Novel treatment planning approaches to enhance the therapeutic ratio: targeting the molecular mechanisms of radiation therapy.

Radiation acts not only through cell death but has also angiogenic, immunomodulatory and bystander effects. The realization of its systemic implications has led to extensive research on the combination of radiotherapy with systemic treatments, including immunotherapy and antiangiogenic agents. Parameters such as dose, fractionation and sequencing of treatments are key determinants of the outcome. However, recent high-quality research indicates that these are not the only radiation therapy parameters that influence its systemic effect. To effectively integrate systemic agents with radiation therapy, these new aspects of radiation therapy planning will have to be taken into consideration in future clinical trials. Our aim is to review these new treatment planning parameters that can influence the balance between contradicting effects of radiation therapy so as to enhance the therapeutic ratio.