Abstract

Standard treatment of locally advanced gynecological cancers relies mainly on platinum-based concurrent chemoradiotherapy followed by brachytherapy. Current chemotherapeutic drugs are only transiently effective and patients with advanced disease often develop resistance and subsequently, distant metastases despite significant initial responses of the primary tumor. In addition, some patients still develop local failure or progression, suggesting that there is still a place for increasing the anti-tumor radiation effect. Several strategies are being developed to increase the probability of curing patients. Vaginal cancer and vulva cancer are rare diseases, which resemble cervical cancer in their histology and pathogenesis. These gynecological cancers are predominantly associated with human papilloma virus infection. Treatment strategies in other unresectable gynecologic cancers are usually derived from evidence in locally advanced cervical cancers. In this review, we discuss mechanisms by which novel therapies could work synergistically with conventional chemoradiotherapy, from pre-clinical and ongoing clinical data. Trimodal, even quadrimodal treatment are currently being tested in clinical trials. Novel combinations derived from a metastatic setting, and being tested in locally advanced tumors, include anti-angiogenic agents, immunotherapy, tumor-infiltrating lymphocytes therapy, adoptive T-cell therapy and apoptosis inducers to enhance chemoradiotherapy efficacy through complementary molecular pathways. In parallel, radiosensitizers, such as nanoparticles and radiosensitizers of hypoxia aim to maximize the effect of radiotherapy locally.