Radiation therapy to the whole breast following BCS is widely accepted as a standard of care for women with early-stage invasive breast cancer.

Long-term results from numerous randomized controlled trials have confirmed overall survival equivalence between BCT and mastectomy for early-stage invasive breast cancer (◘ Table 39.2).

In 1995, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis showed that in the nine trials of mastectomy versus BCS plus radiotherapy, there was no apparent difference in overall mortality (22.9% versus 22.9%) and local recurrences (6.2% with mastectomy as compared with 5.9% with breast conservation) [26]. Although these trials varied in inclusion criteria and in surgical technique and radiotherapeutic and systemic treatment protocols, they showed that BCT can be applied safely in patients with early breast cancer.

In modern practice, 5- and 10-year actuarial local recurrence rates of less than 5% are not uncommon with results near to 0% in some series, as in the ELIOT trial (0.4% in the external beam radiotherapy group after a medium follow-up of 5.8 years). The enormous improvement in surgery and radiotherapy techniques and systemic therapy with more effective cytotoxic, endocrine and targeted treatments, and higher-quality surgical procedures with much more diligent attention to achieving clear margins, has undoubtedly contributed to this reduction in local failure rates after BCT when compared to the historic trials [27, 28].

In addition to the randomized trials comparing breast conservation with mastectomy, different randomized trials have compared conservative surgery alone with conservative surgery and radiation, in order to investigate whether radiation following BCS can be omitted. The majority of randomized trials have demonstrated that radiation therapy following BCS lowers the local relapse rates by at least half and is associated with acceptable toxicity and morbidity [29]. The impact of radiation following BCS on breast cancer mortality or overall survival, however, has been the subject of ongoing debate until very recently. This issue has been clarified by the EBCTCG in three large meta-analyses published in 1995, in 2005 and finally in 2011 [8, 11, 26].

In its recent quinquennial meta-analysis update published in 2011, the EBCTCG included 17 randomized studies comparing adjuvant radiotherapy versus no radiotherapy following BCS. A total of 10,801 patients with pT1–pT2 tumours were recorded, the majority of whom (n = 7287) were node negative, 1050 node positive and 2464 nodal status unknown. The analysis not only reported significant 10-year absolute risk reduction of any (loco-regional or distant) first recurrence by 15.7% with radiotherapy following BCS but showed also that radiotherapy reduced the breast cancer death rate by about one-sixth. Overall, radiotherapy reduced the 15-year risk of breast cancer death from 25.2% to 21.4% (absolute reduction 3.8%, 2p = 0.00005) [8].

Given the impact of radiation on both local control and breast cancer-specific survival, the standard of care for the majority of patients with invasive breast cancers undergoing BCS is the use of radiation following BCS, and the avoidance of radiation therapy outside the context of a clinical trial must be approached cautiously.

There are, however, subsets of patients who are at lower risk of recurrence, for whom the absolute benefit might be clinically not meaningful. A common and clinically relevant example of this is in women over age 70 with hormone receptor-positive tumours, where observation following BCS is considered an acceptable option. However, given these concerns, many clinicians and patients would only consider the avoidance of radiation or the use of APBI in the context of a clinical trial [8, 30] (see ► Chap. 44).

The tumour bed is the area at highest risk for tumour cell contamination, and a number of randomized trials have investigated the effect of an additional dose of radiation to the tumour bed (known as boost) after the administration of WBI.

The European Organisation for Research and Treatment of Cancer (EORTC) has undertaken the 22,881–10,882 (boost versus no boost) trial in order to clarify whether this strategy has any merit or adverse effects [10, 31, 32]. In 5318 patients with a microscopically clear resection margin after surgery to the primary tumour, an additional dose of RT to the tumour bed nearly halved the annual odds of local recurrence (hazard ratio, 0.59), with a 10-year actuarial rate of local recurrence of 10.2% in the «no boost» group and 6.2% in the «boost» group (p < 0.0001). In the latest publication of this trial, with a median follow-up of 17.2 years, ipsilateral breast tumour recurrence had increased in both treatment groups (possibly as a consequence of development of second primaries): 16.4% for the «no boost» group and 12% for the «boost» group. However, the relative benefit of boost for local control remained statistically significant with an HR for an ipsilateral breast tumour recurrence as a first event of 0.65 (p < 0,0001).

Overall, boost did not improve overall survival which was 81.7% for both arms after 10 years of follow-up and 61.1% in the «no boost» group versus 59.7% in the «boost» group after 20 years; the failure of improved local control to increase overall survival has been hypothesized by the authors to derive from successful salvage mastectomy treatment for these breast recurrences.

Boost RT is associated with an increase in breast fibrosis; although not significant at 5 years, at 10- or 20-year follow-up, the extra boost dose has been shown to increase rates of moderate or severe fibrosis from 13% to 28% and from 15% to 30.4%, respectively. For this complication, the boost dose was not the sole factor that affected the cosmetic outcome negatively (other factors included the location of the primary tumour in the lower quadrants, the volume of breast tissue excised, administration of systemic therapy, breast infection or hematoma in the postoperative period and clinical T2 stage).

As early analyses found the largest clinical benefit from boost in younger patients (40 years old or younger), the authors tried to determine whether the effect of an additional radiation dose depended on age. The 2015 analysis confirmed that patients’ age was strongly correlated with the absolute risk of ipsilateral breast tumour recurrence: 20-year cumulative incidence ranged from 34.5% for patients 35 years or younger to 11.1% for patients older than 60 years, and the reduction of risk by giving a boost dose was significant for the younger age groups (for age ≤ 40 years, p = 0.003 and, for age 41–50 years, p = 0.007) [10, 31, 32].

Based on this landmark phase III trial, administration of a boost dose following WBI is strongly indicated especially if patients have high-risk factors for recurrence, such as age < 50 years old, pathologically involved ALN, lympho-vascular invasion and/or a close or positive resection margin. For the older women, its routine use is less clear, but, in patients over 60 years of age with small, node-negative, hormone receptor-positive tumours, omission of a boost may be reasonable [10, 33].

Regional node irradiation (RNI) should be considered in the following circumstances:

RNI includes the infra- and supraclavicular region and any part of axillary bed at risk. A number of radiotherapy centres include the internal mammary chain, irrespective of known neoplastic involvement. In 2016 the NCCN guidelines were extended to include the elective irradiation of internal mammary nodes, in light of recent publications.

Supported by similarities in tumour biology, most of the data available on RNI in patients treated with BCS were extrapolated from studies of patients undergoing mastectomy, in particular from three remarkable randomized clinical trials conducted by Overgaard and Ragaz. Furthermore, the historical recommendation to treat only in cases with more than three positive nodes was made despite the fact that these trials showed a benefit in survival for all node-positive patients [34–36].

Vicini and colleagues first demonstrated a statistically significant reduction in the rate of regional nodal failure in patients with more than three positive lymph nodes treated with BCT and RNI. The authors stated that, combining their study with the available literature, the data were «sufficient to support the inclusion of at least the supraclavicular fossa and level III ALN in patients with four or more positive nodes because of a statistically significant reduction in the rate of regional nodal failure with a relatively mild increase in toxicity» [37].

In 2011, the previously mentioned meta-analysis from the EBCTCG reported a 10-year improvement in the rate of any first recurrence of 21.7% in patients with four or more positive nodes who received adjuvant radiation therapy after BCS [8].

Currently RNI, in cases with more than three positive nodes, is recommended by all national and international guidelines [18, 38, 39].

However, some authors suggest that RNI, in particular RT to the supraclavicular fossa, even in patients with more than three positive nodes, cannot be routinely justified if the intent is to improve survival [40].

The need for RNI in cases of one to three positive nodes is currently an issue of intense debate.

Many studies published in recent years, mostly retrospective, have investigated this question. Despite the heterogeneity of these trials in the number of patients, analysis period, adjuvant systemic therapy regimes and radiotherapy volumes, these studies all emphasized the importance of different risk factors for local relapse, nodal relapse and distant metastases such as young age, tumour size, negative hormonal receptors, extensive intraductal component, high grade and nodal ratio >20–25%. So, in the presence of two or more of these risk factors, RNI should be considered [41–43].

Ideally, treatment recommendations should be made on the basis of well-designed phase III clinical trials. To date, the MA.20 and EORTC 22922/10925, two large randomized clinical trials with 85% and 43.1% of included patients having one to three positive ALNs, respectively, have been published as full papers. Both studies have stressed the need of RNI after BCS regardless of the number of positive lymph nodes, but they have not demonstrated any significant impact on OS from RNI.

The sites of nodes needed to be treated with the intent of improving OS and DFS remain unknown (the EORTC trial included internal mammary and medial supraclavicular lymph nodes; in the MA.20 trial, the internal mammary lymph nodes with the supraclavicular and ALNs were irradiated) [44, 45].

However, they both showed that RNI improves DFS, and distant DFS, without adding substantial toxicity; the EORTC trial also reported a small but significant benefit with respect to death from breast cancer (◘ Table 39.3).

Due to this ongoing uncertainty, RNI in cases with one to three positive ALNs should be discussed in a multidisciplinary team meeting and then discussed with the patient.

The indication for radiotherapy to the axilla is generally restricted to patients with recurrent disease, or if ALNs are clinically involved and no axillary dissection is possible or planned, despite the EORTC 10981–22,023 AMAROS trial, where patients with clinical T1–T2 N0 primary breast cancer were randomly assigned to axillary radiotherapy or axillary lymph node dissection, it showed that, for patients with a positive sentinel lymph node, either modality provides excellent and comparable axillary control. Moreover, the rates of lymphoedema were lower in patients treated with axillary radiotherapy than in those treated with axillary lymph node dissection [46].

There is strong evidence that tumour size greater than 5 cm, as a sole negative feature, is a risk factor for loco-regional recurrence (LRR), so chest wall irradiation is traditionally recommended for these patients, but there is controversy concerning the real need for PMRT for pT3N0M0 breast cancer due to low recurrence rates after a median follow-up time of 10 years or more [12, 47, 48].

A comprehensive review of studies including T3 N0 patients was performed indicating the main risk factors and risk categories for local relapse. These include lympho-vascular invasion, blood vessel invasion, positive lymph node ratio > 20%, close resection margins <3 mm, grade 3, young age/premenopausal status, extracapsular nodal invasion, negative hormone receptor status and invasive lobular cancer. These high-risk factors help to identify T3 N0 patients who will benefit from PMRT [49].

Positive and close surgical margin status is generally believed to be associated with high LRR risks, but there are few available studies examining this issue in the post-mastectomy setting and even fewer analyses focusing on the specific role of PMRT in these patients [50, 51]. In spite of this, chest wall irradiation is recommended in patients with positive surgical margins (if there is no option for further surgery) and should be considered for women with a close resection margin and one or more additional risk factors (age ≤50 years, T2 tumour size, grade 3, lympho-vascular invasion, triple-negative disease) [18, 51, 52].

Regarding nodal status, historically PMRT to the chest wall and regional lymph nodes has been delivered in the case of four or more positive nodes at axillary dissection [47, 53–56]. The background for this indication was the general assumption that only patients with very high risk of LRR will benefit from postoperative radiotherapy in terms of survival and, as expressed in the National Institutes of Health consensus report 2000, «….the high-risk group includes women with four or more positive nodes» [57].

Three well-conducted randomized trials have shown that, for node-positive breast cancer patients unselected for the number of lymph nodes involved, irradiation of the chest wall and regional lymph nodes after mastectomy and ALN dissection improves DFS and OS in addition to loco-regional control [34–36]. In the DBCG 82b trial (1708 high-risk premenopausal patients), the 10-year loco-regional recurrence rate was 9% in PMRT + chemotherapy patients in contrast to 32% in patients treated with chemotherapy alone, and the corresponding survival rates were 54% and 45%, respectively, in favour of PMRT + chemotherapy (p < 0.001). The DBCG 82c trial (1375 high-risk postmenopausal patients) showed a 10-year loco-regional recurrence rate of 8% in PMRT + tamoxifen patients compared to 35% in tamoxifen-only patients with the corresponding 10-year survival rates of 45% and 36%, respectively, in favour of PMRT + tamoxifen (p = 0.03). Remarkably, there has been an ongoing debate on whether or not PMRT should be given to patients with one to three positive ALN. In a subgroup analysis of the Danish trials, the addition of radiation therapy resulted in a substantial reduction in the 15-year LR failure rate from 27% to 4% (p < 0.001) and from 51% to 10% (p < 0.001), in patients with one to three versus four or more axillary positive nodes, respectively. The 15-year survival benefit after radiation therapy was equally pronounced in both groups (57% versus 48%, p = 0.03, and 21% versus 12%, p = 0.03). As PMRT improved the outcome to the same extent in the two groups, the authors suggested considering a «modification of the current guidelines for indications for post-mastectomy irradiation» [34, 35, 58]. Finally, Ragaz and colleagues (318 premenopausal high-risk patients, PMRT + CMF versus CMF without PMRT) observed that after a median follow-up of 15 years, there was a significant absolute improvement of 20% in local relapse free survival (p < 0.003) with a corresponding 8% improvement in survival rates (54% versus 46%, p = 0.07). The 20-year results of this trial confirmed previous analyses showing that the impact of radiation therapy for all survival outcomes in the subgroup with one to three nodes involved was similar to the subgroup with four or more nodes involved and both groups had a risk reduction of the same order of magnitude [36, 59].

The recently published update of the EBCTCG meta-analysis should bring the debate about patients with one to three positive ALN to an end, since it unequivocally demonstrated that these patients receive the same survival benefit from PMRT as patients with more than three involved lymph nodes. In 1314 patients with pN+ (one to three nodes), the risk for local recurrence at 10 years was significantly reduced from 20.3% to 3.8%, and breast cancer mortality decreased significantly by 7.9% after 20 years; in comparison, the risk for local recurrence in 1772 patients with pN+ (four or more) at 10 years was significantly reduced from 32.1% to 13.0%, and breast cancer mortality was also reduced by 9.3% at 20 years. Importantly, after mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes even when systemic therapy was given [13].

Despite these results, routine use of PMRT in the case of less than four ALNs is not yet the standard of care, and consequently its general use in patients with tumours <5 cm is based on the presence of other prognostic risk factors (age < 40–45, tumour diameter > 3.5 cm, ER and PgR negativity, lympho-vascular invasion, grade 3 or a positive lymph node ratio > 20%) [60–62].

The results of the Medical Research Council Selective Use of Postoperative Radiotherapy After Mastectomy (SUPREMO) trial, a randomized phase III trial assessing the role of irradiation in women with intermediate-risk breast cancer following mastectomy, will help determine the real impact of PMRT in this subgroup of patients in terms of loco-regional control and overall survival, but it will take years before a definitive answer is obtained [63].

The role of irradiation of internal mammary nodes (IMNs) remains unclear as a French trial failed to demonstrate a survival benefit for IMN irradiation in patients with positive axillary nodes (pN+) or central/medial tumours with or without pN+, and the EORTC 22922/10925 (23.9% of the entire population were treated with mastectomy) cannot determine whether internal mammary irradiation or medial supraclavicular irradiation contributed more to the outcome [64].

On the other hand, the results from the Danish population-based study in which patients with left-sided node-positive breast cancer underwent only medial supraclavicular irradiation, whereas patients with right-sided node-positive breast cancer underwent both internal mammary and medial supraclavicular irradiation, support the role of including the internal mammary chain in the success of regional nodal radiation therapy (the study included patients treated both with lumpectomy and mastectomy) with a benefit on overall survival [65].

In the meantime, the use of PMRT in patients with early-stage breast cancer should be considered a valuable option, and its recommendation should be individualized according to patient and tumour features.

In ◘ Table 39.4 general indications for radiotherapy in early breast cancer are summarized.