Due to conflicting data from several large studies and concerns about toxicity, the decision on whether to irradiate the internal mammary nodes (IMNs) remains one of the most controversial in radiation oncology. Along with axillary lymph nodes, internal mammary nodes are one of the primary drainage sites for the breast. The inner quadrants are proportionally the most likely to drain into the internal mammary chain. Conversely, the upper outer quadrant is the least likely to drain into the IMNs. The incidence of metastases to the IMNs can vary from 11 percent to 57 percent, with higher incidences of IMN involvement correlated with younger age, tumors larger than 2 cm, and/or the presence of axillary node involvement (JAMA Oncol 2016;2:992-993). As IMNs could harbor tumor cells that may produce higher risks of regional/distant relapse, the optimal patient population in which to treat these nodes remains of great interest.
In a study of surgical patients undergoing mastectomy with IMN dissection, researchers determined no survival benefit to therapeutic IMN dissection. In addition, numerous older, retrospective studies failed to show a benefit in overall survival (OS) in treating IMNs with radiation (Int J Radiat Oncol Biol Phys 2016;95:617-31). Coupled with concerns of increased cardiac and pulmonary toxicity with treatment of IMNs, the technique largely fell out of favor in the late 1980s (Int J Radiat Oncol Biol Phys 2016;95:617-31, N Engl J Med 2015;373:317-27). With the advent of more precise radiotherapy techniques, as well as increasing recognition of the IMNs as potential seeds of metastasis, there has since been a revival of interest in irradiating the nodes in certain subpopulations.
Treatment of the IMNs can be performed by various techniques. The so-called “hockey stick” technique incorporates an L-shaped field setup with photon beams, along with an anterior electron (or mixed photon-electron) field to cover the supraclavicular and internal mammary nodes (Int J Radiat Oncol Biol Phys 2016;95:617-31). Although this technique has the advantage of less lung volume treated, there is an increased risk for the development of “hotspots” superficially. The technique of deep tangential fields allows the inclusion of the IMNs in the tangential field used to treat the chest wall. Compared with the “hockey stick” technique, the use of deep tangents reduces the cardiac dose at the expense of increased lung volumes treated (Int J Radiat Oncol Biol Phys 2016;95:617-31).
Recently, several large prospective studies have evaluated the impact of IMN irradiation in select patients. The Danish Breast Cancer Cooperative Group (DBCG) trial analyzed 3,098 patients treated between 2003 and 2007 with unilateral, early stage, node-positive breast cancer. Patients were allocated the respective arms based on laterality of primary tumor; patients with right-sided disease received IMN radiation, while patients with left-sided disease did not receive IMN radiation due to concerns of potential cardiac toxicity. The median follow-up was 8.9 years. Patients receiving radiation to the IMN experienced increased overall survival at 8 years (75.9% vs. 72.2%, p=0.005), although there was no statistical differences in distant recurrence (27.4% with vs. 29.7% without, p=0.07) (J Clin Oncol 2016;34:314-20).
Next, the MA.20 trial analyzed 1,832 women with node-positive or high-risk node-negative breast cancer. The patients were randomized to one of two arms: whole breast irradiation alone or whole breast irradiation with regional nodal irradiation (RNI), which included IMN and supraclavicular nodal volumes. There was no significant survival advantage to receiving RNI as compared to whole breast radiation alone (82.8% vs. 81.8%, p=0.38); however, there was higher 10-year disease free survival in the RNI arm (82.0% vs. 77.0%, p=0.01). Similarly, locoregional disease free survival was higher in the RNI group (95.2% vs. 92.2%, p=0.009).
The incidence of acute toxicities was increased with RNI, with higher rates of radiation dermatitis (49.5% vs. 40.1%, p<0.001) and pneumonitis (1.2% vs. 0.2%, p=0.01) reported. Likewise, delayed toxicities, such as lymphedema and subcutaneous fibrosis, were higher in the RNI group. There were no significant differences in cardiac events in the two groups (0.9% with vs. 0.4% without, p=0.26) (N Engl J Med 2015;373:1878-9). Results from the MA.20 also suggest a benefit to RNI in a subgroup of patients with estrogen receptor and progesterone receptor negative tumors (Int J Radiat Oncol Biol Phys 2016;95:617-31).
Lastly, the European Organization for Research and Treatment of Cancer (EORTC) 22922 trial enrolled 4,044 patients similarly randomized to receive RNI or lack thereof. With a median follow-up of 10.9 years, the overall 10-year survival for patients with RNI was slightly, although not statistically significantly, improved (82.3% vs. 80.7%, p=0.06). There was a significant improvement in disease-free survival in the RNI group (72.1% vs. 69.1%, p=0.04), as well as distant disease-free survival (78.0% vs. 75.0%, p=0.02). The number needed to treat to avoid one relapse was 30, with 39 as the number needed to avoid a death from breast cancer. Breast cancer specific mortality was decreased in the RNI group (12.5% vs. 14.4%, p=0.02). Although there was an increase in the incidence of pulmonary fibrosis in the RNI group (4.4% vs. 1.7%, p<0.001), there were no differences between the groups with regard to cardiac fibrosis (1.2% vs. 0.6%, p=0.06) and cardiac disease (6.5% vs. 5.6% p=0.25) (N Engl J Med 2015;373:317-27).
These trials have brought forth many controversies, however. Although the DBCG study is the only one to demonstrate an OS benefit with IMN treatment, because patients were randomized according to the laterality of the breast, no conclusions can be drawn as to whether there is an increased incidence of cardiac toxicity when treating IMNs specifically. Furthermore, the study used a now-antiquated regimen of chemotherapy (cyclophosphamide, fluorouracil, and epirubicin or methotrexate) (J Clin Oncol 2016;34:314-20). Although the study included the use of tamoxifen, it predated the widespread use of trastuzumab for HER2-positive disease.
When modern chemotherapy and trastuzumab were utilized in the EORTC 22922 and MA.20 trials, there was no OS advantage discerned in the latter. Moreover, despite the large number of patients in these two trials, there was only a small absolute increase in survival. Another issue arising from these trials is how much benefit comes from specifically irradiating IMNs compared to irradiating IMNs and supraclavicular nodes, recurrence in the latter of which is both more common and a harbinger of poor prognosis. The DBCG attempted to answer this very question; however, the use of chemotherapy and the unilaterality of treatment may be significant confounding variables in data interpretation.
Despite conflicting evidence over the benefit and toxicities of elective IMN-only irradiation, there are several factors to consider. Perhaps the most important factor is individual patient anatomy. Select patients may have an anatomy such that the heart and contralateral breasts are in a position that minimizes dose received with treatment of IMNs.
Based on the MA.20 trial, patients with estrogen- and progesterone-receptor negative tumors benefit from RNI. Again, although not equating with IMN-only irradiation, perhaps this is a subpopulation in which to consider complete RNI. Although the data on toxicities to the heart and lungs are inconclusive, patients with significant cardiac or respiratory comorbidities may have risks that outweigh the benefits of IMN-only treatment.
Newer techniques are in use to better treat IMNs without the increased risk of cardiac and respiratory toxicities. One method is to use a high-energy electron field superiorly, matched with a lower-energy electron field inferiorly. In this plan, the IMNs are covered with the 90 percent isodose line and the electrons can be aligned based on the slope of the chest wall tangents to reduce lung doses. Several studies also have shown IMRT to result in more uniform chest wall coverage while maintaining equivalent or less dosage to the ipsilateral lung and heart as compared to more conventional practices.
Most recently, there is increased interest in the use of protons for the treatment of breast cancer. Radiation pneumonitis is less common with protons, and the mean heart dose is consistently less than 1 Gy, thereby minimizing the risk of cardiac toxicity. However, despite improved dosimetry with proton therapy, there are very few known clinical advantages to date (Clin Breast Cancer 2016;16:145-54). Furthermore, protons have only been shown to be cost-effective in a certain small subpopulation of patients, namely those with high risk of cardiac toxicity from left-sided cancers with pre-existing comorbidities (Cancer 2016;122:1483-501).
Recent studies have shed light on the benefits and toxicities associated with treating IMNs with adjuvant radiation therapy for breast cancer. Some high-quality studies have demonstrated a tangible benefit for OS and disease-free survival, while others failed to show a benefit for overall survival. Additionally, although studies have not shown cardiac toxicity to be increased, the data are limited and further study is warranted. Despite increasing evidence on the benefits and risks for treating IMNs, the issue on whether to treat will likely remain controversial for the foreseeable future.
TIMOTHY MALOUFF, BS, and VIVEK VERMA, MD, are both in the Department of Radiation Oncology, University of Nebraska Medical Center, Omaha.