BACKGROUND The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracicwall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median followup of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).
Background Uncertainty about the benefit/risk ratio of regional lymph node irradiation led to varying clinical protocols. We investigated long-term late side effects after internal mammary and medial supraclavicular (IM-MS) lymph node irradiation to improve shared decision-making. Methods The multicentre EORTC trial (ClinicalTrials.gov, NCT00002851) randomized stage I-III breast cancer patients with involved axillary nodes and/or a medially located primary tumor. We analyzed late side effects, both longitudinally at every follow-up and cross-sectionally at 5-year intervals. All statistical tests were 2-sided. Results Between 1996 and 2004, 46 departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. Longitudinal follow-up data showed cumulative incidence rates at 15 years of 2.9% (95% confidence interval [CI] = 2.2%–3.8%) vs. 5.7% (95% CI = 4.7%–6.9%) (P<.001) for lung fibrosis, of 1.1% (95% CI = 0.7%–1.7%) vs. 1.9% (95% CI = 1.3%–2.6%) (P=.07) for cardiac fibrosis, and of 9.4% (95% CI = 8.0%–10.8%) vs. 11.1% (95% CI = 9.6%–12.7%) (P=.04) for any cardiac disease, when treated without or with IM-MS lymph node irradiation. There was no evidence for differences between left- and right-sided breast cancer (Wald chi-square test of treatment by breast side interaction, P=.33 and P=.35, for cardiac fibrosis and for any cardiac disease, respectively). The cumulative incidence probabilities of cross-sectionally reported side effects with a score of 2 or greater at 15 years were 0.1% (95% CI = 0.0%–0.5%) vs. 0.8% (95% CI = 0.4%–1.4%) for pulmonary (P=.02), 1.8% (95% CI = 1.1%–2.8%) vs. 2.6% (95% CI = 1.8%–3.7%) for cardiac (P=.15), and 0.0% (95% CI not evaluated) vs. 0.1% (95% CI = 0.0%–0.4%) for oesophageal (P=.16), respectively. No difference was observed in the incidence of second malignancies, contralateral breast cancer or cardiovascular deaths. Conclusions The incidence of late pulmonary side effects was statistically significantly higher after IM-MS lymph node irradiation, as were some of the cardiac events, without a difference between left- and right-sided treatments. Absolute rates and differences were very low, without increased non-breast cancer related mortality, even before introducing heart-sparing techniques.
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