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Kolářová, I.; Melichar, B.; Sirák, I.; Vaňásek, J.; Petera, J.; Horáčková, K.; Pohanková, D.; Ďatelinka, F.; Šinkorová, Z.; Vošmik, M. Adjuvant Radiotherapy in the Treatment of Breast Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/55807 (accessed on 03 July 2024).
Kolářová I, Melichar B, Sirák I, Vaňásek J, Petera J, Horáčková K, et al. Adjuvant Radiotherapy in the Treatment of Breast Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/55807. Accessed July 03, 2024.
Kolářová, Iveta, Bohuslav Melichar, Igor Sirák, Jaroslav Vaňásek, Jiří Petera, Kateřina Horáčková, Denisa Pohanková, Filip Ďatelinka, Zuzana Šinkorová, Milan Vošmik. "Adjuvant Radiotherapy in the Treatment of Breast Cancer" Encyclopedia, https://encyclopedia.pub/entry/55807 (accessed July 03, 2024).
Kolářová, I., Melichar, B., Sirák, I., Vaňásek, J., Petera, J., Horáčková, K., Pohanková, D., Ďatelinka, F., Šinkorová, Z., & Vošmik, M. (2024, March 04). Adjuvant Radiotherapy in the Treatment of Breast Cancer. In Encyclopedia. https://encyclopedia.pub/entry/55807
Kolářová, Iveta, et al. "Adjuvant Radiotherapy in the Treatment of Breast Cancer." Encyclopedia. Web. 04 March, 2024.
Adjuvant Radiotherapy in the Treatment of Breast Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/curroncol31030090

The role of postmastectomy radiotherapy and regional nodal irradiation after radical mastectomy is defined in high-risk patients with locally advanced tumors, positive margins, and unfavorable biology. The benefit of postmastectomy radiotherapy in intermediate-risk patients (T3N0 tumors) remains a matter of controversy. It has been demonstrated that radiotherapy after breast-conserving surgery lowers the locoregional recurrence rate compared with surgery alone and improves the overall survival rate. In patients with four or more positive lymph nodes or extracapsular extension, regional lymph node irradiation is indicated regardless of the surgery type (breast-conserving surgery or mastectomy). Despite the consensus that patients with more than three positive lymph nodes should be treated with radiotherapy, there is controversy regarding the recommendations for patients with one to three involved lymph nodes. In patients with N0 disease with negative findings on axillary surgery, there is a trend to administer regional lymph node irradiation in patients with a high risk of recurrence. In patients treated with neoadjuvant systemic therapy and mastectomy, adjuvant radiotherapy should be administered in cases of clinical stage III and/or ≥ypN1. In patients treated with neoadjuvant systemic therapy and breast-conserving surgery, postoperative radiotherapy is indicated irrespective of pathological response.

breast cancer adjuvant radiotherapy whole breast irradiation mastectomy breast-conserving surgery regional node irradiation neoadjuvant chemotherapy

1. Introduction

Adjuvant radiotherapy (RT) after mastectomy or breast-conserving surgery may result in two principal potential benefits, i.e., lower risk of locoregional recurrence, and a reduction in breast cancer mortality risks and overall mortality [1][2][3].
The progress in radiotherapy is based mostly on the use of new technologies. Currently, external-beam radiation is performed using linear accelerators after computed tomography-based imaging (Figure 1) and 3-dimensional planning using sophisticated technologies, including intensity-modulated radiation therapy (IMRT). The control of the accuracy of the dose delivery can be increased with image-guided radiation therapy (IGRT, Figure 2). The dose to the heart can be substantially decreased by delivering radiation in deep inspiration (Figure 3) or prone position [4][5].
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Figure 1. 3D computed tomography deep learning-based organ at risk auto-contouring (Siemens Healthineers AG, Erlangen, Germany) with manual target volume (CTV, PTV) delineation. ETB = Estimated Tumor Bed.
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Figure 2. 2D megavoltage electronic portal imaging (EPID) as a daily IGRT online setup of breast carcinoma radiotherapy: before (left) and after (right) alignment.
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Figure 3. External-beam whole breast irradiation (WBI) and partial breast irradiation (PBI) with and without deep inspiration breath hold (DIBH)—comparison of the same target volume CT slice.
Advances in radiobiology have resulted in an improved understanding of mechanisms of acute and late toxicity leading to a deeper understanding of the biological effects of different fractionation regimens. Owing to this progress, hypofractionated radiotherapy that significantly reduces the treatment duration has been increasingly used in recent years [6].

2. Radiotherapy after Radical Mastectomy

Modified radical mastectomy is the most common procedure after primary (neoadjuvant) systemic therapy in patients with locally advanced breast cancer. The rationale for using modified radical mastectomy also includes planning reconstructive surgery with breast replacement, avoidance of adjuvant radiation therapy, and the presence of mutations associated with a high risk of second primary breast cancer. Adjuvant radiotherapy is indicated after mastectomy not only in patients with locally advanced tumors but also based on the presence of risk factors. In selected patients, radiation therapy after mastectomy improves local control as well as overall survival [7].
The disease recurrence pattern was analyzed in high-risk breast cancer patients after mastectomy treated with systemic therapy with or without radiotherapy. In patients treated with radiotherapy, the incidence of locoregional recurrence and distant metastases was lower compared to patients who had no radiation. The 18-year probability of any first breast cancer event was 73% vs. 59% (p < 0.001) after no RT and RT, respectively (relative risk [RR], 0.68; 95% CI, 0.63 to 0.75) [2].
High-risk patients. The role of PMRT (postmastectomy radiotherapy) and regional nodal irradiation after radical mastectomy is defined in patients with locally advanced tumors—T3, T4, (T3N0 controversial), positive margins, gross extracapsular extension, four or more affected nodes, or grade 3—given the fact that PMRT lowers the risk of locoregional relapse and improves breast cancer-specific and overall survival rates by 4–5% [1].
Intermediate-risk patients. The benefit of postmastectomy radiotherapy in medium-risk patients (T3N0 tumors) remains a matter of dispute. The role of PMRT was studied in a meta-analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) trials. In 313 breast cancer patients with tumors of ≥5 cm and no lymph node involvement, the incidence of locoregional failure as a first event was low leading to the conclusion that PMRT should not be routinely used in this patient population [8][9][10].
In a meta-analysis that included 8 135 patients randomized in 22 trials between 1964 and 1986, between the irradiation of the chest wall and regional lymph nodes after mastectomy and axillary surgery or no radiotherapy, no additional effect of radiotherapy on locoregional recurrence was noted in 700 patients with negative lymph node findings after axillary dissection [11].
On the other hand, in an analysis of 2535 patients from the SEER database treated between 2000 and 2010 with modified radical mastectomy for T3N0M0 tumors, PMRT was associated with a significant improvement in both cancer-specific survival and OS, leading to the conclusion that PMRT should be strongly considered in this patient population. Other risk factors including age, tumor grade, lymphovascular invasion (LVI), and margin status may also be considered [10].
Low-risk patients. Radiotherapy is not routinely recommended for patients after radical mastectomy with T1-2N0 tumors because of the low risk of local recurrence (1–2%) [11]. Nevertheless, adjuvant radiotherapy may be indicated in selected patients who would otherwise be considered low risk, e.g., patients with close/positive margins on mastectomy, patients aged 35 or younger, and patients harboring tumors with LVI and/or grade 3 [12].
Although some studies indicate improved outcomes after PMRT in all patients with positive lymph nodes, some trials demonstrate a low locoregional recurrence rate, even in the absence of radiotherapy in patients with T1 or T2 tumors and one to three involved lymph nodes. In many patients, the probability of locoregional failure is so low that the risk of toxicity associated with the treatment prevails. However, PMRT should be strongly considered in patients with one to three positive lymph nodes and grade 3, or extracapsular extension [13].

3. Radiotherapy after Breast-Conserving Surgery

Residual microscopic disease that may give rise to recurrence may be present in up to 40% of patients after surgical resection. Holland et al. reported that in 43% of cases of apparently unifocal carcinoma, tumor cell nests localized > 2 cm from the primary tumor were present [14].
This observation represents the rationale for whole breast irradiation (WBI) aiming at the eradication of residual disease. It has been demonstrated that WBI after breast-conserving surgery not only lowers the locoregional recurrence rate compared with surgery alone but also improves the overall survival rate at 15 years [1].
The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial reported a 20-year incidence of ipsilateral recurrence after lumpectomy in 14.3% of patients treated with adjuvant radiation and 39.2% of patients with no adjuvant radiation [15].
An Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis that covered 17 trials that enrolled 10 801 patients confirmed a lower risk of recurrence (from 31% to 15.6%) with adjuvant radiation in patients without lymph node involvement. The 15-year risk of death from breast cancer decreased from 20.5% to 17.2%, demonstrating that adjuvant WBI affects the long-term risk of death from breast cancer. This meta-analysis also indicated that no subgroup of patients defined by age, stage, or hormone receptor status would derive benefit from radiotherapy. Thus, WBI is indicated in the majority of patients after breast-sparing surgery [16].

4. Comparison of the Results of Breast-Conserving Surgery and Radical Mastectomy

Several studies address the difference in treatment outcome between radical mastectomy and breast-conserving surgery with subsequent WBI. No difference in overall survival was observed in six large, randomized trials. Consequently, in 1992 the National Cancer Institute put forward a consensus that presented both radical mastectomy and breast-conserving surgery as acceptable standard therapeutic options for patients with operable breast cancer [17].
The Swedish trial published in 2021 compared the efficacy of breast-conserving surgery combined with radiotherapy and radical mastectomy in 48,986 patients who underwent surgery between 2008 and 2017 for T1-2N0-2 breast cancer. The breast cancer-specific and overall survival was significantly better in patients treated with breast-conserving surgery and postoperative radiation compared to radical mastectomy with or without adjuvant radiotherapy. Although this difference remained after correction for tumor characteristics, therapy, demography, comorbid conditions, and socioeconomic status, the effect of selection bias is difficult to exclude. However, these data indicate that breast-conserving surgery with subsequent radiotherapy may improve overall survival [18].
The use of breast-conserving surgery is also supported by the availability of the option to modify adjuvant breast irradiation that would further decrease the side effects of therapy compared to WBI. Selected subgroups of patients can be treated with less extensive radiotherapy techniques, including accelerated partial breast irradiation (APBI, Figure 4), partial breast irradiation (PBI, Figure 3), or intraoperative radiotherapy (IORT) [19].
Curroncol 31 00090 g004
Figure 4. Multicatheter interstitial accelerated partial breast irradiation (APBI): prescribed dose distribution.

5. Radiotherapy after Neoadjuvant Chemotherapy

Neoadjuvant systemic therapy is being increasingly used in the treatment of breast cancer, particularly in patients with HER2-positive and triple-negative tumors. A study evaluating locoregional control in patients treated with breast-conserving surgery after neoadjuvant systemic therapy found after multivariate analysis that increased risk of locoregional relapse was associated with the triple-negative subtype, clinical III stage, and an absence of pathological complete response [20].
A pooled analysis of nine prospective trials of neoadjuvant chemotherapy that included 10,075 patients with a median follow-up of 67 months evaluated the predictors of locoregional recurrence risk. The site of the first relapse was locoregional in 9.5% of patients, distant in 14.5%, and both locoregional and distant in 1.7%. Younger age, clinically positive lymph node, grade 3 tumor, absence of pathological complete response, and triple-negative subtype were independent predictors of locoregional relapse in multivariate analysis. The cumulative 5-year locoregional relapse rate was higher in the absence of pathological complete response compared to patients in whom the pathological complete response has been reached, and this difference reached statistical significance in patients with hormone receptor-positive/HER2-negative, hormone receptor-negative/HER2-positive, and triple-negative tumors, but not in patients with hormone receptor-positive/HER2-positive tumors. Among patients without pathological complete response, the risk of locoregional relapse was higher for patients with hormone receptor-negative/HER2-positive and triple-negative tumors compared to patients with hormone receptor-positive/HER2-negative tumors [21].
In the past, patients treated with neoadjuvant systemic therapy and positive sentinel lymph nodes have been routinely indicated for axillary lymph node dissection. This approach has been recently changed in patients with clinically negative lymph nodes after neoadjuvant therapy. The targeted axillary dissection of a positive lymphatic lymph node marked before neoadjuvant systemic therapy represents a new option in staging [22].
Postoperative WBI is indicated in patients treated with neoadjuvant systemic therapy and breast-conserving surgery irrespective of pathological response. In the case of residual lymph node involvement and patients with clinical stage III disease irrespective of pathological response, regional lymph node irradiation is indicated. In patients treated with neoadjuvant systemic therapy and mastectomy, adjuvant radiotherapy should be administered in cases of clinical stage III and/or ≥ypN1 [23].
The approach to radiotherapy in patients with clinical N1 disease and pathological complete response is a matter of controversy. A meta-analysis investigating the benefit of adjuvant locoregional radiotherapy in patients with clinically positive lymph nodes and pathological complete response treated with mastectomy or breast-conserving surgery demonstrated the benefit of locoregional radiotherapy in lowering locoregional recurrence rate, but no effect on disease-free- or overall survival. However, in clinical practice, the results of this meta-analysis should be interpreted with caution because of the low level of evidence [24].
The results of clinical trials indicate that adjuvant regional lymph node irradiation could be considered in patients with clinical N1 disease and pathological complete response after neoadjuvant systemic therapy. The decision should be based on the evaluation of locoregional relapse risk considering tumor biology, age, and other clinical and pathological characteristics. The optimal management of these patients has yet to be defined (Table 1 and Table 2), and the results of NSABP B-51 are eagerly awaited [25].
Table 1. Considerations for RT in patients receiving preoperative systemic therapy according to NCCN recommendations—version 1.2024 [26].
RT after preoperative therapy and breast-conserving surgery
cN0 → ypN0 (SLNB) WBI + boost to the tumor bed
cN+ → ypN0 WBI + boost to the tumor bed + comprehensive RNI
(ongoing NSABP B-51 trial assessing the benefit of RNI)
cN+→ ypN+ (SLNB) ALND followed by comprehensive RNI
(ongoing A11202 trial assessing the benefit of ALND)
RT after preoperative therapy and mastectomy
cN0 → ypN0 (SLNB) Consider RT to the chest wall without RNI
cN+ → ypN0 (SLNB) RT to the chest wall and comprehensive RNI
cN+ → ypN+ ALND followed by comprehensive RNI
SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection; RT, radiation therapy; RNI, regional nodal irradiation.
Table 2. Considerations for RT in patients receiving preoperative systemic therapy according to the “Lucerne Toolbox” [27].
  ypN Tx: Level I/II RT: Level III/IV ± IM
cN0 → ycN0 → SLNB ypN0 No local Tx No local Tx
ypN+ ALDR or Axillary RT RT if risk factors *
cN+ → ycN0 → TAD ypN0 Axillary RT RT if risk factors *
ypN+ ALND or Axillary RT RT
cN+→ ycN+ → ALND ypN0 No local Tx RT if risk factors *
ypN+ RT (only forgotten nodes) RT
Risk factors: non-luminal A-like, grade 3, middle/high genomic risk, LVI, ECE. * SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection; TAD, targeted axillary dissection; RT, radiation therapy; LVI, lymphovascular invasion; ECE, extracapsular extension; IM, internal mammary; Tx, treatment.

References

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Iveta Kolářová
,
Bohuslav Melichar
,
Igor Sirák
,
Jaroslav Vaňásek
,
Jiří Petera
,
Kateřina Horáčková
,
Denisa Pohanková
,
Filip Ďatelinka
,
Zuzana Šinkorová
,
Milan Vošmik
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