Combining novel agents with radiotherapy for gynecologic malignancies: beyond the era of cisplatin

Therapeutic strategies combining radiation therapy with novel agents have become an area of intense research focus in oncology and are actively being investigated for a wide range of solid tumors. The mechanism of action of these systemic agents can be stratified into three general categories: (1) enhancement or alteration of the immune system; (2) disruption of DNA damage response mechanisms; and (3) impediment of cellular signaling pathways involving growth, angiogenesis, and hypoxia. Pre-clinical data suggest that radiation therapy has immunogenic qualities and may optimize response to immuno-oncology therapies by priming the immune system, whereas other novel systemic agents can enhance radiosensitivity through augmentation of genomic instability and alteration of central signaling pathways related to growth and survival. Gynecologic cancers in particular have the potential for synergistic response to combination approaches incorporating radiation therapy and novel systemic therapies. Several clinical trials have been proposed to elucidate the efficacy and safety of such approaches. Here we discuss the mechanisms of novel therapies and the rationale for these combination strategies, reviewing the relevant pre-clinical and clinical data. We explore their optimal use with respect to indications, interactions, and potential synergy in combination with radiation therapy and review ongoing trials and active areas of investigation.