’ contributions All authors contributed to the planning of the study, the analysis and interpretation of results and to the writing of the manuscript.
11.
12.
Conflict of interest statement 13.
Achim Woeckel and Rolf Kreienberg are members of the German Cancer Aid. None of the authors had a financial relationship with a commercial corporation that has an interest in the subject of this manuscript. None of the authors has any conflict of interest with respect to the topic and content of the manuscript. Acknowledgment We wish to thank Evelyn Auer from the Danube University Krems for administrative support.
15.
16.
17.
18.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.ejca.2012.09.010.
19.
20.
References 1. Mathers C, Boerma T, Mafat D. The global burden of disease: 2004 update. Geneva: World Health Organization; 2008. 2. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46(4):765–81 [epub 2010/02/02]. 3. Johnson A, Shekhdar J. Breast cancer incidence: what do the figures mean? J Eval Clin Pract 2005;11(1):27–31 [epub 2005/01/ 22]. 4. Hemminki K, Rawal R, Bermejo JL. Mammographic screening is dramatically changing age-incidence data for breast cancer. J Clin Oncol 2004;22(22):4652–3 [epub 2004/11/16]. 5. Albert US, Kalder M, Schulte H, et al. The population-based mammography screening programme in Germany: uptake and
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first experiences of women in 10 federal States. Gesundheitswesen 2012;74(2):61–70 [epub 2011/01/14. Das populations bezogene Mammografie-Screening-Programme in Deutschland: Inanspruchnahme und erste Erfahrungen von Frauen in 10 Bundeslandern]. New Zealand Guidelines Group. Management of early breast cancer. New Zealand Ministry of Health 2009. National Collaborating Centre for Cancer. Early and locally advanced breast cancer: diagnosis and treatment National Institute for Health and Clinical Excellence guideline 2009. 2009 Apr. Report No.: 0936-6555 (Print) 0936-6555 (Linking), Contract No.: 3. Wo JY, Chen K, Neville BA, Lin NU, Punglia RS. Effect of very small tumor size on cancer-specific mortality in node-positive breast cancer. J Clin Oncol 2011;29(19):2619–27 [epub 2011/05/ 25]. Tafra L, Lannin DR, Swanson MS, et al. Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye. Ann Surg 2001;233(1):51–9 [epub 2001/01/05]. Kuehn T, Vogl FD, Helms G, et al. Sentinel-node biopsy for axillary staging in breast cancer: results from a large prospective German multi-institutional trial. Eur J Surg Oncol 2004;30(3):252–9 [epub 2004/03/19]. Bergkvist L, Frisell J, Liljegren G, et al. Multicentre study of detection and false-negative rates in sentinel node biopsy for breast cancer. Br J Surg 2001;88(12):1644–8 [epub 2001/12/12]. Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: a metaanalysis. Cancer 2006;106(1):4–16 [epub 2005/12/06]. Scottish Intercollegiate Guidelines Network (SIGN). Management of breast cancer in women. A national clinical guideline; 2005. Brackstone M, Tey R, reviewers. Toronto (ON): Cancer Care Ontario; 2011 Sep 15 [Endorsed 2010 Nov 19]. Program in Evidence-based Care Evidence-Based Series No.: 1-1 Version 3. 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: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 2010;252(3):426–32 [discussion 32–33]. 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(6):569–75 [epub 2011/02/10]. 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(24):3657–63 [epub 2007/05/09]. Jatoi I. Axillary vs sentinel lymph node dissection for invasive breast cancer. JAMA 2011;305(22):2288 [author reply 90–91. Epub 2011/06/07.]. Chen IC, Lin CH, Lu YS. Axillary vs sentinel lymph node dissection for invasive breast cancer. JAMA 2011;305(22):2288–9 [author reply 90–91. epub 2011/06/07]. Carlson GW, Wood WC. Management of axillary lymph node metastasis in breast cancer: making progress. JAMA 2011;305(6):606–7. Wright PA, Zenilman ME. Less may be better: axillary dissection is unnecessary in some patients with a positive sentinel lymph node. Arch Surg 2011;146(8):980–2. Zoras O, Ziogas D, Roukos DH. Omitting axilla lymphadenectomy even by positive sentinel lymph node: a change in breast cancer treatment practice. Womens Health (Lond Engl) 2011;7(4):417–8. Chapman AL, Morgan LC, Gartlehner G. Semi-automating the manual literature search for systematic reviews increases efficiency. Health Info Libr J 2010;27(1):22–7.
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825 25. Higgins JP, Green S. Cochrane Handbook for systematic reviews of interventions. Handbook is 5.1.0 2011. 26. Deeks JJ, Dinnes J, D’Amico R, et al. Evaluating non-randomised intervention studies. Health Technol Assess 2003;7(27):1234, iii–x, 1–173 [epub 2003/09/23]. 27. Shea BJ, Hamel C, Wells GA, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. J Clin Epidemiol 2009;62(10):1013–20 [epub 2009/02/24]. 28. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924–6 [epub 2008/04/26]. 29. 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(18):2946–53 [epub 2009/04/15]. 30. 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(Suppl. 3):343–51 [epub 2010/10/01]. 31. Kell MR, Burke JP, Barry M, Morrow M. Outcome of axillary staging in early breast cancer: a meta-analysis. Breast Cancer Res Treat 2010;120(2):441–7 [epub 2010/01/12]. 32. 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(8):1352–61 [epub 2009/05/27]. 33. Chen JJ, Huang XY, Liu ZB, et al. Sentinel node biopsy and quality of life measures in a Chinese population. Eur J Surg Oncol 2009;35(9):921–7 [epub 2009/02/24].
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34. Kootstra J, Hoekstra-Weebers JE, Rietman H, et al. Quality of life after sentinel lymph node biopsy or axillary lymph node dissection in stage I/II breast cancer patients: a prospective longitudinal study. Ann Surg Oncol 2008;15(9):2533–41 [epub 2008/07/04]. 35. Fleissig A, Fallowfield LJ, Langridge CI, et al. Post-operative arm morbidity and quality of life. Results of the ALMANAC randomised trial comparing sentinel node biopsy with standard axillary treatment in the management of patients with early breast cancer. Breast Cancer Res Treat 2006;95(3):279–93 [epub 2005/09/ 16]. 36. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC trial. J Natl Cancer Inst 2006;98(9):599–609. 37. Jatoi I, Chen BE, Anderson WF, Rosenberg PS. Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol 2007;25(13):1683–90 [epub 2007/04/04]. 38. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol 2003;10(10):1140–51 [epub 2003/12/05]. 39. van Wely BJ, Teerenstra S, Schinagl DA, et al. Systematic review of the effect of external beam radiation therapy to the breast on axillary recurrence after negative sentinel lymph node biopsy. Br J Surg 2011;98(3):326–33 [epub 2011/01/22]. 40. Zackrisson S, Andersson I, Janzon L, Manjer J, Garne JP. Rate of over-diagnosis of breast cancer 15 years after end of Malmo mammographic screening trial: follow-up study. BMJ 2006;332(7543):689–92 [epub 2006/03/07].
Available at www.sciencedirect.com
journal homepage: www.ejcancer.info
Review
Sentinel lymph node dissection only versus complete axillary lymph node dissection in early invasive breast cancer: A systematic review and meta-analysis Anna Glechner a,⇑, Achim Wo¨ckel c, Gerald Gartlehner a,b, Kylie Thaler a, Michaela Strobelberger a, Ursula Griebler a, Rolf Kreienberg c a
Danube University, Department for Evidence-Based Medicine and Clinical Epidemiology, Austria Research Triangle Institute (RTI) International, United States c University Hospital Ulm, Germany b
Available online 17 October 2012
KEYWORDS Systematic review Meta-analysis Breast neoplasms Disease-free survival Lymph node excision Sentinel lymph node biopsy Lymphatic metastasis Neoplasm recurrence Axilla/surgery Survival analysis
Abstract Background: The Z0011-study, a landmark randomised controlled trial (RCT) challenged the benefits of complete axillary lymph node dissection (ALND) compared with sentinel lymph node dissection only (SLND) in breast cancer patients with positive sentinel nodes. The study, however, has been criticised for lack of power and low applicability. The aim of this review was to systematically assess the evidence on the comparative benefits and harms of ALND versus SLND for sentinel node positive breast cancer patients. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and reference lists of pertinent review articles from January 2006 to August 2011. We dually reviewed the literature and rated the risk of bias of each study. For effectiveness, we included RCTs and observational studies of at least 1 year follow-up. In addition, we considered studies conducted in sentinel node-negative women to assess the risk of harms. If data were sufficient, we conducted random effects meta-analysis of outcomes of interest. Results: Meta-analysis of three studies with 50,120 patients indicated similar 5-year survival and regional recurrence rates between patients treated with ALND or SLND, although prognostic tumour characteristics varied among the 3 study-populations. Results from 6 studies on more than 11,500 patients reported a higher risk for harms for ALND than SLND. Long-term evidence on pertinent health outcomes is missing. Conclusion: The available evidence indicates that for some women with early invasive breast cancer SLND appears to be a justifiable alternative to ALND. Surgeons need to discuss advantages and disadvantages of both approaches with their patients. Ó 2012 Elsevier Ltd. All rights reserved.
⇑ Corresponding author: Address: Danube University, Dr.-Karl Dorrek-Straße 30, 3500 Krems, Austria. Tel.: +43 2732 893 2920; fax: +43 2732 893 4910. E-mail address: [email protected] (A. Glechner).
0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.09.010
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
1. Introduction Breast cancer is the most common malignancy in women, comprising 16% of all female cancers.1 In 2008, approximately 332,800 cases of breast cancer occurred in the European Union and almost 90,000 women died of the disease.2 Ecologic studies in Europe have demonstrated a rise in the incidence of breast cancer over the past decades, probably attributable to an increase in breast cancer screening.3,4 Despite the increase in the number of breast cancer sufferers, mortality from the disease has substantially decreased. This has been attributed to both breast cancer screening programmes (which enable detection of cancers at an earlier stage) and improved therapeutic possibilities.5 Axillary surgery is a crucial part of the treatment regimen for early invasive breast cancer. The surgical approach is determined by the staging and the involvement of axillary nodes.6,7 In patients with positive axillary nodes, breast cancer-specific mortality rises markedly.8 Most guidelines recommend sentinel lymph node dissection (SLND) for the staging of the disease in women with clinically negative lymph nodes.6,7 In SLND the surgeon injects dye, traces and selectively resects lymph nodes draining the primary tumour. When SLND is performed according to a standardised and quality-assured technique, accurate staging of the number of positive lymph nodes or the ratio of involved to examined lymph nodes can be used to determine further treatment strategies.6,7,9–13 In women with early invasive breast cancer without metastases in sentinel lymph nodes no further dissection of nodes in the local lymph drainage region is recommended. Most clinical practice guidelines suggest complete axillary lymph node dissection (ALND) in women with early invasive breast cancer and micro- or macro-metastatic disease.13,15 The National Institute for Health and Clinical Excellence differentiates micrometastasis and isolated tumour cells and regards patients found to have isolated tumour cells as lymph node negative with no recommendation for any further axillary surgery. A recent randomised controlled trial (RCT) conducted by the American College of Surgeons Oncology Group (ASOG Z0011 study) challenges the utility of ALND in women with early invasive breast cancer and positive sentinel nodes.16–18 Results indicated that ALND does not lead to a survival benefit compared with SLND only. The ASOG concluded that in patients with clinically-negative axillary lymph nodes, the use of ALND is not justified.16–18 This finding has been controversial, particularly because the Z0011 study failed to enrol the estimated sample size to meet the primary objective.19–23 Some authors argue that the waning utility of ALND has to be recognised and treatment guidelines need to be changed accordingly.21–23 Others claim
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that the Z0011 study results are not applicable to larger populations because it enrolled a greater proportion of oestrogen-receptor positive tumours compared with the current US-population and details about the initiation and intensity of adjuvant chemotherapy are not provided.19,20 To date, no systematic review has assessed the comparative benefits and harms of SLND and ALND in women with T1 or T2 breast cancer and positive sentinel nodes. Our objective was to review systematically the available evidence from RCTs and observational studies to determine the comparative benefits and risks of these two surgical approaches. 2. Methods 2.1. Data sources We searched PubMed, Embase, and the Cochrane Library, from 2006 to August 2011. We restricted our search dates because SLND is a relatively new technique and we did not expect to find comparative studies of ALND and SLND in sentinel positive patients before 2006. We used Medical Subject Headings as search terms when available or key words when appropriate and combined specific terms for breast cancer, sentinel lymph node biopsy, and axillary node dissection. We limited electronic searches to ‘adult 19+ years,’ and ‘human’. We did not apply language restrictions. The complete search strategy is presented in the supplementary file 1. To minimise retrieval bias, we also used semi-automatic manual searches of reference lists of pertinent review articles and letters to the editor employing the ScopusTM citation database (www. scopus.com).24 2.2. Study selection Two persons independently reviewed abstracts and full-text articles. Eligibility criteria for studies were defined a priori and are presented in Table 1. To assess the comparative effectiveness we included RCTs and observational studies that compared the two surgical approaches in sentinel node-positive women. Outcomes of interest were patient-relevant health outcomes (e.g. 5year survival, quality of life, breast cancer recurrence and surgery-associated harms). To assess quality-of-life and harms, we also examined data from studies conducted in sentinel-negative women because the risk of harms of surgical procedures is unlikely to be affected by the lymph node status. We included systematic reviews with meta-analyses where these met our inclusion criteria and were of methodologically good quality. We dually reviewed all citations and resolved disagreements about inclusion or exclusion by consensus or by involving a third reviewer.
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2.3. Data extraction and quality assessment We used standardised data abstraction forms into which trained reviewers abstracted data from each study and assigned an initial rating of the risk of bias. A senior reviewer evaluated the forms. To assess the risk of bias of RCTs, we used predefined criteria based on the Cochrane Risk of Bias tool (ratings: low – unclear – high risk of bias).25 To assess the risk of bias of observational studies, we employed criteria outlined by Deeks et al.,26 for systematic reviews we used the AMSTAR (Assessment of Multiple Systematic Reviews) tool.27 2.4. Data synthesis and analyses Because data on most outcomes of interest were insufficient to conduct meta-analyses, we synthesised the evidence on the majority of outcomes qualitatively. To retrieve data not reported in publications, we contacted authors of the respective papers. When data on a particular outcome of interest were sufficient we conducted meta-analyses of the odds ratio of experiencing an event. For each meta-analysis, we conducted a test of heterogeneity (I2 statistic) and applied both a random and a fixed effects model. If high heterogeneity was present (I2 statistic P 60%) we explored the reasons for heterogeneity. Because of substantial heterogeneity and the combination of RCTs and observational studies, we report random effects model results. We assessed publication bias using funnel plots. Given the small number of component studies in our meta-analyses, however, results must be viewed cautiously. All statistical analyses were conducted using Comprehensive Meta-Analysis, version 2.2.050. 2.5. Grading strength of evidence We evaluated the strength of evidence for critical outcomes using an approach proposed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) working group.28 We dually evaluated the overall strength of evidence for each major outcome. We reconciled all disagreements in grades through consensus discussion. 3. Results Our literature searches identified 254 relevant abstracts. We retrieved 82 full-text articles for more detailed examination. Fig. 1 depicts results of the search and the study selection process. Three studies, one RCT16–18 and two observational studies29,30 met our eligibility criteria for the assessments of the comparative effectiveness. We identified 5 additional studies to determine the comparative risk of harms31–35 Table 2 and Table 3 summarise the population characteristics,
duration of follow-up and endpoints of studies included for the comparative effectiveness and risk of harms. 3.1. The comparative effectiveness of SLND only versus ALND Overall, one RCT16–18 and two cohort studies,29,30 all of unclear risk of bias, provided data on more than 25,000 patients with SLND only and more than 100,000 patients with complete ALND. The study with the lowest risk of bias was the Z0011 study, an open-label RCT that enrolled 891 patients with invasive early stage breast cancer and histologically verifiable positive sentinel lymph nodes.16–18 The study was funded by the United States (US) National Cancer Institute. Patients were randomised to either SLND only with no further axillary treatment or complete ALND. The primary outcome measure of the Z0011-study was the 5-year overall survival rate. Authors pre-specified a non-inferiority margin for SLND only treatment compared with complete ALND as a hazard ratio (HR) for overall-mortality of less than 1.3. Based on this margin, the initial recruitment plan intended to enrol 1900 patients in order to have sufficient statistical power. The target sample size could not be achieved and, consequently, the Z0011 study was underpowered. In addition, the drop-out rate was almost 20%, further reducing the statistical power. In addition to the Z0011 study, we located two retrospective cohort studies: one with data from more than 97,000 patients of the US National Cancer Database29 from the years 1998 to 2005, and one with data of more than 26,000 patients of the SEER (Surveillance, Epidemiology and End Results) database.30 We restricted the results of the two cohort-studies to a population of approximately 49,000 patients to enable a comparison to the current practice of lymph node removal. The US National Cancer Database-study defined performance of SLND as 5 or fewer lymph nodes removed, and ALND as 9 or more lymph nodes removed. The populations of the three studies differed. The cohort-studies included women with stage T3-tumours and patients who had undergone mastectomy, a population who was not eligible for the Z0011 study. In general, women in the cohort studies had more advanced disease than women in the Z0011 trial. Population characteristics are presented in Table 2. In the following sections we present findings with respect to included outcomes. 3.2. 5-year-overall-survival We pooled data of more than 50,000 patients from the three studies described above. Despite the difference in prognosis of populations in the individual studies, all three studies reported similar 5-year survival rates between SLND and ALND-treated patients. Results
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Table 1 Eligibility criteria of included studies. Population
For effectiveness: women with invasive breast cancer and sentinel-positive lymph node biopsy undergoing breast conserving therapy or mastectomy For quality of life and harms: women with invasive breast cancer and sentinel-positive or – negative lymph node biopsy undergoing breast conserving surgery or mastectomy
Intervention
Breast conserving surgery/mastectomy with sentinel node biopsy plus complete axillary lymph node dissection
Control
Breast conserving surgery/mastectomy with sentinel node biopsy without complete axillary lymph node dissection
Outcomes
5-year survival rate Disease-free survival Local breast cancer recurrence Regional breast cancer recurrence Quality of life Surgery-associated harms (e.g. wound infection, lymphedema)
Timing
For effectiveness: study duration at least 1 year For harms and quality of life: no restrictions on study duration
Study design
RCTs, comparative observational studies, systematic reviews with meta-analysis
RCTs, randomised controlled trials.
291 abstracts identified through systematic database-research
18 additional abstracts identified from other sources (hand search, clinical experts)
254 abstracts after exclusion of duplicates
254 abstracts reviewed
82 articles included for review
172 abstracts excluded
72 articles excluded 8– 22 – 35 – 5– 1– 1–
Incorrect publication type Incorrect population Incorrect intervention or control Incorrect endpoints Incorrect study design Incorrect year of publication
Comparative effectiveness: 5 articles (3 studies) Comparative safety: 5 articles
Fig. 1. Disposition of the literature.
for populations with micro- and macroscopic diseases from the individual studies are presented separately in Table 4. Likewise the pooled odds ratio indicates similar survival rates (over 50–60 months follow up) for women treated with SLND only and complete ALND, favouring SLND (Fig. 2: odds ratio [OR] 0.85, 95% confidence interval [CI] 0.68–1.06). This result should be interpreted cautiously because confounding by indication (i.e. a
form of selection bias where the choice of treatment is determined by prognostic factors) is likely to play a role in the observational studies. The numerically higher (albeit not statistically significant) 5-year survival rates of women treated with SLND only might be a result of confounding factors. Confounding by indication could also explain the high statistical heterogeneity (I2 77%) in our meta-analysis. In addition, prognostic
816
Table 2 Main characteristics of the included studies and their populations, Studies for comparative effectiveness. Study design Sample size
Follow-up Risk of bias
Population average age
Z0011 Giuliano et al. (2010, 2011)16,17
RCT Recruitment 1999–2004
Follow-Up: 6.3 years
Patients with positive sentinel lymph nodes
SLND: n = 436 SLND + ALND: n = 420
Risk of Bias unclear
55 years
Retrospective cohort study Recruitment 1998–2005
Median Follow-Up: 63 months
Patients with positive sentinel lymph nodes.
SLND: n = 20,217 SLND + ALND: n = 77,097 SLND (6 5 LN r.): n = 1988 SLND + ALND (P 9 LN r.): n = 20,290
Risk of Bias unclear
56 years
Retrospective cohort study Diagnosis between 1998 – 2004
Follow-Up: 50 months
Patients with positive sentinel lymph nodes
SLND: n = 4425 SLND + ALND: n = 22,561
Risk of Bias unclear
57 years
National Cancer Database Bilimoria et al. (2009)29
SEER Database Yi et al. (2010)30
Intervention
SLND: SLND+ALND:
SLND: SLND + ALND:
SLND: SLND+ALND:
Population characteristics Clinical tumour stage (%)
Histologic tumour grade (%)
Hormon receptor+ (%)
Nodal metastases (%)
BCT/ mastectomy (%)
T1
T2
I
II
III
ER+ PgR+
ER+ PgR-
Micro
Macro
BCT
ME
70.6 67.9
29.4 32.1
25.6 22
46.8 48.9
27.5 29.1
68.9 66.8
13.8 15.9
44.8 37.5
55.2 62.5
100 100
0 0
Micro
Macro
BCT
ME
T1
T2
T3
Low/ intermediate
High
62.9 49.1
34.4 43.7
2.6 7.2
58.8 53.1
32.5 39.2
n.r n.r
n.r n.r
18.2 8.5
81.8 91.5
81.4 49.6
18.6 50.4
T1
T2
T3
Low/ intermediate
high
ER+
PgR+
Micro
Macro
BCT
ME
68.6 50.4
28.2 43.0
3.2 6.7
23 13.1
77 86.9
87.5 80.8
75.0 69.4
54.5 17.2
45.5 82.8
78.7 53.9
21.3 46.1
ALND, axillary lymph node dissection; BCT, breast conserving therapy; ER, oestrogen receptor; LN r., lymph nodes removed (number for nodal evaluation with lymph node count threshold), ME, Mastectomy, n.r., not reported, PgR, progesterone receptor, SEER, Surveillance, Epidemiology, and End Results; RCT, randomised controlled trial; SNLD, sentinel lymph node dissection.
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
Author Year
Table 3 Main characteristics of the included studies and their populations, Studies for harms only. Study Design Sample Size
Follow-Up Risk of Bias
Population Average Age
Intervention
Lucci et al., Z0011-Study (2007)16,18
RCT Recruitment 1999 – 2004 SLND: n = 446 SLND + ALND: n = 445 Meta-Analysis: 7 RCTs Recruitment: 1998–2005
Follow-Up: up to 12 months Risk of Bias unclear
Patients with positive sentinel lymph nodes, 55 years
SLND: SLND + ALND:
Follow-Up: up to 6 months Risk of Bias unclear
Patients with negative and positive sentinel lymph nodes 56 years
5 RCTs comparing SLND versus ALND
Follow-Up: up to 18 months Risk of Bias unclear Follow-up: up to 12 months Risk of Bias unclear
Patients with negative and positive sentinel lymph nodes 57 years
SLND: ALND:
Patients with negative and positive sentinel lymph nodes 48–49 years
SLND: ALND:
Follow-up: up to 12 months Risk of Bias unclear Follow-up: up to 24 months Risk of Bias unclear
Sentinel lymph node status not specified 59 years
SLND: SLND + ALND: ALND:
Patients with negative sentinel and positive sentinel lymph nodes 53–58 years
SLND: SLND + ALND: ALND:
Kell et al. (2010)31 (including Z001118 and the ALMANAC-trial36)
Fleissig et al., ALMANACtrial (2006)35
SLND: n = 636 SLND + ALND: n = 3828 ALND: n = 4389 RCT SLND: n = 424 ALND: n = 405
Chen et al. (2009)33
prospective cohort study SLND: n = 140 ALND: n = 81
Dabakuyo et al. (2009)32
Prospective cohort study SLND: n = 222 SLND + ALND: n = 61 ALND: n = 235 Prospective cohort study SLND: n = 61 SLND + ALND: n = 59 ALND: n = 75 Follow-Up: up to 24 months
Kootstra et al. (2008)34
Population Characteristics Number of nodes removed:
BCT
Mastectomy
Median: 2, interquartile range: 1.4 Median: 17, interquartile range: 1.22 n.r.
100%
0%
n.r.
n.r.
n.r.
93% 90%
7% 10%
median : 2, interquartile range 1–8 median : 13, interquartile range 5– 32 n.r.
32.5% 19.5%
30.8% 17.2%
} 73%
} 27%
69% 71% 40%
31% 29% 60%
n.r.
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Author Year
ALND, axillary lymph node dissection; RCT, randomised controlled trial; n.r., not reported; BCT, Breast conserving therapy; SNLD, sentinel lymph node dissection.
817
818
Table 4 Comparative effectiveness and safety: findings and strength of evidence. Author, Year
Follow-Up
Intervention
Estimate of effect
Direction of effect
5-Year overall survival
Favours SLND 5 years
SLND SNLD + ALND
National Cancer Database Bilimoria et al. (2009)29 Seer Database Yi et al. (2010)30
5-years
SLND SNLD + ALND
50 months
SLND SNLD + ALND
92.5% (403a/436) 91.8% (386a/420) HR 0.87; 90% CI: 0.62–1.23 mac. nodal metastases: 81.3% (1185a/1458) 81.8% (15,229a/18,617) HR 0.89, 95% CI 0.76–1.04 93.4% (4132b/4425) 91.1% (20,561b/22,561) HR 1.0, 95% CI 0.9–1.2
X
mic. nodal metastases: 88.6% (470a/530) 90.9% (1,521a/1673) HR 0.84, 95% CI 0.6–1.19
SLND SNLD + ALND
Yi et al. (2010)30
50 months
SLND SNLD + ALND
1.6% (7a/436) 3.1% (13a/420) OR 0.51, 95% CI 0.2–1.29a 0.95% (42b/4425) 0.63% (142b/22,561) OR 1.51 (95%CI 1.07–2.14)b
SLND SNLD + ALND
Bilimoria et al. (2009)29
5 years
SLND SNLD + ALND
Yi et al. (2010)30
50 months
SLND SLND + ALND
0.9% (4/436) 0.5% (2/420) OR 1.94, 95% CI 0.35–10.62a mac. nodal metastases: 1.2% (18a/1458) 1.0% (186a/18,617) HR 0.58, 95% CI 0.32–1.06 mac. nodal metastases: 0.2% (4b/2185) 0.08% (14b/17,963) HR 0.3, p = 0.02
Disease-free survival Giuliano et al. (2010, 2011)16,17 Quality of life
SLND SNLD + ALND
Evidence LOW
Similar
Favours ALND
X
Evidence LOW
X
mic. nodal metastases: 0.6% (3a/530) 0.2% (3a/1673) OR 3.01(95% CI 0.65–14)a mic. nodal metastases: 0.13 % (3b/2240) 0.087% (4b/4598) OR 1.54 (95% CI 0.34–6.9)b Favours SLND
5 years
Favours ALND
X
Favours SLND 5 years
Similar X
Regional recurrence Giuliano et al. (2010, 2011)16,17
LOW
X
Favours SLND 5 years
Evidence
X
Local recurrence Giuliano et al. (2010, 2011)16,17
Favours ALND
83.9% (366a/436) 82.2% (345a/420) HR 0.88, 95% CI 0.62–1.25
X (mic.)
X (mac.)
Similar
Favours ALND
X
Favours SLND
Similar
Evidence LOW
Favours ALND
Evidence
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Giuliano et al. (2011)17
Similar
Strength of Evidence
12 months
Koostra et al. (2008)34
2 years
Chen et al. (2009)33
12 months
Fleissig et al. ALMANAC-trial (2006)35
18 months
SLND SLND + ALND ALND
Mean Difference GHS + BRAS-Score: GHS: 4.94, p = 0.0185 BRAS: -6.28, p = 0.0013 GHS: 0 (reference) BRAS: 0 (reference) GHS: 2.96, p = 0.1562 BRAS: -0.34, p = 0.8615 (5-point difference = minimum clinically significant difference, GHS: 0 = worse, 100 = best; BRAS 0 = best, 100 = worst) EORTC-questionaire: No significant difference between SNLD and ALND in Quality of life Physical well-being: SLND + BCT > ALND + BCT, p = 0.037 TOI-Score: Significant differences between the treatment groups favouring SLND group at all time points (1 month p < 0.001, 3– 18 months p = 0.001)
Lymphedema Kell et al. (2010)31 (including Z001118 and the ALMANACtrial)36 Chen et al. (2009)33
6 months
Meta-analysis: 5 RCTs (n = 2154 patients) SLND versus ALND: OR 0.3, 95% CI = 0.14–0.66, p = 0.0028
6 months
ALND versus SLND: OR 7.153, 95% CI 1.9–26.8, p = 0.004
Movement restrictions Chen et al. (2009)33:
12 months
Fleissig et al. ALMANAC-trial (2006)35
18 months
Paraesthesia
SLND ALND SLND ALND
Significant differences 1 month postoperative in favour of the SNLD-group (flexion, extension, adduction, abduction, internal and external rotation: p < 0.001–0.038) 1 month postoperative: 6.7% (29a/ 424) 22.1% (90a/405), p < 0.001 OR: 0.26, 95% CI 0.16–0.4a 3 months postoperative: 3.3% (14a/424) 6.6% (27a/405), p = 0.035 OR: 0.48, 95% CI 0.25–0.93a Differences between the groups were no longer significant at later follow-ups (6 months: p = 0.167, 12 months: p = 0.142, 18 months: p = 0,27)
X
MODERATE
X X X
Favours SLND X
Similar
Favours ALND
Evidence MODERATE
X Favours SLND X
Similar
Favours ALND
Evidence MODERATE
X
Favours SLND
Similar
Favours ALND
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Dubakuyo et al. (2009)32
Evidence (continued on next page)
819
820
Table 4 (continued) Author, Year
Follow-Up 31
Kell et al. (2010) (including Z001118 and the ALMANACtrial)36 Fleissig et al. ALMANAC-trial (2006)35
Intervention
6 months
18 months
SLND ALND SLND ALND
Direction of effect
Strength of Evidence
Meta-analysis: 5 RCTs (n = 3265 patients) SLND versus ALND: OR 0.25, 95% CI = 0.10–0.59, p = 0.0018
X
MODERATE
1 month postoperative: 9.3% (40a/ 424) 29.7% (121a/405), p < 0.001 OR: 0.24, 95% CI 0.17–0.36a 18 months postoperative: 8.7% (37a/424) 19% (77a/405), p = 0.001 OR: 0.28, 95% CI 0.19–0.43a Significant differences between the groups at all time points (p < 0.001 at 1, 3, 6, 12 and 18 months) favouring SLND
X
Wound-infections + seroma Kell et al. (2010)31 (including Z001118 and the ALMANACtrial)36
Koostra et al. (2008)34
30 days
SLND SLND + ALND ALND SLND SLND + ALND ALND
Meta-analysis: 3 RCTs (n = 2781 patients) Wound infections: SLND versus ALND: OR 0.58, 95% CI = 0.42–0.80, p = 0.0011 Meta-Analysis: 3 RCTs (n = 2125 patients) Seroma: SLND versus ALND: OR 0.4, 95% CI = 0.31–0.51, p = 0.0071 Wound infections: 6% (3a/54) 21% (12a/56) 12% (8a/65) SNLD versus SLND + ALND: OR 0.22, 95% CI 0.06–0.81a Seroma: 4% (2a/54) 11% (6a/56) 16% (10a/65) SNLD versus SLND + ALND: OR 0.32, 95% CI 0.06–1.66a
Favours SLND X
Similar
Favours ALND
Evidence MODERATE
X
ALND, axillary lymph node dissection; BCT, breast conserving therapy; OR, odds ratio; BRAS, arms symptoms scale; CI, confidence interval; RCT, randomised controlled trial; EORTC QLQ C-30, cancer specific health-related questionnaire (global quality of life score, five functional scales: physical, role, cognitive, emotional and social); FACT-B + 4 questionnaire, physical well-being, social wellbeing, emotional well-being, functional well-being, concerns specific to patients with breast cancer; SD, Standard Deviation; GHS, Global Health Status, EORTC QLQ-C30 plus breast cancer module, tool to assess quality of life in cancer and more specifically breast cancer; SNLD, sentinel lymph node dissection; HR, hazard ratio; TOI, Trial Outcome Index score, physical well-being, functional wellbeing, breast cancer subscales of the FACT-B + 4; Mac., macroscopic; Mic., microscopic. a Internal calculations based on the available data. b Internal calculations based on the available data and additional information supplied by the authors.
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Estimate of effect
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5-year survival Study name
Statistics for each study Upper limit
5-year survival / Total
Odds ratio
Lower limit
Z0011, 2011
0.93
0.56
1.53
Bilimora et al., 2009
0.95
0.84
1.08
16749 / 20290 1655 / 1988
Yi et al., 2010
0.73
0.64
0.83
20561 / 22561 4132 / 4425
0.85
0.68
1.06
ALND
SLND
386 / 420
403 / 436
Odds ratio and 95% CI
0.5
1
Favors SLND
2
Favors ALND
Random Effects Meta Analysis; I-squared 77%
Fig. 2. Meta-analysis of odds ratios of 5-year survival between sentinel lymph node dissection (SLND) only and complete axillary lymph node dissection (ALND).
tumour characteristics substantially varied among the analysed populations.
Out of more than 50,000 patients, only 241 experienced regional recurrences. Results of the individual studies and of macroscopic recurrence are presented in Table 4.
3.3. Local recurrence 3.5. Disease-free-survival Two studies reported on local recurrence, defined as ipsilateral breast cancer recurrence. Both studies had low event rates, decreasing the confidence in the comparisons. In the Z0011 study, the 5-year-localrecurrence-rates were not statistically significantly different between the treatment-groups.16,17 Overall, 20 of 856 patients experienced a local recurrence after 5 years, 1.6% (95% CI 0.7–3.3%) of the SLND only group compared with 3.1% (95% CI 1.7–5.2%) of the complete ALND group (OR 0.51; 95% CI 0.2–1.29). In the SEER Database-study 184 of 22,986 women experienced a local recurrence, and in this case significantly more in the SLND group compared with the ALND group (SLND: 0.95% [42/4425] versus ALND 0.63% [142/ 22,561]; OR 1.51; 95% CI 1.07–2.14).30 The National Cancer Database-study did not report local recurrence rates. 3.4. Regional recurrence Studies defined regional recurrences as recurrence in the axillary, supraclavicular or intramammary nodes. Pooled data of the three included studies presented an inconclusive, non-statistically significant result regarding the comparative risk for regional recurrence (Fig. 3, OR 1.47; 95% CI 0.96–2.24), numerically favouring women treated with complete ALND over those with SLND only. Findings have to be interpreted cautiously though because the number of events are low.
Results for disease-free survival were available only from the Z0011 RCT. Women who underwent SLND only had similar disease-free-survival rates compared with complete ALND (83.9% versus 82.2% respectively; HR 0.88; 95% CI 0.62–1.25 adjusted for adjuvant therapy and age).17 Additional adjustments for tumour-size, oestrogen-receptor-status, modified Bloom-Richardson Score and tumour-type did not affect the result. 3.6. Quality of life For the assessment of quality of life we included four additional studies which enrolled more than 1500 women with sentinel-negative lymph nodes, one RCT35 and three observational studies32–35 The Z0011 study and the two cohort studies did not report on quality of life outcomes. In all included studies, quality of life (physical, emotional and social well-being, and cognitive function) was assessed with validated, partially breast-cancer-specific quality of life-scales. Three out of four included studies, a randomised controlled study and two observational studies, reported that women who underwent SLND only had a better quality of life than women who underwent complete ALND.32,33,35 For example, a cohort study with 222 patients in the SLND-treatment arm and 61 patients in the SLND + ALND-arm, found better Global Health Status scores in the SLND only than
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A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
Regional Recurrence Study name
Statistics for each study
Odds ratio and 95% CI
Odds ratio
Lower limit
Upper limit
SLND
ALND
Z0011, 2011
1.94
0.35
10.62
4 / 436
2 / 420
Bilimora et al., 2009
1.30
0.78
2.14
17 / 1458
168 / 18617
7 / 4425
18 / 22561
Yi et al., 2010
1.98
0.83
4.75
1.47
0.96
2.24
0.1
0.2
0.5
Favours SLND
1
2
5
10
Favours ALND
Random Effects Meta Analysis; I-squared 0 %
Fig. 3. Meta-analysis of odds ratios of regional recurrence between sentinel lymph node dissection (SLND) only and complete axillary lymph node dissection (ALND).
in the ALND group.32 The mean difference in scores was 4.94 (p = 0.018), a 5 point difference was considered to be clinically relevant. This finding was confirmed in two other studies.33,35 One study with 195 patients did not find significant differences between SNLD and ALND in quality of life.34 3.7. Comparative risk of harms of SLND only versus ALND To assess the comparative risk of harms, we included four additional studies and a meta-analysis of seven RCTs with sentinel-positive and -negative populations.31–35 Depending on the presented outcome, the meta-analysis provided data from up to five RCTs.31 The characteristics of the included studies, including the populations, are presented in Table 3. Overall, the risk of harms such as lymphedema, restricted motion, paraesthesia or wound infections was associated with the extent of the surgical intervention and occurred more frequently in patients who underwent complete ALND than SLND only. 3.8. Lymphedema A meta-analysis of five RCTs (including the Z0011study and the ALMANAC [Axillary Lymphatic Mapping Against Nodal Axillary Clearance] – trial36) with data on 2154 patients indicated that the risk of lymphedema after 6 months is 70% lower in patients with SLND only than in those treated with complete ALND (OR 0.3; 95% CI 0.14–0.66, p = 0.0028).31 This result is consistent with a more recent prospective cohort-study not included in the meta-analysis.33
3.9. Restricted motion Two studies with data on more than 1000 patients, the ALMANAC- trial and a prospective cohort study, determined the risk of postoperatively restricted arm motion.33,35 The ALMANAC-trial (n = 829), showed a 74% lower risk of limited range of motion in patients with SLND only than in patients with complete ALND (OR 0.26, 95% CI 0.16–0.4), 1 month after the intervention.35 The difference decreased over time but was still statistically significant after 3 months favouring SLND only over complete ALND (3.3% versus 6.6%; p = 0.035). After 6 and 12 months, no statistically significant differences could be detected between treatment groups. Likewise, results of the cohort study showed significant differences 1 month postoperative in favour of the SNLD-group (flexion, extension, adduction, abduction, internal and external rotation: p < 0.001–0.038).33 These differences had a tendency to decrease over time.
3.10. Paraesthesia The risk of a postoperative paraesthesia was also statistically significantly lower in patients with SLND only than with complete ALND. A meta-analysis of five RCTs with almost 3300 patients determined a 75% lower risk of upper limb-paraesthesia for SLND only than complete ALND after 6 months (OR 0.25, 95% CI 0.10–0.59, p = 0.0018).31 The ALMANAC-trial (n = 829) showed a 72% lower risk of numbness for SLND (OR: 0.28, 95% CI 0.19–0.43*), up to 18 months after the intervention.35 Inadvertent division of the intercostobrachial nerve occurred in 22.6% of complete
A. Glechner et al. / European Journal of Cancer 49 (2013) 812–825
ALND procedures and in 5.3% of operations using SLND only.35 3.11. Wound-infections The risk for wound-infections was lower for women treated with SLND only than complete ALND. A meta-analysis of 3 RCTs with almost 2800 patients, determined a 42% lower risk for wound-infections with SLND only than complete ALND (OR 0.58, 95% CI 0.42–0.8; p = 00011).31 4. Discussion In this systematic review of data on more than 50,000 patients, results indicate similar 5-year survival and local- regional recurrence rates between women with positive sentinel nodes treated with SLND only or complete ALND. Furthermore, women treated with SLND only reported statistically significantly higher scores of quality of life than women undergoing complete ALND which is probably related to the lower rates of harms such as lymphedema, restricted motion, paraesthesia and wound infections. The strength of the evidence is low for some outcomes and moderate for others. Our confidence in some results is reduced because the estimates often have wide confidence intervals which include values for which a clinically important difference between the approaches exists. Issues with applicability also reduce our ability to transpose these results on the wider breast cancer population. Methodological restrictions, for example the lack of information concerning allocation concealment in the Z0011 study and susceptibility of observational studies to selection bias, may also have distorted our findings. The large sample sizes in metaanalyses of observational studies can lead to seemingly precise estimates that can be spurious due to residual confounding. Despite populations with varying prognosis in included studies, results consistently showed similar effectiveness between SLND only and complete ALND, and a higher risk for harm associated with ALND. Our results indicate that surgeons should discuss the option of performing SLND instead of complete ALND with sentinel node-positive patients. This option could be applicable to women with T1 or T2 disease, who have no clinically palpable lymph nodes, and who undergo breast conserving surgery followed by tangential irradiation and systemic therapy. The current state of evidence, however, is not yet sufficient to exactly define the group of patients for whom ALND is never necessary. Considerable uncertainties exist, particularly with respect to long-term recurrences, and in hormonereceptor positive patients. According to a cross-sectional study of the U.S. population, breast cancer patients with hormone-receptor negative tumors have a much greater risk of recurrence during the initial 7 years following
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breast cancer diagnosis than those with hormone-receptor positive tumors, who have a greater risk of recurrence after that period.19,37 In addition, new chemotherapeutic regimens, endocrine therapies and HER2-antibody directed therapies may further tip the balance of benefits and tradeoffs towards a less invasive surgical approach. Criteria to be weighed in the decision-making process for or against ALND may include prognostic factors, isolated tumour cells or micrometastases in the sentinel lymph nodes, or the ratio of involved to the total number of labelled or examined negative lymph nodes. The use of nomograms may be helpful in this process.38 Our review has several limitations. Most important are issues of applicability. Adjuvant opposing tangential field irradiation of the breast nearly always entails unintentional irradiation of the lower portions of the axillary lymph drainage regions, exposing them to a tumoureffective dose.39 No axillary-specific irradiation was performed in the Z0011-population, but it is likely, that a significant portion of the axilla was treated.16 It remains unclear whether modifications should be made to the way adjuvant radiation therapy of the breast is performed to include lymph node sites located inferior to the brachial plexus and axillary vein in cases where ALND is not performed. Furthermore, questions remain regarding the timing and intensity of adjuvant chemotherapy. The proportion of women included in these studies whose cancer was detected by screening is also unclear. A mammographic screening trial with 42,283 women indicated that women who are treated following breast cancer screening may not have developed clinically relevant breast cancer.40 Such women have a good prognosis and would dilute the beneficial effect of one surgical approach over the other. Women whose cancer was detected clinically could possibly benefit from a more invasive approach. Meta-analysis of observational studies has serious limitations and can lead to spurious, overly precise findings. We decided to statistically combine data of the Z0011 study and two observational studies because a major criticism of the Z0011 study was that it was underpowered. Despite the clinical heterogeneity of the study populations, results of all three studies indicated similar effectiveness of SLND and ALND. The uncertainty of these findings, however, is reflected by the low grading of the strength of evidence which indicates that future studies might have a substantial impact on the estimates of the effects. Finally, publication bias is a concern for all systematic reviews. The small number of studies in our metaanalyses limits the validity of statistical approaches to test for publication bias. Although we have searched for unpublished literature, there is no way for us to assess the completeness of the body of evidence.
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In light of the existing uncertainty of the evidence, only further prospective studies with appropriately delineated subgroups will define patient cohorts in whom the need for ALND can be eliminated with certainty. Given the current level of evidence, the effects of irradiation and systemic therapy should be considered and documented, and patients with higher tumour stages included.
6. 7.
Funding source 8.
German Guideline programme in Oncology: Association of the Scientific Medical Societies in Germany, German Cancer Society, German Cancer Aid. The funding sources had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
9.
10.
Authors’ contributions All authors contributed to the planning of the study, the analysis and interpretation of results and to the writing of the manuscript.
11.
12.
Conflict of interest statement 13.
Achim Woeckel and Rolf Kreienberg are members of the German Cancer Aid. None of the authors had a financial relationship with a commercial corporation that has an interest in the subject of this manuscript. None of the authors has any conflict of interest with respect to the topic and content of the manuscript. Acknowledgment We wish to thank Evelyn Auer from the Danube University Krems for administrative support.
15.
16.
17.
18.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.ejca.2012.09.010.
19.
20.
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