**8. Unanswered questions regarding RRHD**

Variability in certain risk factors may influence the development of a radiation-associated heart disease. These factors included patients themselves, RT techniques, the evaluable endpoints, and social-psychological variables [19]. The patient-related factors include age, personal alcohol and tobacco history, systemic anticancer drugs with potential cardiac toxicities such as anthracyclines, trastuzumab, taxanes, tamoxifen, and letrozole, among others, individual sensitivity to late heart morbidity, and hereditary heart disease [19]. The definitions of the heart and its substructures are shown in **Table 1**, and the standardized delineation consensus and atlas should be consulted by radiation oncologists. For the heart and cardiac substructures, further investigation should be conducted regarding which dose-volume limitations were used during the design of radiation planning and what optimal dosimetric parameters were reported to be necessary, such as maximal or mean heart dose, V5Gy, V10Gy, V20Gy, etc. The clinical endpoints included cardiac mortality and radiation-associated clinical and subclinical heart diseases [33]. The optimal RT delivery techniques and reliable methods to evaluate these endpoints will require further studies. The designation of RRHD might unavoidably increase the psychological burden of patients. In addition, to find those patients who may develop late RRHD, health economic evaluations should be critically performed prior to the initiation of screening programs [19].


**Table 1**. Recommended delineations of the heart and substructures.
