Transarterial Chemoembolization with Drug-eluting Beads in Hepatocellular Carcinoma: Usefulness of Contrast Saturation Features on Cone-Beam Computed Tomography Imaging for Predicting Short-term Tumor Response

doi:10.1016/j.jvir.2013.01.001

Journal of Vascular and Interventional Radiology

Volume 24, Issue 4, April 2013, Pages 483-489

https://doi.org/10.1016/j.jvir.2013.01.001 Get rights and content

Abstract

Purpose

To evaluate the predictability of the short-term tumor response and the clinical usefulness of cone-beam computed tomography (CT) performed immediately after drug-eluting bead (DEB) transarterial chemoembolization in patients with unresectable hepatocellular carcinoma (HCC).

Materials and Methods

This retrospective study comprised 90 patients (male-to-female ratio = 66:24; mean age, 60.4 y) with 119 tumors (mean size, 3.2 cm). All patients underwent DEB transarterial chemoembolization and received cone-beam CT after embolization. The marginal contrast saturation was defined as a contrast stasis that was observed along the margin of the tumor on the cone-beam CT images. The degree of marginal contrast saturation was calculated as a percentage and was classified into five grades in 25% increments. The degree of marginal contrast saturation and the tumor response were correlated based on follow-up imaging.

Results

There was a complete response in 63.8% (n = 76) of all tumors. Partial response, stable disease, and progressive disease were identified in 21.8% (n = 26), 13.4% (n = 16), and 0.8% (n = 1) of tumors. Marginal contrast saturation by cone-beam CT was 86%±16.3, 73.2%±28.8, 16.9%±27.2, and 0% for complete response, partial response, stable disease, and progressive disease, which indicated a significant correlation of a higher contrast saturation with a better response (P<.001) by follow-up imaging criteria. The positive predictive value of the G5 group showing a complete response was 98.1%.

Conclusions

Marginal contrast saturation showed a high positive predictive value for short-term tumor response. This technique may improve the success rates of DEB transarterial chemoembolization procedures and may reduce technical difficulties and shorten procedural time.

Section snippets

Patients

This retrospective study was approved by the institutional review board of our institution, and procedural consent was obtained from each patient. The study included 119 tumors (mean diameter, 3.2 cm) in 90 patients (66 men and 24 women; mean age, 60.4 y) who underwent initial DEB transarterial chemoembolization treatment between March 2010 and March 2011. Diagnosis of HCC was made in all patients based on contrast-enhanced CT or magnetic resonance (MR) imaging. Of the 90 patients, 75 had

Results

The mean size of the 119 tumors was 3.2 cm (range, 1.6–13.5 cm). Of all the tumors, 63.9% (n = 76) showed a CR, and 21.8% (n = 26), 13.4% (n = 16), and 0.8% (n = 1) showed PR, SD, and PD. No major or minor complications related to the transarterial chemoembolization procedure occurred.

For CR, PR, SD, and PD, the degrees of contrast saturation were 86%±16.3, 73.2%±28.8, 16.9%±27.2, and 0%, which indicates that the higher the contrast saturation, the better the response (P<.001). Of G5, G4, G3,

Discussion

Earlier determination of the tumor response may help guide decision making for early additional treatments for patients after transarterial chemoembolization. Histopathologic examination for the determination of tumor response after transarterial chemoembolization is neither feasible nor acceptable, and imaging techniques, such as contrast-enhanced ultrasound, CT, and MR imaging, are widely used to make early clinical decisions (10, 11). Lipiodol (Guerbet, Aulnay-Sous-Bois, France), which is

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Whichever the technique employed in the treatment, the Interventional Radiologist (IR) relies upon monitoring of blood flow reduction by virtue of the contrast media mixed with the beads, in order to judge when sufficient embolic has been delivered to reach the intended end-point. As the beads themselves are not radiodense, there is no way of locating their exact location; but instead, it has become commonplace to use the phenomenon of trapped soluble contrast retention as a surrogate for assessing successful devascularization [12,13]. This requires a CT scan to be performed within the first 6 h of bead administration, as the process of devitalising the tumor means that some of the contrast agent that has been delivered in conjunction with the beads becomes resident in the embolized tissue and its elimination by the usual wash-out mechanisms is retarded.
We have developed a straightforward and efficient method of introducing radiopacity into Polyvinyl alcohol (PVA)-2-Acrylamido-2-methylpropane sulfonic acid (AMPS) hydrogel beads (DC Bead™) that are currently used in the clinic to treat liver malignancies. Coupling of 2,3,5-triiodobenzaldehyde to the PVA backbone of pre-formed beads yields a uniformly distributed level of iodine attached throughout the bead structure (~ 150 mg/mL) which is sufficient to be imaged under standard fluoroscopy and computed tomography (CT) imaging modalities used in treatment procedures (DC Bead LUMI™). Despite the chemical modification increasing the density of the beads to ~ 1.3 g/cm³ and the compressive modulus by two orders of magnitude, they remain easily suspended, handled and administered through standard microcatheters. As the core chemistry of DC Bead LUMI™ is the same as DC Bead™, it interacts with drugs using ion-exchange between sulfonic acid groups on the polymer and the positively charged amine groups of the drugs. Both doxorubicin (Dox) and irinotecan (Iri) elution kinetics for all bead sizes evaluated were within the parameters already investigated within the clinic for DC Bead™. Drug loading did not affect the radiopacity and there was a direct relationship between bead attenuation and Dox concentration. The ability (Dox)-loaded DC Bead LUMI™ to be visualized in vivo was demonstrated by the administration of into hepatic arteries of a VX2 tumor-bearing rabbit under fluoroscopy, followed by subsequent CT imaging.
The Role of Cone-Beam CT in Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis
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Finally, several studies have reported the role of cone-beam CT after delivery of the chemoembolic agents. After transcatheter arterial chemoembolization, unenhanced cone-beam CT acquisition provides immediate verification of uniform saturation of the Lipiodol-based emulsion within the tumor for conventional transcatheter arterial chemoembolization (4,34) and circumferential contrast saturation with drug-eluting bead transcatheter arterial chemoembolization (35). The verification of complete coverage establishes technical success and improved likelihood of local control (36–38), increased time to progression (38,39), and increased overall survival (39).
To review available evidence for use of cone-beam CT during transcatheter arterial chemoembolization in hepatocellular carcinoma (HCC) for detection of tumor and feeding arteries.
Literature searches were conducted from inception to May 15, 2016, in PubMed (MEDLINE), Scopus, and Cochrane Central Register of Controlled Trials. Searches included “cone beam,” “CBCT,” “C-arm,” “CACT,” “cone-beam CT,” “volumetric CT,” “volume computed tomography,” “volume CT,” AND “liver,” “hepatic*,” “hepatoc*.” Studies that involved adults with HCC specifically and treated with transcatheter arterial chemoembolization that used cone-beam CT were included.
Inclusion criteria were met by 18 studies. Pooled sensitivity of cone-beam CT for detecting tumor was 90% (95% confidence interval [CI], 82%–95%), whereas pooled sensitivity of digital subtraction angiography (DSA) for tumor detection was 67% (95% CI, 51%–80%). Pooled sensitivity of cone-beam CT for detecting tumor feeding arteries was 93% (95% CI, 91%–95%), whereas pooled sensitivity of DSA was 55% (95% CI, 36%–74%).
Cone-beam CT can significantly increase detection of tumors and tumor feeding arteries during transcatheter arterial chemoembolization. Cone-beam CT should be considered as an adjunct tool to DSA during transcatheter arterial chemoembolization treatments of HCC.
The Role of Dual-Phase Cone-Beam CT in Predicting Short-Term Response after Transarterial Chemoembolization for Hepatocellular Carcinoma
2017, Journal of Vascular and Interventional Radiology
To identify computational and qualitative features derived from dual-phase cone-beam CT that predict short-term response in patients undergoing transarterial chemoembolization for hepatocellular carcinoma (HCC).
This retrospective study included 43 patients with 59 HCCs. Six features were extracted, including intensity of tumor enhancement on both phases and characteristics of the corona on the washout phase. Short-term response was evaluated by modified Response Evaluation Criteria in Solid Tumors on follow-up imaging, and extracted features were correlated to response using univariate and multivariate analyses.
Univariate and multivariate analyses did not reveal a correlation between absolute and relative tumor enhancement characteristics on either phase with response (arterial P = .21; washout P = .40; ∆ P = .90). On multivariate analysis of qualitative characteristics, the presence of a diffuse corona was an independent predictor of incomplete response (P = .038) and decreased the odds ratio of objective response by half regardless of tumor size.
Computational features extracted from contrast-enhanced dual-phase cone-beam CT are not prognostic of response to transarterial chemoembolization in patients with HCC. HCCs that demonstrate a diffuse, patchy corona have reduced odds of achieving complete response after transarterial chemoembolization and should be considered for additional treatment with an alternative modality.
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The recent use of conformal drug-eluting embolics muddies the issue further. In the past, volumetric intense uptake of lipiodol has been correlated with favorable tumor response (22,25), or for drug-eluting beads circumferential contrast retention (26), including a quasi-objective method using semi-automated volumetric segmentation (27). However, the degree of response varies greatly for tumors that demonstrate non-uniform uptake, and thus, is not a reliable surrogate across all tumors (25).
Intra-procedural measurement of hepatic perfusion following liver embolization continues to be a challenge. Blood volume imaging before and after interventional procedures would allow identifying the treatment end point or even allow predicting treatment outcome. Recent liver oncology studies showed the feasibility of parenchymal blood volume (PBV) imaging using an angiographic C-arm system. This study was done to evaluate the reproducibility of PBV measurements using cone beam computed tomography (CBCT) before and after embolization of the liver in a swine model.
CBCT imaging was performed before and after partial bland embolization of the left lobe of the liver in five adult pigs. Intra-arterial injection of iodinated contrast with a 6-second x-ray delay was used with a two-sweep 8-second rotation imaging protocol. Three acquisitions, each separated by 10 minutes to allow for contrast clearance, were obtained before and after embolization in each animal. Post-processing was carried out using dedicated software to generate three-dimensional (3D) PBV maps. Two region-of-interest measurements were placed on two views within the right and left lobe on each CBCT 3D PBV map. Variation in PBV for scans acquired within each animal was determined by the coefficient of variation and intraclass correlation. A Wilcoxon signed-rank test was used to test post-procedure reduction in PBV.
The CBCT PBV maps showed mean coefficients of variation of 7% (range: 2%–16%) and 25% (range: 13%–34%) for baseline and embolized PBV maps, respectively. The intraclass correlation for PBV measurements was 0.89, demonstrating high reproducibility, with measurable reduction in PBV displayed after embolization (P = 0.007).
Intra-procedural acquisition of 3D PBV maps before and after liver embolization using CBCT is highly reproducible and shows promising application for obtaining intra-procedural PBV maps during locoregional therapy.
Long-term biocompatibility, imaging appearance and tissue effects associated with delivery of a novel radiopaque embolization bead for image-guided therapy
2016, Biomaterials
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However, only the degree of blood flow cessation indicates when sufficient embolic agent has been delivered to achieve the desired flow-based embolization end-point. It has been demonstrated using embolic bead devices that there is a degree of trapped residual soluble contrast agent retention at the site of embolization that dissipates over the next several hours post-procedure [6,7]. CT imaging within a 6 h time frame post-delivery therefore, provides contrast retention as a surrogate marker of bead location and some degree of comfort that the correct blood vessels have been embolized.
The objective of this study was to undertake a comprehensive long-term biocompatibility and imaging assessment of a new intrinsically radiopaque bead (LC Bead LUMI™) for use in transarterial embolization. The sterilized device and its extracts were subjected to the raft of ISO10993 biocompatibility tests that demonstrated safety with respect to cytotoxicity, mutagenicity, blood contact, irritation, sensitization, systemic toxicity and tissue reaction. Intra-arterial administration was performed in a swine model of hepatic arterial embolization in which 0.22–1 mL of sedimented bead volume was administered to the targeted lobe(s) of the liver. The beads could be visualized during the embolization procedure with fluoroscopy, DSA and single X-ray snapshot imaging modalities. CT imaging was performed before and 1 h after embolization and then again at 7, 14, 30 and 90 days. LC Bead LUMI™ could be clearly visualized in the hepatic arteries with or without administration of IV contrast and appeared more dense than soluble contrast agent. The CT density of the beads did not deteriorate during the 90 day evaluation period. The beads embolized predictably and effectively, resulting in areas devoid of contrast enhancement on CT imaging suggesting ischaemia-induced necrosis nearby the sites of occlusion. Instances of off target embolization were easily detected on imaging and confirmed pathologically. Histopathology revealed a classic foreign body response at 14 days, which resolved over time leading to fibrosis and eventual integration of the beads into the tissue, demonstrating excellent long-term tissue compatibility.

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: None of the authors have identified a conflict of interest.

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Clinical StudyTransarterial Chemoembolization with Drug-eluting Beads in Hepatocellular Carcinoma: Usefulness of Contrast Saturation Features on Cone-Beam Computed Tomography Imaging for Predicting Short-term Tumor Response

Abstract

Purpose

Materials and Methods

Results

Conclusions

Section snippets

Patients

Results

Discussion

J Hepatol

J Vasc Interv Radiol

Lancet

J Vasc Interv Radiol

Hepatology

J Vasc Interv Radiol

J Vasc Interv Radiol

Hepatic arterial embolization with doxorubicin-loaded superabsorbent polymer microspheres in a rabbit liver tumor model

Cardiovasc Intervent Radiol

Intrahepatic arterial chemoembolization for hepatocellular carcinoma and metastatic neuroendocrine tumors in the era of liver transplantation

Am Surg

Clinical Study
Transarterial Chemoembolization with Drug-eluting Beads in Hepatocellular Carcinoma: Usefulness of Contrast Saturation Features on Cone-Beam Computed Tomography Imaging for Predicting Short-term Tumor Response