Radiotherapy considerations and strategic approaches in phase I trials

Cellular damage by ionizing radiation relies on time to consider DNA damage, repair, reoxygenation, repopulation and redistribution. This means that both tumor kill and toxicity must be considered differently in phase I trials than those from drugs, and the combination of targeted agents and immunotherapy agents with radiation must also be carefully considered. Additionally, timing and logistics of radiation therapy may cause delays or interruptions in phase I study designs in combination with drugs that must also be carefully considered when designing trials. Dose limiting toxicity trials and maximum tolerated dose trials including RT may require longer follow up to fully evaluate toxicity. Adaptive phase I trial designs that consider longer term toxicity in their study design are advantageous for this purpose.