Side Effects 15 Years After Lymph Node Irradiation in Breast Cancer: Randomized EORTC Trial 22922/10925

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- A nd 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- A nd right-sided treatments. Absolute rates and differences were very low, without increased non-breast cancer-related mortality, even before introducing heart-sparing techniques

The association of internal mammary and medial supraclavicular lymph node radiation technique with clinical outcomes: Results from the EORTC 22922/10925 randomised trial.

The multicentre EORTC 22922/10925 trial (ClinicalTrials.gov, NCT00002851) was conducted between 1996 and 2004. The trial evaluated the effect of irradiation of the internal mammary and medial supraclavicular lymph node chains (IM-MS) vs no further radiation therapy (RT) on survival and cause of death in breast cancer stage I-III patients. At 15.7 years of median follow-up, a significant reduction of breast cancer specific mortality (BCSM) and any recurrence, not translating in improved overall survival (OS), and low absolute rates of side effects were found. The aim of the current analysis was to evaluate the association of RT techniques of IM-MS lymph node irradiation with long-term outcomes. Three RT techniques were used for IM-MS: a standard technique using a fixed set-up combining photon/electron beams to the IM and tangential fields to the breast or chest wall vs a standard-modified technique with minor adaptation for beam settings vs a more individualised technique based on individual localisation of the IM. Techniques used were fixed per institution over the duration of the trial. We performed an exploratory and descriptive analysis of the outcomes after 15 years follow-up for the three RT techniques. Between July 1996 and January 2004, 46 radiation oncology departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. The number of patients treated by each technique was 2440 (61%) by standard vs 635 (16%) by standard-modified vs 929 (23%) patients by individualised technique. The absolute improvements of oncological outcomes in terms of disease-free survival (DFS), OS and BCSM with IM-MS RT compared to no IM-MS RT were 6.8%, 4.9% and -5.8% for the individualised technique, vs 1.6%, 2.9% and -4.3% for modified standard and -1.4%, 1.1% and -3% for standard technique, respectively. The increase in 15-year rates of side effects due to IM-MS RT, both scored longitudinally and cross-sectionally, were similar among the techniques. Even though a straightforward comparison by technique is not possible because of variations in baseline characteristics between institutions, our findings suggest that the use of more individualised RT techniques is associated with higher rates of oncological improvements without increased risks for late side effects

Side Effects 15 Years After Lymph Node Irradiation in Breast Cancer: Randomized EORTC Trial 22922/10925.

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. 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. 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. 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

Mapping the location of local and regional recurrences according to breast cancer surgery and radiation therapy: Results from EORTC 22922/10925

The purpose of this study is to evaluate the influence of the extent of surgery and radiation therapy (RT) on the rates and sites of local (LR) and regional recurrences (RR) in the EORTC 22922/10925 trial. PATIENTS AND METHODS All data were extracted from the trial's individual patients' case report forms (CRF) and analysed with a median follow-up of 15.7 years. Cumulative incidence curves were produced for LR and RR accounting for competing risks: an exploratory analysis of the effect of the extent of surgical and radiation treatments on LR rate was conducted using the Fine & Gray model accounting for competing risks and adjusted for baseline patient and disease characteristics. The significance level was set at 5%, 2-sided. Frequency tables were used to describe the spatial location of LR and RR. RESULTS Out of 4004 patients included in the trial, 282 (7%) patients experienced LR and 165 (4.1%) RR, respectively. Cumulative incidence rate of LR at 15 years was lower after mastectomy (3.1%) compared to BCS + RT (7.3%) (F&G: HR (Hazard Ratio) = 0.421, 95%CI = 0.282-0.628, p-value < 0.0001). LR were similar up to 3 years for both mastectomy and BCS but continued to occur at a steady rate for BCS + RT, only. The spatial location of the recurrence was related to the locoregional therapy applied and the absolute gain of RT correlated to stage of disease and extent of surgery. CONCLUSIONS The extent of locoregional therapies impacts significantly on LR and RR rates and spatial location