Multiparametric Imaging of Tumors – an Emerging Paradigm

To date, the main focus for innovations in imaging has been the achievement of excellence in anatomical resolution. In the field of cancer therapy response, morphological imaging is recognized to have significant limitations including the presence of tumors that cannot be measured, poor measurement reproducibility and mass lesions of unknown activity that persist following therapy. In neuro-oncology for example, the full extent of gliomas is poor depicted on contrast enhanced T1-images and by T2-FLAIR hyperintensity. Anatomic imaging techniques may be insensitive to changes that inform on overall therapeutic success of cytostatic therapies, because the basic assumption that changes in tumor size reflect biological activity is violated. An example is pseudoresponse of glioblastomas treated with antiangiogenic therapy, where decreasing enhancement due to vascular normalization can be seen but with increasing mass effect and/or increasing tumor infiltration. The disconnection between anatomically determined progression free survival (PFS) and therapeutic efficacy (overall survival – OS) is recognized for a number of cytostatic therapies. The latter has recently resulted in a recommendation to withdraw the license to use the antiangiogenic drug bevacizumab for metastatic breast cancer by a committee of the US Food and Drug Administration (FDA), because improved PFS which was used for initial licensing did not ultimately result in improved OS. More sophisticated measurement methods such as tumor volume and CT density changes maybe unable to completely address these limitations. Functional-molecular imaging methods made possible by the availability of MRI and PET scanners in particular have enabled many current clinical limitations to be addressed, as well as extending the applications of imaging in medicine. Thus, over the last decade we have seen the increasing use of functional-molecular imaging in the staging of patients with cancer and for monitoring their therapeutic response. Some of these functional-molecular imaging techniques are able to predict the success of therapy before conventional measurements of size are changed. Functional-molecular parameters are also being used as pharmacodynamic biomarkers in early phases of drug development (preclinical and clinical), in order to provide confidence to proceed to more expensive clinically studies of therapeutics with novel mechanisms of action. Advantages of functional-molecular imaging techniques include the fact that quantitative biomarkers obtained are spatially resolved, although resolution is in general less than corresponding anatomical images. Moreover functional-molecular imaging techniques are now beginning to identify the emergence of therapy resistance to a variety of treatments including novels drugs. An example of the latter is new internal enhancement on CT/MRI scans or 18FDG-PET uptake in a size stable gastrointestinal tumor (GIST) treated with imatinib mesylate. Examples of clinically deployed functional imaging MRI and PET techniques and the biological properties that they depict are given in tables 1 & 2. Reviews of the physical basis for MRI and PET and their differing sensitivity to depict biological processes, reveals that MRI is more suited to evaluating the structure and dynamic aspects of microenvironment of tissues (e.g., blood flow, vascular permeability, cell packing, necrosis and pH), some of which requires the administration of exogenous contrast agents or other methods of enhancing MRI sensitivity (e.g., by hyperpolarisation). On the other hand, because PET has a great sensitivity to compounds present at nanomolar or even picomolar concentrations but has a slower mode of acquisition, it more suited to evaluating cellular and molecular processes (depending largely on the radiotracers used). Until recently, these techniques were used mostly in isolation. However, there is now an increasing possibility to undertake multifunctional/multiplex imaging Multiparametric Imaging of Tumors – an Emerging Paradigm