Ten studies documented the definition of ax-pCR: overall FNR was 16% when ax-pCR was defined as ypN0 and 17% when ax-PCR was defined as ypN0/itc+ (P = 0.61, 1 study defined ax-pCR as ypN0/itc+/mi+). FNR was reported for single versus dual-tracer sampling separately in 5 studies and another 6 studies used either single-tracer or dual-tracer sampling in 100% of patients. Pooled FNR was 13% for dual-tracer sampling and 16% for single-tracer sampling (P = 0.53). A total of 14 studies reported on the use of IHC: overall FNR was 15% when IHC was used (either always or in selected patients) versus 17% when IHC was not used (P = 0.47). In 6 studies, FNR was reported separately in relation to the number of SLN(s): all 6 studies reported FNR for excision of 3 or more SLNs (NB: in 1 study, this was 2 or more SLNs) and 5 of 6 studies also reported FNR for excision of <3 SLNs. Overall FNR was 8% with removal of at least 3 SLNs and 22% with removal of < 3 SLN(s) (P < 0.0001). In 7 studies, only cN+ patients with ycN0 status were included. In addition to these studies, another 4 studies reported on FNR separately for patients with any ycN status versus ycN0 status. Overall FNR was 14% when only patients with ycN0 status were taken into account versus 18% when patients irrespective of ycN status were taken into account (P = 0.14).
One study reported on a ML procedure: this study involved the validation of the MARI procedure (marking axillary lymph nodes with radioactive iodine seeds) in 95 patients. In this study, the pathologically proven positive lymph node was marked with an I-125 seed pre-NST. After completion of NST, at the time of surgery, the lymph node with the Iodine seed was removed. The IFR was 97%, the FNR 7%, and the NPV 83.3%. See Table 3 (ML) for characteristics of this procedure.
Two studies investigated a combination procedure: one involved clipping of the positive lymph node pre-NST later followed by I-125 seed localization of the clipped node post-NST in combination with SLNB and one involved clipping of the positive lymph node pre-NST followed by US-guided excision of the clipped-node in combination with SLNB. Table 3 (Combination) shows values for FNR and NPV for the 2 combination procedures. As only 2 studies were available for analysis, pooling of proportions was not performed. The studies appeared clinically similar, as they targeted the same population in terms of inclusion criteria, definition of ax-pCR, and use of IHC.
The MARI procedure was the first ML procedure to be proposed as an alternative to SLNB for axillary staging after NST in cN+ patients.8 By marking the pathologically proven positive lymph node before start of NST, it was expected to enable accurate assessment of treatment response after completion of NST. The MARI procedure was validated in 1 single-center trial with 95 patients. This study reported an improved FNR (7%), but the NPV of 83.3% was less favorable, that is, in 1 of 6 patients with a negative MARI, axillary residual disease is left behind. Therefore, equally to SLNB, MARI as a stand-alone procedure is insufficiently accurate to safely replace ALND. Despite the shortcomings of MARI (potential of missing residual axillary disease and limited evidence by 1 single—dedicated breast cancer—center trial to support this procedure), it is already implemented in clinical practice. A recent publication suggests combining information on axillary burden on pre-NST PET-CT (ie, number of suspicious lymph nodes: <4 vs ≥ 4) with MARI outcome9 to determine adjuvant axillary treatment: no further axillary treatment, axillary radiotherapy, or cALND with axillary radiotherapy. Results of 1 prospective implementation study showed that this treatment strategy indeed results in a major reduction of ALND.43 Data of longer follow-up have to determine whether implementation of this protocol is untimely and whether it does not only reduce morbidity but also preserves oncologic safety in terms of disease-free and overall survival. Prospective trials with sufficient follow-up are therefore urgently needed.
In the Z1071 trial, a clip was placed in the positive lymph node before NST in a subset of patients.44 The trial protocol did not require surgeons to selectively target and remove the clipped node at time of surgery, but did encourage surgeons and pathologists to document whether the clipped node was located in the SLNB or ALND specimen. In 141 of 170 patients with a clipped node, the location of the clipped node was documented: 75.9% in the SLNB specimen and 24.1% in the ALND specimen. This suggested that removing the clipped node together with SLN(s) at time of surgery may improve accuracy of SLNB and may possibly overcome shortcomings associated with SLNB or MARI if used as stand-alone procedures. Up to now, only 2 trials evaluated accuracy of such a combination procedure and were included in our meta-analysis.6,32 This procedure is associated with excellent IFRs. Caudle et al6 confirmed that the clipped node does not necessarily have to be a SLN, as this was the case in only 77%. Furthermore, FNR is low (2% to 4%) and NPV is high (92% to 97%). These results are promising: when ax-pCR is predicted, residual axillary disease is missed in 1 in 12 to 33 patients. The evidence for this procedure is yet limited with only 2 trials available (1 retrospective and 1 prospective study), involving small sample sizes and single-center study designs. The ongoing Dutch RISAS trial (NCT02800317 at https://clinicaltrials.gov) will prove whether the promising results of a combination procedure can be confirmed in a large, prospective, multicenter trial.45
Although evidence to support replacing ALND by less invasive procedures is limited, several reports have been recently published on implementation of such procedures, especially procedures involving excision of the ML and SLNs. A variety of methods are used to target the pathologically proven positive lymph node: marking with a clip pre-NST followed by placing an iodine seed or wire in the clipped node post-NST7,33–35,37 and primary marking with an iodine seed, clip, charcoal, or electromagnetic reflector.36,38 Also, the time of marking the lymph node pre-NST differs: either immediately at time of FNAC/CNB,7,33,34,37 at a second appointment once metastatic burden of the punctured lymph node is confirmed by the pathologist35,36 or even at both occasions.38 Currently, further research has to define which combination procedure is most accurate, patient-friendly, and cost-effective. Identification of the ML at time of surgery is highly feasible, provided that clipping (with/without secondary localization of the clip) of the node was successful. Success rates of this part of the procedure are often not sufficiently reported and may be improved to further optimize combination procedures.
The abovementioned 3 different staging procedures intend to offer a less invasive strategy compared with the conventional ALND, yet ≥ 10 lymph nodes are removed in some patients with SLNB and combination procedures. It is important to realize that these procedures serve as a staging procedure to identify ax-pCR and not as a managing procedure to remove all residual diseases. Hence, it should be the primary goal to remove as few lymph nodes as possible. In this way, patients with ax-pCR can truly benefit from less invasive staging procedures. At the same time, when these procedures identify axillary residual disease, adjuvant axillary treatment plans should consist of cALND. Results of the Alliance 11202 and NSABP-51/RTOG 1304 trials have to be awaited to determine whether cALND may be replaced by axillary radiation therapy.41,42
As this review is limited by the heterogeneity of included studies, results of the review should be interpreted with caution. The random effects model that was used for statistical analysis takes in account that, although similar interventions were studied, different populations were included. Factors such as definition of ax-PCR, sampling method for SLNB, and use of IHC for pathologic assessment of lymph nodes may all impact accuracy of the studied intervention. These factors differed widely among included studies and further research is necessary to determine, among others, what should be the preferred definition of ax-pCR. The prognostic impact of residual ITCs and micrometastasis may be different for patients treated in the neoadjuvant compared with adjuvant setting, as they might be therapy-resistant. A retrospective study of cN+ patients treated with NAC and always followed by ALND suggested that patients with residual ITCs and micrometastases carry a similar prognosis as patients with ypN0.46 These results have yet to be confirmed in trials where patients with ypN0 and ITCs or micrometastasis did not undergo ALND. In addition, the value of IHC has not yet been thoroughly studied, as most studies that used IHC in addition to standard H&E evaluation, did so randomly, and not in a routine matter. Contrary to improving accuracy of detecting residual axillary disease, a potential undesired result of IHC may be detection of residual disease that would have otherwise been left undetected (of which implications on prognosis and need for adjuvant treatment are unknown). The question whether IHC may not only result in improved accuracy but may also result in overtreatment is yet left unanswered.
In this review, we only included patients in whom cN+ status was pathologically proven before NST. This is particularly important to determine true accuracy of the different staging procedures. When patients who are expected to be cN+ based on physical examination or imaging only, the number of true negatives rises and the chance to have false negatives decreases. This may result in a false impression of improved rates of FNR and NPV.
In conclusion, the SLNB as well as ML procedures seem insufficiently accurate as stand-alone procedures for axillary staging after NST in cN+ patients. Accuracy of these procedures may improve by taken in account axillary burden on pre-NST and/or post-NST imaging. A combination procedure involving excision of the ML and SLNs appears most accurate for axillary staging and has the lowest risk of missing axillary residual disease when ax-pCR is predicted. More evidence from prospective multicenter trials is needed to confirm this.
We thank the following individuals for assistance with search strategies and statistical analysis: P.H. Wiersma and F.P. Weijdema, health science librarians, Utrecht University Library.
J.B. Reitsma, clinical epidemiologist, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht.
R.J.P.M. Scholten, professor of clinical epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht.
PubMed search strategy
(“Breast Neoplasms”[Mesh] OR ((carcinoma OR carcinomas OR tumor OR tumours OR tumour OR tumours OR neoplasm OR neoplasms OR malignancy OR adenocarcinoma OR cancer) AND (breast OR mamma))) AND (“Sentinel Lymph Node Biopsy”[Mesh] OR sentinel lymph node biopsy OR slnb OR (MARI[tiab]) OR (Axilla* AND staging[tiab]) OR targeted axillary dissection) AND (sensitivity OR specificity OR “Sensitivity and Specificity”[Mesh] OR “Predictive Value of Tests”[Mesh] OR negative predictive value OR positive predictive value OR likelihood ratio OR diagnosis OR “false-negative” OR “false-positive”) AND (“Lymph Nodes”[Mesh] OR “Lymphatic Vessels”[Mesh] OR “Lymphatic Metastasis”[Mesh] OR “Lymphatic System”[Mesh] OR “Axilla”[Mesh] OR axilla*) AND ((“Neoadjuvant Therapy”[Mesh] OR neoadjuvant OR preoperative* OR primary) AND (“Antineoplastic Agents”[Mesh] OR chemotherapy OR immunotherapy OR systemic therapy))
EMBASE search strategy*
*Search results were restricted to articles, reviews, articles in press, conference paper, conference review
((breast OR mamma) AND (cancer OR carcinoma OR neoplasm OR malignancy OR adenocarcinoma OR ’breast cancer’/exp OR tumor OR carcinomas OR tumors OR tumour OR tumours)) AND (('sentinel lymph node biops*’ OR slnb OR 'sentinel node*’ OR 'sentinel lymph node biopsy’/exp OR ’mari’:ab,ti OR (axilla* AND staging) OR ’targeted axillary dissection’)) AND (sensitivity OR specificity OR ’predictive value’ OR ’likelihood ratio’ OR ppv OR npv OR diagnosis OR ’false negative’ OR ’false positive’) AND ((axilla* OR lymph*) AND (node* OR metastasis)) AND ((neoadjuvant OR primary OR preoperative*) AND (therapy OR immunotherapy OR chemotherapy OR systemic))
Appendix 2. Forest plot of the ax-pCR rate.
ES effect size. The pooled ax-pCR is 37% (33% to 40%).
Appendix 3. Forest plot for the identification rate of SLNB.
ES. effect size. The pooled identification rate of SLNB is 89% (87% to 92%).
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