Prevention of radiation induced cardiotoxicity in patients with left sided breast cancer: results from a phase 2 clinical trial

Background Adjuvant radiotherapy (RT) is an essential component of the optimal management of breast cancer (BC). However, RT-induced risk of cardiac toxicity is a major concern for patients with left sided BC as they are at twice the risk compared to right sided BC. Modern RT-planning techniques that include deep inspiratory breath holding (DIBH) have the potential to mitigate radiation associated cardiotoxicity. Purpose To evaluate the impact of DIBH on cardiac magnetic resonance (CMR) measures of cancer therapy related cardiac dysfunction (CTRCD) in women with left sided breast cancer treated with adjuvant RT in a phase II clinical trial. Methods Eligible patients underwent either free breathing (FB) or DIBH treatment delivery, if the predicted mean heart RT dose was <5 Gy or >5 Gy, respectively. Those eligible for DIBH and FB RT without prior exposure to anthracyclines or trastuzumab (CH) were allocated to cohort I and II respectively, and those receiving DIBH RT with prior exposure to CH were placed in cohort III. Non-contrast CMR scans were acquired at pre-RT and at 16 weeks and 52 weeks post completion of RT to assess left ventricular ejection fraction (LVEF) and LV global longitudinal strain (GLS). CTRCD was defined according to ESC 2022 Cardio-Oncology guidelines with asymptomatic moderate CTRCD defined as a new reduction in LVEF by ≥ 10% to an LVEF of 40-49% and mild CTRCD defined as LVEF ≥ 50% and a new reduction in GLS > 15% from baseline. Change in LV function and CTRCD were compared between groups at 16 and 52 weeks using ANOVA or Chi-square statistics. Results 25 patients received DIBH-RT (cohort 1), 21 received FB-RT (cohort II) and 23 had adjuvant CH prior to DIBH-RT (cohort III). There were significant age differences between cohorts, but baseline LVEF and LV GLS were not significantly different (Table). Mean and maximum heart and LV radiation doses were similar between cohorts (Table). There were no significant changes in LVEF at 16 and 52 weeks and no cases of asymptomatic moderate CTRCD in any of the cohorts. At 16 weeks, mean LV GLS was similar between cohorts but improved from baseline in cohort 1 relative to cohorts 2 and 3, -4.6 ± 15.4% vs. +9.8 ± 8.9 and +4.2 ± 15.4, respectively, p=0.004 (Table, Figure). There were also no cases of mild CTRCD at 16 weeks in cohort 1 compared to 5 in cohort 2 and 6 in cohort 3, p=0.034. The observed group differences in LV GLS and mild CTRCD persisted at 52 weeks. On multivariable regression analysis, baseline LV GLS and maximum heart radiation dose were significant predictors of change in LV GLS at 16 weeks. Conclusions In patients with left-sided breast cancer, mild CTRCD was observed in patients exposed to FB-RT or DIBH-RT plus chemotherapy but not following DIBH-RT alone. Factors predicting change in LV GLS included baseline LV GLS and maximum heart radiation dose.Table Figure