Management of axilla in breast cancer – The saga continues

The Breast xxx (2015) 1e11

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Review

Management of axilla in breast cancer e The saga continues Rakhshanda Layeequr Rahman a, *, Sybil L. Crawford b, Portia Siwawa a a b

Texas Tech University Health Sciences Center, 1400 Coulter, Amarillo, TX, 79106 USA University of Massachusetts Medical School, 419 Belmont Street, Worcester, MA, 01605, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 October 2014 Received in revised form 13 January 2015 Accepted 22 March 2015 Available online xxx

Prospective trials investigating the accuracy of SLNB for cN0 (primary surgical therapy) and cN1 patients (neoadjuvant chemotherapy) have not utilized likelihood ratios (LR) to assess the impact of false negative SLNB. This review evaluates the evidence on accuracy of SLNB using STARD and QUADAS-2 (revised) criteria for patients undergoing primary surgical therapy and primary chemotherapy. It utilizes the: (i) Reported rates for pre-test probabilities of node positive disease from Surveillance, Epidemiology, and End Results (SEER) database for the cN0 patients (primary surgical therapy) for each T stage; calculates the negative LR from cumulative evidence; and uses the Bayesian nomogram to compute the post-test probability of missing the metastatic axillary node based on negative SLNB. (ii) Reported rates of complete axillary response in ACOSOG-Z1071 trial for cN1 patients to calculate the pre-test probabilities of residual nodal disease for each biological tumor sub-type; calculates the negative LR from ACOSOG-Z1071, and SENTINA trial data; and uses the Bayesian nomogram to compute the post-test probability of missing the residual metastatic axillary node based on negative SLNB. For cN0 disease, the odds of missing axillary disease based on negative SLNB for each T stage are: T1a ¼ 0.7%; T1b ¼ 1.5%; T1c ¼ 3%; T2 ¼ 7%; T3 ¼ 18%. For cN1 disease, the odds of missing residual axillary disease based on negative SLNB for each biological subtype are: HER2neuþ ¼ 8%; Triple negative ¼ 15%; ERþ/PRþ/HER2neu- ¼ 45%. Negative LR is more accurate and superior to false negative rate for determining the clinical utility of SLNB by taking into account the changing pre-test probability of disease. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Axilla Sentinel node biopsy Axillary dissection Likelihood ratios Accuracy

Introduction All therapies in medicine carry an inherent associated morbidity; surgery is the starkest example because of its invasive nature. Consequently, all surgical procedures have to be justified via decreased risk/benefit ratio to be ethically acceptable. Therefore, the natural direction of surgical research, development, and innovation gravitates towards less invasive techniques in order to minimize the risk/benefit ratio. The evolution of management of axilla in breast cancer is a classic example of this natural sequence. During the last two decades, sentinel node biopsy (SLNB) has largely replaced axillary node dissection for clinical node negative disease [1,2]. This approach has been validated via two large prospective randomized controlled trials [3,4]. This decade is pushing

* Corresponding author. E-mail addresses: [email protected] (R. Layeequr Rahman), Sybil. [email protected] (S.L. Crawford), [email protected] (P. Siwawa).

the envelope, to ascertain if SLNB can replace axillary dissection in clinical node positive disease [5,6]. Whereas, there is no doubt that SLNB procedure is minimally invasive and is associated with lower complication rate [7,8], reducing the risk; whether it maintains the benefit of axillary dissection across a variety of clinical scenarios, remains controversial [9,10]. To our knowledge, no previous systematic review has assessed the diagnostic accuracy of SLNB in the evaluation of axilla for breast cancer patients utilizing the evaluation criteria for the practice of evidence-based medicine. Tools such as Standards for Reporting of Diagnostic accuracy (STARD) [11] and Revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) [12] have enabled a systematic assessment of articles on diagnostic accuracy. This review attempts to apply the STARD and QUADAS-2 methodology for evaluation of evidence regarding sentinel node biopsy procedure in breast cancer for the principled practice of evidence-based medicine (EBM) [13]. The goals of axillary surgery in breast cancer are: (i) to accurately stage the disease for therapeutic decisions and prognostic

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information, and (ii) to maximize patient survival and loco-regional control. These benefits need to be balanced against the risks of axillary surgery. The results of this systematic review may be used to resolve the controversy surrounding the use of SLNB across diverse clinical scenarios, which can aid the optimization of individualized diagnostic and therapeutic approach to axilla in breast cancer patients.

rated as adequately reported (score ¼ 1), not reported (score ¼ 0), or partially reported (score ¼ 0.5) to yield a semi quantitative numeric summary score. Using QUADAS-2, the seven domains were rated as having low, high or unclear “Risk of Bias” or Applicability Concerns”. Final ratings were agreed upon by consensus. All data was entered in an Excel spread sheet for each review question for analysis.

Methods

Reliability assessment for STARD and QUADAS-2

Review questions

Inter-reader reliability of overall scores was demonstrated by inter-reader intra-class correlation coefficients (ICCs). ICC values 0.40 indicated poor, >0.40 and 0.60 moderate, >0.60 and 0.80 substantial and >0.80 excellent agreement [14]. A semiquantitative score for QUADAS-2 was designed using a dichotomous grading system in which items rated as low risk received a score of 1, and all others a score of 0. The ICC was calculated between the total numeric scores of the two reviewers for STARD and QUADAS-2. Analyses and graphical illustration were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA).

The overarching questions of this review were: 1. Is there direct evidence that SLNB accurately stages the axilla in breast cancer patients who receive primary surgical therapy, clinically staged as T1-3, N0 disease? 2. Is there direct evidence that SLNB (performed after chemotherapy) accurately stages the axilla in breast cancer patients who receive neoadjuvant chemotherapy, clinically staged as T13, N1 disease at the outset?

Data analysis Literature search Two investigators independently performed electronic searches of PubMed (Medline), EMBASE, and Cochrane Library from 1993 to December, 2014. The year 1993 was selected because the first publication on SLNB for breast cancer was published in that year. The search strategy combined the Medical Subject Heading (MeSH), EMBASE terms and free text words. These terms included: (“breast cancer” OR “breast malignancy” OR “breast neoplasm”) AND (“sentinel node biopsy” OR “SLNB” OR “sentinel node dissection” OR “axillary staging” OR “lymph node staging” OR “regional staging”). The bibliographical references of eligible studies were also searched. Study identification Two reviewers independently examined the abstracts to determine if they met the inclusion criteria for each study question. Manuscripts of all relevant studies were retrieved and independently assessed for review eligibility by the same investigators. Disagreements were resolved by consensus.

With a maximum score of 25 using the STARD tool, studies with scores 15 were classified as excellent quality of reporting; 10 and <15 were classified as fair quality; and <10 were classified as poor quality. Using QUADAS-2, studies were given a low risk of bias if both the ‘Index Test’ and ‘Flow and Timing’ items were rated as low risk. If both items were rated as unclear or high risk, a high risk of bias was given. All other studies were considered moderate risk. The same criterion was used to determine applicability concerns using the ‘Patient Selection’ and ‘Index Test’ items. An overall inadequate quality was given if both ‘Risk of Bias and ‘Applicability’ concerns were considered moderate risk or if either was rated high risk. All other studies were considered adequate quality. Likelihood ratios were calculated from pooled data from all selected studies for each of the two review questions to accurately compute the clinical impact of false negative SLNB by utilizing superior statistical measure than false negative rate [15]. Results Review question 1: accuracy of staging with SLNB in cT1-3N0 breast cancer patients undergoing primary surgical therapy

Inclusion criteria For the first review question (cT1-3N0 eprimary surgery), all studies reporting on accuracy of SLNB in unifocal breast cancer patients undergoing primary surgical therapy that listed the numbers of true positive, true negative, and false negative results and had at least 100 successful SLNB's were included. For the second review question (cT1-3N1 epost neoadjuvant chemotherapy), all studies reporting on SLNB after neoadjuvant chemotherapy in patients with clinical diagnosis of axillary metastasis by physical examination, or axillary ultrasound, with pathological confirmation (via fine needle aspiration or core biopsy) at presentation, undergoing completion axillary dissection, were included. Assessment tools and data extraction Two reviewers independently assessed the reporting quality and methodological quality of each selected study using the STARD [11] and QUADAS-2 [12] tools. Using the STARD, the 25 items were

Using the aforementioned search terms and inclusion criteria, 527 citations were identified. Abstract and references from these citations were reviewed and 25 full-text manuscripts were read of which 19 met the search criteria [16e34]. The ICC coefficients between the two reviewers for STARD was 0.98 representing excellent agreement. Thirteen of 19 (68.4%) studies were rated as excellent; 6/19 (31.5%) as fair [inter-reviewer agreement ¼ 89.5%; kappa ¼ 0.76]. The most common inadequacy in reporting across all studies was related to the lack of blinding between the pathologist reporting on SLN and those reporting on non-sentinel axillary nodes. It is conceivable that identification of tumor in a nonsentinel lymph node might lead to more thorough evaluation of SLN potentially contributing to bias in favor of accuracy of the SLNB. Another area of concern was the estimates of variability of diagnostic accuracy between subgroups of participants (cT1-3). The largest study in this review is the NSABP B-32 trial with over 2672 evaluable patients of which only 55 had T3 tumors [31]. For the QUADAS-2 evaluation, the ICC between two reviewers was 1.0, again representing excellent agreement (100%) for all four

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Fig. 1. Nomogram for Interpreting Diagnostic Test Results. Adapted from Fagan TJ. Nomogram for Bayes's theorem. N Engl J Med. 1975; 293:257. Copyright © 1975 Masschusetts Medical Society. All rights reserved. Adapted with permission from the Massachusetts Medical Society.

domains: (i) Patient Selection e 12/19 (63.2%) studies had low risk for bias; 5/19 (26.3%) studies had low risk for applicability concerns. (ii) Index Test e 6/19 (31.6%) studies had low risk for bias; 10/19 (52.6%) studies had low risk for applicability concerns. (iii) Reference Standard e 13/19 (68.4%) studies had low risk for bias; 15/19 (79%) studies had low risk for applicability concerns. Flow/Timing e 16/19 (84.2%) studies had low risk of bias. The issue of which statistical test is best to report accuracy of SLNB requires attention. The most commonly used method for reporting accuracy of a diagnostic test is sensitivity and specificity. These tests are dependent on disease prevalence and therefore are generally used for epidemiological purposes and not for individualized clinical decisions. Initial scrutiny of SLNB carefully focused on calculation of false negative rate [35]. McMasters and colleagues explained in detail why it was important to correctly calculate false negative rate by using all patients with positive nodes (on axillary dissection) as denominator instead of total number of patients that participated because only patients with node-positive disease are at risk of being incorrectly labeled node-negative (False negative rate ¼ false negatives/false negatives þ true positives). Moreover, Jatoi pointed out that some studies on SLNB utilized incorrect calculation of false negative rate [36]. Whereas, false negative rate is superior to negative predictive value in addressing the “at risk” population, i.e. patients with node positive disease; it still does not account for

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changing prevalence of node positive disease across the spectrum of breast cancer (T stage at presentation). Principles of evidencebased medicine dictate the use of likelihood ratios for evaluation of accuracy of SLNB [15]. Likelihood ratios are superior to negative and positive predictive values (and false negative rate alone in this case) because likelihood ratios do not change with disease prevalence and can be used for a range of results. Likelihood ratio uses the pre-test probability of disease (positive node in this case) and sensitivity and specificity of the test to determine the post-test probability of the disease. Likelihood ratio of a positive test or positive likelihood ratio (þLR) ¼ sensitivity/1-specificity. Likelihood ratio of a negative test or negative likelihood ratio (LR) ¼ 1-sensitivity/specificity. Once these ratios are calculated, post-test probability can be determined utilizing the Bayesian nomogram proposed by Fagan (Fig. 1) [37]. This approach provides most individualized interpretation of test results. In case of positive likelihood ratio (þLR), the post-test probability provides the odds of a patient truly having the disease. This is irrelevant in case of SLNB because there are no false positive sentinel nodes. In case of negative likelihood ratio (LR), the post-test probability provides the odds of missing a positive node in the axilla; i.e. the possibility that the sentinel node is negative, despite a positive node in the axilla. The pre-test probability of a positive node according to the tumor size has been reported using SEER public database first by Carter et al. [38] in 1989, followed by Barone et al. [39] in 2005 (Table 1). Table 2 presents the detailed calculations for of sensitivity, specificity, negative and positive predictive values and likelihood ratios for the 19 studies that met review criteria including the largest prospective randomized trial. The pooled false negative rate from these studies reporting large numbers of successful SLNB procedures is 8.6%. This would suggest that a negative sentinel node in a clinically node negative patient is likely to incorrectly label the patient as pathological N0 stage only 8.6% of times. However, since the pre-test probability of node positive disease is vastly different for cT1 disease from cT3 disease, the þLR, and LR are more appropriate tests for calculation of accuracy of SLNB across these clinical spectrums. The þLR would actually be infinite (using the formula cited above) because there is no report of a false positive sentinel node. For computation purposes, if a specificity of 99.99% is used (instead of true specificity of 100%), the cumulative likelihood of a positive SLN e the þLR is 9137 (95% CI, 8934e9340). The nomogram does not list a likelihood ratio of more than 2000. Placing a straight edge on any pre-test probability and approximating the location of posttest using a þLR of 9137 would essentially be 100%. The likelihood ratio of a negative SLNB (LR) is 0.086 (95% CI, 0.066e0.107) from the pooled data in Table 2. The pre-test probabilities for each cancer stage (as listed in Table 1) are marked in Fig. 2. As evident from Fig. 2, the chance of missing a positive axillary node (i.e. the possibility that the SLN is negative, but there is actually a positive node in the axilla) increases as the pre-test probability of a positive node increases. Approximate likelihood of missing a positive node by utilizing SLNB for staging is: 0.7% for

Table 1 Probability of positive nodes according to tumor size (pre-test probability) via SEER data. Author/Year

Carter et al.,/1989 Barone et al.,/2005

Number of patients/positive axillary nodes% T1a

T1b

T1c

T2

T3

Total

339/20.6 16,300/7.8

996/20.6 39,836/13.3

6984/33.1 83,031/28.5

13,723/49.5 63,744/50.2

2698/70.0 10,381/70.11

24,740/45.5 213,292/32.6

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Table 2 Identification and accuracy rates of sentinel node biopsy in breast cancer for patients undergoing primary surgical therapy. Author/Year

Identification of sentinel lymph node/s SLNB attempted

Borgstein et al.,/1998 Krag et al.,/1998 Bass et al.,/1999 Morrow et al.,/1999 Veronesi et al.,/1999 Bergkvist et al.,/2001 Tafra et al.,/2001 Nano et al.,/2002 Wong et al.,/2002 Chua et al.,/2003 Patel et al.,/2003 Veronesi et al.,/2003 Lo et al.,/2006 Varghese et ak/2007 Yen et al.,/2007 Krag et al.,/2007 Somashekhar et al.,/2008 Challa et al.,/2010 Ban et al.,/2011 Total

104 443 186 139 257 498 535 328 3324 547 125 376 175 329 213 2746 100 523 e 10,948

Accuracy of sentinel node biopsy

SLNB successful

Identification rate

FN#

TP#

TN#

FN rate%

Sensitivity

NPV

NLR

104 405 173 110 257 450 465 285 3106 480 119 371 165 321 207 2672 100 478 328 10,596

100% 91% 93% 79% 100% 90% 87% 87% 93% 88% 95% 99% 94% 98% 97% 97% 100% 91% e 93%

1 13 1 4 8 20 18 8 83 34 2 12 3 10 4 75 1 13 12 322

44 101 53 28 83 164 122 93 1225 152 33 168 45 63 77 691 26 141 99 3408

59 291 119 78 166 266 325 184 1898 294 84 191 117 248 82 1853 73 324 217 6869

2.2% 11.4% 1.9% 12.5% 8.8% 10.9% 12.9% 7.9% 6.3% 18.3% 5.7% 6.7% 6.3% 13.7% 4.9% 9.8% 3.7% 8.4% 10.8% 8.6%

0.98 0.89 0.98 0.88 0.91 0.89 0.87 0.92 0.94 0.82 0.94 0.93 0.94 0.86 0.95 0.90 0.96 0.92 0.89 0.91

98% 96% 99% 95% 95% 93% 95% 96% 96% 90% 98% 94% 98% 96% 95% 96% 99% 96% 95% 96%

0.0222 0.1140 0.0185 0.1250 0.879 0.1087 0.1286 0.0792 0.0635 0.1828 0.0571 0.0667 0.0625 0.1370 0.0494 0.0979 0.0370 0.0844 0.1081 0.0863

FN ¼ false negative; TP ¼ true positive; TN ¼ true negative predictive value; NPV ¼ negative predictive value; NLR ¼ negative likelihood ratio. Note:false positive; specificity, positive predictive value, and positive likelihood ratio are not reported because a “false positive” sentinel node has never been reported which would render specificity to be 100%; positive predictive value to be 100% and positive likelihood ratio to be infinite.

Fig. 2. Post etest probability of a positive node after a negative sentinel node biopsy according the negative likelihood ratio calculated from cumulative data including NSABP B-32 trial in Table 2; pre-test probabilities used from Table 1 recent data.

cT1a, 1.5% for cT1b, 3% for cT1c, 7% for cT2, and 18% for cT3. Clearly, the application of an 8.6% false negative rate to cT3 breast cancers is likely to provide a false sense of security for axillary staging. The largest study answering the question of accuracy of SLNB in cT1T3N0 disease is the NSABP B-32 trial [31]. In this trial, clinically node negative patients with invasive breast cancer were randomized to undergo SLNB followed by axillary dissection (group1), or SLNB followed by axillary dissection for SLN positive disease, and no ALND for SLN negative disease. Group 1 is eligible for calculating the LR for SLNB, since accurate sensitivity and specificity can be calculated; LR for B-32 trial is 0.1. It is important to note that only 55 of the 2807 (2.1%) of patients had cT3 disease. Therefore the results of this trial should not be applicable to patients with cT3N0 disease. This evidence is contrary to a recent review that suggests that SLNB should be considered standard of care for staging the axilla in women with T1-T3, clinically node-negative breast cancer [40]. This debate leads to the question whether the size of primary tumor impacts the rate of false negative SLNB? Several studies support the notion that the probability of false negative SLNB increases as the primary tumor size increases (Table 3) [23,25,41e45]. Only 2 of these studies [23,25] met the inclusion criteria for this review; 5 were excluded due to small numbers or inadequate reporting of data. On the contrary, there are studies documenting that the rate of false negative SLNB was not impacted by the size of primary tumor (Table 4) [20,21,46e49]. Once again, only 2of these studies [20,21] met the inclusion criteria for the current review. Interestingly, the data that supports that tumor size does not matter is very scant regarding T3 tumors. Hill et al. [46] report no relationship between tumor size and false negative rate which was 10.6%; however, in a study of 500 cases only 55 tumors are reported to be T2/3. Similarly, Veronesi and co-authors [20] have reported a false negative rate of 6.7% but the study did not include T3 tumors. Bergkvist and group [21] describe a false negative rate of 10.9% and note no relationship to false negative rate. The paper describes the range of tumor sizes between 1 and 100 mm with a mean of 20 mm; however 80% of women underwent breast conservation suggesting that they were likely not very large tumors. Feldman and associates [47] report a false negative rate of 19% unrelated to

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Table 3 Studies supporting that the size of primary tumor impacts the false negative rate of SLNB. Author

Patients#

FN rate

Conclusion

Ozmen et al. Nano et al. Winchester et al. Chua et al. Nason et al. O'Hea et al. Tousimis et al.

111 328 72 480 82 60 70

11.3% 7.9% 8.3% 22.4% 16% 5.4% 8%

Multifocality and tumor size >2 cm was associated with high FN rate Mean tumor size in FN group ¼ 2.4 ± 1.4 cm Tumor size in all FN cases was >2.1 cm FN rate was directly proportional to tumor size FN rate was directly proportional to tumor size FN rate was directly proportional to tumor size Tumor size in all FN cases was >5 cm

Table 4 Studies supporting that the size of primary tumor does not impact the false negative rate of SLNB. Author

Patients#

FN Rate

Conclusion

Hill et al. Veronesi et al. Bergkvist et al. Feldman et al. Chung et al. Wong et al.

104 371 450 70 41 2148

10.6% 6.7% 10.9% 19% 3% 3.4e9%

No difference in FN rate between T1 and T2 No association between tumor size and FN rate No association between tumor size and FN rate Tumor size did not differ between TP and FN Only 1 FN case of 41 T3 cancers FN rate was not different for T1,2 or 3 (Only T1-2 were eligible, some T3 tumors were included because they were cT2)

tumor size but 97% of patients had tumors smaller than 3 cm. Chung et al. [48] report the largest series of 41 T3 tumors; this is a retrospective review of registry data over 10 year period with 100% identification rate. These data have not been reproduced. Lastly, Wong et al. specifically reported no difference between false negative rates for T2 and T3 tumors. It is interesting to note that this is a report on prospectively collected registry data which is maintained only on T1-T2 tumors. The T3 tumors in this series are the ones that were staged clinically as T2 and were found to be larger on pathologic staging. These findings and implications of LR help clarify the discrepancy between the recent review by Ho and Morrow [40] and ASCO guidelines [50], on clinical use of SLNB for axillary staging of T3 breast cancers. Whereas, the review suggests that SLNB is accurate for staging in T1-T3 tumors, the ASCO guidelines do not recommend SLNB for T3 and T4 tumors. Since, SLNB has largely replaced axillary dissection for clinical node negative disease, it is unlikely that a large series of T3 patients will be published; however, this review should provide an important tool for informed consent emphasizing that false negative rate for a T3 clinical node negative disease is 18%. Review question 2: accuracy of staging with post neoadjuvant SLNB in cT1-3N1 (biopsy confirmed) breast cancer patients undergoing primary chemotherapy Using the above-mentioned search terms and inclusion criteria, 437 citations were identified. Abstract and references from these citations were reviewed and 19 full-text manuscripts were read of which 10 met the search criteria (Table 5) [5,51e59]. The ICC coefficient between the two reviewers for STARD was only 0.37, likely due to the low variability in scores, which tends to reduce correlation [60]. However, there was 90% agreement on categorized total score representing the quality of studies; reviewer 1 rated all 10 (100%), while reviewer 2 rated 9 of 10 (90%) studies as excellent and 10% (1 study) as fair. Similar to review question 1, the most common inadequacy in reporting across all studies was related to the lack of blinding between the pathologist reporting on SLN and those reporting on non-sentinel axillary nodes. For the QUADAS-2 evaluation, the ICC between two reviewers was 0.48 e again reflecting low variability in scores e representing moderate agreement for all four domains: (i) Patient Selection e 9/10 (90%) studies had low risk for bias; 8/10 (80%) studies had low risk for

applicability concerns. (ii) Index Test e 9/10 (90%) studies had low risk for bias; 8/10 (80%) studies had low risk for applicability concerns. (iii) Reference Standard e 10/10 (100%) studies had low risk for bias; 10/10 (100%) studies had low risk for applicability concerns. Flow/Timing e 7/10 (70%) studies had low risk of bias. The clinical situation that led to application of SLNB in post neoadjuvant setting stems from the fact that neoadjuvant chemotherapy has played an increasing role in the comprehensive management of breast cancer; and whereas, the advent of SLNB allowed for omission of axillary dissection patients undergoing primary surgical treatment, in all node-negative patients and many nodepositive patients with low risk disease [61,62]; neoadjuvant patients were intuitively obligated to undergo axillary dissection despite a favorable breast tumor response, lest they had node positive disease upfront. Two different approaches emerged: (I) Proponents of accurate staging before treatment planning supported the notion of upfront SLNB followed by chemotherapy. Identification rates with this approach have been 98e100% [63e66]; and the rate of positive nodes range from 29 to 67% [48,67]. A positive SLN upfront would translate into axillary dissection post chemotherapy; and a negative SLN would require no further axillary surgery. This approach provides accurate staging information for treatment planning and prognostication; it however commits all patients with positive SLN to axillary dissection irrespective of axillary status after chemotherapy. (II) Proponents of avoiding axillary dissection in patients, who have complete pathological response in the axilla, support the notion of postchemotherapy SLNB. Advances in chemotherapeutic agents have reduced the rate of node positive disease by 30% for preoperative Adriamycin, and cyclophosphamide (NSABP-18 trial), and by 40% in taxane-based regimens (NSABP-27 trial) [68,69]. The overall rate of complete axillary response to chemotherapy varies between 20 and 42% in patients with pathologically confirmed clinical nodepositive disease at the outset [56,70,71]. If these complete responders can be accurately staged post-chemotherapy, complete axillary dissection could potentially be avoided. However, the reports on post-chemotherapy SLNB clearly have an overlap between two different patient populations; those who present with clinical node-negative disease (who may or may not have pN1 stage) and those who present with clinically node-positive disease (most likely confirmed by biopsy, therefore, pN1 stage) at presentation. Clearly, these two patient populations represent very different risk status in terms of prognosis and assessment of response to

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Table 5 Identification and accuracy rates of sentinel node biopsy in breast cancer for patients post neoadjuvant chemo therapy. Author/Year

Newman et al.,/2007 Shen et al.,/2007 Brown et al.,/2010 Ozmen et al.,/2010 Thomas et al.,/2011 Alvarado et al.,/2012 Boughey et al.,/2013 Park et al.,/2013 Rebollo-Aguirre et al.,/2013 Yagata et al.,/2013 Total

Identification of sentinel lymph node/s

Accuracy of sentinel lymph node biopsy

SLNB attempted

SLNB successful

Identification rate

FN#

TP#

TN#

FN rate%

Sensitivity

NPV

NLR

40 69 e 77 30 150 689 178 45 95 1373

40 64 86 71 26 139 639 169 45 81 1360

100% 93% #VALUE! 92% 87% 93% 93% 95% 100% 85% 93%

3 10 13 7 3 15 56 22 2 8 139

28 30 47 44 15 57 326 78 22 43 690

12 16 26 20 8 39 255 69 21 38 504

9.7% 25.0% 21.7% 13.7% 16.7% 20.8% 14.7% 22.0% 8.3% 15.7% 16.8%

0.90 0.75 0.78 0.86 0.83 0.79 0.74 0.78 0.92 0.84 0.78

80% 62% 67% 74% 73% 72% 69% 76% 91% 83% 72%

0.0968 0.2500 0.2167 0.1373 0.1667 0.2083 0.2557 0.2200 0.0833 0.1569 0.2203

FN ¼ false negative; TP ¼ true positive; TN ¼ true negative predictive value; NPV ¼ negative predictive value; NLR ¼ negative likelihood ratio. Note:false positive; specificity, positive predictive value, and positive likelihood ratio are not reported because a “false positive” sentinel node has never been reported which would render specificity to be 100%; positive predictive value to be 100% and positive likelihood ratio to be infinite.

chemotherapy (pathological axillary response rate cannot be applied to patients whose pathological axillary status at presentation is not known). Several small studies were followed by two meta-analyses that included both cN0 and cN1 patients who underwent post-chemotherapy SLNB and axillary dissection [72,73]. van Deurzen and colleagues analyzed 27 of the 574 eligible studies with 2148 patients [72]. The pooled identification rate of SLN was 90.9% with a false negative rate of 10.5%. The authors did note that the initial node positive state was associated with decreased accuracy of SLNB. Similarly, Xing and colleagues analyzed data from 21 studies including 1273 patients [73]. Meta-analyses performed using Bayesian modeling resulted in identification rate of 91% and sensitivity of 88%. A multicenter prospective study from France reported a lower identification rate and higher false negative rate in clinical node-positive patients compared to node-negative disease at presentation [74]. Given the stark difference between these patient populations, two separate meta-analyses have been reported for cN0 [75] and cN1 [76] patients undergoing post-chemotherapy SLNB and axillary dissection. In 2011, the meta-analysis by Tan et al. indicated that for clinically node negative patients, the false negative rate of 7% is similar to the false negative rate in patients without neoadjuvant chemotherapy [75]. The value of SLNB after neoadjuvant chemotherapy is more significant in clinically confirmed node-positive patients because once SLNB replaces axillary dissection after positive nodes are converted to negative nodes after chemotherapy (ypN0), the number of axillary conserving surgeries should increase. Fu et al. performed a metaanalysis of SLNB procedures done after chemotherapy in nodepositive patients [76]. They reported a pooled identification rate of 89%, and false negative rate of 14%. However, this meta-analysis includes all studies with cN1 at presentation many of which did not require pathological confirmation of N1 status at presentation. To avoid bias created by studies including cN1 disease without pathological confirmation, the current review focuses on studies with confirmed cN1 status at presentation, and reports the detailed calculations for of sensitivity, specificity, negative and positive predictive values and likelihood ratios for 10 studies that met review criteria including the largest prospective randomized trial (Table 5). It is important to note that only one of the two large prospective trials (ACOSOG Z-1071 [5], and the SENTINA study [6]) is included in Table 5. This is because the SENTINA trial did not mandate pathological confirmation of cN1 status at presentation and therefore did not meet inclusion criteria. It is worthwhile to mention that the strength of this trial lies in the post chemotherapy assessment of disease status (ycN1 versus ycN0) to allocate appropriate trial arms. Whereas, ACOSOG Z-1071 did mandate pathological confirmation of nodal status, it does not differentiate

between post chemotherapy clinical stages (ycN) for differential calculation of accuracy of SLNB. Applying the same principles of evidence-based medicine, the LR can be applied to post neoadjuvant situation provided the pre-SLNB probabilities of residual node-positive disease can be calculated. The pooled false negative rate from included studies on post neoadjuvant chemotherapy SLNB procedures is 16.8% (Table 5). First, this false negative rate is substantially higher than the anticipated rate of less than 10%. Second, the attempts to find a subset of patients with low false negative rate, have focused on the impact of technical factors on false negative rate, specifically, the number of sentinel nodes removed; both studies report that as the number of sentinel nodes increases, the false negative rate decreases. The role of number of sentinel nodes is rather confusing because the definition of a sentinel node is specific [77]. For the blue dye technique, a sentinel node is defined as the blue-stained node. For the radioactive tracer technique, it is the most radioactive node by absolute counts, a 10:1 ratio of sentinel node to background count, a 4-fold reduction in count after sentinel node is removed, or a 10 s count greater than 25. In addition, suspicious palpable node can be removed as a sentinel node. Clearly, lymphatic drainage characteristics and not the surgeon, define the number of sentinel nodes in a given patient. Reports that indicate lower false negative rates with increasing the number of sentinel nodes, and recommend at least 2e3 nodes be taken as sentinel nodes may result in unintended consequence of non-sentinel nodes being labeled as sentinel nodes without increasing the accuracy of SLNB. As mentioned above the pre-test probability of node-positive disease is derived from biological factors such as tumor size (at the outset) and response to systemic therapy in the post neoadjuvant setting. It is important to note that the representation of T3 tumors in Z-1071 and SENTINA study was 26% and 8% respectively e the group that is unlikely to be accurately staged with SLNB even in cN0 setting as discussed above. The rate of residual axillary disease after chemotherapy is dictated by tumor biology and provides insight into post chemotherapy pre-SLNB probability of ypN1 disease. Using these probabilities and applying LR is more accurate for computing the impact of a negative SLNB on post neoadjuvant patients. The likelihood ratio of a negative SLNB (LR) is 0.220 (95% CI, 0.178e0.262) from the pooled data in Table 5. The pre-test probabilities for each biological tumor sub-type can be gleaned from the ACOSOG Z-1071 trial team's report in 2014 [78] that documents the accuracy of SLNB as a function of tumor biology which dictates complete pathological response in the breast, axilla or both. Therefore, specific tumor biology related subgroups that did not have complete pathological response in the axilla provide the pre-test probability of a residual positive axillary node. Z-1071 reported complete pathological axillary response in

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41.1% of patients. In other words, the pre-SLNB post-chemotherapy probability of residual disease is 58.9%. The authors report this data according to biological tumor markers, hormone positive/HER2 neu negative tumors being least likely to respond, and HER 2 neu positive tumors being most likely to respond. Applying the EBM principles for interpretation of Z-1071 data, pre-test likelihood ratio can be determined according to biological tumor category. Utilizing the Bayesian nomogram, the pre-test probabilities and the LR can be used to compute the post-test probability of missing a negative node by relying on SLNB (Fig. 3). According to Z-1071 data, the odds of missing a positive axillary node when the SLNB is negative after chemotherapy are: 15% for triple negative cancers; 8% for HER2 neu positive cancers; and 45% for hormone positive/HER2 neu negative cancers. Because of the wide difference in response rates to chemotherapy, which translates into the differences between pre-test probabilities of residual axillary disease based on tumor biology, the impact of a false negative sentinel node should be considered very carefully in this biologically diverse group of patients. This is important because there is suggestion that knowledge of nodal response to chemotherapy is more relevant in terms of prognostication and decision-making for chest-wall/supraclavicular radiotherapy than initial nodal status [79]. NSABP B-51/RTOG 1304 [80] and the Alliance A011202 [81] trials are planned to further examine the role of nodal response and nodal surgery in post-chemotherapy treatment planning. Impact of axillary treatment on locoregional control and survival During the past decade, as profound changes have moved towards a minimalistic approach in the management of axilla in breast cancer patients, there has been a resurgence of controversy about the potential impact of this new approach on survival. Whether axillary dissection should be obsolete in contemporary practice was a subject of debate at the 2014 Annual Meeting of American Society for Breast Surgeons. The most important data to answer this question comes from the NSABP B-04 trial [82]; clinically node-negative patients were randomized to “no axillary treatment”, “axillary

Fig. 3. Postetest probability of a positive node after a negative sentinel node biopsy post neoadjuvant chemotherapy. Pre-test probabilities calculated from ACOSOG e Z1071 trial; negative likelihood ratio calculated from pooled data in Table 5.

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radiation” or “axillary dissection”. At 25-year follow up there is no significant difference in overall survival (p ¼ 0.68 for the three-way comparison ranging between 19% and 26%); however, there is a significant increase in loco-regional recurrence among women receiving no axillary treatment (13%) compared with radical mastectomy (7%) or mastectomy with adjuvant radiation (4%) [p ¼ 0.002]. It is also worth noting that the patients in “no axillary treatment” arm that had axillary failure and were able to receive subsequent axillary dissection were not considered as treatment failure unless the tumor extent prevented complete resection [83]. Until the advent of SLNB, axillary dissection has been mainly used for axillary staging and local control. Four prospective multiinstitutional studies have further endorsed the safety of SLNB [3,61,84,85]. NSABP B-32 study reported no difference in survival between “axillary dissection” versus “no dissection” groups in sentinel node-negative patients at 8-year follow up [91.8% vs. 90.3%; p ¼ 0.12] [3]. ACOSOG Z0011 trial reported 5-year disease free survival to be similar between “axillary dissection” versus “no dissection” groups in SLN positive patients [82.2% vs. 83.9%; p ¼ 0.008 for non-inferiority] [61]. IBCSG 23-01 trial reported a 5-year diseasefree and overall survival to be similar for “axillary dissection versus “no dissection” groups for patients with micrometastatic axillary disease [(disease-free survival ¼ 84.4% vs. 87.8%; p ¼ 0.004 for non-inferiority) (overall survival ¼ 97.6% vs. 97.5%; p ¼ 0.730)] [84]. AATRM 048/13/2000 trial reported no difference in overall survival between “axillary dissection” and “no dissection” groups in clinically node-negative patients at 10-year follow up [95% vs. 93%; p ¼ 0.325] [85]. It is important to note that “no dissection” group does not uniformly mean “no axillary treatment” across these studies; many patients received axillary radiation therapy to some extent. The non-uniformity of patient selection criteria and study design across different studies has led the argument that axillary dissection does confer survival advantage in breast cancer patients [9]. Table 6 depicts the characteristics of these trials; it can be inferred that most data supporting no advantage of axillary dissection come from patients who harbored low risk disease (
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Table 6 Study characteristics for trials documenting no benefit of axillary dissection in breast cancer. Study

Primary characteristics

Approach to axilla in the study arm vs. axillary dissection

Comment

NSABP B04

cNO 66% T1e2

No treatment

ACOSOGZ0011

cNO/pN1(sn) 100% T1e2

Whole-breast opposing tangential field radiation therapy (includes level I axilla)

IBCSG 23-01

cNO/pN1mi(sn) 100%T1e2

80% Whole-breast opposing tangential field radiation therapy (includes level I axilla)

AATRM 048/13/2000

cNO/pN1mi(sn) 100% T < 3.5 cm

90% Whole-breast opposing tangential field radiation therapy (high tangents and third field not allowed to avoid axillary radiation)

 No systemic therapy  Delayed axillary dissection for no therapy arm counted as treatment failure only when delayed dissection not possible  Not powered to assess impact of local failure on survival  Systemic therapy at physician discretion  Ineligible if  3 nodes positive, matted nodes, extra-nodal extension, neadjuvant therapy  Study terminated early for lack of accrual  Systemic therapy at physician discretion  Included mastectomy 10%  2001-6 e only 1 positive sentinel node was eligible  2006-10-1 positive sentinel nodes were eligible  9% patients in both arms had mastectomy without radiation  Systemic therapy at physician discretion  Included mastectomy e 9%  Stratified randomization for tumor size <1 cm, 1e2 cm, and >2 cm  Sample size calculated for 15% disease free survival difference at 5 Years

Role of axillary ultrasound As discussed above, the effective systemic therapy, and advanced radiotherapy techniques have brought the need for axillary dissection into question in patients with clinical early stage disease. As is evident from data presented in Table 6, the therapeutic decisions regarding axillary radiation and/or axillary dissection are a function of the bulk of nodal disease e not a function of whether or not nodal disease is present. Thus, the diagnostic pathway for patients with newly diagnosed breast cancer should ideally have a tool to discern patients with none/ minimal axillary (3 nodes, N1) disease from those with more extensive disease (3 or more nodes, N2) in the axilla. In this context, the diagnostic evaluation of axilla using ultrasonography and biopsy of suspicious nodes has gained significant clinical application. Routine axillary evaluation with ultrasound is recommended by the UK National Institute of Care and Health Excellence (NICE) [87], and Dutch breast cancer guidelines [88]. The criteria for suspicious nodes on ultrasonography have been previously established (defined as nodes that are rounder, have an asymmetric cortex, are thicker than 3 mm, or have lost their hyperechoic hilum) [89]. These criteria can be clinically utilized to perform fine needle aspiration cytology or core needle biopsy to confirm the presence of axillary disease. A recent metaanalysis on axillary ultrasound in breast cancer revealed a median sensitivity of 80% and specificity of 98% [90]. Given the clinically more relevant question of tumor burden in the axilla rather than confirming pN0 versus pN1 disease, van Wely et al. conducted a thorough systematic review using QUADAS criteria to answer the whether there is evidence that axillary ultrasound is accurate in identifying patients with extensive axillary tumor burden that may need appropriate therapeutic planning [91]. They reviewed a total of 115 of 894 articles based on title and abstract information; two independent reviewers selected 18 articles for analysis based on QUADAS quality measures. The QUADAS scores ranged from 8 to 12 on the 14-item score; 12/18 (67%) studies scored more than 10 points representing high quality. Eight studies reported sufficient data to perform a metaanalysis comparing 532 patients with a positive ultrasoundguided biopsy with 248 patients with a negative ultrasoundguided biopsy but a positive SLNB. They analyzed three distinctive groups of node-positive patients: patients who had ALND after a positive ultrasound-guided biopsy of suspicious nodes

(USþ/biopsyþ); patients with a negative ultrasound-guided biopsy of ultrasonographically suspicious nodes but a positive SLNB (USþ/biopsy/SLNBþ); and patients with no ultrasonographically suspicious nodes who had a positive SLNB (US/ SLNBþ). The number of patients with pN1 or pN2 disease was compared across each subgroup. Of the 332 patients in the USþ/ biopsy þ group, 56% had pN2 disease. Of the 458 US/ SLNB þ patients 319 (70%) had pN1 disease; of the 49 patients in the USþ/biopsy/SLNB þ group, 42 (86%) patients had pN1; and of the 432 patients in US/SLNB þ group 311 (72%) patients had pN1 disease. Overall, the number of involved nodes was significantly higher in patients in whom axillary metastasis was detected by ultrasound-guided biopsy (P <0,001). The authors of the review do acknowledge the limited number of studies reporting accurate data and small number of patients, selection bias cannot be excluded. However, it can be concluded that patients with breast cancer in whom axillary metastasis can be detected and confirmed by axillary ultrasound and guided biopsy, have significantly more positive nodes suggesting extensive disease. Patients with no suspicious nodes on ultrasound imaging and those with a negative ultrasound-guided biopsy could possibly be spared the sentinel lymph node procedure. This hypothesis is currently being studied in the SOUND [92] and INSEMA (Intergroup Sentinel Mamma) [93] trials, in which patients with negative axillary findings on ultrasound imaging and T1 breast cancer, suitable for breast-conserving surgery, are randomized to SLNB with or without ALND versus no further axillary staging. Conclusion SLNB is a diagnostic tool for staging of axilla in breast cancer; therefore studies on accuracy should be analyzed using criteria for evidence-based medicine such as STARD or QUADAS tools for appropriate assimilation in guidelines for management. Utilizing these criteria, the most accurate calculation regarding the clinical impact of a negative SLNB is the eLR. Reviewing the literature on SLNB in light of LR, SLNB for staging the axilla is very accurate in patients with T1 breast cancer. The clinical impact of missing positive axillary node 6e7% of times in T2 breast cancer is minimal, and therefore SLNB is safe. However, in early stage disease, the clinical value of accurate determination of pN status via SLNB is questionable in situations where adjuvant therapy decisions are

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unlikely to change. In such a scenario, axillary ultrasound is potentially valuable for triaging patients with low burden axillary disease because: (i) the lack of accuracy seems to reside between pN0 and pN1 disease which may be clinically irrelevant, (ii) it requires modest effort and resources, and (iii) it represents the least invasive option. In clinically advanced disease, such as T3 tumors at presentation, SLNB may not be appropriate based on an 18% rate of missing a positive node and potential detrimental impact on survival unless axillary radiation is planned. In the setting of neoadjuvant therapy the accuracy of sentinel biopsy is same as patients receiving surgery first for clinical node-negative disease; for clinically node-positive disease (including those established by axillary ultrasound), post neo adjuvant SLNB is most reliable in HER2 neu positive disease with 7% chance of missing residual disease. For triple negative cancers, the informed consent process should include information about 13% (1 in 8) chance of missing residual disease in the axilla. Post neoadjuvant SLNB for cN1 hormone positive tumor may not be appropriate. Tumor size at presentation is an important consideration in management of axilla, in addition to the overall plan of systemic and loco-regional therapy because the primary tumor size not only dictates the rate of axillary disease, but independently impacts survival [38]. This is where the interdisciplinary care and communication becomes most relevant between medical, radiation and surgical oncologists to clearly define the role of information gathered by these tests and their impact on the goal of therapy.

Conflict of interest statement None declared.

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Please cite this article in press as: Layeequr Rahman R, et al., Management of axilla in breast cancer e The saga continues, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.03.010