THE WASHOUT PHENOMENON AS A THERANOSTIC CHALLENGE: A KINETIC ANALYSIS OF 18F-PSMA UPTAKE IN ADVANCED HEPATOCELLULAR CARCINOMA

Abstract

Introduction/Justification

Hepatocellular Carcinoma (HCC) is a highly lethal neoplasm characterized by intense angiogenesis. While Prostate-Specific Membrane Antigen (PSMA) was originally associated with prostate cancer, it is extensively overexpressed in the endothelial cells of the tumor neovasculature in HCC, rather than in the tumor cells themselves. This characteristic positions 18F-PSMA PET/CT as a promising in vivo biomarker for angiogenesis. However, unlike the metabolic trapping observed with other tracers, the temporal behavior of PSMA in HCC is not fully understood. Understanding the kinetic profile of this radiotracer is critical for the “Theranostics” approach, as rapid washout poses a significant challenge regarding the absorbed radiation dose and the efficacy of future Radioligand Therapies (RLT). This study investigates the kinetic behavior of 18F-PSMA in HCC, focusing specifically on the washout pattern observed in dual-time point imaging.

Objectives

To evaluate the kinetic profile and temporal stability of 18F-PSMA uptake in patients with advanced Hepatocellular Carcinoma using a dual-time point PET/CT protocol. Specifically,the study aims to quantify the variation in Maximum Standardized Uptake Value (SUVmax) between early and late acquisitions to characterize the washout phenomenon.

Materials and Methods

This prospective, single-center cohort study was conducted at blinding. The protocol included patients with confirmed advanced or unresectable HCC. Participants underwent a dual-time point 18F-PSMA PET/CT scan. Images were acquired at two distinct time points: Early (90 minutes post-injection) and Late (150 minutes post-injection). The primary quantitative parameter analyzed was the SUVmax of the hepatic lesions. The kinetic variation (SUVmax) was calculated using the formula: DeltaSUVmax(%) = [(Late SUVmax - Early SUVmax) /Early SUVmax] × 100. A negative DeltaSUVmax indicates a washout pattern, while a positive value indicates accumulation/retention.

Results

The cohort consisted of 11 patients (median age 77 years). The 18F-PSMA PET/CT showed positive uptake in the 10 of 11 patients. The kinetic analysis revealed a predominant pattern of signal reduction over time. In the early phase, the mean SUVmax of the lesions was (23.9 ± 10.5). In the late phase, there was a decrease in signal intensity, with the mean SUVmax dropping to 18.3 ± 8.3. The calculation of DeltaSUVmax confirmed a consistent washout phenomenon, with a mean variation of -21.69% ± 28.83%. This kinetic behavior contrasts with the progressive accumulation often seen in tumors where the target is internalized and retained intracellularly.

Conclusion

The study demonstrates that 18F-PSMA in Hepatocellular Carcinoma exhibits a distinct kinetic profile characterized by significant washout between 90 and 150 minutes. This finding supports the hypothesis that PSMA uptake in HCC is primarily related to neovascular density and perfusion dynamics rather than metabolic trapping. These results are clinically relevant for the development of Theranostics in HCC: the rapid washout suggests that a therapeutic approach for PSMA-targeted radioligands may not be possible. Furthermore, it indicates that earlier imaging acquisition times may provide better tumor-to-background contrast than delayed images.