Nodal Radiation in Early-Stage Breast Cancer: Who Is Most Likely to Benefit?

Abstract

Whether to irradiate the regional lymph nodes in the adjuvant management of early-stage breast cancer has long been controversial. Isolated local-regional recurrence for women with 1-3 involved axillary nodes in either the supraclavicular/ axillary apex (SCV) or internal mammary (IM) nodal regions is uncommon, but it is likely an imperfect endpoint for judging the benefit of nodal radiation therapy. Despite the low rate of clinically evident IM and SCV nodal recurrences, older trials of postmastectomy radiation therapy, which demonstrated an overall survival benefit, routinely included these nodal regions. It is with this backdrop that the results of MA.20, as reported by Whelan and colleagues, have been of particular interest. While the study was predominantly comprised of patients with node-positive disease, 10% of patients in each arm had high-risk disease characteristics but negative axillary nodes. Ten-year disease-free survival was improved with nodal radiation, but overall survival was not statistically significantly different. Notably, regional irradiation reduced both local and distant disease. The Early Breast Cancer Trialists’ Collaborative Group meta-analysis of patients with positive nodes who underwent mastectomy showed that 1 death could be avoided at 20 years for every first recurrence prevented with irradiation at 10 years. If this pattern is maintained with modern systemic therapy, a small survival benefit from irradiation to the regional nodes is anticipated with longer follow-up. The findings of MA.20 are strengthened by comparable findings from the European Organisation for Research and Treatment of Cancer 22922 randomized study, which showed an improvement in disease-free but not overall survival with a similar randomization to SCV and IM radiation therapy or no regional nodal treatment. The extent to which these findings should be applied to all eligible patients is not known. The benefit in both studies is fairly modest and needs to be balanced against the potential for long-term cardiac (and other) toxicity, which can become evident even after 10 years. While there are multiple techniques for avoiding direct cardiac irradiation, total avoidance of dose (due to scatter) to the heart is not possible. Whether treatment of the SCV field, or the IMNs alone, is a reasonable option in select patients is also not clear. The European Organisation for Research and Treatment of Cancer subset analysis showed a greater relative mortality improvement with nodal radiation for node-negative patients (all with medial or central tumors) compared to node-positive patients, suggesting a benefit from the IMN component (at least in that subset). In addition, it remains to be seen whether there is a differential benefit across biologic subtypes. A subset analysis of MA.20 showed a greater relative benefit in patients with estrogen receptor-negative tumors. This is in contrast to the re-analysis of the Danish 82 b and c trials, which showed a greater benefit for postmastectomy irradiation in patients with estrogen receptorand progesteronepositive and human epidermal growth factor receptor 2 (HER2)-negative disease than in patients with triplenegative tumors. Moreover, given the improvement in local control seen in patients with HER2-positive disease receiving HER2-directed therapy (not used in MA.20), it remains to be seen whether this group will benefit equally from nodal irradiation. Finally, MA.20 accrued patients in the era of routine axillary dissection. These results have been extrapolated to more current patients treated with sentinel node biopsy alone, where the full extent of axillary nodal involvement is not known. Whether the benefit of nodal radiation therapy