Twenty‐year results of the randomized European Organization for Research and Treatment of Cancer trial 22922/10925 evaluating internal mammary chain and medial supraclavicular lymph node irradiation in stage I–III breast cancer

European Organization for Research and Treatment of Cancer trial EORTC 22922/10925 evaluated internal mammary and medial supraclavicular (IM-MS) lymph node irradiation (IM-MS-RT) in patients with stage I-III breast cancer. Eligible patients had involved axillary nodes and/or centrally/medially located tumors regardless of nodal involvement. The primary end point was overall survival, secondary end points were disease-free survival, distant metastases-free survival, breast cancer mortality, and any breast recurrence. Between 1996 and 2004, 4004 patients were randomized. The median patient age was 54 years. At a median follow-up of 22.2 years, 1550 (38.7%) patients died, of whom 796 (51.4%) died from breast cancer. At 20 years, the overall survival rate was 61.8% in the control group versus 61.0% in the IM-MS-RT group (hazard ratio [HR], 1.00; p = .967); the disease-free survival rate was 49.0% versus 48.2%, respectively (HR, 0.97; p = .515); and the distant metastases-free survival rate was 59.8% versus 58.9%, respectively (HR, 0.97; p = .578). The breast cancer mortality rate was 22.4% in the control group and 18.6% in the IM-MS-RT group (HR, 0.82; p = .006), whereas the rate of deaths not from breast cancer or from unknown causes was 15.8% versus 20.4%, respectively (HR, 1.26; p = .002). Lung fibrosis, cardiac fibrosis, and cardiac diseases were more frequent after IM-MS-RT versus no IM-MS-RT (6.3% vs. 3.2%, 2.7% vs. 1.7%. and 15.2% vs. 11.7%, respectively); and the rates of severe cardiac and lung morbidities (scores of 3 or 4) were 1.9% versus 1.7% and 0.3% versus 0.0%, respectively. Breast cancer mortality at 20 years was statistically significantly lower after IM-MS-RT, but deaths not from breast cancer increased after 15 years, resulting in no long-term benefit of IM-MS-RT on overall survival. Therefore, the authors strongly call for very long-term follow-up of treatments for prognostically favorable cancers such as breast cancer.