Survival and axillary recurrence following sentinel node-positive breast cancer without completion axillary lymph node dissection: the randomized controlled SENOMAC trial

Lymph node metastasis is one of the factors of greatest prognostic importance in breast cancer [1‐3]. Lymph node metastases are classified as isolated tumor cells (≤ 0.2 mm and/or <200 cells), micrometastasis (> 0.2 but ≤2 mm and/or >200 cells) and macrometastasis (> 2 mm) [4]. Sentinel node (SN) biopsy has proven to be a reliable method [5], and several follow-up studies have shown that it is safe to refrain from completion axillary lymph node dissection (ALND) in sentinel node-negative breast cancer [6‐10]. The greatest advantage of the SN biopsy approach is the significant decrease in the frequency and severity of arm problems since fewer lymph nodes are removed from the axilla [11‐14].

In SN-positive patients, no additional metastases are found in the remaining lymph nodes removed on ALND in about 50–65% of patients [15]. After the publication of the ACOSOG Z0011 trial in 2011 [16], refraining from completion ALND in SN-positive cases has been embraced widely especially in the US [17, 18]. This trial randomized SN-positive patients to either undergo ALND or to refrain from completion axillary surgery. After a median follow-up period of over 6 years, no difference in the rate of axillary recurrence was found, and survival was even slightly better among patients who only underwent SN biopsy (disease-free survival 83.9%, compared with 82.2% for patients who underwent ALND), although the difference was not statistically significant. The study has received some criticism [19, 20]. ACOSOG Z0011 only included patients with tumors up to 5 cm in size who underwent breast-conserving surgery, receiving whole-breast postoperative radiotherapy.

Another study (IBCSG 23–01), in which SN-positive patients were randomized to either undergo completion ALND or not, was published in 2013 [21]. This study included only patients with SN micrometastases, but also showed slightly better disease-free survival in the group operated with SN biopsy alone (87.8% compared with 84.4% for those who underwent ALND), though the difference was not statistically significant here either. Neither the ACOSOG Z0011 study nor the IBCSG 23–01 study succeeded in enrolling the planned number of patients and the studies do not have sufficiently high power to detect small differences.

There are a few studies suggesting that ALND may still have some therapeutic benefit: The rate of axillary recurrence among SN-positive patients who did not undergo ALND was a striking 2.0% after just 30 months, despite otherwise favorable prognostic factors (compared with 0.4% among those who underwent completion ALND) in a report by Park et al. [22]. In the Dutch MIRROR study [23] the rate of axillary recurrence was more than twice as high among patients with SN micrometastases who did not undergo ALND compared with SN-negative patients.

In Sweden, most patients with SN macrometastases receive adjuvant radiotherapy to the axillary region. A large European study (AMAROS) randomizing over 1400 SN-positive patients, of whom 861 with SN-macrometastases, to either undergo completion ALND or to have axillary radiotherapy showed no difference in disease-free or overall survival [24]. Subsequently, several countries now approve axillary radiotherapy in lieu of axillary lymph node dissection.

None of the described trials included a sufficient amount of patients treated by mastectomy to draw any conclusions on the need of ALND. It is also unclear whether the tumor size should be limited to 5 cm at most or whether larger, although not locally advanced tumors may be included along the same line of thought. Finally, as the rates of breast cancer treated by neoadjuvant systemic therapy (NAST) are rising internationally, the question how to surgically treat the axilla post NAST in the event of a positive pre-NAST SN biopsy needs to be answered. The SENOMAC trial attempts to answer these highly important questions in an international collaborative effort.

This prospective multicenter non-inferiority trial randomizes breast cancer patients with macrometastasis in at most two sentinel nodes to either undergo completion ALND (arm A) or not to have any further axillary surgery (arm B), and is conducted according to Good Clinical Practice (GCP) guidelines. For inclusion and exclusion criteria, see Table 1.

Despite a general decline in the use of ALND after the first publication of the results from the ASOSOG Z0011 trial in 2011 [16], there is still considerable variation in surgical management of the axilla across European centers [31]. Even after the recent publication of long-term results from the same study, showing essentially no difference in recurrence rates between patients undergoing or omitting completion ALND [32], the base of evidence remains small. A review by Schmidt-Hansen et al. [33] identified only three prospective randomized trials comparing SN-biopsy with or without completion ALND in patients with SN metastases, reporting on a total of 2020 patients. This said, two of these three trials did exclusively include cases of SN-micrometastasis (AATRM 048/13/2000 and IBCSG-23-01) and the third trial (ACOSOG Z0011) included only 430 patients with SN-macrometastases while the remaining 301 patients had SN-micrometastases only; the size of SN-metastasis was not reported on the 125 patients left in the intent-to-treat sample (N = 856). Thus, evidence on the significance of completion ALND in patients with SN-macrometastasis is limited to a small sample of individuals with T1-T2 tumors treated by breast-conserving surgery. Despite this, the use of ALND in SN-positive disease seems to decrease even in patients treated by mastectomy [34]; in other instances, ALND may be replaced by regional radiotherapy after the results of the AMAROS trial [24]. This clearly leaves a need for further prospective trials, including patients treated by mastectomy.

In the setting of neoadjuvant systemic therapy (NAST), it has been argued that SN biopsy pre NAST has the disadvantage to necessitate a second axillary intervention (ALND) in case of SN-macrometastases in cN0 patients [35]. The false negative rate in repeat SN biopsy after NAST is high [36] but is acceptable if performed primarily after NAST in case at least three SN can be identified. While the latter has become routine in some countries, SN biopsy is still performed prior to NAST in Sweden and other countries in case of clinical node negativity. The SENOMAC trial gives the opportunity to benefit from the up-front staging information the SN biopsy can offer in cN0 patients while investigating whether a completion ALND is necessary in those with up to two SN macrometastases. Thus, this trial may conclude whether or not ALND is at all indicated in patients with pre NAST SN macrometastases, given that no tumor progression is observed during NAST.

In summary, the SENOMAC trial aims to answer the clinically pending questions concerning the indications for ALND in T1-T3 tumors in cN0 patients. Importantly, it not only includes both breast conservation and mastectomy but also patients selected for neoadjuvant systemic therapy.