The measurement and modification of hypoxia in colorectal cancer: overlooked but not forgotten.

Tumour hypoxia is the inevitable consequence of a tumour's rapid growth and disorganized, inefficient vasculature. The compensatory mechanisms employed by tumours, and indeed the absence of oxygen itself, hinder the ability of all treatment modalities. The clinical consequence is poorer overall survival, disease-free survival, and locoregional control. Recognizing this, clinicians have been attenuating the effect of hypoxia, primarily with hypoxic modification or with hypoxia-activated pro-drugs, and notable success has been demonstrated. However, in the case of colorectal cancer (CRC), there is a general paucity of knowledge and evidence surrounding the measurement and modification of hypoxia, and this is possibly due to the comparative inaccessibility of such tumours. We specifically review the role of hypoxia in CRC and focus on the current evidence for the existence of hypoxia in CRC, the majority of which originates from indirect positron emission topography imaging with hypoxia selective radiotracers; the evidence correlating CRC hypoxia with poorer oncological outcome, which is largely based on the measurement of hypoxia inducible factor in correlation with clinical outcome; the evidence of hypoxic modification in CRC, of which no direct evidence exists, but is reflected in a number of indirect markers; the prognostic and monitoring implications of accurate CRC hypoxia quantification and its potential in the field of precision oncology; and the present and future imaging tools and technologies being developed for the measurement of CRC hypoxia, including the use of blood-oxygen-level-dependent magnetic resonance imaging and diffuse reflectance spectroscopy.