Visualization, imaging and new preclinical diagnostics in radiation oncology
© Cyran et al.; licensee BioMed Central Ltd. 2014
Received: 17 June 2013
Accepted: 20 December 2013
Published: 3 January 2014
Innovative strategies in cancer radiotherapy are stimulated by the growing knowledge on cellular and molecular tumor biology, tumor pathophysiology, and tumor microenvironment. In terms of tumor diagnostics and therapy monitoring, the reliable delineation of tumor boundaries and the assessment of tumor heterogeneity are increasingly complemented by the non-invasive characterization of functional and molecular processes, moving preclinical and clinical imaging from solely assessing tumor morphology towards the visualization of physiological and pathophysiological processes. Functional and molecular imaging techniques allow for the non-invasive characterization of tissues in vivo, using different modalities, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET) and optical imaging (OI). With novel therapeutic concepts combining optimized radiotherapy with molecularly targeted agents focusing on tumor cell proliferation, angiogenesis, and cell death, the non-invasive assessment of tumor microcirculation and tissue water diffusion, together with strategies for imaging the mechanisms of cellular injury and repair is of particular interest. Characterizing the tumor microenvironment prior to and in response to irradiation will help to optimize the outcome of radiotherapy. These novel concepts of personalized multi-modal cancer therapy require careful pre-treatment stratification as well as a timely and efficient therapy monitoring to maximize patient benefit on an individual basis. Functional and molecular imaging techniques are key in this regard to open novel opportunities for exploring and understanding the underlying mechanisms with the perspective to optimize therapeutic concepts and translate them into a personalized form of radiotherapy in the near future.
KeywordsRadiation oncology Molecular imaging Functional imaging Preclinical models
The effective use of radiation for cancer treatment is closely linked to the optimal application of imaging for staging and tumor characterization. Therefore any improvement in the field of imaging will impact on radiation oncology per se. In a broader sense the term imaging may not only be used to cover aspects of patho-anatomical imaging but may also cover all relevant aspects of additional functional visualization. The growing knowledge on the pathophysiology of cancer and the associated paradigm shift in therapeutic concepts are moving preclinical and clinical imaging from exclusively assessing tumor morphology towards the visualization of physiological and pathophysiological processes on a molecular level. Functional and molecular imaging allows for the non-invasive characterization of tissues in vivo, and comprises techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET) and optical imaging (OI). These novel imaging techniques have the potential for the visualization of functional tumor properties and the quantification of molecular pathways regulating the hallmarks of cancer . As such, signaling pathways orchestrating proliferation, survival, angiogenesis, invasiveness, metastasis, and different types of cell death can be visualized either directly or indirectly via surrogate markers . Imaging the mechanisms of cellular injury, repair, and cell death is of particular interest for characterizing the tumor microenvironment prior to and in response to irradiation, and hence for optimizing the outcome of radiotherapy (RT) .
RT is an established, highly effective cancer treatment option applied for definite, curative treatment as well as for palliative care. Together with surgery and/or chemotherapy it is an integral part of multimodality approaches. Novel therapeutic concepts include optimized radiotherapy in combination with molecularly targeted agents focusing on tumor cell proliferation, angiogenesis, and cell death . Importantly, these concepts require predictive biomarkers in order to stratify tumors for the appropriate therapy according to their individual molecular profile as well as biomarkers for monitoring the therapeutic outcome on a non-invasive and serial basis in vivo. E.g. with regard to tumor heterogeneity, the non-invasive evaluation of cellular tumor properties, such as proliferation, using molecular imaging methods could be of great interest for radiotherapy planning, for the identification of highly proliferative tumor areas. Functional and molecular imaging techniques may be key in this regard, since they open novel and exciting opportunities for exploring the molecular mechanisms in radiation biology with the possibility to optimize therapeutic concepts and translate them into a personalized form of radiotherapy in future.
Computed Tomography (CT)
CT is one of the leading imaging modalities in medical imaging and standard-of-care in RT planning. Advantages include short examination times allowing for whole body imaging within seconds, broad availability of the technique as well as low costs. Additionally, CT offers high spatial resolution at the submillimeter level. In small animal imaging, morphologic micro CT has shown significant potential with benefits, including high throughput and superior resolution. Winkelmann and colleagues investigated micro CT in a bone metastasis model of prostate cancer in mice and found that bone micro CT was able to non-invasively follow the onset and progression of bone metastatic lesions as small as 300 μm in diameter . Although radiation dose per micro CT scan approached 7–9 cGy, with six to nine micro CT examinations per mouse over a 7-week period, the applied radiation dose did not induce tumor stasis. However, the radiation dose applied by diagnostic micro CT has to be taken into account, particularly, when investigating micro CT for RT planning in small animal tumor models. A study by Boll and colleagues  investigated a dedicated alkaline earth metal-based nanoparticulate contrast agent for micro CT imaging of liver metastases in a colon carcinoma metastasis model in mice and reported that liver metastases as small as 300 μm were detectable after a single injection. The authors concluded that the investigated nanoparticulate contrast agent is suitable to compensate for the limited soft tissue contrast of unenhanced micro CT and allows for high resolution and high soft tissue contrast imaging of tumors in small animal models. Therefore, micro CT enhanced with dedicated contrast media may be of particular interest for the delineation and non-invasive characterization of tumors before and during radiotherapy in the preclinical setting.
Recent studies also support the value of perfusion CT as a functional imaging method in oncology . Perfusion imaging techniques based on CT, MRI and ultrasound have been applied for the non-invasive quantification of functional parameters of tissue microcirculation [8–11]. It has also been shown that dynamic contrast-enhanced CT (DCE-CT) allows for the assessment of pathologically increased tissue perfusion, blood volume and permeability , reflecting typical features of angiogenically active tissues, such as tumors. Surrogate parameters of tumor microcirculation assessed by DCE-CT have the potential to predict response to chemotherapy or irradiation in various cancers, e.g. cancers of the head and neck, lung, and rectum [13–15]. In anti-angiogenic tumor therapy, DCE-CT has shown its applicability for early assessment of the therapeutic effect on tumor vascularization, identifying treatment responders from non-responders, and optimizing personalized molecular therapies on an individualized patient basis.
Dual-energy CT (DECT) offers high soft tissue contrast and a clear differentiation between soft tissue, iodine contrast and bone. Dual source DECT can provide iodine maps which reflect iodine content in a tissue of interest and which have been demonstrated to show good correspondence to perfusion images in the lung and heart [16, 17]. In an experimental study of a VX2-rabbit model of liver cancer Zhang and colleagues reported that DECT iodine maps correlated well with multiparametric perfusion CT measurements for monitoring tumor angiogenesis with a significantly lower effective radiation dose. It was concluded that DECT might have the potential for serially monitoring angiogenesis in solid tumors with a significant reduction in radiation dose compared to perfusion CT techniques . This technique may be of particular interest for serially monitoring tumor heterogeneity and angiogenesis in the planning and monitoring of RT combined with anti-angiogenic agents.
Magnetic Resonance Imaging (MRI)
Based on strong magnetic fields (clinically between 1.5 and 3 Tesla, human research scanners up to 7 Tesla) MRI is able to provide superior soft tissue contrast and high spatial resolution without the application of ionizing radiation. Besides its morphologic capabilities useful for clinical staging and RT planning purposes [19, 20], MRI is increasingly developed for functional and molecular imaging methods, among them perfusion and diffusion imaging as well as MR spectroscopy and molecular MRI. Perfusion MRI can be applied to quantify functional parameters of tissue microcirculation, which have been shown to reflect tissue properties such as vitality, angiogenesis and proliferation . Novel imaging methods such as 23Natrium MRI have been proposed as a potential imaging biomarker for the assessment of tumor viability and the evaluation of therapy response in cancer patients .
Magnetic Resonance Proton Spectroscopy (MRS)
MR spectroscopy uses selective radiofrequency pulses for the investigation of the molecular composition of tissues [23, 24]. The Fourier transformation of the acquired signal generates a defined spectrum allowing for the discrimination of different metabolites in the investigated tissue, which may be pathognomonic for certain underlying pathologies. Metabolites detected in tumor tissues include choline-containing compounds, creatine, glutamate, lactate, N-acetyl aspartate (NAA), myoinositol (mI) and taurine . The concentration of each of these metabolites can be mapped on spectroscopic images with a voxel size of 0.7-1 cm3. NAA is predominantly a neuronal marker and decreases associated with neuronal damage and dysfunction . Choline is associated with cell membrane synthesis as well as increased metabolic turnover and is elevated in tumors and inflammatory processes . Creatine has been shown to be a marker of energy metabolism in the brain , while mI was confirmed as a glial cell marker and has been used as an indicator of myelin breakdown . In glioblastomas increased levels of creatine and choline as well as a lowered level of N-acetyl aspartate were found . Additionally, MRS can be applied for pre-operative staging of gliomas  and for monitoring tissue pH and temperature . With regard to radiation therapy, MRS may be a sensitive tool for monitoring radiation-induced changes in tumors based on the acquired spectrum of metabolites. MRS has also been postulated to be of particular interest in focal dose escalation in prostate cancer patients . Significant technical challenges for clinical translation remain particularly with regard to reproducibility in the quantification of chemical metabolites in tumors as well as impeded data quality due to local-field inhomogeneities caused by healthy tissue adjacent to the tumor .
MR perfusion represents one of the most promising methods of functional MR imaging. Perfusion imaging is defined as the in vivo assessment and quantification of microcirculatory parameters in different tissues, which may allow for the characterization of an underlying pathology. Depending on the imaging protocol and kinetic models applied for data analysis different parameters of microcirculation, such as plasma flow, extraction fraction, or relative plasma volume, can be assessed reflecting tissue properties, such as tissue perfusion, endothelial permeability, and tissue vascularity , in vivo. Technically, MR perfusion imaging can be performed by dynamic contrast-enhanced imaging (DCE), dynamic susceptibility contrast imaging (DSC), and arterial spin labeling (ASL) techniques. The most common method for perfusion imaging, however, is dynamic contrast-enhanced imaging.
Several recent studies have also discussed a possibly enhanced diagnostic value of multiparametric MRI combining morphologic and functional information from perfusion and diffusion parameters for the non-invasive characterization and differentiation of tumors . The recently published guidelines of the European Society of Urogenital Radiology (ESUR) describe the application of multiparametric MRI for the detection and staging of prostate cancer, a separate protocol for node and bone imaging as well as a standardized reporting system (PI-RADS), analogue to breast imaging .
Molecular MRI (mMRI)
mMRI applies targeted, gadolinium- or iron-based contrast agents of different designs, which allow for the dedicated depiction of molecular processes in vivo using antibodies, peptides or peptidomimetics [49, 50]. Based on Gadolinium (Gd) or iron, these contrast agents cause a shortening of the T1- (Gd) or the T2/T2* time (iron) and lead to a change in tissue contrast. To achieve highly specific binding properties, Gd-chelates or nanoparticles are conjugated to antibodies, peptides or peptidomimetics for the dedicated in vivo visualization of molecular processes . Serres and co-workers developed a targeted MRI contrast agent based on iron oxides that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1), which is known to be up-regulated on vessels of cerebral metastases . They investigated whether MRI enhanced with the targeted anti-VCAM-1 microparticles of iron oxide (anti-VCAM-1 MPIO) would be able to depict up-regulated VCAM-1 in a model of human breast carcinoma cerebral metastasis in mice and if early detection of these metastases would be feasible. The results indicated that by use of the VCAM-1 targeted MRI contrast agent, it is possible to detect brain metastases substantially earlier than with the established gadolinium-based small molecular contrast media and concluded that this approach represents a highly sensitive method for the early detection of brain metastases with the potential for clinical translation . Recently, enzymatic reporter systems for the non-invasive investigation of gene expression patterns detectable by MRI have been investigated combining the relatively high spatial and temporal resolution of MRI with the ability of each genetically-expressed enzyme to generate many MRI-detectable product molecules . Currently, most of these molecular MR contrast agents are experimental and not approved for human use. Particularly concerns of potential immunogenicity and incomplete bio-elimination of targeted MR contrast agents hamper clinical translation.
Compared to the currently established proton-based MR imaging, other nuclei like 3He, 129Xe or 13C have lower occurrence in the human body. If these alternative nuclei were used for the generation of the radiofrequency signal in MRI, the resulting signal-to-noise ratio (SNR) would be quite low. By means of hyperpolarization, however, it is possible to excite specific nuclei, thereby potentiating their MR signal to achieve a better SNR. 3He und 129Xe can be polarized by optical pumping, while 13C can be polarized using parahydrogen and dynamic polarization . Different studies have investigated 13C in MR angiography- und perfusion studies as well as 129Xe for lung imaging [54, 55]. Experimental, hyperpolarized MR contrast agents such as 13C-urea do not alter relaxation time, as established Gd- or iron based MR contrast media, but resemble in their function radioactive tracers, with the hyperpolarized nuclei representing the basis for the MR signal.
To date, 13C pyruvate has been the most widely used hyperpolarized substrate for MRS, which has also been applied for tumor response monitoring , and was the first to be used in a clinical trial of the technique . In a study investigating the effects of the mTOR inhibitor everolimus on a highly invasive orthotopic glioblastoma model in rats. Chaumeil and colleagues demonstrated that hyperpolarized 13C MRS can be used on a clinical MR system to monitor early metabolic response by means of measurement of the HP lactate-to-pyruvate ratios . Similarly, Day et al. showed the applicability of hyperpolarized 13C pyruvate MRS for the detection of treatment response 72 h following a whole brain irradiation with 15Gy in a rat glioma model . Golman and colleagues investigated 13C pyruvate in P22 tumors in rats for the non-invasive imaging of the anaerobic glycolysis of the injected pyruvate to alanine and lactate, analogue to imaging of aerobic glycolysis with 18 F-FDG-PET . Further perspectives of hyperpolarized MRI were discussed in a paper of Mansson et al. who were able to show that the signal of 13C nuclei varies depending on the hosting molecule, which could allow for refined discrimination of different 13C-containing molecules. This could be an advantage over radionuclide-based imaging modalities such as PET and SPECT . Main problems of the still experimental hyperpolarization MRI include the very high costs as well as the rapid decline of the hyperpolarization, which allow only for a very short interval between application and imaging .
In recent years, ultrasound has undergone significant technological advancement with an evolution from a simple morphology-based gray-scale image to a multiparametric high-resolution real-time imaging system. Major developments include the introduction of functional imaging options including sophisticated Doppler ultrasound, contrast-enhanced ultrasound (CEUS), and elastography for the non-invasive characterization of tissues with significantly improved spatial and temporal resolution. The development of gas-filled blood-pool microbubble contrast agents has significantly enhanced clinical and pre-clinical research applications with particular regard to the in vivo characterization of tissue microcirculation in a semi-quantitative and quantitative manner . Novel targeted microbubble contrast agents available for research purposes open the door for a molecular evaluation of tissues, e.g. by selectively binding to vascular endothelial growth factor receptor (VEGFR-2) [64–68] and a possible theranostics application linked to high intensity focused ultrasound (HIFU) which may be used in recurrent prostate cancer  and the microbubble-assisted delivery of drugs and genes .
Clinically, in recent years image-guided radiotherapy has been a major issue in research and development for (mage-guided radiotherapy (IGRT) and may be regarded as standard-of-care, especially in high-precision radiotherapy. One newly developed system is based on ultrasound – the Clarity 3D™ ultrasound system (Elekta, Stockholm, Sweden) is designed to track exemplarily the prostatic gland and adjacent organs-at-risk in order to minimize setup errors caused by organ motion, displacements and different filling states . Furthermore, ultrasound has great potential to be established as a sensor for intrafractional movement as the tumor or organ motion can be tracked online as compared to a static cone beam CT (pre or post application of the individual fraction), e.g. in liver cancer/metastases or prostate cancer . This in turn allows for an early detection of significant deviations and could in principle be used for real tumor tracking during irradiation.
Contrast-enhanced sonography (CEUS)
Apart from non-targeted, blood-pool ultrasound contrast media, targeted microbubbles have been developed as a molecular imaging technique by attaching specific ligands to the coating of gas-filled microbubbles. These targeted microbubbles can be applied for the non-invasive characterization of molecular tissue properties in vivo. As ultrasound microbubble contrast media remains intravascularly after intravenous injection, molecular targets have to be located on the luminal surface of vascular endothelium. Targeted microbubbles have been conjugated to ligands specific for highly expressed molecular markers of tumor angiogenesis such as VEGFR-2 and αvβ3-integrin [64, 65, 68, 70] to allow for the assessment of tumor angiogenic activity and for monitoring anti-angiogenic therapies in preclinical tumor models [90–92]. Together with potential application in theranostics multiparametric, contrast-enhanced ultrasound has developed to a high-potential tool for research and patient care combining high sensitivity, real-time morphological imaging, with functional and molecular imaging options with a lack of ionizing radiation and at comparably low costs .
Optical imaging employs light for the assessment of functional and molecular tissue information. This light can either originate from administered, elicited fluorescent tracers or – as bioluminescence – from genetically modified cells . Upon excitation with externally applied light of the proper wavelength, fluorescent tracers emit light with a higher wavelength that can be detected by a CCD (charged-coupled device) camera. Different forms of tracers have been described. For visualization of blood flow, unspecific, blood-flow distributing agents can be used, much resembling established contrast agents for x-ray computed tomography or magnetic resonance tomography . For visualization of molecular processes, targeted probes have been designed, typically consisting of a fluorescent dye (e.g. Cy 5.5) and a binding moiety – e.g. an antibody or smaller peptide with binding specificity for the target of interest. To minimize tissue absorption and scattering of the emitted light, the optimal spectral range for in vivo applications has been defined as the near-infrared optical window (wavelengths 650–900 nm), with lowest tissue absorbance for hemoglobin, water and lipids. In bioluminescence, an in vivo enzymatic reaction is responsible for the emission of light. The most common enzymatic tool is the firefly luciferase system, where D-luciferine is oxidized using ATP (adenosine-tri-phosphate) and oxygen in a two-step mechanism. The resulting emission of yellow-green light at 575 nm can be employed to visualize luciferase-expressing cells in vivo following intravascular injection of D-luciferine, the substrate of firefly luciferase, or after providing D-luciferine in the drinking water. Advantages of bioluminescence imaging include (1) an exquisite imaging sensitivity due to a high signal-to-noise ratio caused by the lack of bioluminescence background signal (in mammals) and (2) the luciferase system does not require excitation light from outside to be activated. Disadvantages include the need for cell transfection with the luciferase reporter genes, substrate injection (D-luciferine), and the poor spatial resolution of bioluminescence imaging compared to tracer-mediated fluorescence optical imaging. In recent years, many studies have investigated the luciferase bioluminescence assay to visualize a wide array of molecular pathways for the non-invasive characterization of the tumor microenvironment as useful tools in radiation and cancer biology research.
The study of Backer and colleagues exemplary illustrates strengths and drawbacks of targeted optical imaging with near-infrared fluorescent tracers. Human vascular endothelial growth factor (VEGF) was labeled with the fluorescent dye Cy5.5 (emission maximum 696 nm) for application in an in vivo tumor model . The elevated contrast, observed in the tumor following tracer administration was assigned to elevated VEGFR expression on tumor cells and adjacent endothelia. Unfortunately, the question remained unanswered, how specific this accumulation was. The authors missed to provide data on essential parameters, including whole body distribution of the tracer or an unspecific control of equal size and distribution. Importantly, biodistribution studies and blocking experiments are a crucial requirement for such imaging studies in order to convincingly show that tracer-mediated fluorescence in fact is a reliable measure of tracer to target binding.
Mostly due to restricted penetration depth of light and strong scatter, clinical translation of optical imaging techniques seems to be limited to lesions in or close to the skin, lesions accessible by endoscopy (e.g. colon polyps), or intraoperative applications. To solve some of these limitations, current technical developments in optical imaging focus on scanners with improved penetration depth and sensitivity, including photoacoustic imaging systems as well as hybrid fluorescence molecular tomography x-ray computed tomography scanners (FMT-XCT) [112–114]. The application of either or both technologies will help to provide significant insights into the molecular mechanisms of radiation and tumor biology in vivo. However, even state of the art optical imaging is a valuable modality for preclinical imaging in small animals, allowing for the non-invasive characterization of cells and tissues on a molecular level. The use of highly specific tracers or reporter gene-based bioluminescence imaging systems will help to gain a better understanding of the molecular processes, which take place in tumors in response to irradiation and/or targeted therapy, and will finally result in a more efficient pre-therapeutic stratification of tumors for multimodal therapy.
Positron emission tomography (PET)/single photon emission computed tomography (SPECT)
Novel PET tracers for research and patient care beyond 18 F-fluor-desoxyglucose ( 18 F-FDG) aim at molecular targets such as integrins and somatostatin receptors or a sensitive for up-regulated amino acid turnover or cell membrane synthesis of tumor cells
11C - Methionine
Increased amino acid uptake and turnover of tumor cells
11C - Leucine
18 F - Fluoruracile
18 F - Fluorethyltyrosine
Amino acid derivative
Longer half-life of 18 F allows for application of tracers in imaging centers without cyclotron
(18 F - FET)
18 F - Fluordesoxyglucose
(18 F – FDG)
18 F –Fluorazomyzinarabinoside
(18 F – FAZA)
18 F – Fluoromisonidazole
(18 F – FMISO)
18 F – Fluorthymidine
(18 F – FLT)
18 F - Galacto-RGD
[18 F- Arg-Gly-Asp (RGD) Peptide]
18 F - Choline
18 F - Fluoride
Somatostatin receptors (SSR)
In morphologic imaging, particularly tomographic modalities such as CT and MRI underwent tremendous innovation during the last 15 years currently providing excellent spatial resolution, 3D imaging and increasingly also functional information from tissue perfusion and diffusion. To combine morphological and functional/molecular information in diagnostic decision making, hybrid imaging with PET/CT has entered clinical routine in oncologic imaging using mostly 18 F-fluordesoxyglucose (FDG) for cancer diagnosis, as predictive imaging biomarker , for monitoring of therapy response and radiotherapy planning [118–120]. As a highly sensitive imaging modality based on molecular biology, PET has the ability to assess functional and molecular processes in benign and malignant tissues, which are altered in the earliest stages of virtually all diseases, before morphological changes occur. It compares normal and abnormal tissues on a functional rather than morphological level as MRI and CT. Functional and molecular imaging techniques such as 18 F-FDG-PET/CT can be applied to define a metabolically active biological tumor volume (BTV) for radiation therapy planning [121, 122], still limited by its lack of spatial resolution and relatively low specificity to reliably delineate the tumor as accurately as required by precision RT techniques like intensity-modulated radiotherapy (IMRT). 18 F-FDG-PET/CT has the potential to safely decrease radiotherapy volumes by better delineation of tumor and better lymph node detection [123, 124] and may be used as predictive/prognostic marker [125, 126]. It enables radiation dose escalation , and experimentally permits the definition of regions in heterogeneous tumor at greatest risk of recurrence, thus facilitating the redistribution of radiation doses within the tumor to focus on these regions – a principle which is called dose-painting by contours (DPBC) . Another method of specific dose escalation in a PET-positive area is dose painting by numbers (DPBN), where an inhomogeneous radiation dose distribution is intended on a voxel-by-voxel base . Recent developments in PET reconstruction focusing on time-of-flight (TOF) and point spread function (PSF) modeling bear the potential for further improvements in diagnostic performance, as shown by Schaefferkoetter and colleagues . They investigated four different reconstruction schemes on real tumor patient images and found that the application of TOF and PSF modeling may help to optimize particularly the detection of small, low-intensity, focal disease in larger patients.
However, FDG is not a tumor-specific tracer and accumulation in benign lesions, such as regions of inflammation, causes false-positive results with consecutively low specificity . Therefore, novel alternative tracers with higher specificity are under investigation (Table 1), including radiolabeled amino acids for monitoring protein synthesis and radiolabeled choline for monitoring cell membrane synthesis, which may allow for a dedicated characterization of the tumor microenvironment on a molecular level prior to as well as during RT and especially useful in radiotherapy planning, e.g. in high-risk prostate cancer . The amino acid methionine has been used for grading, prognostication and tumor extent delineation for RT planning and showed promising results in the detection and delineation of viable tumors particularly in low-grade gliomas . In clinical practice however, 18 F-labeled PET molecules have revealed advantages compared to those that are 11C-labeled due to a longer physical half-life of 110 min vs. 20 min. In this regard, 18 F-labeled O–(2) fluoroethyl-L-tyrosine ([18 F]-FET) is one of the most widely used amino acid tracers . Available data suggests that for RT planning the additional use of [18 F]-FET-PET to conventional imaging might improve gross tumor volume delineation [135, 136]. For PET-based imaging of tumor hypoxia, tracers such as 18 F-fluoromisonidazole (18 F-FMISO) and 124I-iodoazomycin galactopyranoside (124I-IAZG) were investigated by Riedl and colleagues in rats bearing liver tumors with peritoneal metastasis by dynamic microPET imaging. The authors demonstrated that 18 F-FMISO and 124I-IAZG localized the same tumor regions to be hypoxic, however with superior diagnostic quality of 18 F-FMISO images in the investigated Morris hepatoma model due to higher count statistics of 18 F-FMISO. Clinically, Thorwarth and colleagues investigated reoxygenation dynamics and its relationship to local control after radiotherapy in a small group of head-and-neck cancer patients (n = 10), based on repeated dynamic 18 F-FMISO PET examinations. The authors reported that a tumor control probability model was developed based on repeated 18 F -FMISO PET scans during RT to estimate reoxygenation time which may be applicable for hypoxia image-guided dose escalation in RT .
Recently, first hybrid MRI/PET scanners have been installed for patient care combining the excellent soft tissue contrast of MRI with the options of PET in functional and molecular imaging. Compared to CT, MRI provides superior soft tissue contrast together with options for perfusion, diffusion and spectroscopic imaging, as complementing functional parameters, without the use of ionizing radiation [50, 138]. The combination of both imaging modalities therefore provides strong synergies for imaging physiological and pathophysiological processes in vivo following multiparametric morphological, functional and molecular imaging concepts in oncology, neurology and cardiology.
Accurate delineation of gross tumor volume is a prerequisite for a successful treatment of cancer with radiotherapy. FDG-PET plays an increasingly important role in radiotherapy that goes beyond staging and selection of patients. For some tumors, such as NSCLC, FDG-PET has led to the safe decrease of radiotherapy volumes, enabling radiation dose escalation and redistribution of radiation doses within the tumor (tumor heterogeneity), along with a significant role in monitoring radiotherapy response. In esophageal cancer and bronchial cancer, FDG-PET/CT has gained significant predictive importance in multimodal treatment settings particularly before, during and after neo-adjuvant radio-chemotherapy and is very helpful in target volume delineation [139, 140]. Currently, besides for staging/re-staging purposes, PET/CT is playing a complementary role to other modalities such as CT and MRI for target volume delineation in radiotherapy. Standardized protocols should be established to better define what role PET and/or PET/CT scans should play in radiotherapy planning.
Advances in the understanding of the pathophysiology of cancer have triggered profound developments in multimodality treatment concepts comprising surgery, radiotherapy and molecularly targeted anti-cancer agents. These novel concepts of personalized cancer therapy require careful pre-treatment stratification and timely and efficient therapy monitoring to maximize patient benefit on an individual basis. Therefore, different functional and molecular imaging methods with corresponding biomarkers are currently being developed and characterized pre-clinically with the perspective of clinical translation. Molecularly tailored adaption of MRI, CT, ultrasound, PET/CT (-MRI) and optical imaging modalities represent promising approaches for the demands of targeted combination therapy in radiation oncology.
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