How the histological structure of some lung cancers shaped almost 70 years of radiobiology

Pivotal research led by Louis Harold Gray in the 1950s suggested that oxygen plays a vital role during radiotherapy. By proving that tumours have large necrotic cores due to hypoxia and that hypoxic cells require significantly larger doses of ionising radiation to achieve the same cell kill, Thomlinson and Gray inspired the subsequent decades of research into better defining the mechanistic role of molecular oxygen at the time of radiation. Ultimately, the work pioneered by Thomlinson and Gray led to numerous elegant studies which demonstrated that tumour hypoxia predicts for poor patient outcomes. Furthermore, this subsequently resulted in investigations into markers and measurement of hypoxia, as well as modification strategies. However, despite an abundance of pre-clinical data supporting hypoxia-targeted treatments, there is limited widespread application of hypoxia-targeted therapies routinely used in clinical practice. Significant contributing factors underpinning disappointing clinical trial results include the use of model systems which are more hypoxic than human tumours and a failure to stratify patients based on levels of hypoxia. However, translating the original findings of Thomlinson and Gray remains a research priority with the potential to significantly improve patient outcomes and specifically those receiving radiotherapy.