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Biological and clinical background

Three key radiobiological parameters have been identified, which to a large degree can account for the biological heterogeneity in squamous cell carcinomas: 

  • Hypoxia
  • Tumour cell proliferation
  • Intrinsic radioresistance

Hypoxia is the parameter that has received the greatest attention in relation to biological imaging because it is a major reason for failure of radiotherapy. New imaging techniques such as PET-CT coupled with the use of specific biological tracers are now available and has formed the basis for the concept of dose painting in which radiotherapy planning is based on biological imaging and biological conformality. Also, new perfusion techniques for use with magnetic resonance imaging (MRI) have been developed for quantification of hypoxic poor perfusion regions in solid tumour.
Hypoxia and tumour cell proliferation are now firmly established as important factors for clinical radioresistance in squamous cell carcinoma of the head and neck. The DAHANCA trials ( have demonstrated that the risk of loco-regional failure and death is significantly reduced in the overall patient cohort when these parameters are modified, thus increasing the loco-regional 5-year tumour control from 22% to 60% and the disease specific 5-year survival from 35% to 62%. However, it has become clear that hypoxia and tumour cell proliferation are not equally important in all patients, and that there are individual variations. Non-invasive assays for hypoxia imaging, Dynamic Contrast Enhanced-MRI, and PET-CT using hypoxic tracers such as 18FAZA and 18FMISO, have been developed.

Recent technological development has improved significantly our possibilities to individualize radiotherapy dose distributions to match the 3-D tumour shape. The currently applied technology is commonly described as intensity-modulated radiotherapy (IMRT) as it involves beams with varying intensity across the fields. Furthermore, a 2nd generation dose conformation technique, so-called intensity modulated arc therapy (IMAT), is currently being developed. These techniques have shown great potential to improve normal tissue avoidance, tumour coverage and dose sculpting abilities and thus enable tumour dose escalation. In spite of our ability to shape the dose to the tumour, geometrical and anatomical uncertainties have until recently severely restricted the treatment accuracy actually obtained as all RT delivery has been based on the patient anatomy as seen in a single pre-treatment CT study (i.e., a snapshot of the internal anatomy). Such uncertainties have an adverse effect on the treatment of most tumour sites, e.g. in the treatment of abdominal and pelvic tumour sites where internal organ motion takes place at various time scales – from seconds (circulation and ventilation) to minutes (bladder and intestinal filling) – and in the treatment of head-and-neck cancer where tumour shrinkage and weight loss – occurring over days and weeks – causes changes in the external and internal patient geometry. These uncertainties are today accounted for by irradiating a safety volume outside the target, leading to increased normal tissue doses. Technological solutions are now being developed to actively account for these factors, allowing for adaptive image-guided RT (IGRT), covering daily on-line volumetric imaging for treatment correction and ultimately treatment adaptation, 4D CT scanning, gating of treatment according to the ventilation cycle and MCL-tracking based on soft-tissue/marker imaging.