Kinetic analysis of 3′-deoxy-3′-fluorothymidine PET studies: Validation studies in patients with lung cancer

Mark Muzi, Hubert Vesselle, John R. Grierson, David A. Mankoff, Rodney A. Schmidt, Lanell Peterson, Joanne M. Wells, Kenneth A. Krohn

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Abstract

Assessing cellular proliferation provides a direct method to measure the in vivo growth of cancer. We evaluated the application of a model of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) kinetics described in a companion report to the analysis of FLT PET image data in lung cancer patients. Compartmental model analysis was performed to estimate the overall flux constants (KFLT) for FLT phosphorylation in tumor, bone marrow, and muscle. Estimates of flux were compared with an in vitro assay of proliferation (Ki-67) applied to tissue derived from surgical resection. Compartmental modeling results were compared with simple model-independent methods of estimating FLT uptake. Methods: Seventeen patients with 18 tumor sites underwent up to 2 h of dynamic PET with blood sampling. Metabolite analysis of plasma samples corrected the total blood activity for labeled metabolites and provided the FLT model input function. A 2-compartment, 4-parameter model (4P) was tested and compared with a 2-compartment, 3-parameter (3P) model for estimating KFLT. Results: Bone marrow, a proliferative normal tissue, had the highest values of KFLT, whereas muscle, a nonproliferating tissue, showed the lowest values. The KFLT for tumors estimated by compartmental analysis had a fair correlation with estimates by modified graphical analysis (r = 0.86) and a poorer correlation with the average standardized uptake value (r = 0.62) in tumor. Estimates of KFLT derived from 60 min of dynamic PET data using the 3P model underestimated KFLT compared with 90 or 120 min of dynamic data analyzed using the 4P model. Comparison of flux estimates with an independent measure of cellular proliferation showed that KFLT was highly correlated with Ki-67 (Spearman ρ = 0.92, P < 0.001). Ignoring the metabolites of FLT in blood underestimated KFLT by as much as 47%. Conclusion: Compartmental analysis of FLT PET image data yielded robust estimates of KFLT that correlated with in vitro measures of tumor proliferation. This method can be applied generally to other imaging studies of different cancers after validation of parameter error. Tumor loss of phosphorylated FLT nucleotides (k4) is notable and leads to errors when FLT uptake is evaluated using model-independent approaches that ignore k4, such as graphical analysis or the SUV.

Original languageEnglish (US)
Pages (from-to)274-282
Number of pages9
JournalJournal of Nuclear Medicine
Volume46
Issue number2
StatePublished - 2005

Keywords

  • 3′-deoxy-3′-fluorothymidine
  • Cell proliferation
  • Ki-67
  • Kinetic modeling
  • Thymidine kinase 1

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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    Muzi, M., Vesselle, H., Grierson, J. R., Mankoff, D. A., Schmidt, R. A., Peterson, L., Wells, J. M., & Krohn, K. A. (2005). Kinetic analysis of 3′-deoxy-3′-fluorothymidine PET studies: Validation studies in patients with lung cancer. Journal of Nuclear Medicine, 46(2), 274-282.