Significant Influence of Cardiac Radiation Dose on the Risk of Cardiotoxicity in Patients Receiving Adjuvant Trastuzumab and Radiation Therapy for Breast Cancer

Purpose: This study aimed to analyze the incidence of cancer therapy-related cardiovascular toxicity (CTRCVT) and identify the radiation dosimetric and clinical risk factors for these events in patients with human epidermal growth factor receptor 2-positive breast cancer. Methods and Materials: Data from 1378 patients who were treated with curative surgery and adjuvant trastuzumab for breast cancer were retrospectively analyzed. A total of 959 patients underwent postoperative radiation therapy (RT), whereas 419 patients were managed without RT (no-RT). CTRCVT were categorized according to the time of occurrence in relation to trastuzumab as follows: during trastuzumab cycles (CTRCVT-during T) or after completing trastuzumab (CTRCVT-after T). The cardiac radiation dose was extracted from the RT plan of each individual patient. The incidence of and contributing factors for CTRCVT-during T and -after T were evaluated. Results: After a median follow-up of 95.8 months (range, 4.3-181.1 months), 69 patients (5.0%) had experienced CTRCVT. CTRCVT-during T was detected in 41 patients (3.0%), and the 8-year rate of CTRCVT-after T was 2.2%. Of the patients developing CTRCVT-during T, 27 (2.0%) discontinued trastuzumab. The cardiac radiation doses were significantly associated with the risk of both CTRCVT-during T (odds ratio, 1.087; P =.001) and -after T (hazard ratio, 1.177; P <.001). The 8-year rates of CTRCVT-after T were not significantly different between the no-RT and RT groups (2.0% vs 2.4%, P =.956). However, the rate was significantly higher in patients with heart V_25Gy ≥3% compared with those with heart V_25Gy <3% (5.7% vs 1.5%, P =.019). Patients who received <17 cycles of trastuzumab had worse oncological outcomes than those who received ≥17 cycles. Conclusions: Both CTRCVT-during T and -after T were associated with the cardiac radiation dose. Therefore, evaluation of the cardiac radiation dose is necessary to prevent early termination of trastuzumab treatment, which could lead to worse outcomes.