480
Views
1
CrossRef citations to date
0
Altmetric
Editorial

Imaging radiation biology for optimised radiation therapy

, , &
Pages 729-731 | Received 09 Jun 2009, Accepted 15 Jun 2009, Published online: 22 Sep 2009

Imaging has always been a major prerequisite for radiation therapy and developments in radiation oncology have been interdigitated with more advanced techniques to visualise the target as accurately as possible. Multiplanar projection radiography, sometimes supported by invasive techniques, permitted a rough depiction of pathology and treatment planning but had to be supplemented by comprehensive clinical knowledge of common pathways of tumour spread and prognosis. Target localisation was significantly improved by computed tomography (CT), preferably including contrast-enhanced series allowing for better lesion differentiation and detection. Today, due to better soft tissue contrast, magnetic resonance imaging (MRI) is a reference standard for radiotherapy target definition of cancers of the head and neck, cervix and prostate; however, this still means anatomy-based treatment planning. These developments have led to significant improvements of target coverage and normal tissue sparing, thereby improving the therapeutic ratio of radiation oncology. Further improvements are expected from the use of dedicated in-room imaging techniques that allow taking tumour and organ movements during radiotherapy into consideration.

Beyond anatomical-morphological information, imaging of tumour biology is expected to substantially enhance options for individualisation of radiotherapy. Over the last decade radiation oncologists have increasingly included positron emission tomography (PET) into therapeutic decision making, treatment planning and monitoring. Most studies so far use glucose metabolism as a general surrogate marker for hallmarks of malignancy. More recently more specific tracers such as hypoxia markers have been introduced into preclinical, physical-planning and early clinical studies to finesse the planning clinical target volume and to visualise potential sub-regions of radioresistance or to monitor early treatment response. Other functional techniques to assess the tumour microenvironment including diffusion weighted imaging (DWI) by MRI and tumour perfusion assessment by MRI and CT to visualise vascularity and tumour lacunarity (i.e., spatial heterogeneity) are on the horizon and will without doubt contribute further to this avenue of research.

The verification of imaging data with histopathologically defined tumour borders in the field of clinical radiation therapy has always been a challenge. The key issue for radiation therapy in patients, namely to tell where and ‘how’ the tumour is, has been tackled only by a small number of clinical researchers in the field of imaging and there is still a great need for such investigations. Before assessing histology for correlation, from a clinical imaging point of view, three major and somewhat overlapping tumour characteristics may be distinguished: (1) Morphology, delivering size and relative position, (2) functional information, i.e., blood volume or water mobility, with yet not completely unfolded importance, and (3) metabolism, e.g., glucose turnover and hypoxia being currently under intensive investigation. These questions require fusion of imaging with histological and tumour biological data. Despite progress in hard- and software development this continues to be a formidable task necessitating multidisciplinary and multiprofessional approaches. However, even if biological imaging information obtained with different state-of-the-art techniques could be fused and anatomically exactly localised, this information must still be related to outcome to address its biological and clinical importance. Finally such preclinical or clinical outcome studies need to include interventions to establish the potential of a novel bioimaging technique as a predictor for individualised tailoring of radiotherapy.

Researchers from all over the world and representing all relevant disciplines gathered last year in the summer to discuss the results of their investigations on the relevance of imaging in this field. The workshop on ‘New Developments in Molecular Imaging for Translational Research for Clinical Applications’, held in Dresden from 19–21 June 2008, provided new insights into current imaging focused on the application of radiation biology to radiation therapy. It was organised by OncoRay (Radiation Research in Oncology), Carl Gustav Carus Medical Faculty and University Clinics, Dresden University of Technology, Dresden, Germany; Gray Institute for Radiation Oncology & Biology (ROB), Radiobiology Research Institute, Churchill Hospital, Oxford, UK and STTARR (Spatio-Temporal Targeting and Amplification of Radiation Response) from Toronto, and Princess Margaret Hospital, Toronto, Canada, in cooperation with the Interdisciplinary German Network Molecular Imaging and gave a broad, translational and highly focused overview of imaging in the field. This issue of International Journal of Radiation Biology covers major research discussed during this highly recognised workshop.

A starting point of the discussion was basic research on DNA repair after radiation by Bhogal et al. Robert Bristow and his group investigated repair foci by microscopic imaging in normal tissues. Visualisation of these therapeutic effects demonstrates one subject of imaging research in this field: to show the localisation of foci in tissue is the first task, colocalisation with nuclei or different types of chromatin is the next challenge, even for high resolution microscopy. Laser scanning microscopy could resolve spatial distribution of fluorescence, but might not be available for high throughput investigations and is biased by tumour hypoxia and proliferation.

Microscopic colocalisation is similar to rigid fusion of images in the way that in both processes fiducial markers are preferably utilised to optimise registration. A new concept of fusing multiple histological images demonstrating different characteristics of vascularisation was presented by Tokalov et al. The authors showed how difficulties in registration of images with highly specific probes can be addressed to achieve correct rigid co-localisation. The presented technique provides accurate fusion of light and fluorescent imaging received during multistep microscopy imaging analysis and may be applied to the study of neo-angiogenesis.

In a review, Wolf et al. discussed essential and advanced prerequisites for experimental imaging of tumour-bearing animals. The authors focused on techniques available at typical imaging sites (e.g., radiology, nuclear medicine) where researchers can make use of clinical scanners. They showed that even though signal to noise and spatial resolution are the main limiting factors of these systems, fast translation using identical imaging techniques with minor adaptations can be realised. Newly developed or specifically optimised imaging techniques may be taken from experimental systems into clinical research and patient care, introducing true translation into practice.

Even though PET imaging mainly interrogates the utilisation of selective metabolic pathways in tissues, quantification of tracer uptake will be more accurate at higher spatial resolution. Therefore, specific tumour xenograft models are usually investigated with micro-PET systems. Debucquoy et al. found different responses of cell cultures and in vivo tumour tissues of Cyclo-oxygenase 2 (COX-2) negative and COX-2 positive colorectal cell lines to radiotherapy combined with celecoxib. In congruency with others the authors showed that the radiosensitising effect of COX-2 inhibitors in colorectal cancer is very controversial. With their approach they were able to identify the tumour micro-environment as the main factor in the radiosensitising effect of COX-2 inhibitors. Furthermore, the application of not only 18F-fluorodeoxyglucose (18F-FDG) but also 18F-3′-deoxy-3-fluorothymidine (18F-FLT) PET revealed the potential of the latter tracer to be a good alternative for the follow-up of treatment that includes irradiation. Nevertheless, the differentiation between tumour regrowth and inflammation might remain difficult.

In a further tumour xenograft study, Bruechner et al. used the potential of image coregistration to compare in vivo 18F-FDG uptake using autoradiography with several markers of functional histology staining in human head and neck squamous cell carcinomas. They utilised repetitive non-invasive quantification of glucose metabolism before and after single dose irradiation to demonstrate the decrease of 18F-FDG uptake in vital and particularly in hypoxic tumour segments in contrast to the stable uptake of 18F-FDG in necrotic areas. After detailed analysis the authors concluded that the maximum standardised uptake value (SUVmax) does not necessarily reflect changes in tumour biology after irradiation.

A new method to quantify vascularity was presented by Abramyuk et al. They hypothesised that small sized microspheres should freely circulate in the blood pool and quantify the spatial distribution in parenchymal organs. Quantitative circulation of microspheres was found only in the first minutes after intravenous injection, but later, different mechanisms specific for the organs eliminated the microspheres from blood flow. Consequently, microspheres might supplement the armamentarium to allow for histological verification of non- invasive perfusion imaging of tumours by PET, CT and MRI.

Sisodia et al. investigated biochemical and behavioural alterations in the cerebellum of Swiss albino mice following irradiation.

Three important clinical papers were presented during the workshop and also appear in this issue. Hentschel et al. presented results on serial 18F-FDG PET in patients with head and neck cancers with the aim to reduce the treatment volume during radiation therapy based on the visualised glucose metabolism. They investigated patients before and three times (biweekly) during radiotherapy and analysed PET data using a source-to-background based algorithm. While the median SUVmax decreased, the median values of the PET-based gross tumour volume and the metabolic volume increased. Intraindividually, the development of SUVmax could be divided into approx. equal number of patients revealing a continuous decrease or a temporary increase of SUVmax. The authors concluded that a reduction of treatment volume is not possible by an adaptive re-planning and linked this to the detection of therapy associated inflammation.

Chopra et al. fused the sites of needle biopsies of the human prostate with oxygen-sensitive MRI (using blood oxygen level dependent 1/T2* (R2*) imaging) in a pilot study and found that R2* quantification is a promising tool for non-invasive imaging of hypoxia in prostate cancer. Biopsies were evaluated for carbonic anhydrase, hypoxia inducible factor and the glucose 1 transporter and the corresponding regions in MRI were investigated by calculation of the median R2*. Even though the results were promising, the authors asked for further technical developments to extract oxygenation effects robustly from tissue signal relaxation metrics.

Prostate cancer was also the focus of a paper presented by Schmuecking et al. The authors found in an unpaired analysis that dynamic contrast enhanced MRI has the same potential for correctly locating prostate cancer as compared to 11C-choline PET/CT and is superior to magnetic resonance spectroscopy using a single voxel technique. They concluded that precise biopsies of the prostate are preferably done by multimodality imaging including different MRI techniques as well as PET. By these data sets, individualised patient management will result in the highest therapeutic success possible.

As every participant of this workshop experienced, molecular imaging in the field of radiation biology and therapy is a highly exciting but also a still emerging field. The rapid progress and the complexity of the issues to be addressed urges researchers to network beyond the narrow limits of their disciplines in order to take full advantage of all currently available methodology and knowledge.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.