Reduced Breast Cancer Mortality and Risk of Recurrence With Internal Mammary and Medial Supraclavicular Nodal Irradiation in Stage I to III Breast Cancer

15-Year Results of the EORTC 22922/10925 Trial

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As reported in The Lancet Oncology by Philip M. Poortmans, PhD, and colleagues, 15-year outcomes of the phase III EORTC 22922/10925 trial show continued reductions in both breast cancer mortality and recurrence with postsurgery internal mammary and medial supraclavicular (IM-MS) lymph node chain irradiation in patients with stage I to III breast cancer, with no significant difference in overall survival.

Study Details

The open-label trial included 4,004 women aged ≤ 75 years with unilateral stage I to III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumor from sites in 13 countries. Patients were randomly assigned between August 1996 and January 2004 to receive IM-MS irradiation at 50 Gy in 25 fractions (n = 2,002) or no IM-MS irradiation (control group; n = 2,002).

Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. The primary endpoint was overall survival on intention-to-treat analysis. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after random assignment.

Philip M. Poortmans, PhD

Philip M. Poortmans, PhD

Efficacy Endpoints

Median follow-up was 15.7 years (interquartile range = 14.0–17.6 years). Overall, death from any cause occurred in 27.7% of patients in the IM-MS irradiation group and 28.4% of patients in the control group.

Overall survival at 15 years was 73.1% vs 70.9% (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.84–1.06, P = .36). Median overall survival was not reached in either group; overall survival duration associated with the 75% survival probability (third quartile overall survival) was 14.2 years vs 13.0 years. In analysis excluding 25 patients without data on final pathologic T and N stage, the difference in overall survival remained nonsignificant (HR = 0.92, 95% CI = 0.82–1.04, P = .18).

Overall, 37.5% vs 39.1% of patients had breast cancer recurrence, a second breast cancer, or died. Disease-free survival at 15 years was 60.8% vs 59.9% (HR = 0.93, 95% CI = 0.84–1.03, P = .18). Overall, 29.2% vs 30.7% of patients developed distant metastases or died, with 15-year distant metastasis–free survival rates being 70.0% vs 68.2% (HR = 0.93, 95% CI = 0.83–1.04, P = .18). The cumulative incidence of any type of breast cancer recurrence at 15 years was 24.5% vs 27.1% (HR = 0.87, 95% CI = 0.77–0.98, P = .024).

Among patients who died, the cause of death was breast cancer in 56.7% of the IM-MS irradiation group vs 66.4% of the control group. Non–breast cancer death accounted for 30.9% vs 26.4% of deaths and cause of death was unknown for 12.5% vs 7.2% of deaths.

The cumulative incidence of breast cancer mortality at 15 years was 16.0% vs 19.8% (HR = 0.81, 95% CI = 0.70­–0.94, P = .0055). At 15 years, the cumulative incidence of death not due to breast cancer was 7.8% vs 7.0% (HR = 1.13, 95% CI = 0.91–1.40, P = .29) and the cumulative incidence of death from an unknown cause was 3.1% vs 2.3% (HR = 1.66, 95% CI = 1.13–2.44, P = .010).

Second Cancers

Second cancers occurred in 14.1% vs 14.8% of patients, including ipsilateral breast cancer in 0.6% vs 0.5% and contralateral breast cancer in 6.2% vs 6.9%. Second nonbreast cancers occurred in 8.3% vs 8.5% of patients. The distribution of nonbreast cancers indicated no obvious increase in lung, thyroid, esophageal, and mediastinal malignancies in the IM-MS group, with the exception of in-field tumors in four patients (three with angiosarcoma and one with pleural fibrosarcoma).


  • At 15 years, patients in the IM-MS irradiation group had reduced risks of breast cancer mortality and any breast cancer recurrence.
  • No difference in overall survival was observed.

Late Adverse Effects

Late adverse effects were evaluated in 1,922 patients in the IM-MS irradiation group and 1,944 in the control group who received study treatment at every follow-up visit until progression or development of new primary cancer. Any-grade pulmonary fibrosis occurred in 5.1% vs 2.3% of patients, cardiac fibrosis in 2.0% vs 1.1%, and any cardiac disease in 8.6% vs 7.2%.

Among the 935 vs 952 patients with right breast cancer, 2.0% vs 0.9% had clinical evidence of cardiac fibrosis and 8.3% vs 6.3% had any evidence of cardiac disease. Among the 987 vs 992 patients with left breast cancer, 1.9% vs 1.3% had clinical evidence of cardiac fibrosis and 8.8% vs 8.0% had any evidence of cardiac disease. Among the total study population, death due to cardiovascular disease occurred in 1.2% of patients in each group.

The investigators concluded, “The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I–III breast cancer. However, this is not converted to improved overall survival.”

They noted, “Although overall disease-free survival was not significantly longer with IM-MS irradiation, breast cancer recurrence at 15 years was significantly lower. The fact that this does not translate into longer overall survival might be explained by non–breast cancer–related deaths or those from an unknown cause, which together constituted 38% of all deaths, an imbalance in missing data on the cause of death between treatment groups, and salvage treatment after recurrence.”

Dr. Poortmans, of the Faculty of Medicine and Health Sciences, University of Antwerp, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the U.S. National Cancer Institute, Ligue Nationale contre le Cancer, and KWF Kankerbestrijding. For full disclosures of the study authors, visit

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