Reduced oxygen levels (hypoxia) is one of the most important factors influencing clinical outcome after radiotherapy. This is primarily because hypoxic cells are resistant to radiation treatment; hence, the greater the number of clonogenic cancer stem cells that exist under hypoxia, the lower the local tumour control. Reduced local control will influence overall survival, as may the hypoxic conditions by increasing malignant progression; however, to fight hypoxia, we should first be able to see it. We need noninvasive approaches that can accurately and reliably image hypoxia in tumours, especially using techniques that are routinely available in the clinic, such as PET, MRI and CT. All these imaging methods are already under clinical evaluation in this context. Such data should allow us to identify those patients on an individual basis who have hypoxic tumours and, thus, at the very least should receive some form of hypoxic modifier in conjunction with radiotherapy. Alternatively, the radiation dose could be either increased to the whole tumour or, if the imaging is accurate enough, only to the hypoxic subvolumes. The aim of this Review is to critically assess the potential use of imaging to help improve clinical outcome to radiotherapy.

This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC.

LET-painting was suggested as a method to overcome tumour hypoxia. In vitro experiments have demonstrated a wellestablished relationship between the oxygen enhancement ratio (OER) and linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation also increases the risk for side effects in normal tissue. LET-painting attempts to restrict high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues. Methods. Carbon-12 and oxygen-16 ion treatment plans with four fi elds and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identifi ed hypoxic entity within the tumour. The target dose is optimised to achieve a tumour control probability (TCP) of 95% when assuming a fully normoxic tissue. Using the same primary particle energy fl uence needed for this plan, TCP is recalculated for three cases assuming hypoxia: fi rst, redistributing LET to match the hypoxic structure (LET-painting). Second, plans are recalculated for varying hypoxic tumour volume in order to investigate the threshold volume where TCP can be established. Finally, a slight dose boost (5-20%) is additionally allowed in the hypoxic subvolume to assess its impact on TCP. Results. LET-painting with carbon-12 ions can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm 3. Using oxygen-16 ions, tumour control can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm 3. Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting. Conclusion. Our fi ndings clearly indicate that a substantial increase in tumour control can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost.

Technical validation of the 15-gene hypoxia classifier demonstrated that it is suitable for implementation in prospective clinical trials.

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