Analysis of Tumor Burden as a Biomarker for Patient Survival with Neuroendocrine Tumor Liver Metastases Undergoing Intra-Arterial Therapies: A Single-Center Retrospective Analysis.

PURPOSE: To assess the value of quantitative analysis of tumor burden on baseline MRI for prediction of survival in patients with neuroendocrine tumor liver metastases (NELM) undergoing intra-arterial therapies. MATERIALS AND METHODS: This retrospective single-center analysis included 122 patients with NELM who received conventional (n = 74) or drug-eluting beads, (n = 20) chemoembolization and radioembolization (n = 28) from 2000 to 2014. Overall tumor diameter (1D) and area (2D) of up to 3 largest liver lesions were measured on baseline arterially contrast enhanced MR images. Three-dimensional quantitative analysis was performed using the qEASL tool (IntelliSpace Portal Version 8, Philips) to calculate enhancing tumor burden (the ratio between enhancing tumor volume and total liver volume). Based on Q-statistics, patients were stratified into low tumor burden (TB) or high TB. RESULTS: The survival curves were significantly separated between low TB and high TB groups for 1D (p < 0.001), 2D (p < 0.001) and enhancing TB (p = 0.008) measurements, with, respectively, 2.7, 2.6 and 2.2 times longer median overall survival (MOS) in the low TB group (p < 0.001, p < 0.001 and p = 0.008). Multivariate analysis showed that 1D, 2D, and enhancing TB were independent prognostic factors for MOS, with respective hazard ratios of 0.4 (95%CI: 0.2-0.6, p < 0.001), 0.4 (95%CI: 0.3-0.7, p < 0.001) and 0.5 (95%CI: 0.3-0.8, p = 0.003). CONCLUSION: The overall tumor diameter, overall tumor area, and enhancing tumor burden are strong prognostic factors of overall survival in patients with neuroendocrine tumor liver metastases undergoing intra-arterial therapies.

Lipiodol Deposition and Washout in Primary and Metastatic Liver Tumors After Chemoembolization.

BACKGROUND/AIM: Lipiodol is the key component of conventional trans-arterial chemoembolization. Our aim was to evaluate lipiodol deposition and washout rate after conventional trans-arterial chemoembolization in intrahepatic cholangiocarcinoma and hepatic metastases originating from neuroendocrine tumors and colorectal carcinoma. PATIENTS AND METHODS: This was a retrospective analysis of 44 patients with intrahepatic cholangiocarcinoma and liver metastasis from neuroendocrine tumors or colorectal carcinoma who underwent conventional trans-arterial chemoembolization. Lipiodol volume (cm3) was analyzed on non-contrast computed tomography imaging obtained within 24 h post conventional trans-arterial chemoembolization, and 40-220 days after conventional trans-arterial chemoembolization using volumetric image analysis software. Tumor response was assessed on contrast-enhanced magnetic resonance imaging 1 month after conventional trans-arterial chemoembolization. RESULTS: The washout rate was longer for neuroendocrine tumors compared to colorectal carcinoma, with half-lives of 54.61 days (p<0.00001) and 19.39 days (p<0.001), respectively, with no exponential washout among intrahepatic cholangiocarcinomas (p=0.83). The half-life for lipiodol washout was longer in tumors larger than 300 cm3 compared to smaller tumors (25.43 vs. 22.71 days). Lipiodol wash out half-life was 54.76 days (p<0.01) and 29.45 days (p<0.00001) for tumors with a contrast enhancement burden of 60% or more and less than 60%, respectively. A negative exponential relationship for lipiodol washout was observed in non-responders (p<0.00001). CONCLUSION: Lipiodol washout is a time-dependent process, and occurs faster in colorectal carcinoma tumors, tumors smaller than 300 cm3, tumors with baseline contrast enhancement burden of less than 60%, and non-responding target lesions.

Role of 3D quantitative tumor analysis for predicting overall survival after conventional chemoembolization of intrahepatic cholangiocarcinoma.

This study was designed to assess 3D vs. 1D and 2D quantitative tumor analysis for prediction of overall survival (OS) in patients with Intrahepatic Cholangiocarcinoma (ICC) who underwent conventional transarterial chemoembolization (cTACE). 73 ICC patients who underwent cTACE were included in this retrospective analysis between Oct 2001 and Feb 2015. The overall and enhancing tumor diameters and the maximum cross-sectional and enhancing tumor areas were measured on baseline images. 3D quantitative tumor analysis was used to assess total tumor volume (TTV), enhancing tumor volume (ETV), and enhancing tumor burden (ETB) (ratio between ETV and liver volume). Patients were divided into low (LTB) and high tumor burden (HTB) groups. There was a significant separation between survival curves of the LTB and HTB groups using enhancing tumor diameter (p = 0.003), enhancing tumor area (p = 0.03), TTV (p = 0.03), and ETV (p = 0.01). Multivariate analysis showed a hazard ratio of 0.46 (95%CI: 0.27-0.78, p = 0.004) for enhancing tumor diameter, 0.56 (95% CI 0.33-0.96, p = 0.04) for enhancing tumor area, 0.58 (95%CI: 0.34-0.98, p = 0.04) for TTV, and 0.52 (95%CI: 0.30-0.91, p = 0.02) for ETV. TTV and ETV, as well as the largest enhancing tumor diameter and maximum enhancing tumor area, reliably predict the OS of patients with ICC after cTACE and could identify ICC patients who are most likely to benefit from cTACE.

Theranostic application of lipiodol for transarterial chemoembolization in a VX2 rabbit liver tumor model.

The goal of this study was to investigate the role of Lipiodol as a tumor-specific imaging biomarker to determine therapeutic efficacy of cTACE and investigate its inter-dependency with tumor perfusion using radiological-pathological correlation in an animal model of liver cancer. METHODS: A total of N=36 rabbits were implanted in the left lobe of the liver with VX2 tumors, treated with cTACE using doxorubicin suspended in Lipiodol, and randomly sacrificed at 24 h, 7 days, or 20 days post-TACE. Unenhanced and contrast-enhanced CT scans including a perfusion protocol were obtained before cTACE and immediately before sacrifice. Tumor vascularity and Lipiodol deposition within tumors and hepatic tissue (non-target deposits) were quantified using 3D quantitative assessment tools and measurements of arterial flow, portal flow, and perfusion index (PI). After sacrifice histologic staining, including hematoxylin and eosin (H&E), CD31, and Oil Red O (ORO) were performed on tumor and liver samples to evaluate necrosis, microvascular density (MVD), and Lipiodol retention over time. Transmission electron microscopy (TEM) was performed to assess Lipiodol deposition and clearance over time. RESULTS: All cTACE procedures were carried out successfully except for one, which was excluded from further analysis. Twenty-four hours post-TACE, tumor PI (p=0.04) was significantly decreased, which was maintained at 7 days (p=0.003), but not at 20 days (p=0.4). A strong correlation (R2 = 0.894) was found between the volume of enhancing tumor tissue at baseline and Lipiodol-positive tumor volume post-TACE. Both ORO and TEM showed deposition of Lipiodol across all imaging time points within the VX2 tumors. However, gradual and ultimately near-complete Lipiodol washout was observed over time in the non-tumoral liver. MVD decreased between 24 h and 7 days post-TACE, and then increased 20 days post-TACE (both p<0.01). CONCLUSIONS: Our data provide radiology-pathology evidence for the function of Lipiodol as a theranostic, tumor-specific drug delivery agent because it is both imageable and tumor-seeking, whereby it is preferentially taken up and retained by tumor cells. Those tumor-specific functions also enable Lipiodol to act as an imaging biomarker for the therapeutic efficacy of cTACE. Together with volumetric quantification of tumor vascularization on CT, Lipiodol could be used as a predictor of a patient's response to cTACE and contribute to the therapeutic management of patients with liver cancer.