AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.

At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).

Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.

With irradiation, "we might be able to stop metastasis at their source," he said.

Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.

The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.

More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).

Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.

Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.

After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.

A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.

Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.

Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).

He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.

"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.

The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.

pwendling@frontlinemedcom.com

Internal mammary chain radiation ups breast cancer survival