Targeting Tumor Hypoxia

Hypoxia (oxygen levels below 1–2%) is a common finding in solid tumors. The development of tumor hypoxia can be viewed as an imbalance between oxygen supply and demand. Tumor hypoxia significantly impacts tumor radiosensitivity and subsequently leads to poor clinical outcomes in patients treated with radiation therapy. The presence of molecular oxygen supports the production of lethal DNA damage in irradiated cells; therefore, the radiation dose required under severely hypoxic conditions to achieve a certain biological effect is generally 2- to 3-fold higher than the dose needed under normoxic conditions (i.e., oxygen enhancement ratio (OER) = 2–3). Several therapeutic approaches have been historically used and are emerging to target tumor hypoxia in order to improve radiation therapy outcomes. These include hyperbaric oxygen, correction of anemia, combination of radiation with carbogen and nicotinamide (ARCON), oxygen mimetics such as nimorazole, hypoxia-activated prodrugs, vascular normalization strategies (reviewed in Chap. 12), and emerging therapies to target tumor oxidative phosphorylation. Even though tumor hypoxia has long been established as a negative factor for radiation therapy outcomes in the clinic, we still lack robust, widely available, and adequately validated biomarkers for assessing tumor hypoxia in patients. This has not only significantly impeded the investigation of the efficacy of hypoxia modifiers, but it has also resulted in an inability to accurately select patients who are likely to benefit from such treatment. It is likely that only when hypoxia biomarkers are widely available will hypoxia modification enter the era of personalized medicine and improve outcomes.