Clinical assessment of FLT-PET for the in vivo measurement of cell proliferation in cancer
2000 - 12 / 2004
Introduction: A sensitive and specific monitoring technique to diagnose tumors is very helpful in the management of cancer patients. It is of utmost importance to predict the presence or absence of metastatic disease, tumor grade, and the result of chemotherapy or radiotherapy in an early treatment phase. Also the localization of an unknown primary tumor is crucial for the treatment of cancer patients. Techniques that depict anatomy (CT, MRI, ultrasound) are not adequate for therapy evaluation and tumor grading, since changes in tumor volume and changes in tumor viability are not very well correlated. Tumor metabolism may be a more accurate parameter to detect small tumor deposits and to monitor the effect of chemotherapy on tumor size. Positron emission tomography (PET) is the unsurpassed technique to investigate metabolism in vivo. For many tumors PET has been found to be superior to CT and MRI regarding sensitivity, specificity and accuracy of tumor detection. The radiopharmaceutical 18F-fluoro-2-deoxy-D-glucose (FDG) is used worldwide for this purpose, but has disadvantageous properties, e.g. accumulation in inflammatory tissue. Recently a new radiopharmaceutical reflecting DNA synthesis has emerged, i.e. [18F]-3'-fluoro-3'-deoxy-L-thymidine (FLT), which shows promising clinical potential, since it is expected that FLT accumulates more specifically in tumor tissue than FDG. Imaging of the DNA synthesis rate with FLT is a direct measure of cell proliferation and tumor growth, whereas glucose consumption (FDG-PET) is a derivative of tumor growth. Purposes: - Investigation of the scope and limitations of FLT-PET for tumor detection, tumor staging or grading as well as the evaluation of chemo- or radiotherapy. - Comparison of FLT-PET with FDG-PET and conventional imaging modalities. Imaging data will be correlated with tumor biological markers, like mitotic activity, cell proliferation and tumor grade using immunohistochemistry. Plan of investigation: FLT-PET will be performed in patients with breast, lung, brain, soft tissue, testicular and laryngeal tumors. For therapy evaluation, dynamic PET scans will be made before and shortly after the beginning of therapy, and prior to surgery. For tumor detection (sensitivity, specificity and accuracy) and staging, whole-body PET images will be produced. The outcome of the FLT-PET scans will be compared to FDG-PET and other imaging modalities. In addition to imaging, PET scanning provides data to allow calculation of DNA synthesis rate (reflecting cell proliferation) in the tumor. A mathematical three-compartment model describing the tissue kinetics, analogous to FDG is available. The scanning results will be correlated with the results of extensive macroscopical and microscopical pathological examination of the tumors after surgical resection or biopsy (preferably PET-driven biopsies to avoid sampling errors). Possible results: On the basis of preliminary results, it has been suggested that FLT-PET is a more specific tool than FDG-PET for tumor detection, staging of tumors and evaluation of chemo- or radiotherapy. FLT may become a valuable complementary diagnostic tool to and possibly replace FDG in oncological PET. Relevance for cancer research: Besides increased knowledge of tumor biochemistry, FLT-PET might be a more accurate imaging tool, resulting in better monitoring of treatment strategies for the cancer patients in the near future.