Annals of Surgical Oncology 15(12):3378–3383

DOI: 10.1245/s10434-008-0041-9

Sentinel Lymph Node Biopsy After Preoperative Chemotherapy for Breast Cancer: Findings from the Austrian Sentinel Node Study Group Christoph Tausch, MD,1 Peter Konstantiniuk, MD,2 Franz Kugler, MD,3 Roland Reitsamer, MD,4 Sebastian Roka, MD,5 Sabine Po¨stlberger, MD,6 Anton Haid, MD, FACS7 and for the Austrian Sentinel Node Study Group

1

IRIS—Institute for Risk Assessment and Prevention of Breast Diseases, Krankenhausstrasse 1, A-4020 Linz, Austria 2 Department of Vascular Surgery, University Medical School, Auenbruggerplatz 1, A-8036 Graz, Austria 3 1st Department of Surgery, General Hospital, Grieskirchnerstrasse 42, A-4600 Wels, Austria 4 Breast Center, Paracelsus Private Medical School, Mu¨llner Hauptstraße 48, A-5020 Salzburg, Austria 5 Department of Surgery, Vienna University Medical School, Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria 6 Department of Surgery, Barmherzige Schwestern Hospital, Seilersta¨tte 4, A-4010 Linz, Austria 7 Department of Surgery, Landeskrankenhaus Feldkirch, Carinagasse 47, A-6800 Tisis, Austria

Background: Sentinel lymph node biopsy (SLNB) has become an accurate alternative to axillary lymph node dissection for early breast cancer. However, data are still insufficient as regards the combination of SLNB with preoperative chemotherapy (PC). Methods: The Austrian Sentinel Node Study Group investigated 167 patients who underwent SLNB and axillary lymph node dissection after 3 to 6 courses of PC. SLNB was limited to patients with a clinically negative axilla after PC. Blue dye was used in 29 cases (17%), and tracers were used in 20 (12%). A combination of the two methods was applied in most patients (n = 120; 72%). Results: At least 1 sentinel lymph node (SLN) was identified in 144 patients (identification rate, 85%): in 86% by blue dye alone, in 65% by tracers alone, and in 88% by a combination of methods. The SLN was positive in 70 women (42%) and was the only positive node with otherwise negative axillary nodes in 39 patients (23%). In 6 cases, the SLN was diagnosed as negative although tumor infiltration was detected in an upper node of the axillary basin (falsenegative rate, 8%; 6 of 76 patients; sensitivity, 92%). At least 62 patients (37%) were free of tumor cells in the SLN and in the axillary nodes. Conclusion: The results of SLNB after PC are comparable to the results of SLNB without PC. Further investigation in a prospective setting is warranted to confirm these promising results. Key Words: Sentinel biopsy—Preoperative chemotherapy—Identification rate—Sensitivity.

Preoperative chemotherapy (PC) is an approved tool in breast cancer treatment. It is applied to downsize locally advanced tumors and, as a conse-

quence, to increase the rate of breast-conserving procedures. PC-induced downstaging of axillary nodes is another well-known effect.1,2 Randomized trials of PC1,3 have failed to demonstrate improvements in disease-free and overall survival. In a subgroup analysis of the National Surgical Adjuvant Breast and Bowel Project B-18 trial,1 a significantly improved outcome was observed only in patients who experienced a pathologic complete response (pCR)

Published online July 6, 2008. Address correspondence and reprint requests to: Christoph Tausch, MD; E-mail: [email protected]. Published by Springer Science+Business Media, Inc.
2008 The Society of Surgical Oncology, Inc.

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after PC. Subsequently, attempts have been made to increase the rate of pCR by using more effective PC regimens.4 PC is thus becoming more important as an in vivo test for the response to specific chemotherapy and is no longer exclusively applied to large tumors. PC is offered to a wider range of patients at high risk, whose status is clarified by primary core biopsy. Only some of these patients show clinical signs of axillary node involvement. Sentinel lymph node biopsy (SLNB) is accepted, as an alternative to axillary lymph node dissection (ALND), for accurate axillary node staging in the early stages of breast cancer.5–8 Patients with any form of preoperative treatment were excluded from SLNB to avoid an increased number of false-negative results. In view of (1) the fact that the application of PC is extended to a large number of node-negative patients and (2) the faculty of PC in terms of axillary downstaging, the question arises whether some of these patients might benefit from the advantages of PC and SLNB. Such a strategy is supported by the finding, in multicenter trials, that larger tumors barely decrease the sensitivity of SLNB.9,10 As reported previously,11,12 the Austrian Sentinel Node Study Group (ASNSG) has been prospectively examining the issue of safely performing SLNB after PC. The ASNSG was founded at 1998 annual meeting of the Austrian Breast and Colorectal Cancer Study Group, with the intention to establish nationwide guidelines for implementing SLNB in a clinical setting.

METHODS The trial was a retrospective investigation concerning the feasibility and accuracy of the combination of PC and SLNB. The aim of the study was to evaluate of the identification rate (IR) and the sensitivity of SLNB after PC. Further investigation is targeted on clinical patient and tumor characteristics and their influence on the false-negative rate. Up to August 2003, 3218 patients from 17 departments were registered in the Multicentre Data Base Project that the ASNSG set up by using MS Access 97 (Microsoft Corp., Redmond, WA). Of these patients, 167 women from 9 departments with 169 unifocal breast tumors underwent SLNB after PC followed by obligatory ALND. The patients’ median age was 50 years (range, 28–77 years); 86 (51%) of these patients were premenopausal. At the beginning of treatment, 46 women (28%) had clinically positive axillary nodes,

TABLE 1. Injection sites for lymphatic mapping Agent

Blue dye

Peritumoral Subcutaneous Intradermal Subareolar Not available Total

32 18 6 90 3 149

Radiocolloid 94 36 – 9 1 140

whereas most (121 women; 72%) had no clinical signs of enlarged axillary lymph nodes. The 3 to 6 cycles of administered PC consisted of a combination of epidoxorubicin and docetaxel in 128 cases; doxorubicin and docetaxel in 7 cases; epidoxorubicin and cyclophosphamide in 21 cases; and cyclophosphamide, methotrexate, and fluorouracil in 8 cases. SLNB was performed only in the presence of a clinically negative axilla at the time of operation. The surgical technique of SLNB was left to the discretion of the participating surgeon. In the course of SLNB, blue dye was applied exclusively in 29 women (17%), tracers were used in 20 cases (12%), and a combination of the two methods was used in most patients (120 cases; 71%). Injection sites are listed in (Table 1). All blue and hot nodes were removed and separately marked as sentinel lymph nodes (SLNs). The SLNB procedure was obligatory, followed by standard axillary dissection of level I and II. Details of histological SLN examinations according to the common guidelines of the Austrian Institutes of Pathology have been published elsewhere.13 Tumor size was initially determined by radiological examination (mammography, ultrasonography, or magnetic resonance imaging) and, after treatment, on the histological specimen. Statistical analyses were carried out by using SPSS 8.0 (SPSS Inc., Chicago, IL). All calculations were two sided. P values <.05 were considered significant. Correlations between sensitivity and potentially influencing parameters were analyzed by Fisher’s exact test.

RESULTS PC reduced an average tumor size of 33 mm (range, 8–80 mm) to an average of 22 mm (range, 0–100 mm). The invasive portion of the tumors shrank to an average size of 5 mm (range, 0–100 mm). Clinical complete remission was achieved in 46 cases (28%), 18 (11%) of which were pCRs. Partial remission was observed in 90 women (54%). In 27 cases, tumor size did not change significantly (stable disease), and progression of disease was observed 4 Ann. Surg. Oncol. Vol. 15, No. 12, 2008

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TABLE 2. Effect of preoperative chemotherapy Variable Schedule CMF EC ED DD Others Effect of PC pCR cCR PR SD PD NA T-stage after PC T0 Tis T1 T2 T3 T4 Tx Breast surgery Mastectomy Breast-conserving therapy Total

TABLE 3. Sensitivity of sentinel lymph node biopsy according to clinical patient und tumor characteristics

n (%) 8 21 128 7 3

(5%) (13%) (76%) (4%) (2%)

18 28 90 27 4 2

(11%) (17%) (53%) (16%) (2%) (1%)

11 7 82 50 10 4 5

(6%) (4%) (49%) (30%) (6%) (2%) (3%)

43 (25%) 126 (75%) 169

CMF, cyclophosphamide, methotrexate, and fluorouracil; EC, epirubicin and cyclophosphamide; ED, epidoxorubicin and docetaxel; DD, doxorubicin and docetaxel; PC, preoperative chemotherapy; pCR, pathologic complete remission; cCR, clinical complete remission; PR, partial remission; SD, stable disease; PD, progression of disease; NA, not available.

times (2%). This reduction of tumor size resulted in 126 (75%) breast-conserving procedures and 43 mastectomies (25%; Table 2). Clinical downstaging by means of PC was observed in all patients with palpable axillary lymph nodes at the beginning of preoperative treatment (46 patients). One or more SLNs were identified in 144 of 169 SLNBs (IR, 85%). An IR of 65% (13 of 20) was achieved by using radiocolloid only, an IR of 86% (25 of 29) was achieved with blue dye only, and an IR of 88% (106 of 120) was achieved by using a combination of the two methods. An average of 1.99 nodes were detected. A positive SLN was removed in 70 cases. Thirtynine of the SLNs were the only positive axillary nodes. In six cases, the SLN was negative although a positive node was found in the axillary basin. The result was a false-negative rate of 8% [6 false negatives/(6 false negatives + 70 true positives) 9 100; sensitivity, 92%]. In 62 cases, a negative SLN was proven by metastasis-free axillary nodes. There was no significant difference in sensitivity according to patient and tumor characteristics. Patient age (£50/>50 years) did not correlate with the grade of sensitivity (P = .69). Even tumor size Ann. Surg. Oncol. Vol. 15, No. 12, 2008

Patients with positive nodes Sensitivity % P value

Characteristic Age (y) £50 >50 Primary tumor size (cm) £30 >3 Primary clinical nodal status Positive Negative Injection technique Single agent Combined Injection site (blue dye) Subareolar Other sites Response to PC Clinical complete remission Other types of response

42 34

90 94

NS

41 35

95 89

NS

25 51

88 94

NS

21 55

95 91

NS

44 21

95 81

NS

12 63

75 95

.048

(£3/>3 cm) failed to demonstrate a correlation with the grade of sensitivity. We identified a trend toward higher sensitivity (94%) in cases in which the nodal status was clinically negative before PC (P = .39). A sensitivity of 88% was achieved in the presence of evidence for clinically involved nodes before PC. No significant difference was obvious with respect to the injection technique. We found no correlation comparing single-agent with combination techniques (P = 0.467); a trend toward significance was observed when blue dye subareolar injection was compared with other injection sites of blue dye (P = .08). In view of the tumor response to PC, we compared complete response (clinical and pathologic) with any other type of response (partial remission, stable disease, or progression of disease). We observed a sensitivity of 75% among the group of complete responses, compared with a sensitivity of 95% for the other group, and this difference was statistically significant (P = .048; Table 3).

DISCUSSION There have been few reports regarding the effects of combined PC and SLNB. Most of these investigations performed SLNB after PC. The issue is whether SLNB after PC results in an IR and sensitivity that are comparable to those with SLNB without PC. PC is able to alter the lymphatic drainage patterns by shrinkage and fibrosis of lymph vessels and a fatty degeneration due to apoptosis of tumor cells, thus resulting in a pathway to a false-negative SLN.14 In

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TABLE 4. Single-institution series for sentinel lymph node biopsy after preoperative chemotherapy Study

n

Breslin et al. (2000)17 Nason et al. (2000)18 Fernandez et al. (2001)19 Julian et al. (2001)20 Brady et al. (2002)21 Stearns et al. (2002)22 Miller et al. (2002)23 Piato et al. (2003)24 Balch et al. (2003)25 Reitsamer et al. (2003)26 Kang et al. (2004)27 Total

51 15 40 31 14 34 35 42 32 30 54 378

Identification rate (%)

No. of false-negative cases

84 79 81 94 93 85 86 98 97 96 72 86

3/25 3/9 4/20 0/11 0/10 3/21 0/19 3/18 1/19 1/15 3/27 21/194

analogy, we observed such chemotherapy-induced changes in lymph nodes and the afferent lymph vessels on histological slides. This may serve to explain the increase in IR with blue dye after PC, because color particles have a smaller diameter and therefore can be transported quite easily. There is little solid evidence15,16 concerning SLNB before PC. Two reports demonstrated an IR of 100%: whereas Schrenk et al.16 achieved a sensitivity of 100%, Sabel et al.15 did not confirm the accuracy by ALND. The total number of women who underwent SLNB before PC was 47. The advantage of this reversed order is that PC does not alter lymphatic drainage patterns. However, patients then undergo additional surgery and cannot profit from a potential PC-induced downstaging in the axillary nodes. Over the past 5 years, several articles have been published concerning SLNB after PC. Data derive from 11 single-institutions series with a total of 378 patients.17–27 They are marked by fewer cases (range, 14–54) and larger differences in IR and sensitivity: 72% to 98% (median, 86%) for IR and 67% to 100% for sensitivity (median, 89%). An IR of 84% (range, 74%–97%) and a sensitivity of 95% (range, 93%– 100%) were observed in comparing the first 11 singleinstitution series of SLNB without preoperative treatment from 1993 to 1997 in 912 patients (Table 4).5–8,28–34 This comparison shows a similarly high IR yet a distinctly lower sensitivity when SLNB is applied after PC; 1 out of 10 cases with histologically evidenced lymph node metastasis is not detected. Reports about SLNB without PC derive from the initial phase, as shown by the low IR, whereas reports about SLNB after PC show a clearer learning curve in that the most recent articles from the series with PC achieve a clearly higher sensitivity. Our results were generated on a multicenter basis. Apart from our first report, two other multicenter studies have been published with respect to SLNB

Sensitivity (%) 88 67 80 100 100 86 100 83 95 93 89 89

after PC35,36: whereas Tafra et al.35 reported on only 29 patients (IR, 93%; sensitivity, 100%), Mamounas and colleagues’ study36 included 427 women who underwent SLNB after PC in the course of the National Surgical Adjuvant Breast and Bowel Project B-27 trial (n = 2411). This trial evaluated the effect of neoadjuvant or adjuvant docetaxel after four cycles of neoadjuvant doxorubicin and cyclophosphamide chemotherapy. The investigation reported an IR of 85% and a sensitivity of 89%. The results presented here yield a similar IR yet a higher sensitivity. In view of all published multicenter studies, we still observe an IR of 85% and a sensitivity of 91%. We then drew comparisons with multicenter series not applying PC. Our own data from the initial phase of the ASNSG37 were combined with an axillary dissection at each department. SLNs were identified in 458 of 587 patients (IR, 78%). The 10 false-negative cases identified correspond to a sensitivity of 94%. Analyzing our own data with three other multicenter studies,9,10,38 we see an IR of 87% and a sensitivity of 90%. Of course, multicenter studies reflect clinical reality more clearly than single-institution series from a highly specialized center. Multicenter studies have investigated several tumor- and patient-specific characteristics (tumor size, lymph node metastasis, localization, initial biopsy, and age), as well as specifics of the procedure applied (injection agent, injection site, preparation technique, time interval, the surgeon’s experience, and department), as correlated with sensitivity. In one study only, the multivariate analysis showed that tumor size influenced sensitivity. Mamounas et al.36 additionally analyzed responses to PC. A trend was observed with respect to tumor size and the method of lymphatic mapping. The response to PC showed a trend toward lower sensitivity with a poor response and toward increases along with more successful tumor shrinking. This Ann. Surg. Oncol. Vol. 15, No. 12, 2008

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result contradicts our finding, according to which a significantly higher sensitivity corresponds to a poorer response to PC. The controversy in results may possibly be due to the low number of falsenegative cases, which did not allow for multivariate evaluation. Although generated retrospectively, our group’s results are encouraging and equal the multicenter series involving PC and no PC in terms of feasibility and accuracy. In an attempt to prospectively confirm these promising results, the Austrian Breast and Colorectal Cancer Study Group has initiated a neoadjuvant protocol (trial 24) in which SLNB is performed in the framework of mandatory axillary dissection. The objective is to preserve the breast and axilla in a selected patient group after PC.

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