Moving Beyond the Standard of Care: Accelerate Testing of Radiation-Drug Combinations.

ABTRACT Radiotherapy is a major treatment modality used in over 60% of cancer patients, as definitive local treatment for inoperable locoregionally confined tumors and as palliative therapy. While cytotoxic chemotherapy enhances the effectiveness of treatment, the benefit over radiotherapy alone is still quite modest. There is a need to further enhance the effectiveness of local tumor control over what sequentially or concurrently administered cytotoxic chemotherapy provides. Although many biologic pathways are known to enhance the effectiveness of radiotherapy, there is currently a paucity of drugs approved for use in combination. While several clinical trials have tested the effectiveness of combining targeted agents or immunotherapies with radiotherapy, the results of these trials have so far been negative, likely stemming from the relative lack of preclinical evidence using appropriate experimental standardization or model systems. Accelerating the identification of agents tested in appropriate clinical context and experimental systems or models would greatly enhance the potential to bring forward early testing of drugs that would not only be safe but also more effective. This paper provides an overview of the opportunities and challenges of developing therapeutics to combine with radiotherapy, and some guidance towards preclinical and early clinical testing to improve the chance that advanced phase testing of drug-radiation combinations would be successful in the long run.