Realistic biological approaches for improving thermoradiotherapy.

There is now definitive clinical evidence that hyperthermia can successfully improve the response of certain human tumour types to radiation therapy, but, there is still the need for improvement. From a biological standpoint this can be achieved by either targeting the cellular or vascular components of tumours. Strategies include targeting the radiation DNA repair processes, improving drug delivery using nanoparticles, exploiting immunotherapy mechanisms, reducing tumour pH, or modifying the tumour vascular supply. All of these approaches have been combined with either hyperthermia or radiation in preclinical models and clear benefits in tumour response observed. But few of these methods have actually been combined with thermoradiotherapy. Furthermore, very few combinations have been tested in relevant normal tissue studies, despite the fact that it is the normal tissue response that controls the maximal heat or radiation treatment that can be applied. Here we review the most clinically relevant biological approaches that have been shown to enhance thermoradiotherapy, or have the potential to be applied in this context, and suggest how these should be moved forward into the clinic.