Elsevier

The Lancet Oncology

Volume 14, Issue 7, June 2013, Pages 609-618
The Lancet Oncology

Articles
Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study

https://doi.org/10.1016/S1470-2045(13)70166-9Get rights and content

Summary

Background

The optimum timing of sentinel-lymph-node biopsy for breast cancer patients treated with neoadjuvant chemotherapy is uncertain. The SENTINA (SENTinel NeoAdjuvant) study was designed to evaluate a specific algorithm for timing of a standardised sentinel-lymph-node biopsy procedure in patients who undergo neoadjuvant chemotherapy.

Methods

SENTINA is a four-arm, prospective, multicentre cohort study undertaken at 103 institutions in Germany and Austria. Women with breast cancer who were scheduled for neoadjuvant chemotherapy were enrolled into the study. Patients with clinically node-negative disease (cN0) underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arm A). If the sentinel node was positive (pN1), a second sentinel-lymph-node biopsy procedure was done after neoadjuvant chemotherapy (arm B). Women with clinically node-positive disease (cN+) received neoadjuvant chemotherapy. Those who converted to clinically node-negative disease after chemotherapy (ycN0; arm C) were treated with sentinel-lymph-node biopsy and axillary dissection. Only patients whose clinical nodal status remained positive (ycN1) underwent axillary dissection without sentinel-lymph-node biopsy (arm D). The primary endpoint was accuracy (false-negative rate) of sentinel-lymph-node biopsy after neoadjuvant chemotherapy for patients who converted from cN1 to ycN0 disease during neoadjuvant chemotherapy (arm C). Secondary endpoints included comparison of the detection rate of sentinel-lymph-node biopsy before and after neoadjuvant chemotherapy, and also the false-negative rate and detection rate of sentinel-lymph-node biopsy after removal of the sentinel lymph node. Analyses were done according to treatment received (per protocol).

Findings

Of 1737 patients who received treatment, 1022 women underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arms A and B), with a detection rate of 99·1% (95% CI 98·3–99·6; 1013 of 1022). In patients who converted after neoadjuvant chemotherapy from cN+ to ycN0 (arm C), the detection rate was 80·1% (95% CI 76·6–83·2; 474 of 592) and false-negative rate was 14·2% (95% CI 9·9–19·4; 32 of 226). The false-negative rate was 24·3% (17 of 70) for women who had one node removed and 18·5% (10 of 54) for those who had two sentinel nodes removed (arm C). In patients who had a second sentinel-lymph-node biopsy procedure after neoadjuvant chemotherapy (arm B), the detection rate was 60·8% (95% CI 55·6–65·9; 219 of 360) and the false-negative rate was 51·6% (95% CI 38·7–64·2; 33 of 64).

Interpretation

Sentinel-lymph-node biopsy is a reliable diagnostic method before neoadjuvant chemotherapy. After systemic treatment or early sentinel-lymph-node biopsy, the procedure has a lower detection rate and a higher false-negative rate compared with sentinel-lymph-node biopsy done before neoadjuvant chemotherapy. These limitations should be considered if biopsy is planned after neoadjuvant chemotherapy.

Funding

Brustkrebs Deutschland, German Society for Senology, German Breast Group.

Introduction

Axillary-lymph-node status is one of the strongest prognostic factors for patients with breast cancer and it guides adjuvant local and systemic treatment decisions. In recent years, sentinel-lymph-node biopsy has replaced full axillary-lymph-node dissection as a staging procedure for patients who undergo primary surgery and have clinically negative lymph nodes. Sentinel-lymph-node biopsy provides an accurate assessment of histological nodal status and is associated with less acute and chronic morbidity than axillary-lymph-node dissection.1, 2, 3 Neoadjuvant chemotherapy is established for treatment of locally advanced disease and is being used increasingly for early-stage breast cancer.4 This therapeutic approach provides in-vivo chemosensitivity testing and prognostic information. Patients with an unfavourable tumour-to-breast ratio can be downstaged to allow less radical surgery and to increase the rate of breast-conserving treatment.5, 6

Timing of sentinel-lymph-node biopsy in the neoadjuvant setting is controversial. Reliable data for the detection rate, accuracy (the false-negative rate), and the number of regional relapses are available for when biopsy is done before systemic adjuvant treatment in patients with clinically node-negative (cN0) disease,7, 8 but limited data are available in the context of neoadjuvant chemotherapy. One advantage of doing sentinel-lymph-node biopsy before neoadjuvant chemotherapy is that knowledge of the initial histological nodal status can be used to guide postoperative locoregional treatment decisions. However, the best surgical approach in the axilla for the 20–40% of patients with initially positive lymph nodes (cN+) who are downstaged after neoadjuvant chemotherapy to a clinically negative lymph node status (ycN0) is unclear.5, 6 In this population, biopsy done after neoadjuvant chemotherapy would increase the overall rate of axilla-conserving treatment. Furthermore, growing evidence suggests that the nodal stage after neoadjuvant chemotherapy reflects prognosis more accurately than does initial axillary status9 and could, in the near future, lead to tailoring of regional treatment.10

The feasibility and accuracy of doing sentinel-lymph-node biopsy after neoadjuvant chemotherapy is of some concern. For example, lymphatic drainage from the breast could be impaired, thus hampering detection of the sentinel lymph node. Furthermore, tumour regression in the axilla could follow a non-uniform pattern, leading to an unacceptable false-negative rate. Many cohort studies have been done of sentinel-lymph-node biopsy after neoadjuvant chemotherapy, and findings of three meta-analyses showed detection rates of 63–100% and false-negative rates of 0–39%.11, 12, 13 However, most of these trials were either retrospective or single-centre in design and included only a few patients who had predominantly cN0 disease before neoadjuvant chemotherapy. A few, small, retrospective series have been published of patients who presented initially with cN+ disease and converted to negative axillary status after neoadjuvant chemotherapy; detection rates were 77·6–98·0% of patients and false-negative rates were registered for 5·6–35·5%.14, 15, 16, 17, 18, 19 In a prospective multicentre study of sentinel-lymph-node biopsy after neoadjuvant chemotherapy,20 the detection rate was 94·6% for patients with cN0 disease before neoadjuvant chemotherapy and 81·5% for those who presented initially with cN+ status; false negatives were noted in 9·4% and 15·0%, respectively. However, the low statistical power of this study precludes reliable evidence for subgroups of patients who initially have cN0 or cN+ disease.

Khan and colleagues21 reported 33 patients undergoing a second sentinel-lymph-node biopsy after neoadjuvant chemotherapy. These patients had initially presented with a clinically negative axilla before neoadjuvant chemotherapy but were found to have an involved sentinel lymph node at a first sentinel-lymph-node biopsy done before neoadjuvant chemotherapy. The detection rate for this second sentinel-lymph-node biopsy was 97·0% and the false-negative rate was 4·5%.21

The SENTINA (SENTinel NeoAdjuvant) study was designed to provide reliable data for the feasibility and accuracy of a standardised sentinel-lymph-node biopsy procedure in different settings before and after neoadjuvant chemotherapy. We included several clinical scenarios, with the aim to ascertain the best timing strategy for sentinel-lymph-node biopsy in breast cancer patients treated with neoadjuvant chemotherapy.

Section snippets

Study design

The SENTINA study is a four-arm, prospective, multicentre cohort study undertaken at 103 centres in Germany and Austria. We enrolled patients with breast cancer who were scheduled for neoadjuvant chemotherapy, which had to include at least six cycles of an anthracycline-based regimen recommended by German guidelines for use in the neoadjuvant setting. All patients provided written informed consent. The protocol was reviewed by a central ethics committee (University of Tübingen) and approved by

Results

Between September, 2009, and May, 2012, 2234 patients entered the trial, and of these, 1737 women from 103 institutions fulfilled criteria for the final per-protocol analysis (figure 2). A median of eight (range 1–138) patients were accrued per institution. Nine institutions accrued more than 50 patients each.

1022 (59%) of 1737 patients in the per-protocol analysis presented initially with an unsuspicious clinical lymph-node status and underwent sentinel-lymph-node biopsy before neoadjuvant

Discussion

Our findings show that sentinel lymph nodes were detected in almost all patients who were clinically node-negative and underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (ie, those women in arms A and B), whereas the detection rate was 80·1% for patients who converted after chemotherapy from clinically positive to negative axillary status (ie, those in arm C). The overall false-negative rate was 14·2% for patients who converted, and it was around 20% if only one or two

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