Surgical Management of the Axilla in Primary Surgery
For many decades, complete dissection of the ipsilateral axillary lymph nodes (ALND – axillary lymph node dissection) in addition to breast surgery was considered the standard procedure to treat breast cancer. The aim of lymph node dissection was to determine the histological node status (pN stage) as one of the most important parameters determining the appropriate adjuvant therapeutic approach. Moreover, ensuring locoregional tumour control by removing the tumour burden was considered an important objective of the procedure. However, ALND is associated with high morbidity rates, which have a sustained negative impact on the long-term quality of life of affected women [2 ].
In women who underwent primary surgery with no suspicion of axillary lymph node involvement, the use of ALND for staging has been replaced by sentinel lymph node excision (SLNE), which has a lower morbidity without compromising disease-free survival (DFS) or overall survival (OS) (NSABP B 32 [3 ]).
In women with a clinically normal lymph node status and limited SLN involvement, randomised studies showed that in certain cases it is possible to avoid ALND (ACOSOG Z0011, AMAROS) [4 ], [5 ]. According to the updated recommendations of the AGO Breast Committee, the German S3 guideline (registry number 032 – 045OL), and the NCCN and ESMO guidelines, ALND can be avoided in selected patients with 1 – 2 affected lymph nodes [6 ], [7 ], [8 ], [9 ].
Surgical Management of the Axilla After Neoadjuvant Chemotherapy
Sentinel lymphadenectomy and axillary dissection
When SLNE became the standard procedure, the aim was to combine the smallest possible surgical intervention with a precise diagnostic workup and the lowest side effect profile. Although the data on SLNE performed during primary surgery showed good results, for a long time the feasibility and safety of SLNE after neoadjuvant chemotherapy was considered to be controversial, particularly in cases with a positive axillary lymph node status before the start of therapy and conversion to clinically undetectable lymph node involvement after NACT (cN+ → ycN0 stage). Two large prospective multicentre studies reported a false-negative rate (FNR) of 12% and 14% respectively for this patient population, although the FNR decreased when increasing numbers of lymph nodes were removed [10 ], [11 ]. This figure exceeds the generally accepted (but arbitrarily selected) cut-off value of 10%. However, the clinical impact of an FNR
of > 10% on oncological endpoints (DFS, OS) is still unclear. For this reason, numerous national guidelines still recommend carrying out ALND in this patient population [5 ], [6 ].
Targeted axillary dissection (TAD)
In recent years, the question of how the FNR can be improved in patients with primary lymph node involvement (cN+) has been intensively discussed. In 2016, Caudle et al. published a report of a new procedure, TAD (targeted axillary dissection), in which both the SLN and one (or even several) lymph node(s) found to be affected prior to treatment are dissected after being marked with a clip before the start of therapy [12 ]. The initially biopsied and investigated lymph node is marked and is referred to as the target lymph node (TLN). When TAD (SLNE + TLNE) was used, the FNR was only 2.0% (95% CI: 0.05 – 10.7; p = 0.13), a figure that was significantly superior to a FNR of 10.1% with SLNE and a FNR of 4.2% when only the target lymph node was resected. These retrospectively evaluated data from a prospective database support the hypothesis that TAD could be a suitable procedure to improve the limited success rate of SLNE and additionally reduce
the morbidity associated with ALND using a gentler form of surgery. A number of validation studies have been published in recent years which address the question of whether target lymph nodes need to be marked and which method should be used to mark them to ensure a reliably low FNR for TAD procedures. The studies did not just investigate the reproducibility of TAD, they also examined the clinical benefit of different marking techniques (carbon dye, clip, radioactive seed) [13 ], [14 ] ([Table 4 ])
Table 4 Trials evaluating different marking techniques.
Study
Country
Marking technique
Case numbers (n)
Detection rate
FNR
SENTA [15 ] (NCT 03012307)
D
clip placement
473
77.3%
4.30% (95% CI: 0.5 – 14.8 )
RISAS [16 ], [17 ] (NCT 02800317)
NL
radioactive seed placement
227
98.0%
3.47% (95% CI:1.38 – 7.16)
TATTOO [18 ] (DRKS 00013169)
D, S
dye (carbon tattooing)
110
93.6%
9.10%
In the report on the SENTA trial by Kümmel et al., the detection rate for the target lymph node was 77.3% and the FNR for TAD was 4.3% (95% CI: 0.5 – 14.8) [15 ]. In the RISAS trial, the reported FNR was 3.47% (95% CI:1.38 – 7.16) with a relatively small confidence interval, and the detection rate was 98% [16 ], [17 ]. In contrast, Hartmann et al. reported a lower detection rate of 93.6% and a higher FNR of 9.1% for the TATTOO trial [18 ].
None of the above-mentioned studies collected data on oncological endpoints such as disease-free survival and overall survival, quality of life, or effort and expense, so that it still remains unclear to what extent the different FNRs of the various methods affect the clinical outcome. Recommendations on TAD are therefore based on the reported FNRs and their perceived clinical relevance. The continuous improvement of local therapies and the use of individualised systemic therapy have led to continuously increasing rates of complete histopathological remission (pCR). In some groups, the rate may be as high as 70% [19 ]. Even in women with an initially positive lymph node status, the lymph node conversion rate may be as high as 50% [11 ], [20 ]. This means that the percentage of patients who have a negative node status (ypN0) after NACT and are then overtreated by undergoing ALND
is continually increasing. For this reason, limiting the extent of radical surgery required to determine node status is a matter of urgency, especially as the removal of clinically unremarkable axillary lymph nodes is increasingly viewed as being done for the purposes of staging alone.
According to verified data on the reduction of surgical radicality, the data on the long-term oncological outcome of minimally-invasive staging methods (SLNE, TAD) after conversion from cN1 to ycN0 has not yet been validated. For this reason, various surgical axillary procedures (ALND, TAD, SLNE, TLNE) are still carried out after NACT in Europe and worldwide (based on the assessment of the respective national professional societies and surgeons).
Recommendation of the AGO Breast Committee to reduce the rate of false negatives during the surgical staging of biopsy-confirmed axillary lymph node metastasis (pN+CNB ) before NACT and ycN0
Using currently available data [21 ], [22 ], [23 ], [24 ], [25 ], [26 ], [27 ], [28 ], [29 ], [30 ], [31 ], [32 ], [33 ], [34 ], [35 ], [36 ], [37 ], [38 ], [39 ], [40 ], [41 ], [42 ], [43 ], [44 ], [45 ], [46 ], [47 ], [48 ], [49 ], [50 ], [51 ], [52 ], [53 ], [54 ], [55 ], [56 ], [57 ], [58 ], [59 ], [60 ], the AGO has evaluated the following procedures to reduce false negative rates during the surgical staging of cases who are pN+CNB before NACT and ycN0 after NACT with AGO + ([Fig. 1 ]):
Fig. 1 Algorithm of axillary surgical procedures before and after NACT. [rerif]
Targeted axillary dissection (TAD) (LoE 2b, GR: B, AGO +)
Dissection of > 2 SLNs (SLNE, no untargeted axillary sampling) (LoE 2a, GR: B, AGO +)
Immunohistochemical evaluation to detect isolated tumour cells or micro-metastasis (LoE 2b, GR: B, AGO +)
In principle, the AGO classified performing SLNE before neoadjuvant chemotherapy as a minus (LoE 2b, GR: B, AGO −), which means it is no longer recommended ([Table 5 ]). The prime reason for this is that pCR assessment is no longer possible when SLNE is performed prior to NACT, and the patient is additionally subjected to an unnecessary surgical procedure.
Table 5 Surgical axillary interventions and NACT.
Oxford
LoE
GR
AGO
* Participation in AXSANA trial recommended; ** only radiotherapy for ypN1 (sn), ypN+ not recommended; ***recommendation grade is referred to staging for cN0 and cN+ ypN0.
SLNE after NACT
SLNE before NACT
2b
2b
B
B
++
–
cN status (before NACT)
pN status (before NACT)
cN status (after NACT)
Surgical axillary intervention (after NACT)
pN status (after NACT and surgery)
Surgical consequences of histological findings
cN0
–
ycN0
SLNE alone
ypN0 (sn)
–
2b
B
++***
ypN0 (i+)
ypN1mic (sn)
ALND
2b
C
+ (+/– with i+)
none**
5
D
+/−
ypN1 (sn)
ALND
2b
C
++
none**
5
D
+/−
cN+
pN+CNB
ycN0
SLNE alone*
TAD (TLNE + SLNE)*
ALND*
ypN0
ypN0
ypN0
–
2b
2b
2b
B
B
B
+/−***
+***
+***
SLNE alone*
TAD (TLNE + SLNE)*
ypN+ incl. ypN0 (i+)
ALND
2b
B
+ (+/– with i+)
ALND
ypN+
–
2b
B
++
none
n. d.
none**
5
D
–
cN+
pN+CNB
ycN+
ALND
ypN+ incl. ypN0 (i+)
–
2b
B
++
None
n. d.
none**
5
D
–
In contrast, carrying out axillary staging after systemic NACT therapy is recommended.
In this case, it is important to differentiate between two baseline situations ([Fig. 1 ] and [Table 5 ]):
Patients who are node-negative on clinical and ultrasound examination before NACT
Patients who are node-positive on clinical and ultrasound examination before NACT
Patients who are node-negative on clinical and ultrasound examination before NACT
In clinically node-negative patients, SLNE should be carried out after neoadjuvant chemotherapy. If the histomorphological findings for SLN are normal, i.e., ypN0(sn), then no further axillary procedures are necessary.
If macro-metastasis is present in the SLN after NACT, then axillary dissection is indicated and classified as ++ (LOE 2b, GR: C, AGO +).
If micro-metastasis is present in the SLN after NACT, then ALND is an option and is classified as + (LOE 2b, GR: C, AGO +), as additional LN metastases outside the SLN tend to be present in this setting in around 60% of cases [45 ].
If isolated tumour cells are detected in SLN after NACT, the AGO classifies ALND as +/− (LOE 2b, GR: C, AGO +/−) and ALND may be considered in selected cases. Based on the currently available data, additional LN metastases may be present in around 17% of cases [45 ].
Patients who are node-positive on clinical and ultrasound examination before NACT
If there is a primary suspicion of axillary lymph node involvement, a punch biopsy (pN+CNB ) carried out prior to NACT for histopathological verification is recommended, with marking of the suspicious axillary lymph node (LOE 2b, GR: B, AGO +) to permit TAD after NACT.
If the axilla are normal on clinical and ultrasound examination after NACT (ycN0) , ALND and TAD are considered to be equivalent treatment options (LOE 2b, GR: B, AGO +), although TAD is a less invasive procedure with a low false-negative rate [12 ]. Lymph nodes which are found to be histomorphologically normal with TAD (ypN0) require no further surgical axillary intervention. Therapeutic ALND is recommended in cases with histologically verified lymph node involvement after TAD (ypN1), and the AGO classifies this as + (LOE 2b, GR: B, AGO +). ALND may be considered in selected cases with evidence of isolated tumour cells in LNs after TAD (ypN0[i+]); the AGO classifies this as +/− (LOE 2b, GR: B, AGO +/−).
ALND is indicated in cases with axillary involvement (ycN+ ) detected on clinical or ultrasound examination (LOE 2b, GR: B, AGO ++). Further axillary procedures such as radiotherapy of the operated area are not indicated after complete ALND.
Because of its high false-negative rate of almost 17%, caution should be used with regard to SLNE alone after NACT in cases with conversion from cN+ → ycN0 [45 ]. The AGO therefore classifies this option as +/− (LOE 2b, GR: B, AGO +/−).
A lot of questions with regard to currently used surgical procedures still remain unsolved. Because of the lack of data, recommendations for patient populations which are ycN0 after NACT [conversion from pN+CNB (after punch biopsy) ] vary greatly across the world. The current ESMO guideline permits SLNE alone; if the findings are negative, no further lymph nodes need to be removed in selected cases. However, the ESMO guideline emphasises that the FNR of SLNE alone can be improved by marking the lymph nodes which were positive on the initial biopsy, followed by targeted dissection. The guideline recommendations in Germany also vary. After its last revision in 02/2020, the S3 guideline still recommends ALND as the preferred procedure for primary node-positive patients after NACT. In contrast, the AGO amended its recommendations in 2019 to the effect that it now classes TAD an equivalent procedure. However, ALND is still the only accepted standard procedure in
a number of European countries, (Sweden, Norway, Finland). In other countries (Italy), SLNE is carried out as a routine procedure without additional marking of a TLN. The American NCCN guidelines recommend carrying out TAD as an optional procedure. A prospective comparison of the different techniques with regard to their feasibility, safety, morbidity and surgical cost is urgently required. Because of the complexity and costs involved and the very different guideline recommendations, carrying out a randomised comparison would not be useful to generate the necessary data which could resolve the many outstanding issues within a short space of time.
The therapeutic axillary approach in cases where the initial node status on clinical examination is normal but lymph node metastasis is detected following histopathological examination after NACT (cN0 → ycN0 → ypN1) is not yet been investigated much, meaning that ALND continues to be the standard recommended approach in most guidelines. Although the AMAROS trial proved that radiotherapy was equivalent to ALND in patients with a clinically occult nodal status who underwent primary surgery and the ACOSOG Z0011 trial has shown that axillary interventions can successfully be dispensed with in patients with positive SLNs, it is not clear whether these data can be transferred to cases with chemotherapy-resistant lymph node involvement (after NACT) [4 ], [5 ]. The Alliance A011202 trial should provide important answers to this question [60 ].
There is even less evidence available on the appropriate approach for small metastases (micro-metastasis, isolated tumour cells) after NACT (ypN1mi or ypN0i+). Although minimal lymph node involvement in patients who underwent primary surgery has no impact on adjuvant therapy planning, it is not clear whether ALND might be necessary for diagnostic purposes (because of the high rate of downstream non-SLNs which might lead to an upgrade of patientsʼ nodal status) or for therapeutic reasons (tumour cells resistant to systemic therapy) in cases with limited lymph node involvement after NACT.
Innovative methods have reduced the radicality of axillary surgery, but this reduced radicality should always be considered in the context of other therapeutic modalities. Even though studies have demonstrated the local efficacy of radiotherapy, with much of the data extrapolated from the adjuvant setting, carrying out the smallest possible axillary intervention and avoiding ALND should not be used as a justification for expanding radiotherapy measures, which have their own specific side effect profile.
Prospective studies are urgently required to close the existing knowledge gaps. The AXSANA/EUBREAST-0 3 trial ([Fig. 2 ]), which is supported by the AGO-B, is an international project which currently includes 20 participating countries. The aim is to investigate the impact of different axillary staging measures on invasive disease-free survival, axillary rate of recurrence and quality of life [13 ]. The trial will also be analysing different therapeutic procedures in patients with ypN1 status and studying the importance of micro-metastasis and isolated tumour cells after NACT.
Fig. 2 AXSANA trial flowchart. [rerif]
