Monitoring response to transarterial chemoembolization in hepatocellular carcinoma using ¹⁸F-Fluorothymidine Positron Emission Tomography

Abstract

Accurate disease monitoring is essential following transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) due to potential for profound adverse event and large variation in survival outcome. Post-treatment changes on conventional imaging can confound determination of residual/recurrent disease, magnifying the clinical challenge. Based on increased expression of thymidylate synthase (TYMS), thymidine kinase-1 (TK-1) and SLC29A1 (Equilibrative nucleoside transporter 1, ENT1) in HCC compared with liver tissue, we conducted a proof of concept study evaluating the efficacy of ¹⁸F-fluorothymidine (¹⁸F-FLT)-PET to assess response to TACE. As previous PET studies in HCC have been hampered by high background liver signal, we investigated if a temporal-intensity voxel-clustering (“Kinetic Spatial Filtering”) (KSF) improved lesion detection. Methods: A tissue microarray (TMA) was built from 36 HCC samples and matched surrounding cirrhotic tissue and was stained for thymidine kinase-1 (TK-1). A prospective study was conducted; eighteen patients with a diagnosis of HCC by American Association for the Study of Liver Diseases criteria (AALSD) who were eligible to treatment with TACE were enrolled. Patients underwent baseline conventional imaging and dynamic ¹⁸F-FLT-PET/KSF followed by TACE. Repeat imaging was performed 6-8 weeks post TACE. PET parameters were compared with modified-Response Evaluation in Solid Tumours (mRECIST) enhancement-based criteria. Results: Cancer Genome Atlas analysis revealed increased RNA expression of TYMS, TK-1 and SLC29A1 in HCC. TK-1 protein expression was significantly higher in HCC (p<0.05). The sensitivity of ¹⁸F-FLT-PET for baseline HCC detection was 73% (SUV_max of 9.7 ± 3.0; tumour to liver ratio of 1.2 ± 0.3). Application of KSF did not improve lesion detection. Lesion response following TACE by mRECIST criteria was 58% (14 patients with 24 lesions). A 30% reduction in mean ¹⁸F-FLT-PET uptake was observed following TACE correlating to an observed PET response of 60% (n = 15/25). A significant and profound reduction in radiotracer delivery parameter, K1, following TACE was observed. Conclusion: ¹⁸F-FLT-PET can differentiate HCC from surrounding cirrhotic tissue, with PET parameters correlating with TACE response. KSF did not improve visualization of tumour lesions. These findings warrant further investigation.