Final results from a landmark European Organisation for Research and Treatment of Cancer (EORTC) randomized trial with more than 20 years of follow-up have shown that irradiation of the internal mammary and medial supraclavicular (IM-MS) lymph nodes reduces breast cancer mortality but does not improve overall survival. The findings highlight the importance of very long-term follow-up when evaluating cancer treatments, particularly in patients with otherwise favorable prognosis. The results stem from EORTC trial 22922/10925 and were presented at the ESTRO 2026 Congress in Stockholm during the Plenary Session: Joint Green Journal – The Lancet Oncology Top Clinical Trials (Abstract 5580). The planned 20-year analysis of the full trial population was simultaneously published by Kaidar-Person et al in CA: A Cancer Journal for Clinicians, while The Lancet Oncology will soon publish a complementary paper reporting an unplanned subset analysis in patients with node-negative (pN0) breast cancer.
Between 1996 and 2004, the trial enrolled 4,004 patients with stage I to III breast cancer at 46 centers in 13 countries. Patients were randomly assigned to receive postoperative radiation therapy with or without elective irradiation of the IM-MS lymph nodes. At final analysis, the median follow-up was 22.2 years—the longest-planned follow-up of any randomized breast cancer radiation therapy trial.
Long‑Term Outcomes Across the Overall Trial Population
At 20 years, overall survival was similar in patients treated with or without IM-MS irradiation. However, breast cancer–related mortality was significantly lower among patients who received IM-MS irradiation. This benefit was counterbalanced over time by an increase in deaths from causes other than breast cancer, which emerged after approximately 15 years, resulting in no survival advantage.
Long-term cardiac and pulmonary toxicity was reported more frequently after IM-MS irradiation, although severe side effects remained very uncommon. Of note, patients were treated using radiation therapy techniques available more than 2 decades ago.
Outcomes in Node-Negative Disease
The proffered paper presented at ESTRO also included the subset analyses on the 1,778 patients with node-negative (pN0) breast cancer and centrally or medially located tumors. Despite a lower absolute risk of breast cancer death in this group, the long-term pattern closely mirrored that of the overall trial population.
Reductions in breast cancer mortality were again offset by a later increase in non–breast cancer–related deaths, resulting in no improvement in overall survival. These findings suggest that long‑term trade‑offs must be considered even in patients with a favorable prognosis and call for careful evaluation of nodal irradiation in axillary node–negative disease.
“This trial clearly shows why long-term follow-up over decades is essential in breast cancer,” said Philip M.P. Poortmans, MD, PhD, senior and presenting author.
“Short- or medium-term benefits may not reflect the full balance between efficacy and late side effects, particularly in patients with an otherwise favorable prognosis,” added first author Orit Kaidar-Person, MD, PhD, Associate Member of the EORTC Breast Cancer Group.
“Such large, decades-long trials with rigorous quality assurance, allowing clinically meaningful subgroup analyses, are only possible thanks to the sustained support and collaboration fostered by organizations like EORTC,” added Drs. Poortmans and Kaidar-Person.
Conducted by the EORTC Radiation Oncology and Breast Cancer Groups, trial 22922/10925 remains a cornerstone study for understanding the long‑term impact of locoregional treatments in breast cancer and for guiding future research aimed at improving both survival and quality of life.
DISCLOSURE: This study was supported by donations from the La Ligue nationale contre le cancer from France; the KWF Kanker Bestrijding from the Netherlands; and from the Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society from Belgium. For full disclosures of the study authors, visit acsjournals.onlinelibrary.wiley.com.
