Lipiodol as an intra-procedural imaging biomarker for liver tumor response to transarterial chemoembolization: Post-hoc analysis of a prospective clinical trial

Abstract

Background: The use of the ethiodized oil- Lipiodol in conventional trans-arterial chemoembolization (cTACE) ensures radiopacity to visualize drug delivery in the process of providing selective drug targeting to hepatic cancers and arterial embolization. Lipiodol functions as a carrier of chemo drugs for targeted therapy, as an embolic agent, augmenting the drug effect by efflux into the portal veins as well as a predictor for the tumor response and survival.

Purpose: To prospectively evaluate the role of 3D quantitative assessment of intra-procedural Lipiodol deposition in liver tumors on CBCT immediately after cTACE as a predictive biomarker for the outcome of cTACE.

Materials & methods: This was a post-hoc analysis of data from an IRB-approved prospective clinical trial. Thirty-two patients with hepatocellular carcinoma or liver metastases underwent contrast enhanced CBCT obtained immediately after cTACE, unenhanced MDCT at 24 h after cTACE, and follow-up imaging 30-, 90- and 180-days post-procedure. Lipiodol deposition was quantified on CBCT after cTACE and was characterized by 4 ordinal levels: ≤25%, >25-50%, >50-75%, >75%. Tumor response was assessed on follow-up MRI. Lipiodol deposition on imaging, correlation between Lipiodol deposition and tumor response criteria, and correlation between Lipiodol coverage and median overall survival (MOS) were evaluated.

Results: Image analysis demonstrated a high degree of agreement between the Lipiodol deposition on CBCT and the 24 h post-TACE CT, with a Bland-Altman plot of Lipiodol deposition on imaging demonstrated a bias of 2.75, with 95%-limits-of-agreement: -16.6 to 22.1%. An inverse relationship between Lipiodol deposition in responders versus non-responders for two-dimensional EASL reached statistical significance at 30 days (p = 0.02) and 90 days (p = 0.05). Comparing the Lipiodol deposition in Modified Response Evaluation Criteria in Solid Tumors (mRECIST) responders versus non-responders showed a statistically significant higher volumetric deposition in responders for European Association for the Study of the Liver (EASL)-30d, EASL-90d, and quantitative EASL-180d. The correlation between the relative Lipiodol deposition and the change in enhancing tumor volume showed a negative association post-cTACE (30-day: p < 0.001; rho = -0.63). A Kaplan-Meier analysis for patients with high vs. low Lipiodol deposition showed a MOS of 46 vs. 33 months (p = 0.05).

Conclusion: 3D quantification of Lipiodol deposition on intra-procedural CBCT is a predictive biomarker of outcome in patients with primary or metastatic liver cancer undergoing cTACE. There are spatial and volumetric agreements between 3D quantification of Lipiodol deposition on intra-procedural CBCT and 24 h post-cTACE MDCT. The spatial and volumetric agreement between Lipiodol deposition on intra-procedural CBCT and 24 h post-cTACE MDCT could suggest that acquiring MDCT 24 h after cTACE is redundant. Importantly, the demonstrated relationship between levels of tumor coverage with Lipiodol and degree and timeline of tumor response after cTACE underline the role of Lipiodol as an intra-procedural surrogate for tumor response, with potential implications for the prediction of survival.

Keywords: Imaging biomarker; Lipiodol; Liver cancer; TACE; Tumor response; ceMRI.

Conflict of interest statement

Conflict of Interest: Financial remuneration to authors and family members related to the subject of this article: T.S. and J.C. have a grant with Guerbet Pharmaceuticals for conduct of this study. M.L. is a Visage Imaging Research North America employee. Q.R. was a Philips Healthcare employee partly during the conduction of this study.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1:

A three panel CT scan image from one representative patient (HCC in the left hepatic lobe, lobar embolization with catheter positioned in the left hepatic artery) highlighting the Lipiodol segmentation and quantification process. In panel A) the red outline depicts a semi-automated segmentation of the tumor. Panel B) shows the overlay of the three-dimensional structure of the tumor as generated by the segmentation software on a cross-sectional imagine slice. Panel C) depicts the overlay of the quantified Lipiodol deposition heatmap (using a technique analogous to qEASL computation) over a cross-sectional imaging slice.

Figure 2:

Figure depicts a Bland-Altman analysis on the percentage of Lipiodol deposition on intra-procedural CBCT versus 24-hour post-TACE CT. The y-axis represents the percentage difference in amounts of Lipiodol (in the tumor) between the two imaging modalities on a particular patient whereas the x-axis represents the average percentage of Lipiodol deposition (in the tumor) between the two imaging modalities. A high agreement was demonstrated, with a mean bias of 2.7% and 95% limits of agreement (plotted in black dotted lines) between −16.6% and 22.1%.

Figure 3:

Figure depicts a 3-panel scatter plot with error bar measurements, with two subsets of our patient cohort (divided into responders [in black] and non-responders [in gray]). The y-axis in all the panels is the percentage of Lipiodol deposition (in the tumor) on the CBCT scan. The x-axis represents the three post-procedure time points imaging was performed: 30, 90, and 180 days. The three panels depict different tumor response assessment criterion: Panel A) represents mRECIST, Panel B) represents EASL, and Panel C) represents qEASL

Figure 4:

Figure depicts a 3-panel scatter plot with a linear regression trend line. The y-axis in all the panels represents the difference in percentage of residual enhancing tumor volume (normalized to baseline imaging) on the follow-up ceMRI scans. The x-axis represents the percentage of Lipiodol deposition (in the tumor) on CBCT. The three panels depict different time points post-procedure that imaging was performed: Panel A) represents 30 days, Panel B) represents 90 days, and Panel C) represents 180 days. Spearman correlation analysis results and the associate p-values are present in the respective panels as well.

Figure 5:

Figure depicts a Kaplan-Meier survival analysis between patients with high Lipiodol deposition (above the median value, depicted in black) and low Lipiodol deposition (below the median value, depicted in gray). The y-axis represents the percentage of patients in a particular cohort who survived while the x-axis represents the time (number of months post-TACE).