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 chemoradiotherapy may lead to individualized therapeutic approaches and improved clinical outcomes. We assessed the ability of 3′-deoxy-3′-¹⁸F-fluorothymidine positron emission tomography (FLT-PET) to detect early changes in tumor proliferation after chemoradiotherapy in experimental models of esophageal carcinoma. Experimental Design: The in vitro and ex vivo tumor uptake of [³H]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 [¹⁸F]FLT micro-PET imaging. Imaging-histologic correlation was determined by comparing spatial Ki-67 and [¹⁸F] FLT distribution in autoradiographs. Comparison with fluorodeoxyglucose (FDG) was done in all experiments. Results: In vitro [³H] FLTand [³H]THd uptake rapidly decreased in SEG-1 cells 24 hours after docetaxel with a maximal reduction of over 5-fold (P - 0.005). The [³H]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 [3H] FDG uptake was gradual and less pronounced. Tumor uptake of [³H] FLT was more closely correlated with Ki-67 expression (r = 0.89, P < 0.001) than was [³H]FDG (r = 0.39, P = 0.08). Micro-PET images depicted similar trends in reduction of [¹⁸F]FLT and [ ¹⁸F]FDG tumor uptake. Autoradiographs displayed spatial correlations between [¹⁸F] 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.