IM-MS Irradiation Reduces Breast Cancer Mortality but Fails to Improve Overall Survival in Node-Negative Disease: 20-Year EORTC Analysis

A new 20-year unplanned subset analysis of the phase III EORTC 22922/10925 trial reveals that internal mammary and medial supraclavicular (IM-MS) lymph node irradiation significantly reduces breast cancer (search)Search disease mortality in patients with node-negative (pN0) stage I–III breast cancer, but this disease-specific benefit does not translate into improved overall survival. The findings, reported in The Lancet Oncology by Kaidar-Person et al, add important nuance to the long-standing debate over regional nodal irradiation in early breast cancer.

At a median follow-up of 22.2 years, breast cancer (search)Search disease mortality was 10.0% (95% CI 8.0%–12.3%) in the IM-MS irradiation (search)Search drug group compared with 14.2% (95% CI 11.9%–16.8%) in the control group, corresponding to a hazard ratio of 0.70 (95% CI 0.53–0.92, p=0.010). Despite this statistically significant reduction, overall survival at 20 years was nearly identical: 69.0% (95% CI 65.4%–72.3%) with IM-MS irradiation versus 68.4% (95% CI 64.8%–71.6%) without it (HR 0.98, 95% CI 0.83–1.15, p=0.77).

A Late Signal in Non-Breast Cancer (search)Search disease Mortality

The analysis also uncovered a concerning late signal. Cumulative mortality from unknown or non-breast cancer (search)Search disease causes was higher in the IM-MS irradiation (search)Search drug group after 15 years, reaching 20.9% (95% CI 17.9%–24.1%) at 20 years compared with 17.4% (95% CI 14.7%–20.3%) in the control group (HR 1.24, 95% CI 1.00–1.53, p=0.048). The authors noted that non-breast cancer mortality was numerically higher in the IM-MS irradiation group after 15 years of follow-up.

This finding reinforces a central principle in breast radiotherapy: long-term organ-at-risk exposure matters, particularly when the expected breast cancer (search)Search disease benefit is modest. As the investigators concluded, "Breast cancer mortality at 20 years was significantly lower in the IM-MS irradiation (search)Search drug group, whereas non–breast cancer mortality was numerically higher in the IM-MS irradiation group after 15 years, resulting in no long-term benefit of IM-MS irradiation on overall survival."

Trial Design and Patient Population

EORTCView company profile 22922/10925 was a randomized, open-label, phase 3 trial conducted across 46 radiation oncology departments in 13 countries. The full trial enrolled 4,004 women up to age 75 with unilateral, histologically confirmed stage I–III breast adenocarcinoma between August 1996 and January 2004. Patients were randomly assigned to receive either IM-MS irradiation (search)Search drug at 50 Gy in 25 fractions or no IM-MS irradiation.

The current analysis focused on the subgroup of 1,778 patients with pN0 disease—890 in the IM-MS irradiation (search)Search drug group and 888 in the control group. The median age was 55 years. At the 20-year mark, 276 deaths (31.1%) had occurred in the IM-MS group and 277 deaths (31.1%) in the control group; of these, 87 (31.5%) and 122 (44.0%) were due to breast cancer (search)Search disease, respectively.

Late Toxicity Findings

Late toxicity data were also reported. Among patients with left-sided breast cancer (search)Search disease, late cardiac fibrosis occurred in 3.4% of patients in the IM-MS irradiation (search)Search drug group versus 2.8% in the control group. Lung fibrosis of any grade was observed in 6.4% of patients receiving IM-MS irradiation compared with 2.1% in the control group.

While these data do not suggest a dramatic excess of severe cardiac events, the higher rate of lung fibrosis with IM-MS irradiation (search)Search drug is notable. The broader message, however, is that the benefit-risk balance depends heavily on patient selection and radiation technique.

Implications for Contemporary Practice

The investigators emphasized that their results "emphasize the importance of very long–term follow-up and advanced irradiation techniques to reduce the dose to organs of interest." Modern radiotherapy planning—including deep inspiration breath hold for left-sided cancers, image guidance, more conformal planning, and careful heart and lung dose constraints—may reduce organ exposure compared with older-era techniques used during trial enrollment from 1996 to 2004.

For clinicians, this analysis supports individualized decision-making. Patients with higher estimated risk of occult regional disease or distant recurrence may be most likely to benefit from IM-MS irradiation (search)Search drug, while those with lower baseline risk may have smaller absolute benefit and less tolerance for additional organ exposure.

Philip Poortmans, PhD, of the Faculty of Medicine and Health Sciences at the University of AntwerpView company profile, served as the corresponding author for the Lancet Oncology article.