Positron emission tomography in colorectal cancer using 3'-18F fluoro-3'-deoxythymidine: A clinical and biological study.

The success of Positron Emmission Tomography (PET) in oncological imaging is based on the fact that malignancy leads to an alteration in cellular biochemical reactions. PET tracers, used for detecting malignancies, are synthetic positron emitting analogues of molecules involved in these metabolic processes. The recent development of the thymidine analogue [18F]3'-deoxy-3'-fluorothymidine (FLT) targets the salvage pathway of DNA synthesis and it is thought to have the potential to visualise cellular proliferation. The aim of this thesis was to investigate the potential clinical use of FLT in colorectal cancer (CRC). FLT pharmacokinetics in patients with CRC were mapped, and methodologies for the quantitative analysis of in vivo FLT uptake were defined; subsequently the accuracy of semi-quantitative indices (SUVs) was assessed. FLT uptake was compared to that of the established glucose analogue radiotracer [18F]fluoro-2-deoxy-D-glucose FDG (calculated using SUVs), in patients with primary and/or metastatic disease. Both FLT and FDG were compared with Ki67 immunohistochemistry in the same patients to determine whether PET can quantify cellular proliferation in vivo. FLT was also used to assess response to cytotoxic drug treatment 5-Fluorouracil (5FU) in cultured CRC cells. Semi-quantitation in the form of SUVs allowed an accurate interpretation of the uptake rate of the tracer. FLT PET provides acceptable imaging of primary colorectal tumours, but there are inherent difficulties in diagnosing the presence of liver metastases, secondary to the hepatic metabolism of the tracer. There was excellent correlation between FLT SUVs and Ki67 immunohistochemistry (R=0.8), which can be interpreted as a true reflection of the proliferative rate of colorectal cancer tissue. In vitro, cell killing caused by exposure to 5FU resulted in increased FLT uptake, with excellent correlation (R=0.9). FLT PET could in the future contribute to a non-invasive method of in vivo grading of malignancy and be used to predict early response to adjuvant chemotherapy