Philip M Poortmans1,2, Henk Struikmans3, Peter De Brouwer4, Caroline Weltens5, Catherine Fortpied6, Carine Kirkove7, Volker Budach8, Karine Peignaux-Casasnovas9, Femke van der Leij10, Ernest Vonk11, Mariacarla Valli12, Geertjan vanTienhoven13, Nicola Weidner14, Georges Noel15, Matthias Guckenberger16, Eveline Koiter17, Erik vanLimbergen5, Antoine Engelen4, Alain Fourquet18, Harry Bartelink19. 1. Department of Radiation Oncology, Iridium Netwerk, Wilrijk-Antwerp, Belgium. 2. Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk-Antwerp, Belgium. 3. Department of Radiation Oncology, Leiden University Medical Centre, Leiden, the Netherlands. 4. Department of Radiation Oncology, Institute Verbeeten, Tilburg, the Netherlands. 5. Department of Radiation Oncology, University Hospital Leuven, KU Leuven Faculty of Medicine, Leuven, Belgium. 6. European Organisation for Research and Treatment of Cancer (EORTC), Headquarters, Brussels, Belgium. 7. Department of Radiation Oncology, University Hospital Saint Luc, Université Catholique de Louvain, Brussels, Belgium. 8. Department of Radiation Oncology, Charité-Universitaetsmedizin Berlin, Free University Berlin, Humboldt-University Berlin, Berlin Institute of Health, Berlin, Germany. 9. Department of Radiation Oncology, Centre Georges François Leclerc, Dijon, France. 10. Department of Radiation Oncology, University Medical Centre Utrecht, Utrecht, the Netherlands. 11. Institute for Radiation Oncology RISO, Deventer, the Netherlands. 12. Department of Radiation Oncology, Sant Anna Hospital, Como, Italy. 13. Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands. 14. Department of Radiation Oncology, University Hospital, Tübingen, Germany. 15. Department of Radiation Oncology, Centre Paul Strauss, Strasbourg, France. 16. Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. 17. Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands. 18. Department of Radiation Oncology, Institut Curie, Paris, France. 19. Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Abstract
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 multicenter European Organization for Research and Treatment of Cancer trial (ClinicalTrials.gov, NCT00002851) randomly assigned 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% to 3.8%) vs 5.7% (95% CI = 4.7% to 6.9%) (P < .001) for lung fibrosis, 1.1% (95% CI = 0.7% to 1.7%) vs 1.9% (95% CI = 1.3% to 2.6%) (P = .07) for cardiac fibrosis, and 9.4% (95% CI = 8.0% to 10.8%) vs 11.1% (95% CI = 9.6% to 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 χ2 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% to 0.5%) vs 0.8% (95% CI = 0.4% to 1.4%) for pulmonary (P = .02), 1.8% (95% CI = 1.1% to 2.8%) vs 2.6% (95% CI = 1.8% to 3.7%) for cardiac (P = .15), and 0.0% (95% CI not evaluated) vs 0.1% (95% CI = 0.0% to 0.4%) for esophageal (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.
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 multicenter European Organization for Research and Treatment of Cancer trial (ClinicalTrials.gov, NCT00002851) randomly assigned 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% to 3.8%) vs 5.7% (95% CI = 4.7% to 6.9%) (P < .001) for lung fibrosis, 1.1% (95% CI = 0.7% to 1.7%) vs 1.9% (95% CI = 1.3% to 2.6%) (P = .07) for cardiac fibrosis, and 9.4% (95% CI = 8.0% to 10.8%) vs 11.1% (95% CI = 9.6% to 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 χ2 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% to 0.5%) vs 0.8% (95% CI = 0.4% to 1.4%) for pulmonary (P = .02), 1.8% (95% CI = 1.1% to 2.8%) vs 2.6% (95% CI = 1.8% to 3.7%) for cardiac (P = .15), and 0.0% (95% CI not evaluated) vs 0.1% (95% CI = 0.0% to 0.4%) for esophageal (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.