Early detection of chemoradioresponse in esophageal carcinoma by 3′-deoxy-3′-3H-fluorothymidine using preclinical tumor models

Purpose: Early identification of esophageal cancer patients who are responding or resistant to combined chemo radiotherapy may lead to individualized therapeutic approaches and improved clinical outcomes. We assessed the ability of 3'-deoxy-3'-F-18-fluorothymidine positron emission tomography (FLT-PET) to detect early changes in tumor proliferation after chemo radiotherapy in experimental models of esophageal carcinoma. Experimental Design: The in vitro and ex vivo tumor uptake of [H-3] FLT in SEG-1 human esophageal adenocarcinoma cells were studied at various early time points after docetaxel plus irradiation and validated with conventional assessments of cellular proliferation [thymidine (Thd) and Ki-67] and [F-18] FLT micro-PET imaging. Imaging-histologic correlation was determined by comparing spatial Ki-67 and [F-18] FLT distribution in autoradiographs. Comparison with fluorodeoxyglucose (FDG) was done in all experiments. Results: In vitro [H-3]FLT and [H-3]Thd uptake rapidly decreased in SEG-1 cells 24 hours after docetaxel with a maximal reduction of over 5-fold (P = 0.005). The [H-3] FLT tumor-to-muscle uptake ratio in xenografts declined by 75% compared with baseline (P < 0.005) by 2 days after chemoradiotherapy, despite the lack of change in tumor size. In contrast, the decline of [H-3] FDG uptake was gradual and less pronounced. Tumor uptake of [H-3] FLT was more closely correlated with Ki-67 expression (r = 0.89, P < 0.001) than was [H-3] FDG (r = 0.39, P = 0.08). Micro-PET images depicted similar trends in reduction of [F-18] FLT and [F-18] FDG tumor uptake. Autoradiographs displayed spatial correlations between [F-18] FLT uptake and histologic Ki-67 distribution in preliminary studies. Conclusions: FLT-PET is suitable and more specific than FDG-PET for depicting early reductions in tumor proliferation that precede tumor size changes after chemoradiotherapy.