Whole breast radiotherapy in cN0 early breast cancer patients with pathological sentinel lymph nodes (pN1mic, pN1a) without axillary dissection: preliminary results of the observational LISEN trial

In the context of more conservative surgical techniques, axillary management is constantly evolving in breast cancer (BC) treatment. In the past, axillary lymph node dissection (ALND) was always performed as a tumour staging procedure and to improve regional control (RC) [1]. However, ALND may cause significant complication, such as lymphoedema, seroma and infection, with potential impairment of upper limb motion [2, 3].

Sentinel lymph node (SLN) biopsy was introduced in the early 1990s to avoid ALND for negative lymph nodes [4]. In comparison to ALND, SLN technique may yield fewer side effects, allowing an approximately three-fold reduction in the incidence of lymphoedema [5]. Hence, SLN biopsy became an alternative to ALND in patients with clinically (cN0) and pathologically (pN0) node-negative stage. Otherwise, the optimal management of the SLN has long been debated when a clinical negative node (cN0) result is pathologically positive (pN1) for the likelihood of additional axillary node metastases [6].

In this scenario, the randomized clinical trial American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) was conducted to determine whether overall survival (OS) of pathologically positive node patients treated with breast conserving surgery (BCS) and SLN biopsy alone was noninferior to OS in women treated with ALND. All patients had a planned lumpectomy, tangential whole breast radiotherapy (WBRT) and adjuvant systemic therapy, without nodal irradiation. The authors concluded that ALND could be safely omitted with good results in OS [3]. Similar promising results were confirmed in more recent prospective studies, with good rates of OS or disease-free survival (DFS) [7, 8]. The ACOSOG trial received several critiques, especially regarding the nonuniformity of RT treatment fields and the lack of RT records, which were available for approximately one-third of treated patients [9]. However, since 2011, this study represented a revolution in daily surgical practice and in currently guidelines, although the optimal radiation approach had still not been defined and there were several uncertainties [10‐13].

The objective of this study is to report the preliminary results of the “LInfonodo SENtinella” (LISEN) trial, an observational study aimed to confirm the long-term efficacy of ALND omission, in terms of local recurrence (LR), regional recurrence (RR), local and regional recurrence (LRR), distant metastasis (DM), DFS and OS, in cT1‑2 cN0 M0 patients undergoing conservative surgery with 1 or 2 positive SLN. In this study, the WBRT was always planned with tangential fields without nodal irradiation.

The study was designed as a prospective observational study by the Interdisciplinary Group for Oncological Care of the EUSOMA Breast Center of Lanciano–Vasto–Chieti ASL and was definitively approved on the 24 January 2013 by the Ethics Committee of the “SS. Annunziata” Hospital, “G. d’Annunzio” University, Chieti, Italy.

In total, as depicted in Fig. 1, 133 patients met our inclusion criteria in the median age of 56 years (range 35–83 years) and were divided into two groups, according to their lymph node status: 41 patients (30.8%) in the micrometastatic (group 1) and 92 (69.2%) in the macrometastatic (group 2). Patients, tumour and treatment characteristics were summarized in Table 1.

We conducted the LISEN trial with the aim to evaluate LR, RR, LRR, DM, DFS and OS in BC patients with one or two metastatic SLN, without nodal surgery neither nodal RT, in de-escalation strategy, in patients with ACOSOG Z0011 criteria [2, 3], achieving excellent local, regional and distant disease control. The risk of disease recurrence seems not to increase with ALND and nodal irradiation omissions.

Over the last few years, breast surgery and management of the axilla has become more conservative [4]. The increased use of screening mammography in the 1990s contributed to decrease axillary involvement by up to 22% [15]. Furthermore, in clinical practice, SLN biopsy represents a routine approach, allowing ALND omission in patients with clinical negative SLN. In case of pathological negative SLN, axillary recurrence occurs in about 1% of patients [16].

The NSABP B‑32 enrolled 5611 BC patients with clinically negative nodes. Their analysis was conducted only on node negative patients: 1978 in SLN resection plus ALND group (group 1) and 2011 in SLN resection alone group (group 2). The authors reported no statistically significant difference in OS (p = 0.12), DFS (p = 0.54) and regional control (p = 0.55), respectively, with fewer side effects in the second group. The NSABP B‑32 trial demonstrated no statistically significant difference in survival between ALND and SLN surgery alone in patients with negative SLN [17].

From 1999–2001, several patients were enrolled in different studies evaluating ALND omission in positive SLN. The phase III IBCSG, the AMAROS and the ACOSOG Z0011 trials reported first results comparing clinical outcomes of patients who underwent SLN biopsy respect to ALND.

The multicenter IBCSG 23-01 trial evaluated the impact of micrometastatic SLN, comparing the non-ALND group with the ALND group. Patients receiving breast-conserving surgery received WBRT or intraoperatively partial breast irradiation. Only 5% of these patients was treated with axillary lymph nodes RT. The 5‑year DFS was 87.8% in the non-ALND group and 84.4% in the ALND group (p = 0.16): the DFS in the non-ALND group was non-inferior to the ALND group (p = 0.0042). Therefore, ALND should be avoided when the sentinel node is minimally involved, reducing axillary surgery morbidity with no impact on survival [18]. These results were confirmed at 10 years with a DFS of 76.8% in the non-ALND group and 74.9% in the ALND group (p = 0.24; p = 0.0024 for non-inferiority) [19].

The non-inferiority of axillary radiation treatment respect to ALND in regional control, with fewer side-effects, was confirmed in the multicenter AMAROS trial.

Positive sentinel node occurred in 1425 patients; 744 of them had been assigned to ALND and 681 to axillary radiotherapy. All three levels of the axilla and the medial part of the supraclavicular fossa were included in radiation treatment. Axillary recurrence occurred in 4 patients in the ALND group and 7 in the axillary radiotherapy group. The 5‑year axillary recurrence was 0.43% for the ALND group versus 1.19% for the axillary radiotherapy group. The 5‑year DFS and OS were 86.9 and 82.7% (p = 0.18) and 93.3 and 92.5% (p = 0.34), respectively, with no statistically significant differences between the two groups. The authors concluded that both ALND and axillary radiotherapy could provide excellent and comparable axillary control in positive SLN, with significantly less morbidity in case of RT [20].

The ACOSOG Z0011 trial, where cT1‑2 N0 M0 BC patients were treated with BCS and SLN, aimed to demonstrate the impact of ALND omission on OS in patients with SLN metastases treated with lumpectomy, adjuvant systemic therapy and tangential field RT without a third field nodal irradiation. Of the 891 patients enrolled, 445 were randomized in the ALND group and 446 in the SLN-alone group [6]. Preliminary results, with a median follow-up of 6.3 years, demonstrated that the use of SLN alone did not negatively impact both 5‑year OS and DFS compared with ALND group (92.5 vs 91.8%, p = 0.008; and 83.9 vs 82.2%, p = 0.14, respectively) [2]. Ten-year results confirmed the non-inferiority of SLN compared to ALND, both in term of DFS (86.3 vs 83.6%, p = 0.02) and OS rate (80.2 vs 78.2%, p = 0.32), respectively [3].

However, the ACOSOG Z0011 trial received several critiques especially regarding the favourable selection bias (median age was 55 years, 70% had T1 tumours, 82% had oestrogen receptor-positive disease, 71% had only one positive SLN, and 44% had micrometastasis) and the variability in the extent and the administration of radiation treatments [9, 13]. Jagsi et al. tried to demonstrate that, although the Z0011 design did not contemplate nodal treatment, there were differences in radiation fields based on the extent of axillary surgery. Detailed radiation treatment records were obtained only for 228 patients in the ACOSOG trial, 124 in the SLN arm and 104 in the ALND arm. Most patients received tangential field RT alone: 103 patients (83.1%) and 82 (78.8%) in the SLN and ALND, respectively. Furthermore, 43 patients (18.9%) received directed regional nodal RT using ≥ three fields: 21 in the SLN arm and 22 in the ALND arm. There was no statistically significant difference between the two arms in the use of protocol-prohibited nodal RT fields, even if the treatment of a posterior axillary boost field was more common in patients who received SLN biopsy alone (p = 0.067). The authors concluded that, in the 228 patients analysed from the ACOSOG trial, most of them received tangential field RT alone, without significant differences in tangential field height between the two arms. Furthermore, it is worth considering additional nodal treatment in selected high-risk patients [9].

From these critiques, we conducted our observational study in a homogeneous population of cT1‑2 cN0 M0 patients treated with a radiotherapy fields uniformity, with only tangential RT without nodal irradiation, after SLN alone. Our preliminary results for DFS and OS rates in the SLN group are comparable to the ACOSOG Z0011 trial results (93.6 vs 83.9% and 96.9 vs 92.5%, respectively), in patients with similar favourable characteristics (pT1, positive hormonal receptors).

Concurrently, different studies have been conducted to verify the results of the ACOSOG study (Table 3). The prospective study of Kittaka et al. was conducted to confirm that the ACOSOG Z0011 criteria apply to Japanese early BC patients. The authors reported that the low RR rate could have been achieved by high tangent irradiation to all eligible patients and by adjuvant systemic therapy administration to most patients [7].

The findings of ACOSOG Z0011 results were applied in a prospective study of 793 BC patients, cT1-2N0 with 1–2 positive SLN [8]. The 5‑year rate of breast-only recurrences, breast and nodal, and nodal and distant recurrence were 1.6, 0.7 and 0.7%, respectively. In particular, the authors examined a subset of 484 patients treated with SLN biopsy alone with known RT fields (21.0% prone breast RT, 58.0% supine tangent breast RT and 21% breast and nodal RT). At a median follow-up of 37 months, there were 5 nodal recurrences among this subgroup: 4 nodal and distant and 1 breast and axillary, with a 5-year cumulative rate of nodal recurrence of 1% [8].

Moreover, some retrospective studies reported clinical outcomes in patients with SLN biopsy alone or SLN biopsy followed by ALND, with or without specific information regarding types of RT (supine or prone WBRT, high tangents RT, nodal irradiation) [21‐24]. Despite the heterogeneity of the analysed patients, clinical outcomes are favourable in patients treated with SLN biopsy alone followed by radiotherapy (Table 3; [21‐24]).

It is well known as tumour size, grade, receptor status and different molecular profiles determined systemic therapy decisions, rather than the number of positive nodes. The ALND has a twofold role, i.e. for staging and cure. The ALND findings had always helped radiation oncologists in the decision of radiation treatment fields. The Z0011 trial publication made the optimal radiation fields for patients with positive SLNs who did not undergo ALND uncertain [13]. The lack of prospective data regarding field design led to consider some issues such as the probability of residual disease burden with the help of validated nomograms, in combination with clinical judgment. Tumour size, grade, histology, receptor status, lymphovascular invasion and number of positive SLN can be helpful in estimating the risk of additional positive nodes and guiding radiation field design.

In our study, most patients had positive oestrogen and progesterone receptors, normally considered as favourable prognostic factors, resulting in a well-represented group of patients as in the ACOSOG Z0011 trial. In our patients who developed LR, LRR and/or DM, the median age was 47 years (range 41–56 years). In 6 of 7 patients, Ki-67 expression was high with a median percentage of 35% (range 12–70%); only 1 patient had low Ki-67 expression (5%).

The prognostic value of Ki-67 was analysed regarding OS and DFS (in 25 and 29 studies, respectively) in the meta-analysis by Petrelli et al. A high Ki-67 cut-off level (at least 10%) resulted associated with more than 50% risk of death among early BC patients, particularly in those with ER + disease, and it was also associated with a greater risk of recurrence [25]. Therefore, Ki-67 represents an important prognostic factor and it could be considered also a predictive factor in terms of adjuvant therapy benefit in node-positive BC patients.

Our study has some limitations. First, our median follow-up is relatively short (50 months against 111 months of the ACOSOG trial). Considering our preliminary encouraging results, a prolonged follow-up will be necessary to confirm LR, RR, LRR, DM, DFS and OS good rates for patients treated with SLN and ALND omission.

Another limitation could be the lower percentage of patients with common negative prognostic factors, such as basal-like type neoplasms (triple-negative tumours), G3 tumour or lymphovascular invasion. Our positive survival results could have been influenced by endocrine therapy, in positive oestrogen and progesterone receptor status.

We report our prospective observational study on 133 breast cancer patients with cT1‑2 cN0 invasive cancer and 1 or 2 positive sentinel lymph nodes, treated with breast conserving surgery and sentinel lymph node biopsy alone, and blinded planned tangential field radiotherapy without nodal irradiation. We achieved excellent local, regional and distant disease control. Our preliminary results suggest that axillary lymph node dissection (ALND) could be omitted, without nodal irradiation, sparing the patient from potential morbidity without increasing the risk of disease recurrence.