Abstract
Regional lymph node irradiation is usually indicated in patients with positive node breast cancer. However, there are some controversies regarding the clinical benefits of adding regional nodal irradiation to whole-breast or thoracic-wall irradiation after breast surgery especially for patients with 1 to 3 positive axillary lymph nodes. More recently, two important studies (NCIC MA.20 and EORTC 22,922–10925) were published to address this significant issue and some further points need to be discussed.
Breast cancer is one of the most frequent tumors in women and a significant cause of tumor-related death. As standard, patients with breast cancer receive multidisciplinary treatment including surgery, systemic and hormone therapy and radiation therapy.[Citation1,Citation2]
With the goal of reducing ipsilateral and contralateral rates of recurrence, disease-free survival and overall mortality rates, patients who underwent breast-conserving surgery should be managed with postoperative adjuvant treatment that can involve external beam whole breast radiation therapy (WBRT), chemotherapy and/or hormone therapy.[Citation3,Citation4]
Similarly, patients who received mastectomy and present with a high risk of recurrence (large tumor size – T3/T4, positive margins, and/or positive axillary lymph nodes), postmastectomy radiation therapy to the thoracic wall should be performed since the clinical outcomes, as breast cancer-specific survival, local recurrence and overall mortality rates were significantly improved.[Citation5,Citation6]
Over the last few decades, the indications of breast postoperative radiation therapy in patients with involved axillary lymph nodes have been discussed. It has been postulated that the risk for locoregional recurrence rises proportionally according to the absolute number of positive axillary lymph nodes recognized.[Citation7]
Regional lymph-node irradiation for women with pathologically involved lymph nodes can improve outcome. Nevertheless, whether the benefits of regional node irradiation prevail over the risks for all groups of patients is still unknown. There might be a setting of patients with low percent of regional nodal disease that the risk of relapse is very low. Thus, the radiation therapy for regional nodal stations could not impact on a fair clinical benefit ratio. However, it is not clearly defined which group could benefit more from this approach.
Recently, two important studies the NCIC MA.20 Study Investigators (MA.20 trial – Whelan et al.) and the European Organization for Research and Treatment of Cancer (EORTC) 22,922–10,925 trial (EORTC trial – Poortman et al.) [Citation8,Citation9] reported their results on whether the addition of regional nodal irradiation to whole-breast or thoracic-wall irradiation improved outcomes in breast cancer patients with node-positive or high-risk node-negative.
MA.20 trial [Citation8] included 1832 patients who underwent breast-conserving surgery and adjuvant systemic therapy and were randomly assigned (year 2000–2007) to undergo whole-breast irradiation alone or whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular and axillary lymph node). Similarly, EORTC trial [Citation9] randomized 4004 patients (year 1996–2004) to undergo postoperative whole-breast radiation therapy or thoracic-wall irradiation with or without regional nodal irradiation (including supraclavicular and internal mammary). In both studies, after long-term follow-up (10 years), overall survival was not significantly different between the two groups and ranged from 80.7 to 82.8% (hazard ratio, 0.91; p = 0.38 and hazard ratio, 0.87; p = 0.06, for the MA.20 trial and the EORTC trial, respectively).
At a 10-years follow-up, the clinical benefit of regional nodal irradiation was highlighted on disease-free survival rates of 82.0 versus 77.0% (hazard ratio, 0.76; p = .01 – MA-20 trial) and 72.1 versus 69.1% (hazard ratio, 0.89; p = 0.04 – EORTC trial); and distant disease-free survival 78.0 versus 75.0% (hazard ratio, 0.86; p = 0.02 – EORTC trial) and 86.3 versus 82.4% (hazard ratio, 0.76; p = 0.03 – MA-20 trial). Breast-cancer mortality was statistically significantly low in EORTC trial (12.5 vs 14.4%; hazard ratio, 0.82; p = 0.02), however, no significant difference was observed in MA-20 trial (10.3 vs 12.3%; hazard ratio, 0.80; p = 0.11).
In a subgroup analysis, patients with 1 to 3 positive axillary nodes (1558 patients in MA.20 trial; 1725 patients in EORTC trial) who underwent regional nodal irradiation did not show a clear survival benefit. Considering this specific population only, the EORTC and MA.20 studies reports differ from those published in a recent EBCTCG meta-analysis of 22 randomized trials, on which benefits were evident on a postmastectomy scenario (Early Breast Cancer Trialists’ Collaborative Group – EBCTCG).[Citation10]
The EBCTCG meta-analysis demonstrated that postmastectomy radiation therapy (patients received thoracic-wall and regional lymph-node) reduced breast cancer mortality [rate ratio (RR) 0.80, 95% CI 0.67–0.95, two-sided significance level (2p) = 0.01] and overall recurrence (RR 0.68, 95% CI 0.57–0.82, 2p = 0.00006) in patients with 1 to 3 positive axillary lymph nodes even when systemic therapy was associated. This improvement is not only statistically significant, but also clinically important.
Thus, based on the EBCTCG meta-analysis, postmastectomy radiation therapy should be strongly considered for women with 1 to 3 positive axillary lymph nodes. The similar considerations about regional irradiation also appear to be true for patients who received breast-conserving surgery.[Citation10]
Given this controversy, the presence of recognized risk factor for breast cancer recurrence [(such as age (<50 years), lymphovascular invasion, involved margins, unfavorable molecular profile (such as triple negative tumor), extracapsular extension] can be used to support in decision on whether to recommend or not postoperative regional irradiation in patients with 1 to 3 positive axillary lymph nodes. In addition an individual based data analysis of MA.20 and EORTC trials including patients with 1 to 3 positive axillary nodes should be very valuable in order to clarify the real impact of the regional nodal irradiation in this population corroborating or not the EBCTCG meta-analysis findings.
In all, given the presented data, it is important to consider and discuss the potential benefits of radiation therapy among all patients who have node-positive disease, as there is a high level of evidence that radiation therapy is associated with a clinically significant benefit in the majority of patients with positive nodes, including patients with 1 to 3 involved nodes.
And also some pitfalls from de MA.20 trial, EORTC trial and EBCTCG meta-analysis deserve some discussion: the studies did not include current chemotherapy treatment such as taxanes and trastuzumab. This could play a role in overall survival rates. On the other hand, MA.20 and EORTC studies showed that regional irradiation was generally well tolerated (some increase rates of pneumonitis, lymphedema and skin tissues) which may reflect better radiation therapy technology and treatment.
Thus, besides not reporting better OS rates, the MA.20 trial and EORTC trial showed that treatment selection for the individual patient is key of success. And that clinically better rates of disease-free survival and metastasis-free survival may play a great part on patient treatment decision.
Fabio Ynoe de Moraes
Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil and Instituto de Radiologia InRad, Faculdade de Medicina, da Universidade de São Paulo, São Paulo, Brazil
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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