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

Abstract

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.

Determinants of Sensitivity to Radiotherapy in Endometrial Cancer

“…There, it is shown that the efficacy of low doses of fractionated RT can be enhanced when delivered in combination with antibodies against PD-1 and PD-L1 [ 87 ]. Currently, there are several ongoing clinical trials in patients with advanced uterine cancers testing monoclonal antibodies against key immune checkpoint inhibitors, such as durvalumab (PD-1), pembrolizumab (PD-1), tremelimumab (CTLA-4) or TSR-042 (PD-1), administrated simultaneously or sequentially to RT [ 88 ].…”

New small‐molecule compound Hu‐17 inhibits estrogen biosynthesis by aromatase in human ovarian granulosa cancer cells

“…3,4 Surgery followed by chemotherapy is currently the standard therapy for ovarian cancers. 5 Platinum-based drugs (e.g., cisplatin and carboplatin) and paclitaxel are traditional first-line therapies. 6,7 Although ovarian cancer diagnosed in the early stage may be treated successfully, as the disease progresses, most advanced-stage patients develop resistance to first-line drugs.…”

“…Ovarian cancer is the second most commonly diagnosed cancer in women worldwide, 2 and the mortality rate is worse than other reproductive cancers because of difficulty in early diagnosis 3,4 . Surgery followed by chemotherapy is currently the standard therapy for ovarian cancers 5 . Platinum‐based drugs (e.g., cisplatin and carboplatin) and paclitaxel are traditional first‐line therapies 6,7 .…”

Innovation abounds in cancer therapy

“…Several of the mentioned ongoing clinical trials are supported by rationale that exploits ‘in-field’ tumor–tissue interactions of radiotherapy and various biological agents. Since radiotherapy can cause direct injury to tumor DNA, many of the most promising strategies are directed at perturbation of high-fidelity DNA damage response (DDR) repair 9. Although mechanistically, inhibition of DNA damage response elements and cell-cycle checkpoints appear to have differing levels of individual lethality, their combination with radiotherapy increases the probability of success through sensitization or modality–drug synergy.…”

“…It is in this latter case that the availability of specific immune checkpoint inhibitors, such as those targeting PD-1/PD-L1, have changed the landscape of systemic therapy for a number of solid tumors, including gynecologic cancer. Lin and colleagues outline these effects and strategies nicely in their review 9. Perhaps one of the most intriguing effects is that related to remote tumor control following localized radiation - termed the ‘abscopal’ (or ab scopal, ‘away from target’) effect.…”