Clinical Trial Strategies to Compare Protons With Photons

The favorable beam properties of protons can be translated into clinical benefits by target dose escalation to improve local control without enhancing unacceptable radiation toxicity or to spare normal tissues to prevent radiation-induced side effects without jeopardizing local tumor control. For the clinical validation of the added value of protons to improve local control, randomized controlled trials are required. For the clinical validation of the added value of protons to prevent side effects, both model-based validation or randomized controlled trials can be used. Model-based patient selection for proton therapy is crucial, independent of the validation approach. Combining these approaches in rapid learning health care systems is expected to yield the most efficient and scientifically sound way to continuously improve patient selection and the therapeutic window, eventually leading to more cancer survivors with better quality of life.