Use of sentinel lymph node biopsy in elderly patients with breast cancer – 10-year experience from a Swiss university hospital

The Choosing Wisely campaign was developed to reduce low value surgical procedures with the aim of de-implementing potentially harmful and costly procedures that do not improve survival. In August 2016, the initiative recommended to omit routine use of SLNB in women ≥ 70 years with clinically node-negative early stage HR positive and Her2 negative BC [11], which is not the main cause of death in those patients [9]. Furthermore, the SLN procedure is questioned as it is neither causing a survival benefit, nor a clinically relevant benefit in locoregional control. Moreover, a clear indication for adjuvant endocrine therapy is given, irrespective of nodal status [9, 18].

The present retrospective cohort study aimed to investigate the impact of the Choosing Wisely recommendations on clinical practice at a Swiss university hospital. It showed that SLNB did not decrease in elderly patients with small clinically node-negative BC after the publication of these recommendations. This is in line with findings from a retrospective US multi-center study that showed institutional variation ranging from 25%-97%, with overall stable use of SLNB in the Choosing Wisely group before and after its publication (88% in 2013, and 87% in 2016), while the later period may have been too early to detect any impact of the recommendations on clinical practice [12]. Earlier real-world data clearly showed routine axillary staging by SLNB in the elderly [19].

The present study showed that the omission of SLNB in elderly BC patients was not associated with an increase in the use of adjuvant radiotherapy of the breast. In fact, the fraction of patients undergoing radiotherapy was significantly smaller when SLNB was omitted. Whilst this is in line with the study protocol of the CALGB 9343 trial, applicability of the other landmark trial protocol concerning the omission of radiotherapy in elderly BC patients—PRIME II—depended on surgically confirmed negative nodal status of the axilla [9, 18, 20, 21]. Surgical axillary staging was also mandatory in the majority of trials laying the foundation for a recent European consensus recommendation on hypofractionated radiotherapy and partial breast irradiation [22]. The Florence trial being the only exception, including however only 23 patients without axillary surgery, currently preventing any evidence-based conclusions [23]. Therefore, interdisciplinary consensus should be sought in the tumor boards that de-escalation of surgical staging of the axilla does not result in overuse of adjuvant radiotherapy of the breast and axilla. A recent Canadian population-based study has shown lower rates of adjuvant radiotherapy to the breast, however higher rates of axillary radiotherapy in patients ≥ 70 years with stage I or II BC after omission of surgical axillary staging [24]. In earlier studies, axillary surgery was found to be associated with adjuvant therapy in the elderly [19, 25, 26]. Nevertheless, whilst the rate of neoadjuvant and adjuvant chemotherapy, as well as adjuvant radiotherapy in our general population showed age-dependent differences, omission of axillary surgery did not differ by age. Interestingly, ALND showed a numerical decrease in the elderly after August 2016, potentially representing the influence of the Z0011 trial on clinical practice [4].

What is the potential benefit of SLNB omission? SLNB-associated morbidity is still considered relevant especially in the elderly with significant co-morbidities. Subjective arm and shoulder morbidity is reported to be present in one-quarter of patients one week after undergoing SLNB, according to results from the SOUND trial [27]. Similar findings were recently shown in the quality of life report of the INSEMA study [28]. Compound arm morbidity one year after SLNB, including arm swelling, lymphedema, pain, paresthesia, and decreased shoulder mobility, was reported in the OTOASOR trial as being 4.7% [6]. SLNB has been associated with lymphedema in 1–15% in cohorts receiving axillary radiotherapy (2.6% in our elderly-cohort) [1, 5,6,7]. Furthermore, short-term shoulder mobility impairment is reported (4.3% in our elderly-cohort), and chronic pain in 1–7% (14.5% in our elderly-cohort, with 6.8% reporting chronic axillary pain, and 0.9% chronic arm pain) [1, 7]. These results also hold true for women with DCIS undergoing SLNB [29]. Despite guidelines discouraging the use of SLNB in DCIS patients undergoing BCS, result from the US have shown an increase of SLNB in these patients between 2005–2017 to 20.9%-22.8% corresponding to the reported rates in our study of 27–40% [30]. In summary, arm morbidity may cause functional impairment with reduced autonomy in activities of daily living, particularly in the earliest postoperative period, potentially also aggravating underlying conditions.

However, nodal status is still the most important prognostic factor and needed for local as well as adjuvant treatment decisions. De-escalating and tailoring axillary surgery has seen major developments from the Halstedian radical mastectomy, to standard ALND [31] and SLNB [1,2,3], as well as ALND omission in clinically node-negative, SLN positive BC patients [4, 5]. ALND is an accurate staging procedure, but causes much morbidity [1, 6,7,8, 32, 33]. SLNB is standard of care in axillary staging and remains primarily a diagnostic procedure. A relevant therapeutic potential of SLNB has been suggested when omission of ALND in clinically node-negative BC patients with positive SLNs was shown to be safe. Importantly, residual nodal disease after SLNB was found in 27%, 33%, and 44% in the Z0011, AMAROS, and SINODAR trials respectively, which did not translate into worse oncologic outcomes [4, 5, 34].

Finally, the omission of any axillary surgery is not a new paradigm. Several trials randomized patients with clinically node-negative BC to omission of ALND without showing worse oncologic outcomes [31, 35,36,37,38]. The Choosing Wisely recommendations to omit SLNB in elderly patients with luminal BC was primarily inspired by the CALGB 9343 trial, which randomized elderly patients to receive tamoxifen with or without radiotherapy, with 62% of patients forgoing any axillary surgery [9, 21]. Of those, none experienced an axillary recurrence in the group with radiotherapy, compared to six patients without radiotherapy after a median follow-up of 12.6 years. In the general study population, no significant differences in overall survival, breast-cancer specific survival, time to distant metastases, and time to mastectomy were noted. Of the recorded deaths in the study population, only 6.7% were breast cancer related [9]. Recently, a nomogram was developed for selective omission of SLNB. It is based on age, cN0, histologic subtype, tumor grade, multifocality, and tumor size. The calculated false-negative rate of 5% for macrometastatic disease would allow one-third of patients to safely forego SLNB [39].

Axillary imaging has traditionally been considered not accurate enough to stage the axilla by itself and consists primarily of ultrasound, which showed a positive-predictive value of 58–81% and a negative predictive value of 71–79% [40,41,42]. Even though imperfect when used alone, axillary ultrasound helps refine SLN positivity prediction when incorporated into a nomogram [43]. A negative ultrasound was also the main eligibility criterion for patients to enter randomized trials that investigated the use of SLNB in contemporary patients with low risk early breast cancer [44,45,46,47,48]. Pending results have the potential to change practice toward complete de-escalation of axillary surgery in many patients with negative ultrasound. Even though some of these trials are restricted to candidates for BCS, most of them include cancers up to 5 cm, all age groups, and all intrinsic subtypes, and the benefit of SLNB in patients undergoing mastectomy is increasingly questioned [49]. As results of these potentially practice changing trials are eagerly expected, it will be important to assess their impact on surgical clinical practice, adjuvant treatments and oncologic outcomes also by intrinsic subtypes in subsequent implementation studies. Finally, the question pertains whether a more sophisticated examination including comorbidities and life-expectancy as well as functional capacities within e.g., a comprehensive geriatric assessment should play a stronger role in selection of patients for omission of SLNB [50, 51]. As long as SLNB remains standard care in most women with clinically node-negative invasive breast cancer, morbidity should be minimized by adequate training of the next generation of breast surgeons. Quality indicators could be based on minimum caseload and reflected by quality assurance and certification programs.

Limitations

The main limitation of our study is the retrospective, single center, observational design, which carries an inherent potential for selection bias. Our analysis does not account for co-morbidities as potential confounding factors. In addition, the sample size was limited, making larger prospective datasets necessary to validate our findings.

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