Tumour hypoxia: imaging and modification
Cells short of oxygen are up to three times harder to kill with radiation. Finding hypoxic tumours and fixing the shortage, with drugs, breathing gases or dose escalation, is one of radiobiology's oldest ideas and still unfinished business.
Overview
Gray and colleagues showed in 1953 that oxygen is needed to fix radiation damage in DNA, and hypoxic regions in bulky tumours have been blamed for treatment failure ever since. Attempts to fix it include hyperbaric oxygen, carbogen and nicotinamide breathing (the ARCON approach), hypoxic cell sensitisers such as nimorazole, hypoxia-activated prodrugs such as evofosfamide (which failed in phase 3), and hyperthermia. PET tracers such as FMISO and FAZA map hypoxia, and gene signatures now select patients in trials; dose-painting the hypoxic subvolume is being tested in head and neck cancer.
How it works
Oxygen makes radiation damage permanent, so hypoxic cells survive; measuring hypoxia and raising oxygen delivery or mimicking oxygen's action restores radiosensitivity.
- Strong biological rationale
- Imaging can select patients
- Nimorazole benefit shown in randomised trials
- Most hypoxia drugs failed in phase 3
- Hypoxia is dynamic and patchy
- Imaging not yet routine
Evofosfamide was the most advanced hypoxia-activated drug, designed to kill the oxygen-starved tumour cells radiotherapy and chemotherapy miss, but it failed both of its phase 3 trials in 2015.
Nimorazole is the one hypoxic radiosensitiser in routine use: given with radiotherapy for head and neck cancer in Denmark since the DAHANCA 5 trial improved control, and tested across Europe in patients whose tumours carry a hypoxia gene signature.
Latest papers
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