The Therapeutic Potential of Imidazole or Quinone-Based Compounds as Radiosensitisers in Combination with Radiotherapy for the Treatment of Head and Neck Squamous Cell Carcinoma.

Abstract

Simple SummaryPatients with curable head and neck cancers are usually treated with a combination of chemotherapy and radiotherapy, but they experience significant, severe side effects, which greatly affect their quality of life. Some of these patients still experience disease relapse after an intensive course of treatment due to tumours that are resistant to radiotherapy and chemotherapy because of hypoxia (lack of oxygen). In addition, some patients are not suitable for and/or are not able to have combined chemotherapy with radiotherapy due to their age or other physical conditions. Certain small-molecule drugs, which are used to treat various infections including malaria, have been shown to reduce hypoxia and thus make radiotherapy more effective. Therefore, their combination with radiotherapy could have less toxicities compared with the combination of chemotherapy with radiotherapy. Here, we discuss the promising results from preclinical work and clinical trials of these agents, and their potential use in the clinic, to reduce hypoxia and to sensitise radiotherapy. These agents could potentially be used for patients who are not suitable for combined chemotherapy and radiotherapy; they may also be used to reduce the dose of radiotherapy if able to enhance radiotherapy effect at lower dose in order to reduce toxicities while maintaining the treatment efficacy in a more personalised manner. The addition of platinum chemotherapy to primary radiotherapy (chemoradiation) improves survival outcomes for patients with head and neck squamous cell carcinoma (HNSCC), but it carries a high incidence of acute and long-term treatment-related complications, resulting in a poor quality of life. In addition, patients with significant co-morbidities, or older patients, cannot tolerate or do not benefit from concurrent chemoradiation. These patients are often treated with radiotherapy alone resulting in poor locoregional control and worse survival outcomes. Thus, there is an urgent need to assess other less toxic treatment modalities, which could become an alternative to chemoradiation in HNSCC. Currently, there are several promising anti-cancer drugs available, but there has been very limited success so far in replacing concurrent chemoradiation due to their low efficacy or increased toxicities. However, there is new hope that a treatment strategy that incorporates agents that act as radiosensitisers to improve the efficacy of conventional radiotherapy could be an alternative to more toxic chemotherapeutic agents. Recently, imidazole-based or quinone-based anti-malarial compounds have drawn considerable attention as potential radiosensitisers in several cancers. Here, we will discuss the possibility of using these compounds as radiosensitisers, which could be assessed as safe and effective alternatives to chemotherapy, particularly for patients with HNSCC that are not suitable for concurrent chemotherapy due to their age or co-morbidities or in metastatic settings. In addition, these agents could also be tested to assess their efficacy in combination with immunotherapy in recurrent and metastatic settings or in combination with radiotherapy and immunotherapy in curative settings.