Nevertheless, with the increased experience gained and the widespread use of the technique, the indications to SLNB have since been extended to encompass most of patients with non-metastatic disease previously excluded for technical or only theoretical reasons. So, most of the historical contraindications to SLNB are being questioned and the initial restrictive selections of patients are now progressively enlarging. The suitability of SLNB is well established in the settings of intraductal carcinoma and microinvasive cancers, in multifocal and multicentric disease, and following neo-adjuvant chemotherapy.
Early concerns about SLNB performed after a surgical biopsy of the primary tumor has proved unfounded. Using particular technical precautions, SLNB has been recently demonstrated to be safe and sure in pregnancy and can be considered in patients with clinically suspicious axillary nodes if preoperative palpation or ultrasonography-guided fine needle aspiration cytology is non diagnostic.
Finally, SLNB should be also considered in patients previously submitted to breast conserving surgery and SLNB alone (with negative SLN), when an invasive local recurrence with clinically unsuspicious axillary nodes occurs.
Today, SLNB is indicated for virtually all patients with clinically node-negative invasive breast cancer. New open questions recently arose. The results of the Z0011 Trial designed by the American College of Surgeons Oncology Group (ACOSOG) which randomized patients with 1-2 positive SLNs to receive either axillary lymph node dissection (ALND) or no further axillary surgery, exploded like a bomb over the surgical community. Even though the early interruption of accrual made this study theoretically underpowered to completely fulfill the primary endpoint (Overall Survival), the clinical relevance of these data is in no way diminished by statistical evaluations. They confirm that removal of lymph nodes does not have curative intent as previously pointed out by prospective randomized clinical trials carried out in the pre-SLNB era.
Furthermore, the results showed that excellent local control can be achieved foregoing ALND in the presence of SLN involvement. A further possible interpretation of these data is that the concept itself of the SLNB lost much of its importance. In fact, SLNB was developed as a method to obtain information on axillary lymph node status allowing surgeons on the one hand to spare the morbidity of axillary clearance in patients with negative nodes, and on the other hand to identify patients with positive nodes as candidates for a wider surgical extent.
The Z0011 trial showed that there is no outcome advantage in dissecting the axilla in the presence of positive SLN, meaning not only that wider surgery in the axilla is not improving outcome but also that the information achieved by removing lymph nodes does not change the prognosis of the disease. Moreover, to date the impact of prognostic information of axillary lymph node status on the decision-making process is less important than it was in the past as the adjuvant treatment is more and more tailored towards the biological features of the disease rather than on the risk of recurrence. In another important study on SLNB, the AMAROS trial, which randomized patients with positive SLNs to receive either axillary clearance or axillary radiotherapy, the type of adjuvant treatment did not change between the two groups suggesting that detailed information on axillary status is not going to change treatment recommendations.
So, if axillary reappearance is lower than expected in patients with negative SLNBs, if an excellent local control can be achieved without dissecting the axilla even in patients with positive SLNs, and if the information on extent of nodal involvement does not change type of treatment and mostly nor does it change prognosis, the following questions immediately arise: do we really need to look for a SLN? Do we really need the information obtained by identifying and examining the SLN?
Therefore, at the European Institute of Oncology of Milan we designed the SOUND trial (Sentinel node vs Observation after axillary Ultra-SouND) which is a prospective randomized controlled multicentric study representing a further step forward in the conservative approach to breast cancer aimed at improving patients’ quality of life. Primary endpoint of the trial is distant disease-free survival.
This endpoint, a proxy of overall survival, will allow reliable results to be obtained in a shorter period of time compared to overall survival. Secondary endpoints will be the cumulative incidence of distant recurrences, the cumulative incidence of axillary recurrences, the disease-free survival (DFS) and the overall survival (OS). Other secondary endpoints are quality of life and evaluation of type of adjuvant treatment administered. Overall, 1560 women (780 per arm) will be enrolled to decide whether the group without treatment of the axilla is no worse than the reference group, given a margin ? of non-inferiority of 2.5% (maximum tolerable 5-years DDFS = 94%). There are several concepts behind this study. First the acknowledgement that imaging may play a role in axillary staging. Secondly, we are convinced that decisions on adjuvant systemic treatment should be taken considering the prediction of response rather than prognosis as this attitude reflects a higher probability for the patient to benefit from a certain type of treatment. Finally, a less invasive surgery associated with a more tailored medical approach is aimed at improving patients’ quality of life.
Mattia Intra, MD