Keywords

1 Introduction

Isolated locoregional recurrence (ILRR) of breast cancer is defined as the reappearance of tumor cells in the ipsilateral breast or chest wall while regional recurrence is in ipsilateral draining lymph nodes (ipsilateral axillary, supraclavicular, and less commonly internal mammary). The majority of what is known concerning the risks associated with (isolated) local and regional recurrences of breast cancer comes from more than a few decades earlier, a time when the first-line treatment approach was either modified radical mastectomy or lumpectomy followed by radiation therapy to the whole breast for the primary tumor and axillary node dissection for the regional disease [1,2,3]. Twenty years ago for patients who had been treated with either mastectomy or lumpectomy for breast cancer, 5-year local and regional disease control rates were reported as approximately the same and 60% which had been improved over the last two decades [4]. In a meta-analysis including 53 randomized clinical trials with a total of 86,598 patients between 1990 and 2011, the proportion of locoregional recurrences has decreased approximately from 30 to 15% (p < 0.001) [5].

Radiotherapy (RT) by itself reduced the 10-year risk of a recurrence of any type by 10.6% and the 20-year risk of death from breast cancer by 8.1% [6]. Also many other factors are responsible for this reduction, including routine use of systemic therapies (chemotherapy, targeted therapies, and endocrine therapy), improvements in surgical (oncoplastic surgery, complete tumor excision, sentinel lymph node biopsy) and radiotherapy techniques (3D conformal, intensity-modulated RT, and partial breast irradiation), and better selection of appropriate candidates for breast-conserving surgery with the use of imaging techniques like breast MRI and PET/CT. Therefore, local and regional recurrences are being encountered less often, but data from randomized trials still reports an importantly high 10-year incidence of LRR as 5–20% after surgery [6,7,8].

2 Principles of Treatment

Regardless of the relatively low incidence rate, ILRR of breast cancer poses an increased risk in terms of both distant metastases that can compromise survival expectations [4]. Therefore, the approach towards ILRR should also take into account those risk factors associated with an increased risk of distant metastases. This should mean tailoring the overall management strategy (i.e., systemic treatment strategy as well local and regional treatment strategy in accordance with the perceived risk of distant metastases. An ILRR of a breast cancer should always receive treatment with an intention to cure, preferably attempting for a complete surgical resection whenever possible. Due to the low number of events thanks to the extensive use of adjuvant treatments, the similar absence of prospective randomized trials addressing the issue outside of systemic therapy, and the considerable heterogeneity of the patient population in question, oncologists from any discipline (surgery, radiation oncology, and medical oncology) are challenged in their respective contributions towards the management of patients with ILRR. This is quite in contrast to the decision-making process in breast cancer in the adjuvant setting where it is customary to obtain guidance from an abundance of randomized trials that report on thousands of patients.

The National Comprehensive Cancer Network (NCCN) classifies ILRRs into three groups based on prior therapy: (1) recurrences that occur after breast-conserving surgery that was followed by radiotherapy, (2) those that occur after mastectomy and level I/II axillary lymph node dissection (ALND) followed by postmastectomy RT (PMRT), and (3) those that occur after mastectomy and axillary lymph node dissection (ALND) in the absence of PMRT [9]. Hence, management options should evolve in accordance with this grouping.

3 ILRR in Patients Who Had Undergone BCS that Was Followed by RT

3.1 Isolated Breast Recurrence

3.1.1 Salvage Total Mastectomy

The standard treatment approach for an ILRR after BCS followed by RT is total mastectomy and axillary staging if a level I/II axillary dissection was not done previously [9]. This decision comes from all retrospective series also with different methods of detection. In this series the 5-year overall and disease-free survivals, following a salvage mastectomy, were more than 50% and 70%, respectively [3, 10, 11]. Still many factors are associated with poorer outcomes after salvage surgery; invasive histologic recurrence, shorter time to recurrence (a disease-free interval from mastectomy to distant relapse of less than 2 years is a poor prognosticator), unfavorable initial tumor stage, large tumor size, tumor biology (triple-negative and human epidermal growth factor receptor 2 (HER2)-positive primary tumors have been shown to have a shorter disease-free survival after recurrence than those with ER-positive cancers), and nonadministration of adjuvant chemotherapy and radiotherapy [2, 3, 11,12,13,14].

In addition to total mastectomy, another issue to be evaluated is the need for axillary staging. Since the last decade, there has been a shift of axillary staging from ALND to the removal of the sentinel lymph nodes. ALND remains as a viable option in the setting of isolated recurrences limited to the breast. In favor of this argument, Kurtz et al. have reported the presence of regionally recurrent disease in not less than one-third of patients undergoing an ALND in the setting of recurrences apparently limited to the breast, a finding that could affect the need for systemic adjuvant treatment options in some patients [15]. Accordingly, salvage total mastectomy (with or without ALND) results in local and regional disease control rates in the order of 85 to 95% [10].

A few studies have evaluated the impact of diagnosing nodal recurrence through SLNB on the management of ILRR. In one study, Johnson et al. reported that out of 12 patients with isolated recurrences on the chest wall following a mastectomy, 10 patients had undergone a successful mapping through a SLNB and that 7 patients had a sentinel node in the axilla [16]. In another study, however, Ugras et al. reported that in 83 patients (who were clinically free from nodal disease) with recurrences either in the breast or on the chest wall, the rates of recurrence in the axilla, the rates of distant metastases, and the rates of survival were not significantly different in 47 patients who had undergone axillary surgery as compared to 36 patients who had not undergone axillary surgery at slightly more than 4 years following ILRR [17]. A meta-analysis by Maaskant-Braat et al. also showed that sentinel node identification was significantly higher in patients who had undergone previous SLNB compared to previous ALND (81.0 vs. 52.2%), and in patients with successful lymphatic mapping, aberrant drainage pathways were visualized (43.2%), which were seen more frequently after previous ALND than after previous SLNB (69.2 vs. 17.4%) [18]. In this study with the information derived from the repeat SLNB, 17.9% of the patients led to a change in adjuvant radiotherapy or systemic treatment plans.

3.1.2 Salvage Breast-Conserving Surgery

Salvage breast-conserving surgery to be followed by a second course of radiotherapy appears to be a viable management option for patients with ILRR falling in this category who still demand for breast conservation. This approach has been evaluated in a multicenter randomized trial by the GEC-ESTRO Breast Cancer Working Group on 217 patients undergoing salvage breast-conserving surgery followed by partial breast irradiation in the form of interstitial brachytherapy [19]. The results of this study appear to be promising both in terms of disease control and treatment-related toxicity. The second (local or regional) recurrence rate was 5.6%, the distant metastases rate was 9.6%, and the overall survival rate was 88.7% at 5 years (at a median follow-up of 3.9 years), whereas cosmesis was rated as excellent or good in 85% of the patients. The possible contributions of cautious patient selection and expertise in interstitial brachytherapy being noted, these results should be regarded as non-inferior to those provided by salvage mastectomy. Based on the comparatively low toxicity associated with the second course of (partial breast) radiotherapy in the form of external beam radiotherapy, as observed in the preliminary results of the ongoing RTOG-1014 trial, this form of radiotherapy might also be utilized in the setting of re-irradiation of the (partial) breast as well [20].

Despite what has already been mentioned above concerning salvage breast-conserving surgery, randomized trials, with more specific eligibility criteria, are needed to determine the optimal approach for patients who may benefit from repeat BCS, with or without additional RT, and the standard of care should still be viewed as total mastectomy for patients who had undergone BCS that was followed by RT. For patients with ILRR, total mastectomy has not been compared to a salvage breast-conserving surgery in the setting of a randomized trial. In the context of retrospective studies, Salvadori et al. have reported a better overall survival rate at 5 years for patients with ILRR undergoing salvage breast-conserving surgery (85%) as compared to those undergoing salvage mastectomy (70%), although at the expense of a higher second local recurrence rate (19% following salvage breast-conserving surgery versus 4% following salvage mastectomy) [21].

4 ILRR in Patients Who Had Undergone Mastectomy and ALND that Was Followed by PMRT

4.1 Isolated Chest Wall Recurrence

Treatment of ILRR after mastectomy and PMRT is more difficult, and recurrences tend to occur earlier after mastectomy (median 2–3 years) which are possibly more likely to involve regional nodes, and these cases are associated with higher rates of simultaneous distant metastases and poorer cause-specific survival [22]. So detailed systemic imaging should be done before treatment to rule out distant metastasis. Thirty to 40% of patients have a local plus regional recurrence in the supraclavicular, axillary, or internal mammary nodes, with the supraclavicular nodes being the most common site [23]. Treatment of an isolated chest wall recurrence must be a wide surgical excision with negative tumor margins as possible, and sometimes skin grafts or myocutaneous flaps should be used. Also with the advances in surgical techniques, more aggressive surgeries were reported to be done. In the study by D. Levy Faber et al., 33 women with isolated locally recurrent breast cancer underwent en bloc full-thickness chest wall resection and reported a 5-year survival rate of 63% with a postoperative complication rate of 36%, with no deaths [24]. However, for patients who have an unresectable chest wall recurrence, re-irradiation alone or with hyperthermia (HT) (for radiosensitization and to decrease RT dose) sometimes has to be done. But, caution is warranted in re-irradiation of the chest wall as aggregate doses of 100Gy or higher can cause a significant risk of acute and late morbidity (e.g., skin ulceration, rib fractures, radiation pneumonitis, brachial plexopathy, pericarditis). The meta-analysis of five different randomized trials encompassing 306 patients, made by Vernon et al., showed that the combination of HT and RT improved complete response (CR) rates (59% vs. 41%), but had no impact on survival [25]. Recently a meta-analysis was published by Datta et al. 2110 patients totally from 34 studies which were excluding surgery, concurrent chemotherapy, and/or brachytherapy [26]. The mean external RT dose was 38.2 Gy (range, 26–60 Gy), and higher CR rates were achieved with RT with HT as compared with RT alone (60.2% vs. 38.1%; P < 0.0001). The mean acute and late grade 3/4 toxicities for combined modality were 14.4% and 5.2%, respectively.

5 ILRR in Patients Who Had Undergone Mastectomy and ALND in the Absence of PMRT

5.1 Isolated Chest Wall Recurrence

Isolated chest wall recurrence of patients after primary mastectomy and absence of RT should be wide surgical excision and adjuvant RT. If there’s an unresectable chest wall recurrence, the disease should be treated with radical RT. The benefit of large field radiation has been demonstrated by Halverson et al. The entire chest wall is irradiated along with regional nodes [27]. In patients with solitary chest wall recurrences, large field radiotherapy encompassing the entire chest wall resulted in a 5- and 10-year freedom from chest wall re-recurrence of 75% and 63% in contrast to 36% and 18% with small field irradiation (p = 0.0001). For the group with recurrences completely excised, tumor control was reported as adequate at all doses ranging from 4500 to 7000 cGy. For the recurrences <3 cm, 100% were controlled at doses >6000 cGy versus 76% at lower doses.

6 Treatment of Regional Axillary Supraclavicular and/or Internal Mammary Recurrence

After primary treatment of breast cancer either with ALND or SLNB, isolated axillary recurrence is very uncommon with a very low reported incidence of 0–1% [28,29,30]. The management of axillary recurrences with such a limited event rate, coming from the eras when most patients were treated with axillary lymph node dissection, is more complex and should be done in a multidisciplinary setting. Also seen less, historically isolated axillary local recurrence do worse than patients with isolated chest wall/breast recurrence, and nearly half of them are diagnosed with distant metastasis at the same time or within 3 months. After the validation of the studies that regional recurrence and overall survival were equivalent between SLNB and ALND in patients with clinically node-negative breast cancer, for a longer period of time, SLNB have been done in node-negative disease, and under these circumstances we don’t really know if they’re prognostically different or not in recurrence.

The management of an isolated axillary recurrence depends on the initial treatment of the patient whether or not ALND was undertaken previously. For now, for patients who had an initially negative SLNB, complete axillary lymph node dissection (levels I and II) is recommended. For patients who recur after a prior ALND, axillary exploration should be done with the aim of complete resection. Adjuvant RT for the ones who have not previously received RT is offered by some institutions, but for previously irradiated patients, limited field re-irradiation may only be considered in the setting of an incompletely resected axillary regional recurrence and for inoperable or progressive local disease that is nonresponsive to systemic therapy. Most importantly, before re-irradiation treatment, toxicity risks and benefits should be discussed with the patient.

SCV recurrences are the second most common site after the axilla in newer studies and considered to be associated with metastatic disease until some data showed that aggressively treating patients with SCV disease at the time of diagnosis has an improved overall survival rate comparable to patients without metastatic disease. So in 2002 the staging system was revised to classify primary SCV disease as stage III [31]. In the largest study of specifically studying isolated SCV recurrence after mastectomy, among 23 patients with isolated SCV recurrence, OS was not statistically different between isolated chest wall and isolated SCV recurrence [32]. Also only 6 LRR of 23 patients were treated with aggressive local therapy, including surgery, chemotherapy, and radiation (alone or in combination); this study suggests the use of curative local therapeutic modalities, such as surgery or radiotherapy, in patients with isolated SCV recurrence for selected patients.

Locoregional failures involving internal mammary nodes (IMN) have been reported to comprise only 1% of locoregional failures in the literature, but still it’s the second most common site of drainage after axilla and in patients with local recurrence, who have been previously managed with axillary dissection or axillary SLNB. It’s possible that IMN can be an alternative lymphatic drainage. Port ER et al. who reported non-axillary drainage in only 6% for primary breast cancer operations showed this rate to be 30% in the subset of patients having operations for recurrence [33]. Like SCV metastasis, the treatment of isolated IMN recurrence should be curative intent. In the literature salvage multimodality treatment with surgery, radiation, and chemotherapy were associated with the best outcomes [34].

7 Role of Adjuvant Systemic Therapy After Locally Curative Treatment of ILRR

Systemic therapy in patients with ILRR of breast cancer has been used as a primary therapy to treat inoperable recurrence for tumor downstaging and achieve operability and for tumors not amenable to RT due to prior irradiation and also after curative treatment as a second adjuvant therapy. If adjuvant systemic therapy can further increase DFS and OS was explained with two prospective randomized trials including the SAKK trial and the multicenter international CALOR trial. A Swiss Group for Clinical Cancer Research (SAKK 23/82) study randomized 167 patients with “good risk” ILRR (estrogen receptor positive in the LRR, disease-free interval of >12 months, and ILRR consisting of ≤3 or tumor nodules, each ≤3 cm in diameter) to tamoxifen or no therapy. All patients underwent mastectomy for their primary cancer surgery and had no prior exposure to tamoxifen therapy. The ILRR was treated by complete surgical resection and radiation therapy (50 Gy) to the site of recurrence. At a median follow-up of 11.6 years, post-ILRR DFS was 6.5 years in the tamoxifen arm and 2.7 years with observation alone (p = 0.053). The CALOR trial studied the contribution of systemic therapy in patients with ILRR. Patients were randomized to receive chemotherapy or observation. The 5-year DFS was 69% with chemotherapy versus 57% without chemotherapy (HR 0.59, 95% CI 0.35–0.99; p = 0.046). OS was significantly improved with chemotherapy (HR for death of any cause 0.41, 95% CI 0.0.19–0.89; p = 0.024) corresponding to a 5-year survival of 88% versus 76%. The benefit of adjuvant chemotherapy was most significant for patients with hormone receptor-negative locoregional recurrence. Trastuzumab and other HER2-directed therapies have not been assessed in a clinical trial for ILRR, so we can extrapolate the therapeutic regimens established in the metastatic setting [35].

8 Conclusion

The management of patients with an ILRR is complex and usually requires multidisciplinary assessment and planning. Compared to patients with distant metastasis, a curative approach is possible with an individualized and multidisciplinary strategy and includes surgical therapy with or without radiotherapy and/or systemic therapy.

Tips and Tricks

  • In a meta-analysis including 53 randomized clinical trials with a total of 86,598 patients between 1990 and 2011, the proportion of locoregional recurrences has decreased approximately from 30 to 15%.

  • Radiotherapy (RT) by itself reduced the 10-year risk of a recurrence of any type by 10.6% and the 20-year risk of death from breast cancer by 8.1%

  • The standard treatment approach for an ILRR after BCS followed by RT is total mastectomy and axillary staging if a level I/II axillary dissection was not done previously.

  • Salvage total mastectomy (with or without ALND) results in local and regional disease control rates in the order of 85–95%.

  • Salvage breast-conserving surgery to be followed by a second course of radiotherapy appears to be a viable management option for patients with ILRR falling in this category who still demand for breast conservation. However, for patients with ILRR, total mastectomy has not been compared to a salvage breast-conserving surgery in the setting of a randomized trial.

  • Treatment of ILRR after mastectomy and PMRT is more difficult, and recurrences tend to occur earlier after mastectomy (median 2–3 years) which are possibly more likely to involve regional nodes, and these cases are associated with higher rates of simultaneous distant metastases and poorer cause-specific survival.

  • Treatment of an isolated chest wall recurrence must be wide surgical excision with negative tumor margins as possible, and sometimes skin grafts or myocutaneous flaps should be used.

  • However, for patients who have an unresectable chest wall recurrence, re-irradiation alone or with hyperthermia (HT) (for radiosensitization and to decrease RT dose) sometimes has to be done. But, caution is warranted in re-irradiation of the chest wall as aggregate doses of 100 Gy or higher can cause a significant risk of acute and late morbidity (e.g., skin ulceration, rib fractures, radiation pneumonitis, brachial plexopathy, pericarditis).

  • The management of an isolated axillary recurrence depends on the initial treatment of the patient whether or not ALND was undertaken previously. For now, for patients who had an initially negative SLNB, a complete axillary lymph node dissection (levels I and II) is recommended. For patients who recur after a prior ALND, axillary exploration should be done with the aim of complete resection. Adjuvant RT for the ones who have not previously received RT is offered by some institutions but for previously irradiated patients limited field re-irradiation may only be considered in the setting of an incompletely resected axillary regional recurrence and for inoperable or progressive local disease that is nonresponsive to systemic therapy.

  • Locoregional failures involving internal mammary nodes (IMN) have been reported to comprise only 1% of locoregional failures in the literature, but still it’s the second most common site of drainage after axilla and in patients with local recurrence.

  • Like SCV metastasis, treatment of isolated IMN recurrence should be curative intent. In the literature salvage multimodality treatment with surgery, radiation, and chemotherapy were associated with the best outcomes.