Radiation of the Internal Mammary Nodes: Is There a Benefit?

Abstract

Regional nodal irradiation as a component of both postmastectomy and postlumpectomy radiation has been shown in numerous randomized trials and meta-analyses to have a significant impact on locoregional control, breast cancer mortality, and, in some cases, overall survival. A recent meta-analysis of postmastectomy radiation demonstrated a breast cancer mortality benefit in patients with involved axillary nodes, independent of the use of chemotherapy or the number of nodes involved. From a more current era, two recently reported randomized trials also demonstrated a benefit to regional nodal irradiation in early-stage breast cancer in which the majority of patients had one to three involved nodes or high-risk/medial location node-negative disease. These trials included patients who had undergone lumpectomy or mastectomy, and patients were randomly assigned to breast/chest wall irradiation alone or to breast/chest wall irradiation plus regional nodal irradiation. In both trials, radiation to the nodes was directed at the internalmammary, supraclavicular, and undissected levels II to III lymph nodes. Although neither trial reached the primary goal of demonstrating statistically significant improved survival, they both reported an improvement in disease-free and distant metastasis–free survival with regional nodal irradiation. The European Organisation for the Research and Treatment of Cancer (EORTC) trial demonstrated a nearly significant improvement in survival and a significant improvement in breast cancermortality, whereas theMA.20 trial demonstrated a survival improvement in a prespecified subgroup of patients who had hormone receptor–negativedisease. Because, in both studies, all regional lymphatics were targeted, the relative benefit specific to internal mammary irradiation could not be determined. Although controversies about the selection of patients for regional nodal irradiation remain, there is general consensus and acceptance of the fact that the risks and benefits of regional nodal irradiation should be discussed and considered in appropriately selected patients. However, significant debate and wide variability in practice persist regarding radiation field design and the relative benefit of targeting the internal mammary nodes. The retrospective data, both supporting and refuting the benefits of internal mammary radiation, suffer from the usual limitations of such studies, including selection biases, heterogeneous patient populations, variability of treatment over time, and other confounding factors that cannot be accounted for in retrospective series. Arguments against internal mammary irradiation and barriers to its use point to potential added cardiac and pulmonary toxicity with larger irradiated volumes, increased complexity of treatment setup, and low rates of detectable internal mammary recurrences. Proponents of internal mammary irradiation would argue that all prospective, randomized trials that demonstrated the benefits of regional nodal irradiation routinely included internal mammary irradiation and that, therefore, one cannot exclude specific targeting of the internal mammary nodes as a contributing factor to the improved outcomes reported in these studies and meta-analyses. In addition, with modern radiation treatment planning and the use of a wide range of radiation treatment modalities and techniques—including three-dimensional conformal techniques, intensity-modulated radiation therapy, combination of photons and electrons, deep inspiration breath holding, and even proton beam therapy in selected cases— acceptable radiation doses to the critical cardiac and pulmonary organs at risk for toxicity can be achieved in the majority of patients. These doses lead to an acceptably low risk for toxicity, such that the potential benefit outweighs the potential risks. One recently published randomized trial, which patients who received postmastectomy radiation were specifically randomly assigned to radiation of the internal mammary nodes or not showed an insignificant improvement in survival of 3.3%, from 59.3% to 62.6%, at 10 years in the group randomly assigned to internal mammary radiation. That trial, however, had a number of major limitations. There was, at the time of the study design, an overestimation of the degree of internal mammary involvement, and the number of patients to be included was estimated to detect a 10% difference in survival at 10 years. In retrospect, this was too optimistic, given subsequent meta-analysis that demonstrated a smaller 5% improvement in overall survival at 15 years with any postmastectomy radiation. Furthermore, the actual survival rate observed in the trial was considerably greater than the original design’s expected survival rate. Because of this, the trial was underpowered, and the authors acknowledged that the trial could not rule out a smaller, more realistic potential benefit in survival; they concluded that “we cannot reliably recommend for or against internal mammary irradiation after mastectomy.” In the article that accompanies this editorial, Thorsen et al report the results of the Danish Breast Cancer Cooperative Group (DBCG) internal mammary node (IMN) study, an important,