Background and purpose: Ultra-hypofractionated whole breast irradiation (WBI) following breast-conserving surgery (BCS) is increasingly adopted as standard of care. However, its potential impact on subclinical myocardial function remains poorly characterised. The SAFE-FORWARD study (NCT04842409) prospectively investigated early cardiac effects of the 26 Gy in five fractions regimen using advanced echocardiographic techniques. Materials and methods: Fifty women with early-stage breast cancer (median age 67 years) were enrolled and received postoperative WBI to 26 Gy in five fractions. The primary endpoint was the detection of subclinical myocardial impairment at 12 months, defined as a ≥ 10 % decline from baseline in at least one of the following parameters: three-dimensional left or right ventricular ejection fraction (3D-LVEF, 3D-RVEF), left ventricular global longitudinal strain (LV-GLS), or right ventricular free wall longitudinal strain (RV-FWLS). Echocardiography was performed at baseline, and at 2, 6, and 12 months post-WBI. Cardiac substructures were delineated for dosimetric correlation. Adverse events were recorded using CTCAE v5.0. Results: No patient met the predefined criteria for subclinical myocardial impairment. Mean baseline 3D-LVEF was 64.1 % (±3.1) and remained stable at 12 months (63.1 %, ±2.9; p = 0.97). LV-GLS showed no significant change from baseline (–20.5 % ± 1.8) to 12 months (–20.3 % ± 1.6; p = 0.34). 3D-RVEF and RV-FWLS remained unchanged throughout follow-up. A modest but statistically significant increase in LV end-diastolic volume index (LV-EDVI) was observed at 12 months in patients receiving left-sided WBI, without correlation to dosimetric parameters. Mean heart dose was 0.73 Gy (0.94 Gy for left-sided cases). No grade ≥ 3 adverse events occurred. The most common acute toxicities were grade 1 radiodermatitis (32 %) and fatigue (28 %). At 48 months’ median follow-up, all patients were alive, with one ipsilateral and three contralateral breast events reported. Conclusion: Ultra-hypofractionated WBI using the FAST-Forward schedule was not associated with early subclinical myocardial dysfunction. These prospective findings support the cardiac safety of this regimen and may inform future cardio-oncology surveillance strategies.
Cardiac safety of ultra-hypofractionated whole breast irradiation: Results from the SAFE-FORWARD observational prospective cohort study / Salvestrini V.; Marrazzo L.; Barletta G.; Becherini C.; Visani L.; Valzano M.; Desideri I.; Francolini G.; Caprara L.; Mattioli C.; Bertini N.; Petruccioli C.; Simontacchi G.; Nori Cucchiari J.; Orzalesi L.; Bianchi S.; Del Bene M.R.; Pallotta S.; Livi L.; Meattini I.. - In: RADIOTHERAPY AND ONCOLOGY. - ISSN 0167-8140. - ELETTRONICO. - 214:(2026), pp. 111267.0-111267.0. [10.1016/j.radonc.2025.111267]
Cardiac safety of ultra-hypofractionated whole breast irradiation: Results from the SAFE-FORWARD observational prospective cohort study
Marrazzo L.;Barletta G.;Desideri I.;Bertini N.;Orzalesi L.;Bianchi S.;Pallotta S.;Livi L.;Meattini I.
2026
Abstract
Background and purpose: Ultra-hypofractionated whole breast irradiation (WBI) following breast-conserving surgery (BCS) is increasingly adopted as standard of care. However, its potential impact on subclinical myocardial function remains poorly characterised. The SAFE-FORWARD study (NCT04842409) prospectively investigated early cardiac effects of the 26 Gy in five fractions regimen using advanced echocardiographic techniques. Materials and methods: Fifty women with early-stage breast cancer (median age 67 years) were enrolled and received postoperative WBI to 26 Gy in five fractions. The primary endpoint was the detection of subclinical myocardial impairment at 12 months, defined as a ≥ 10 % decline from baseline in at least one of the following parameters: three-dimensional left or right ventricular ejection fraction (3D-LVEF, 3D-RVEF), left ventricular global longitudinal strain (LV-GLS), or right ventricular free wall longitudinal strain (RV-FWLS). Echocardiography was performed at baseline, and at 2, 6, and 12 months post-WBI. Cardiac substructures were delineated for dosimetric correlation. Adverse events were recorded using CTCAE v5.0. Results: No patient met the predefined criteria for subclinical myocardial impairment. Mean baseline 3D-LVEF was 64.1 % (±3.1) and remained stable at 12 months (63.1 %, ±2.9; p = 0.97). LV-GLS showed no significant change from baseline (–20.5 % ± 1.8) to 12 months (–20.3 % ± 1.6; p = 0.34). 3D-RVEF and RV-FWLS remained unchanged throughout follow-up. A modest but statistically significant increase in LV end-diastolic volume index (LV-EDVI) was observed at 12 months in patients receiving left-sided WBI, without correlation to dosimetric parameters. Mean heart dose was 0.73 Gy (0.94 Gy for left-sided cases). No grade ≥ 3 adverse events occurred. The most common acute toxicities were grade 1 radiodermatitis (32 %) and fatigue (28 %). At 48 months’ median follow-up, all patients were alive, with one ipsilateral and three contralateral breast events reported. Conclusion: Ultra-hypofractionated WBI using the FAST-Forward schedule was not associated with early subclinical myocardial dysfunction. These prospective findings support the cardiac safety of this regimen and may inform future cardio-oncology surveillance strategies.
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