Monitoring Response to Transarterial Chemoembolization in Hepatocellular Carcinoma Using ¹⁸F-Fluorothymidine PET

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 voxelclustering ("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.

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline

“…This was then followed by tracer injection (a maximum dose of 370MBq of [ 18 F]D4-FCH) and dynamic imaging (single-bed position over thorax and mediastinum) for 66 min followed by a half-body static (mid-thigh to vertex) attenuation CT and PET scan (3 min per bed position). Discrete venous bloods and plasma (at 5, 10, 15, 30, 60 min post injection) were obtained for radioactivity counting and metabolite analysis, as previously described 16 , 17 and applied in oncological studies 18 , 19 . The time course of metabolite and parent fraction measured directly by HPLC (experimental data) for D4 Choline are summarized in Figure S1 .…”

The Role of ¹⁸F-FLT PET/CT in Assessing Early Response to Transarterial Radioembolization and Chemoembolization in Patients with Primary and Metastatic Liver Tumors

“…PET/CT imaging with 18 F-FLT, which reflects cell proliferation, is a non-invasive imaging method and has been used for the response evaluation ( 24 , 25 , 26 , 27 ). In addition to complex and competing factors in the FLT uptake mechanism, there are notable differences between patient preparation, imaging time after injection, protocol, amount of injected activity, reconstruction method, analysis techniques, timing before and after treatment, patient numbers, and disease groups in studies with F- 18 FLT PET/CT ( 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ).…”

“…There are few studies investigating the role of FLT PET/CT in evaluating the liver-specific treatment response, considering high background liver uptake especially in HCC patients that hamper the detection of liver/lesions. Studies evaluated therapy of TACE-receiving HCC patients and systemic chemotherapy-receiving liver metastatic colorectal cancer patients ( 28 , 29 , 32 ).…”

“…Sharma et al ( 32 ) investigated the role of 18 F-FLT PET/CT in assessing treatment response to TACE in HCC patients. They used temporal-intensity voxel clustering [kinetic spatial filtering (KSF)] in lesion detection to overcome high background liver signal and thus 18 F-FLT uptake but they could not achieve improvement in lesion detection by applying it.…”

Comparison of the [18F]-FDG and [18F]-FLT PET Tracers in the Evaluation of the Preclinical Proton Therapy Response in Hepatocellular Carcinoma

“…Despite this physiologic retention in the liver, Eckel et al [18] reported a median 20% higher focal uptake by malignant tumors than the surrounding liver, leading to a 69% sensitivity for the detection of HCC. To optimize the tumor-to-liver contrast, Sharma et al proposed in a pilot study to classified each voxel according to their time activity curve [42]. However, they showed that the high and variable SUV limited the improvement of tumor visualization.…”