Sentina
Sentina
Summary
Background The optimum timing of sentinel-lymph-node biopsy for breast cancer patients treated with neoadjuvant Published Online
chemotherapy is uncertain. The SENTINA (SENTinel NeoAdjuvant) study was designed to evaluate a specific May 15, 2013
http://dx.doi.org/10.1016/
algorithm for timing of a standardised sentinel-lymph-node biopsy procedure in patients who undergo neoadjuvant S1470-2045(13)70166-9
chemotherapy. See Online/Comment
http://dx.doi.org/10.1016/
Methods SENTINA is a four-arm, prospective, multicentre cohort study undertaken at 103 institutions in Germany S1470-2045(13)70180-3
and Austria. Women with breast cancer who were scheduled for neoadjuvant chemotherapy were enrolled into the Interdisciplinary Breast Centre,
study. Patients with clinically node-negative disease (cN0) underwent sentinel-lymph-node biopsy before neoadjuvant Department of Gynaecology
and Obstetrics, Klinikum
chemotherapy (arm A). If the sentinel node was positive (pN1), a second sentinel-lymph-node biopsy procedure was Esslingen, Esslingen, Germany
done after neoadjuvant chemotherapy (arm B). Women with clinically node-positive disease (cN+) received (Prof T Kuehn MD); Department
neoadjuvant chemotherapy. Those who converted to clinically node-negative disease after chemotherapy (ycN0; of Gynaecology and Obstetrics,
arm C) were treated with sentinel-lymph-node biopsy and axillary dissection. Only patients whose clinical nodal Klinikum Landshut, Landshut,
Germany (I Bauerfeind MD);
status remained positive (ycN1) underwent axillary dissection without sentinel-lymph-node biopsy (arm D). The Department of Gynaecology
primary endpoint was accuracy (false-negative rate) of sentinel-lymph-node biopsy after neoadjuvant chemotherapy and Obstetrics, University of
for patients who converted from cN1 to ycN0 disease during neoadjuvant chemotherapy (arm C). Secondary endpoints Düsseldorf, Düsseldorf,
included comparison of the detection rate of sentinel-lymph-node biopsy before and after neoadjuvant chemotherapy, Germany (Prof T Fehm MD);
Department of Pathology
and also the false-negative rate and detection rate of sentinel-lymph-node biopsy after removal of the sentinel lymph (B Fleige MD) and Department
node. Analyses were done according to treatment received (per protocol). of Gynaecology and Obstetrics
(Prof M Untch MD),
Findings Of 1737 patients who received treatment, 1022 women underwent sentinel-lymph-node biopsy before Multidisciplinary Breast
Centre, Helios Klinikum
neoadjuvant chemotherapy (arms A and B), with a detection rate of 99·1% (95% CI 98·3–99·6; 1013 of 1022). Berlin-Buch, Berlin, Germany;
In patients who converted after neoadjuvant chemotherapy from cN+ to ycN0 (arm C), the detection rate was 80·1% Spital Rheinfelden,
(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 Rheinfelden, Switzerland
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 (M Hausschild MD);
Department of Gynaecology
nodes removed (arm C). In patients who had a second sentinel-lymph-node biopsy procedure after neoadjuvant and Obstetrics (G Helms MD)
chemotherapy (arm B), the detection rate was 60·8% (95% CI 55·6–65·9; 219 of 360) and the false-negative rate was and Department of Pathology
51·6% (95% CI 38·7–64·2; 33 of 64). (A Staebler MD), University
Medical Centre Tübingen,
Tübingen, Germany;
Interpretation Sentinel-lymph-node biopsy is a reliable diagnostic method before neoadjuvant chemotherapy. After Department of Pathology,
systemic treatment or early sentinel-lymph-node biopsy, the procedure has a lower detection rate and a higher false- University Medical Centre,
negative rate compared with sentinel-lymph-node biopsy done before neoadjuvant chemotherapy. These limitations Hamburg-Eppendorf,
Hamburg, Germany
should be considered if biopsy is planned after neoadjuvant chemotherapy.
(A Lebeau MD); Department of
Gynaecology and Obstetrics,
Funding Brustkrebs Deutschland, German Society for Senology, German Breast Group. University Hospital
Schleswig-Holstein Campus
Lübeck, Lübeck, Germany
Introduction locally advanced disease and is being used increasingly
(C Liedtke MD); German Breast
Axillary-lymph-node status is one of the strongest for early-stage breast cancer.4 This therapeutic approach Group, Neu Isenburg, Germany
prognostic factors for patients with breast cancer and it provides in-vivo chemosensitivity testing and prognostic (Prof G von Minckwitz MD,
guides adjuvant local and systemic treatment decisions. information. Patients with an unfavourable tumour-to- V Nekljudova PhD); University
Women’s Hospital Frankfurt,
In recent years, sentinel-lymph-node biopsy has replaced breast ratio can be downstaged to allow less radical
Frankfurt, Germany
full axillary-lymph-node dissection as a staging procedure surgery and to increase the rate of breast-conserving (Prof G von Minckwitz);
for patients who undergo primary surgery and have treatment.5,6 Elisabeth-Krankenhaus Kassel
clinically negative lymph nodes. Sentinel-lymph-node Timing of sentinel-lymph-node biopsy in the neo- gGmbH, Kassel, Germany
(S Schmatloch MD); and Breast
biopsy provides an accurate assessment of histological adjuvant setting is controversial. Reliable data for the Cancer Center, General
nodal status and is associated with less acute and chronic detection rate, accuracy (the false-negative rate), and the Hospital Linz, Linz, Austria
morbidity than axillary-lymph-node dissection.1–3 Neo- number of regional relapses are available for when (P Schrenk MD)
adjuvant chemotherapy is established for treatment of biopsy is done before systemic adjuvant treatment in
Correspondence to: patients with clinically node-negative (cN0) disease,7,8 but disease before neoadjuvant chemotherapy. A few, small,
Prof T Kuehn, Interdisciplinary limited data are available in the context of neoadjuvant retrospective series have been published of patients who
Breast Center, Department for
Gynecology and Obstetrics,
chemotherapy. One advantage of doing sentinel-lymph- presented initially with cN+ disease and converted to
D-73730 Esslingen, Germany node biopsy before neoadjuvant chemotherapy is that negative axillary status after neoadjuvant chemotherapy;
t.kuehn@klinikum-esslingen. knowledge of the initial histological nodal status can be detection rates were 77·6–98·0% of patients and false-
de used to guide postoperative locoregional treatment negative rates were registered for 5·6–35·5%.14–19 In a
decisions. However, the best surgical approach in the prospective multicentre study of sentinel-lymph-node
axilla for the 20–40% of patients with initially positive biopsy after neoadjuvant chemotherapy,20 the detection
lymph nodes (cN+) who are downstaged after rate was 94·6% for patients with cN0 disease before
neoadjuvant chemotherapy to a clinically negative lymph neoadjuvant chemotherapy and 81·5% for those who
node status (ycN0) is unclear.5,6 In this population, biopsy presented initially with cN+ status; false negatives were
done after neoadjuvant chemotherapy would increase noted in 9·4% and 15·0%, respectively. However, the low
the overall rate of axilla-conserving treatment. statistical power of this study precludes reliable evidence
Furthermore, growing evidence suggests that the nodal for subgroups of patients who initially have cN0 or cN+
stage after neoadjuvant chemotherapy reflects prognosis disease.
more accurately than does initial axillary status9 and Khan and colleagues21 reported 33 patients undergoing
could, in the near future, lead to tailoring of regional a second sentinel-lymph-node biopsy after neoadjuvant
treatment.10 chemotherapy. These patients had initially presented
The feasibility and accuracy of doing sentinel-lymph- with a clinically negative axilla before neoadjuvant
node biopsy after neoadjuvant chemotherapy is of some chemotherapy but were found to have an involved
concern. For example, lymphatic drainage from the breast sentinel lymph node at a first sentinel-lymph-node
could be impaired, thus hampering detection of the biopsy done before neoadjuvant chemotherapy. The
sentinel lymph node. Furthermore, tumour regression in detection rate for this second sentinel-lymph-node biopsy
the axilla could follow a non-uniform pattern, leading to was 97·0% and the false-negative rate was 4·5%.21
an unacceptable false-negative rate. Many cohort studies The SENTINA (SENTinel NeoAdjuvant) study was
have been done of sentinel-lymph-node biopsy after designed to provide reliable data for the feasibility and
neoadjuvant chemotherapy, and findings of three meta- accuracy of a standardised sentinel-lymph-node biopsy
analyses showed detection rates of 63–100% and false- procedure in different settings before and after neo-
negative rates of 0–39%.11–13 However, most of these trials adjuvant chemotherapy. We included several clinical
were either retrospective or single-centre in design and scenarios, with the aim to ascertain the best timing
included only a few patients who had predominantly cN0 strategy for sentinel-lymph-node biopsy in breast cancer
patients treated with neoadjuvant chemotherapy.
chemotherapy (pN1sn) who underwent a second biopsy subcutanous, peritumoral) and injected dose and
procedure after chemotherapy, followed by axillary- volume, within the frame of the national consensus, and
lymph-node dissection. Arm C included patients with we recorded these details. We did histological assessment
initially node-positive disease (cN1 or cN2) who of the sentinel lymph node, which included slicing of
underwent neoadjuvant chemotherapy and then had nodes at 2·0–3·0 mm intervals, embedding of all slices
both sentinel-lymph-node biopsy and axillary-lymph- in paraffin, and complete step-sectioning of slices at
node dissection if they converted to a clinically negative intervals of 500 μm or less.22 We did not require
axillary status (ycN0). Finally, arm D included patients immunohistochemistry to be used. We classified tumour
who had suspicious nodes before and after neoadjuvant deposits with the Union for International Cancer Control
chemotherapy (ycN1) and who subsequently received TNM classification system.24
axillary-lymph-node dissection. All patients underwent preoperative clinical assessment
We standardised the sentinel-lymph-node biopsy of lymph-node status by palpation and axillary ultrasound.
procedure according to recommendations made by We asked institutions to describe lymph-node status as
multidisciplinary consensus of the German Society for either positive (including cN1 and cN2) or negative. We
Senology and guidelines from the American Society of judged patients to be node-negative when palpation and
Clinical Oncology.22,23 Use of radiocolloid and preoperative ultrasound showed no suspicious nodes (cN0). In case of
lymphoscintigraphy was necessary for all patients, but palpable nodes, we regarded patients as node negative if
additional application of blue dye was optional. We ultrasound showed normal-sized or enlarged lymph
allowed individual choice of injection site (periareolar, nodes with regular morphological structure of hilum and
1334 patients with clinically node-negative 900 patients with clinically node-positive
disease (cN0) disease (cN+)
1 screening failure
102 no second report
684 were pathologically node-negative (pN0) 455 were pathologically node-positive (pN1) 642 converted to clinically node-negative 123 remained clinically node-positive (ycN+)
disease (ycN0)
662 had no axillary treatment (arm A) 360 received sentinel-lymph-node biopsy and 592 received sentinel-lymph-node biopsy and 123 received axillary-lymph-node dissection
axillary-lymph-node dissection (arm B) axillary-lymph-node dissection (arm C) (arm D)
cortex. No uniformly accepted standard for sonographic Role of the funding source
lymph-node assessment is available. We classified lymph The sponsor of the study had no role in study design,
nodes as suspicious in case of cortex asymmetry or loss or data collection, data analysis, data interpretation, or
displacement of the hilum relation (hilum:cortex writing of the report. TK had full access to raw data in the
ratio >2:1, or total loss of hilum). To restrict our clinical study and final responsibility for the decision to submit
findings to simple and reproducible criteria, we did not for publication.
assess cN1 and cN2 status separately. Ultrasound-guided
fine-needle aspiration or core-needle biopsy was Results
recommended but not mandatory. Patients underwent Between September, 2009, and May, 2012, 2234 patients
sentinel-lymph-node biopsy in case of negative aspiration entered the trial, and of these, 1737 women from
or core biopsy. 103 institutions fulfilled criteria for the final per-protocol
The primary outcome of our study was accuracy of analysis (figure 2). A median of eight (range 1–138)
sentinel-lymph-node biopsy (measured as the false- patients were accrued per institution. Nine institutions
negative rate) in patients who presented initially with accrued more than 50 patients each.
clinically positive lymph nodes (cN+) and subsequently 1022 (59%) of 1737 patients in the per-protocol analysis
converted to a clinically negative axillary status (ycN0) presented initially with an unsuspicious clinical lymph-
after neoadjuvant chemotherapy (those in arm C). We node status and underwent sentinel-lymph-node biopsy
before neoadjuvant chemotherapy. Of these 1022 patients, institution (defined as ≥50 patients or <50 patients) did not
662 (65%) had a tumour-free sentinel lymph node affect the detection rate. However, we noted a difference in
(included in arm A) and 360 (35%) had pN1sn status the detection rate for patients who underwent a combined
(included in arm B). 715 (41%) of 1737 patients presented detection procedure (radiocolloid and blue dye) compared
with initially suspicious nodes and underwent with use of radiocolloid alone (figure 3). No difference was
neoadjuvant chemotherapy as their first treatment. Of
these, 592 (83%) converted from a clinically positive to a Arms A and B, Arm B, after Arm C, after Total (n=1974)
negative axillary status after neoadjuvant chemotherapy before NACT NACT (n=360) NACT
(included in arm C), whereas 123 (17%) had persistent (n=1022) (n=592)
suspicious nodes and underwent primary axillary-lymph- Tracer
node dissection alone after neoadjuvant chemotherapy Radiocolloid alone 580 (57%) 238 (66%) 389 (66%) 1207 (61%)
(included in arm D). Pre-treatment nodal status was Blue dye alone 7 (1%) 5 (1%) 7 (1%) 19 (1%)
confirmed in 149 (25%) of 592 women in arm C by fine- Combined 401 (39%) 105 (29%) 164 (28%) 670 (34%)
needle aspiration or core-needle biopsy. Unknown 34 (3%) 12 (3%) 32 (5%) 78 (4%)
Patients’ characteristics showed, as expected, different Injection site, multiple choice
risk profiles between groups (table 1). Individuals with Periareolar 606 (59%) 230 (64%) 396 (67%) 1232 (62%)
positive lymph nodes had more advanced tumours and Peritumoral 342 (33%) 125 (35%) 207 (35%) 674 (34%)
less favourable biological features than patients with Subcutaneous 433 (42%) 128 (36%) 276 (47%) 837 (42%)
uninvolved nodes Median injected dose (MBq) 89·8 95·0 100 94·0
Some variations in sentinel-lymph-node biopsy Protocol
procedures occurred (table 2). Exclusive use of a
1 day 334 (33%) 97 (27%) 143 (24%) 574 (29%)
radiocolloid was preferred by surgeons in 1207 (61%) of
2 days 676 (66%) 227 (63%) 415 (70%) 1318 (67%)
1974 biopsy procedures, whereas a combined detection
Unknown 12 (1·2%) 36 (10%) 34 (6%) 82 (4%)
technique with additional use of a blue dye was used in
670 (34%). The injection site varied between institutions, Data are number of patients (%), unless otherwise stated. NACT=neoadjuvant chemotherapy.
but was well balanced within groups. 76 institutions did
Table 2: Technical aspects of sentinel-lymph-node biopsy procedures in the trial
multiple injections, to various sites. The injected dose of
radiocolloid was similar in all groups.
Table 3 presents rates of detection of sentinel lymph Arms A and B Arm B Arm C p
nodes. Lymphoscintigraphy indicated a hot spot in Hot spot on 1014/1022 (99%) 236/360 (66%) 476/592 (80%) <0·0001
1014 (99·2%) of 1022 patients in arms A and B (before lymphoscintigraphy
neoadjuvant chemotherapy), 236 (65·6%) of 360 in Overall surgical detection 99·1% (1013/1022; 60·8% (219/360; 80·1% (474/592; <0·0001
arm B (after neoadjuvant chemotherapy), and 476 (80·4%) rate (n/N; 95% CI) 98·3–99·6) 55·6–65·9) 76·6–83·2)
of 592 in arm C. At surgery, one or more sentinel lymph Overall surgical detection 98·8% (573/580; 52·9% (126/238; 77·4% (301/389; ··
nodes were detected in 1013 (99·1%) of 1022 patients rate with radiocolloid 97·5–99·5) 46·4–59·4) 72·9–81·4)
alone
in arms A and B (before neoadjuvant chemotherapy), in
Overall surgical detection 99·5% (399/401; 76·2% (80/105; 87·8% (144/164; ··
219 (60·8%) of 360 patients in arm B (after neoadjuvant rate with radiocolloid and 98·2–99·9) 66·9–84·0) 81·8–92·4)
chemotherapy), and in 474 (80·1%) of 592 patients in blue dye
arm C. The median number of sentinel lymph nodes Sentinel lymph nodes
removed was two, which was similar between groups. removed
When sentinel-lymph-node biopsy was done before 0 9/1022 (1%) 141/360 (39%) 118/592 (20%) ··
neoadjuvant chemotherapy (arms A and B), no difference 1 284/1022 (28%) 96/360 (27%) 142/592 (24%) ··
in the detection rate was recorded between the combined 2 294/1022 (29%) 56/360 (16%) 131/592 (22%) ··
(radiocolloid and blue dye) and single-agent (radiocolloid 3 186/1022 (18%) 22/360 (6%) 81/592 (14%) ··
alone) detection techniques (99·5% [399 of 401] vs 98·8% 4 114/1022 (11%) 20/360 (6%) 59/592 (10%) ··
[573 of 580]; table 3). When sentinel-lymph-node biopsy >4 135/1022 (13%) 25/360 (7%) 61/592 (10%) ··
was done after neoadjuvant chemotherapy, in arms B At least one sentinel node
and C, the additional use of blue dye was associated with removed
a significant increase in the detection rate (76·2% All patients Mean 2·7, median 2·0 Mean 2·4, median Mean 2·7, median <0·0001
2·0 2·0
[80 of 105] vs 52·9% [126 of 238] in arm B, and 87·8%
[144 of 164] vs 77·4% [301 of 389] in arm C) and a higher Radiocolloid alone Mean 2·6, median Mean 2·3, median Mean 2·6, median 0·012
number of nodes were detected in arm C (median three 2·0 2·0 2·0
vs two in arm B; p=0·0059). Radiocolloid and blue Mean 2·8, median Mean 2·6, median Mean 2·9, median 0·059
dye 2·0 2·0 3·0
In arm C, we did a multivariate analysis of factors that
could potentially affect the detection rate (figure 3). Data are n/N (%), unless otherwise stated.
Morphological or biological features, tumour involvement
Table 3: Detection of sentinel lymph nodes, according to selected factors
of the sentinel lymph node, or the case load of the
colleagues,21 who reported a false-negative rate of 4·5% indicate that sentinel-lymph-node biopsy is less accurate
in this group of patients. The low detection rate and high in the specific setting of initially node-positive patients
false-negative rate for repeat sentinel-lymph-node biopsy who undergo sentinel-lymph-node biopsy after
after neoadjuvant chemotherapy can be explained by the neoadjuvant chemotherapy, particularly if only one or
notion of lymphatic mapping, which is based on an two sentinel nodes are identified.
orderly lymphatic spread of tumour cells. Possibly, In our study, addition of blue dye to radiolabelled
additional lymph-node involvement cannot be detected tracer could not improve further the detection rate for
once the primary drainage has been destroyed. This sentinel-lymph-node biopsy before surgery because
situation is, however, different to a second sentinel- radiocolloid alone already had a good detection rate. In
lymph-node biopsy procedure in recurrent disease. By patients with initially suspicious nodes who underwent
contrast with the setting investigated in our study, sentinel-lymph-node biopsy after neoadjuvant chemo-
tumour spread from a de-novo lesion happens after therapy (those in arm C), the additional blue dye resulted
preceding axillary surgery. Our results, therefore, cannot in a significant improvement in detection rate, from
be transferred to this clinical setting. 77·4% to 87·8%. This result is similar to data from
In patients whose axillary status converted from Mamounas and colleagues,27 who reported an increase in
clinically positive to clinically negative after neoadjuvant the detection rate after neoadjuvant chemotherapy, from
chemotherapy (those in arm C), we noted a false-negative 78·1% to 87·6%, if a blue dye was used in addition to
rate of 14·2% for sentinel-lymph-node biopsy. Compared radiocolloid. In arm C, we noted a non-significant
with our large prospective study, findings of smaller association between the false-negative rate and mapping
retrospective series show a wide range of false-negative technique (8·6% for combined tracer vs 16·0% for
rates (5–35%) for this group of patients.14–18 Our findings radiocolloid alone). Similar findings were reported from
accord with a subgroup analysis of the only prospective ACOSOG Z1071.26 Use of a combined tracer was
trial we could identify, by Classe and colleagues,20 who associated with a false-negative rate of 10·8%, whereas
reported a false-negative rate of 15%. the single tracer technique gave false-negative rates of
In several trials addressing the accuracy of sentinel- 22·2% for use of blue dye and 20·0% for radiocolloid
lymph-node biopsy at primary surgery for breast cancer, alone. We also noted a significantly higher lymph-node
false-negative rates of less than 10% have been noted yield for patients who underwent the dual-tracer
consistently.1,8,25 The accuracy of sentinel-lymph-node technique (median three sentinel nodes vs two for
biopsy after neoadjuvant chemotherapy for patients with radiocolloid alone), thus, whether the lower false-
initially positive lymph nodes is, therefore, less negative rate associated with the combined tracer is the
favourable compared with sentinel-lymph-node biopsy effect of the mapping technique or an effect of the
before systemic treatment. additional lymph-node harvest is unclear.
The accuracy of sentinel-lymph-node biopsy was Since sentinel-lymph-node biopsy has good feasibility
closely related to the number of sentinel nodes removed before systemic treatment, this procedure remains an
in our study. This association has been shown in several attractive option for clinically node-negative patients
trials of primary surgery and in the neoadjuvant scheduled for neoadjuvant chemotherapy. About two-
setting.6,17,22 In the National Surgical Adjuvant Breast and thirds of patients do not need axillary-lymph-node
Bowel Project (NSABP) protocol B32 study,8 a false- dissection if sentinel-lymph-node biopsy is undertaken
negative rate of 9·8% was reported for all patients who before neoadjuvant chemotherapy and shows uninvolved
underwent sentinel-lymph-node biopsy in primary nodes. Even in some cases of nodal involvement, patients
surgery. However, women with only one detected might be spared from axillary dissection, according to
sentinel node had a false-negative rate of 17·7%, the results of ACOSOG Z0011.28 In this trial, no benefit of
whereas those with at least two removed sentinel lymph axillary-lymph-node dissection was seen in patients with
nodes had a false-negative rate of 10·0% or better. In T1/T2 tumours and one or two involved sentinel lymph
our study, we recorded a false-negative rate of 14·2% for nodes who underwent breast-conserving treatment and
all patients who converted axillary status from positive radiotherapy to the breast. Compared with sentinel-
to negative after neoadjuvant chemotherapy (ie, those in lymph-node biopsy in primary surgery, the feasibility and
arm C). The group of women who had only one sentinel accuracy of sentinel-lymph-node biopsy after neoadjuvant
node resected had a false-negative rate of 24·3% and the chemotherapy is less favourable if patients are
group with two removed sentinel nodes had a false- downstaged from an initially positive to a negative
negative rate of 18·5%. Data presented recently from axillary status. However, this group of patients might
the American College of Surgeons Oncology Group derive significant benefit from sentinel-lymph-node
(ACOSOG) Z1071 study26 support our findings. For cN1 biopsy after neoadjuvant chemotherapy, because more
patients who underwent sentinel-lymph-node biopsy than 50% of them might be spared from either axillary
after neoadjuvant chemotherapy, the false-negative rate dissection or regional radiotherapy, or both. By contrast,
was 31·5% and 21·1%, respectively, if only one or two patients with one or two removed sentinel lymph nodes
sentinel lymph nodes were harvested. These results have an unacceptable false-negative rate, so this approach
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