Pr?klinische Bildgebung im Tiermodell bei Strahlentherapie

CLINICAL/METHODICAL ISSUE: Modern radiotherapy benefits from precise and targeted diagnostic and pretherapeutic imaging. STANDARD RADIOLOGICAL METHODS: Standard imaging modalities, such as computed tomography (CT) offer high morphological detail but only limited functional information on tumors. METHODICAL INNOVATIONS: Novel functional and molecular imaging modalities provide biological information about tumors in addition to detailed morphological information. PERFORMANCE: Perfusion magnetic resonance imaging (MRI) CT or ultrasound-based perfusion imaging as well as hybrid modalities, such as positron emission tomography (PET) CT or MRI-PET have the potential to identify and precisely delineate viable and/or perfused tumor areas, enabling optimization of targeted radiotherapy. Functional information on tissue microcirculation and/or glucose metabolism allow a more precise definition and treatment of tumors while reducing the radiation dose and sparing the surrounding healthy tissue. ACHIEVEMENTS: In the development of new imaging methods for planning individualized radiotherapy, preclinical imaging and research plays a pivotal role, as the value of multimodality imaging can only be assessed, tested and adequately developed in a preclinical setting, i.e. in animal tumor models. PRACTICAL RECOMMENDATIONS: New functional imaging modalities will play an increasing role for the surveillance of early treatment response during radiation therapy and in the assessment of the potential value of new combination therapies (e.g. combining anti-angiogenic drugs with radiotherapy).     

Nanomedicine: Perspective and promises with ligand-directed molecular imaging

Molecular imaging and targeted drug delivery play an important role toward personalized medicine, which is the future of patient management. Of late, nanoparticle-based molecular imaging has emerged as an interdisciplinary area, which shows promises to understand the components, processes, dynamics and therapies of a disease at a molecular level. The unprecedented potential of nanoplatforms for early detection, diagnosis and personalized treatment of diseases, have found application in every biomedical imaging modality. Biological and biophysical barriers are overcome by the integration of targeting ligands, imaging agents and therapeutics into the nanoplatform which allow for theranostic applications. In this article, we have discussed the opportunities and potential of targeted molecular imaging with various modalities putting a particular emphasis on perfluorocarbon nanoemulsion-based platform technology.     

Single-photon emission computed tomography and positron emission tomography evaluations of patients with central motor disorders

Neuroimaging biomarkers in movement disorders during the past decade have served as diagnostic agents (Europe), tools for evaluation of novel therapeutics, and a powerful means for describing pathophysiology by revealing in vivo changes at different stages of disease and within the course of an individual patient's illness. As imaging with agents tracking dopaminergic function become more available, the next decade promises to enhance our clinical sophistication in the optimal use of dopaminergic imaging biomarkers for differential diagnosis, characterization of at-risk populations, guiding selection and management of appropriate treatments. The clinical role of these agents as clinical tools goes hand in hand with the development and availability of disease-modifying drugs, which carry the additional requirement for early and accurate diagnosis and improved clinical monitoring once treatment is initiated. Challenges remain in the ideal application of neuroimaging in the clinical algorithms for patient assessment and management. Further, the application of imaging to other targets, both monamineric and nonmonoaminergic, could serve a function beyond the important delineation of pathologic change occurring in patients with Parkinson's disease to suggest some role in improved phenotyping and classification of patients with Parkinson's disease presenting with different symptom clusters. New areas of focus based on the elucidation of mechanisms at the cellular and molecular level, including intense interest in alpha-synuclein and other protein inclusions in neurons and glia, have piqued interest in their in vivo assessment using scinitigraphic methods. Perhaps ultimately, treatment that is targeted to a better delineated pathophysiology-based characterization of movement disorder patients will emerge. The application of neuroimaging biomarkers to multiple ends in movement disorders provides an important model for the multiple roles diagnostic imaging agents can serve in neurodegenerative disorders; for diagnosis, for elaborating pathophysiology in patient populations, for developing new drugs, ultimately for improving clinical management.     

Molecular imaging: an overview and clinical applications

Molecular imaging is a new medical discipline that integrates cell biology, molecular biology and diagnostic imaging. Clinical applications of molecular imaging include the use of nuclear medicine, magnetic resonance imaging (MRI) and ultrasound (US). The nuclear medicine applications utilize devices such as single photon emission computerized tomography (SPECT) and positron emission tomography (PET). Molecular imaging has two basic applications. The first is diagnostic imaging, which is used to determine the location and extent of targeted molecules specific to the disease being assessed. The second is therapy, which is used to treat specific disease-targeted molecules. The basic principle of the diagnostic imaging application is derived from the ability of cell and molecular biologists to identify specific receptor sites associated with target molecules that characterize the disease process to be studied. The biology teams then develop molecular imaging agents, which will bind specifically to the target molecules of interest. The principle for using molecular targeting therapy is based on an extension of the diagnostic imaging principle. Basically, it is assumed that if the molecular probe does target the specific disease molecules of interest, the same molecular agent can be loaded with an agent that will deliver therapy to the targeted cells. Patients and physicians have the clinical expectation that molecular imaging, when used for diagnostic purposes, will significantly improve the time-liness as well as the accuracy of detecting the presence and extent of disease. When applied to therapy, the expectation is that FDA-approved agents will have been shown in clinical trials to provide a significant improvement in clinical outcomes over traditional therapy methods. The eventual clinical owners of molecular imaging may be a specialty group that is a hybrid by conventional measures. For example, the clinical owner should have fundamental knowledge in basic cellular and molecular biology but must also be certified as well as competent in the specific diagnostic imaging specialty applied (i.e. nuclear, MR or ultrasound). If the owner is also to be involved with therapy, experience and appropriate certification will also be required. Another issue relates specifically to the therapy applications in oncology. It is conceivable that traditional chemotherapy and radiotherapy may be replaced in part with molecular imaging therapy that utilizes target-specific agents to treat cancer on a non-toxic, outpatient basis. The issue to be addressed by the radiology administrator is whether this new discipline will be performed in the radiology department or oncology and radiotherapy departments. Clearly, radiology and its associated diagnostic imaging subspecialties are the most logical owner of molecular imaging. However, to make this ownership a reality will require major shifts in training requirements, as well as exertion of political influence from the radiology administrators against other specialties that have much to lose in terms of patient populations and revenue to their practice.     

Effect of Chemoprotection by Cystamine on Urinary Excretion of 5-hydroxyindoleacetic Acid in X-irradiated Rats

Biologically targeted radiotherapy entails the preferential delivery of radiation to solid tumours or individual tumour cells by means of tumour-seeking delivery vehicles to which radionuclides can be conjugated. Variant forms of this are the binary strategies (neutron capture therapy, photodynamic therapy) in which cell killing by the targeting moiety is dependent on activation by an external radiation beam. Monoclonal antibodies have attracted attention for some years as potentially selective targeting agents, but advances in tumour and molecular biology are now providing a much wider choice of molecular species. General radiobiological principles may be derived which are applicable to most forms of targeted radiotherapy. These principles provide guidelines for the appropriate choice of radionuclide in specific treatment situations and its optimal combination with other treatment modalities. In the future, the availability of gene targeting agents will focus attention on the use of Auger electron emitters whose high potency and short range selectivity makes them attractive choices for specific killing of cancer cells whose genetic peculiarities are known.     

Echographic imaging of tumoral cells through novel nanosystems for image diagnosis

Since the recognition of disease molecular basis, it has become clear that the keystone moments of medical practice, namely early diagnosis, appropriate therapeutic treatment and patient follow-up, must be approached at a molecular level. These objectives will be in the near future more effectively achievable thanks to the impressive developments in nanotechnologies and their applications to the biomedical field, starting-up the nanomedicine era. The continuous advances in the development of biocompatible smart nanomaterials, in particular, will be crucial in several aspects of medicine. In fact, the possibility of manufacturing nanoparticle contrast agents that can be selectively targeted to specific pathological cells has extended molecular imaging applications to non-ionizing techniques and, at the same time, has made reachable the perspective of combining highly accurate diagnoses and personalized therapies in a single theranostic intervention. Main developing applications of nanosized theranostic agents include targeted molecular imaging, controlled drug release, therapeutic monitoring, guidance of radiation-based treatments and surgical interventions. Here we will review the most recent findings in nanoparticles contrast agents and their applications in the field of cancer molecular imaging employing non-ionizing techniques and disease-specific contrast agents, with special focus on recent findings on those nanomaterials particularly promising for ultrasound molecular imaging and simultaneous treatment of cancer.     

Glioblastoma multiforme: emerging treatments and stratification markers beyond new drugs

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults. The standard therapy for GBM is maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). In spite of the extensive treatment, the disease is associated with poor clinical outcome. Further intensification of the standard treatment is limited by the infiltrating growth of the GBM in normal brain areas, the expected neurological toxicities with radiation doses >60 Gy and the dose-limiting toxicities induced by systemic therapy. To improve the outcome of patients with GBM, alternative treatment modalities which add low or no additional toxicities to the standard treatment are needed. Many Phase II trials on new chemotherapeutics or targeted drugs have indicated potential efficacy but failed to improve the overall or progression-free survival in Phase III clinical trials. In this review, we will discuss contemporary issues related to recent technical developments and new metabolic strategies for patients with GBM including MR (spectroscopy) imaging, (amino acid) positron emission tomography (PET), amino acid PET, surgery, radiogenomics, particle therapy, radioimmunotherapy and diets.     

In-room CT techniques for image-guided radiation therapy.

Accurate patient setup and target localization are essential to advanced radiation therapy treatment. Significant improvement has been made recently with the development of image-guided radiation therapy, in which image guidance facilitates short treatment course and high dose per fraction radiotherapy, aiming at improving tumor control and quality of life. Many imaging modalities are being investigated, including x-ray computed tomography (CT), ultrasound imaging, positron emission tomography, magnetic resonant imaging, magnetic resonant spectroscopic imaging, and kV/MV imaging with flat panel detectors. These developments provide unique imaging techniques and methods for patient setup and target localization. Some of them are different; some are complementary. This paper reviews the currently available kV x-ray CT systems used in the radiation treatment room, with a focus on the CT-on-rails systems, which are diagnostic CT scanners moving on rails installed in the treatment room. We will describe the system hardware including configurations, specifications, operation principles, and functionality. We will review software development for image fusion, structure recognition, deformation correction, target localization, and alignment. Issues related to the clinical implementation of in-room CT techniques in routine procedures are discussed, including acceptance testing and quality assurance. Clinical applications of the in-room CT systems for patient setup, target localization, and adaptive therapy are also reviewed for advanced radiotherapy treatments.     

Validation of functional imaging as a biomarker for radiation treatment response

Major advances in radiotherapy techniques, increasing knowledge of tumour biology and the ability to translate these advances into new therapeutic approaches are important goals towards more individualized cancer treatment. With the development of non-invasive functional and molecular imaging techniques such as positron emission tomography (PET)-CT scanning and MRI, there is now a need to evaluate potential new biomarkers for tumour response prediction, for treatment individualization is not only based on morphological criteria but also on biological tumour characteristics. The goal of individualization of radiotherapy is to improve treatment outcome and potentially reduce chronic treatment toxicity. This review gives an overview of the molecular and functional imaging modalities of tumour hypoxia and tumour cell metabolism, proliferation and perfusion as predictive biomarkers for radiation treatment response in head and neck tumours and in lung tumours. The current status of knowledge on integration of PET/CT/MRI into treatment management and bioimage-guided adaptive radiotherapy are discussed.Advances in understanding the molecular biology of cancer and the ability to translate these advances into therapeutic approaches are important achievements towards individualized cancer treatment. With the development of non-invasive functional and molecular imaging modalities such as positron emission tomography (PET)-CT scanning and MRI, there is now a need to evaluate potential new biomarkers for tumour response prediction. It is noteworthy that treatment individualization is not only based on morphological criteria but also on biological tumour characteristics such as metabolic and proliferative activity, and hypoxic tumour status before and during treatment.¹ The validation and integration of imaging biomarkers before and early during therapy are important tasks for further clinical research and may help to individually select, adapt and optimize treatment schedules for patients in order to improve treatment outcomes, that is, to increase tumour control probability and/or to reduce chronic treatment-related toxicity.²The primary aim of a predictive biomarker is to accurately determine the outcome of a given treatment. Therefore, the accurate prediction may help facilitate potential interventions early during the course of treatment. By contrast, prognostic markers show an association with patient outcome independent of a given treatment. The increasing use and availability of PET/CT as well as of MRI in radiotherapy will make it feasible to incorporate imaging predictive tests into clinical practice if validation studies confirm the utility of specific PET tracers or functional MRI or CT parameters. In this review, the capacity to use these functional imaging biomarkers is focused on PET, MRI and CT for radiotherapy response detection in head and neck tumours and in lung tumours.     

Nanotechnology development and utilization: a primer for diagnostic and interventional radiologists

The term nanotechnology refers to the design, creation, and manipulation of structures on the nanometer scale. Much of the ongoing research and development of nanotechnology is focused on the development of novel methods of imaging and delivery of therapeutics through minimally invasive means. Multifunctional nanoparticles offer great promise for molecular imaging and directing novel therapeutics to molecular targets, which was never before possible. Nanoparticle-based contrast agents have been developed for all imaging modalities. A rapidly increasing number of companies and government funding initiatives have led to a large number of novel agents in various stages of development, ranging from in vitro and in vivo animal studies to clinical use. However, barriers to the delivery of nanoparticles for tumor imaging and therapy exist. Interventional radiologists may circumvent these barriers by using imaging to guide delivery of nanoparticles.     

Monitoring response to treatment in patients utilizing PET

Establishing new surrogate end points for monitoring response to treatment is needed for current therapy modalities and for new therapeutic strategies including molecular targeted cancer therapies. PET as a functional imaging technology provides rapid, reproducible, noninvasive in vivo assessment and quantification of several biologic processes targeted by these therapies. PET is useful in a variety of clinical relevant applications, including distinguishing between radiation necrosis and tumor recurrence, determining the resectability of recurrent tumor, and evaluating response to therapy. FDG-PET has demonstrated efficacy for monitoring therapeutic response in a wide range of cancers, including breast, esophageal, lung, head and neck, and lymphoma. FDG-PET can assess tumor glucose use with high reproducibility. Following therapy, the decrease of glucose use correlates with the reduction of viable tumor cells. FDG-PET allows the prediction of therapy response early in the course of therapy and determining the viability of residual masses after completion of treatment. The molecular basis for the success of FDG-PET is the rapid reduction of tumor glucose metabolism in effective therapies. Of even higher clinical relevance is the accurate identification of nonresponders in patients without a significant change in tumor glucose metabolism after initiation of therapy. PET imaging can easily visualize these changes in metabolic activity and indicate, sometimes within hours of the first treatment, whether or not a patient will respond to a particular therapy. In contrast to CT, MR imaging, or ultrasound, PET imaging allows identification of responding and nonresponding tumors early in the course of therapy. With this information, physicians can rapidly modify ineffective therapies for individual patients and thereby potentially improve patient outcomes and reduce cost. One of the major limitations for the routine application of FDG-PET imaging for therapy monitoring is that no generally accepted cutoff values have been established to differentiate optimally between responders and nonresponders. The patient series are still relatively small and frequently consist of different tumor types and different therapy regimens. Prospective studies including a sufficient number of patients are needed to define cutoff values to differentiate between responder and nonresponder for different tumors and different treatment regimes. In the future, PET imaging can also serve in the evaluation of new therapeutic agents, new experimental treatments, and specifically in monitoring clinical phase II studies.     

Hypoxia imaging markers and applications for radiation treatment planning

Tumor hypoxia presents a unique therapeutic challenge in the treatment of solid malignancies. Not only does the presence of hypoxia compromise the efficacy of locally-directed therapies, such as radiotherapy, but the proteomic and genomic changes activated by hypoxia can promote malignant progression and systemic dissemination. In an effort to improve therapeutic ratios and treatment outcomes, therapies that specifically target areas of hypoxia are actively being investigated. Therefore, functional noninvasive methods of assessing tumor hypoxia, such as imaging via positron emission tomography/computed tomography, are warranted. Multiple imaging agents are currently being used or investigated to evaluate hypoxia status before therapy and to measure changes in oxygenation during treatment, as a means to optimizing therapeutic regimens. Advances in therapeutic radiation delivery, such as intensity-modulated radiation therapy, and proton therapy now allow for differential targeting of tumor areas, with potential dose escalation via dose painting to areas of greatest treatment resistance. The incorporation of novel imaging markers into the multimodal treatment paradigm, whether with radiation dose escalation or in concert with agents that reverse tumor hypoxia, hypoxic radiosensitizers, or hypoxic cytotoxins, will be a vital component of advancing clinical individualized cancer care and improving cure rates.     

Impact of PET on radiation therapy planning in lung cancer

The superiority of PET imaging to structural imaging in many cancers is rapidly transforming the practice of radiotherapy planning, especially in lung cancer. Although most lung cancers are potentially treatable with radiation therapy, only patients who have truly locoregionally confined disease can be cured by this modality. PET improves selection for high-dose radiation therapy by excluding many patients who have incurable distant metastasis or extensive locoregional spread. In those patients suitable for definitive treatment, PET can help shape the treatment fields to avoid geographic miss and minimize unnecessary irradiation of normal tissues. PET will allow for more accurately targeted dose escalation studies in the future and could potentially lead to better long-term survival.     

Radiation damage and radioprotectants: new concepts in the era of molecular medicine

Exposure to ionising radiation results in mutagenesis and cell death, and the clinical manifestations depend on the dose and the involved body area. Reducing carcinogenesis in patients treated with radiotherapy, exposed to diagnostic radiation or who are in certain professional groups is mandatory. The prevention or treatment of early and late radiotherapy effects would improve quality of life and increase cancer curability by intensifying therapies. Experimental and clinical data have given rise to new concepts and a large pool of chemical and molecular agents that could be effective in the protection and treatment of radiation damage. To date, amifostine is the only drug recommended as an effective radioprotectant. This review identifies five distinct types of radiation damage (I, cellular depletion; II, reactive gene activation; III, tissue disorganisation; IV, stochastic effects; V, bystander effects) and classifies the radioprotective agents into five relevant categories (A, protectants against all types of radiation effects; B, death pathway modulators; C, blockers of inflammation, chemotaxis and autocrine/paracrine pathways; D, antimutagenic keepers of genomic integrity; E, agents that block bystander effects). The necessity of establishing and funding central committees that guide systematic clinical research into evaluating the novel agents revealed in the era of molecular medicine is stressed.     

Non-small cell lung cancer (NSCLC)

The goal of radiation therapy for non-small cell lung cancer (NSCLC) is to improve the survival rate of patients without increasing treatment-related toxicity and to improve patients' quality of life. Several prospective randomized trials have demonstrated a survival advantage in combined modality treatment over radiotherapy or chemotherapy alone when a cisplatin-based chemotherapy regimen is utilized in the treatment plan. Combined modality treatment of cisplatin-based chemotherapy and radiotherapy is standard treatment for selected patients such as those with better performance status with locally or regionally advanced lung cancer including T3-T4 or N2-N3. Determining the contribution of new agents in combined modality treatment will require carefully designed and conducted clinical trials. High-dose involved field radiation therapy using 3D-conformal radiation therapy potentially enables the use of higher doses than standard radiation therapy, because less normal tissue is irradiated, and may improve local control and survival. The combination of radiotherapy with chemotherapy and dose escalation using 3D-conformal radiation therapy is also a possibility in unresectable NSCLC. In surgery cases, the results of several Phase III trials of cisplatin-based preoperative chemotherapy have suggested survival improvement. But the concept needs to be tested in a larger Phase III trial.     

MR imaging-guided interventions in the genitourinary tract: an evolving concept

MR imaging-guided interventions are well established in routine patient care in many parts of the world. There are many approaches, depending on magnet design and clinical need, based on MR imaging providing excellent inherent tissue contrast without ionizing radiation risk for patients. MR imaging-guided minimally invasive therapeutic procedures have advantages over conventional surgical procedures. In the genitourinary tract, MR imaging guidance has a role in tumor detection, localization, and staging and can provide accurate image guidance for minimally invasive procedures. The advent of molecular and metabolic imaging and use of higher strength magnets likely will improve diagnostic accuracy and allow targeted therapy to maximize disease control and minimize side effects.     

MINERVA-a multi-modal radiation treatment planning system.

Researchers at the Idaho National Engineering and Environmental Laboratory and Montana State University have undertaken development of MINERVA, a patient-centric, multi-modal, radiation treatment planning system. This system can be used for planning and analyzing several radiotherapy modalities, either singly or combined, using common modality independent image and geometry construction and dose reporting and guiding. It employs an integrated, lightweight plugin architecture to accommodate multi-modal treatment planning using standard interface components. The MINERVA design also facilitates the future integration of improved planning technologies. The code is being developed with the Java Virtual Machine for interoperability. A full computation path has been established for molecular targeted radiotherapy treatment planning, with the associated transport plugin developed by researchers at the Lawrence Livermore National Laboratory. Development of the neutron transport plugin module is proceeding rapidly, with completion expected later this year. Future development efforts will include development of deformable registration methods, improved segmentation methods for patient model definition, and three-dimensional visualization of the patient images, geometry, and dose data. Transport and source plugins will be created for additional treatment modalities, including brachytherapy, external beam proton radiotherapy, and the EGSnrc/BEAMnrc codes for external beam photon and electron radiotherapy.     

Fundamentals of molecular imaging: rationale and applications with relevance for radiation oncology

Molecular imaging allows for the visualization and quantification biologic processes at cellular levels. This article focuses on positron emission tomography as one readily available tool for clinical molecular imaging. To prove its clinical utility in oncology, molecular imaging will ultimately have to provide valuable information in the following 4 pertinent areas: staging; assessment of extent of disease; target delineation for radiation therapy planning; response prediction and assessment and differentiation between treatment sequelae and recurrent disease. These issues are addressed in other contributions in this issue of Seminars in Nuclear Medicine. In contrast, this article will focus on the biochemical principles of cancer metabolism that provide the rationale for positron emission tomography imaging in radiation oncology.     

MR-guided radiotherapy for prostate cancer: state of the art and future perspectives

Advances in radiotherapy technology have increased precision of treatment delivery and in some tumour types, improved cure rates and decreased side effects. A new generation of radiotherapy machines, hybrids of an MRI scanner and a linear accelerator, has the potential to further transform the practice of radiation therapy in some cancers. Facilitating superior image quality and the ability to change the dose distribution online on a daily basis (termed “daily adaptive replanning”), MRI-guided radiotherapy machines allow for new possibilities including increasing dose, for hard to treat cancers, and more selective sparing of healthy tissues, where toxicity reduction is the key priority.These machines have already been used to treat most types of cancer, although experience is still in its infancy. This review summarises the potential and current evidence for MRI-guided radiotherapy, with a predominant focus on prostate cancer. Current advantages and disadvantages are discussed including a realistic appraisal of the likely potential to improve patient outcomes. In addition, horizon scanning for near-term possibilities for research and development will hopefully delineate the potential role for this technology over the next decade.