Comparison of methodologies for the in vivo assessment of 18 FLT utilisation in colorectal cancer

Abstract

Fluorine-18 3'-deoxy-3'-fluorothymidine (18FLT) is a tissue proliferation marker which has been suggested as a new tumour-specific imaging tracer in positron emission tomography (PET). The objectives of this study were to investigate the pharmacokinetics of 18FLT in patients with colorectal cancer, defining methodologies for the quantitative analysis of the in vivo 18FLT uptake and subsequently assessing the accuracy of semi-quantitative measures. Dynamic acquisitions over a single field of view of interest identified by computed tomography were carried out for up to 60 min following injection of 18FLT (360 +/- 25 MBq). Dynamic arterial blood sampling was carried out in order to provide a blood input function. Simultaneous venous samples were also taken in order to investigate their potential utilisation in deriving a hybrid input function. Arterial and venous blood samples at 5, 15, 30, 60 and 90 min p.i. were used for metabolite analysis. Eleven patients with primary and/or metastatic colorectal cancer were studied on a lesion by lesion basis (n = 21). All acquired images were reconstructed using ordered subsets expectation maximisation and segmented attenuation correction. Time-activity curves were derived by image region of interest (ROI) analysis and image-based input functions were obtained using abdominal or thoracic aorta ROIs. Standardised uptake values (SUVs) were calculated to provide semi-quantitative indices of uptake, while non-linear regression (NLR) methodology in association with a three-compartment model and Patlak analysis were carried out to derive the net influx constant Ki. The metabolite analysis revealed two radioactive metabolites, with the parent compound representing approximately 80% of the total radioactivity in the 30-min plasma sample. In the case of NLR, better fits were obtained with a 3k model (i.e. k4 = 0) for both lesion and bone marrow time-activity curves. For the same lesions, a high correlation was observed between the Ki derived from either Patlak analysis or NLR(3k) and the corresponding SUVs. Our results also suggest that the quantitative behaviour of 18FLT in vivo (up to 60 min p.i.) may be characterised using a 3k model or Patlak analysis in combination with image-derived input functions. The good correlation found between the SUVs (at 60 min) and Ki values supports the use of semi-quantitative indices to assess the proliferation rate of colorectal cancer lesions in vivo with 18FLT.

Heterogeneity in stabilization phenomena in FLT PET images of canines

“…Direct or indirect scaling of input function with venous blood samples is supported by some clinical evidence in humans; e.g. the use of venous blood samples was not found to make a statistically significant difference in FLT kinetic analyses despite the systematically marginally higher concentration of FLT in venous plasma samples as compared to the concentration in arterial plasma samples (Visvikis et al 2004, Menda et al 2009) and venous input functions exhibited good correlation with the aortic image-derived input functions (Shields et al 2005). The absolute scaling of input function does not impact the stabilization curves and stabilization parameters for the same reason as the scaling of SUV.…”

“…While the negligible FLT metabolite fraction in blood plasma has not been reported yet for canines, it has been observed in mice tumour models (Barthel et al 2003, Kim et al 2008). Assumption that parent plasma FLT activity is equal to the whole-blood activity was based on the statistically insignificant differences between plasma and whole-blood specific activities found in humans (Visvikis et al 2004). Direct or indirect scaling of input function with venous blood samples is supported by some clinical evidence in humans; e.g.…”

18F-FLT and 18F-FDOPA PET kinetics in recurrent brain tumors

“…Instead, theoretical curves were fitted to FLT and FDOPA metabolite data that were pooled from previous publications [40, 48, 49]. The fitted curves were then used as an approximation of the expected metabolite fraction over time for each individual’s blood curve.…”

“…For FLT, the measured metabolite data in lung cancer and colorectal cancer were extracted from previous publications [40, 48]. Because the metabolite data from these two studies appeared similar, they were pooled together and fitted with a theoretical curve, as an approximation of the metabolite fraction over time.…”

A Pilot Study of the Value of 18F-Fluoro-Deoxy-Thymidine PET/CT in Predicting Viable Lymphoma in Residual 18F-FDG Avid Masses After Completion of Therapy

“…Recently, the thymidine analogue 18 F-FLT has been suggested as an in-vivo marker of a tumor’s proliferative activity and possibly as a more specific tumor-imaging agent. Several groups have addressed the feasibility of studying 18 F-FLT PET in numerous types of cancers [13, 25–27] including lymphoma [16]. 18 F-FLT uptake by lymphoma cells has been shown to closely reflect the S phase of the cell cycle [10].…”