Prospective study of Lipiodol distribution as an imaging marker for doxorubicin pharmacokinetics during conventional transarterial chemoembolization of liver malignancies.

OBJECTIVES: To evaluate the prognostic potential of Lipiodol distribution for the pharmacokinetic (PK) profiles of doxorubicin (DOX) and doxorubicinol (DOXOL) after conventional transarterial chemoembolization (cTACE). METHODS: This prospective clinical trial ( ClinicalTrials.gov : NCT02753881) included 30 consecutive participants with liver malignancies treated with cTACE (5/2016-10/2018) using 50 mg DOX/10 mg mitomycin C emulsified 1:2 with ethiodized oil (Lipiodol). Peripheral blood was sampled at 10 timepoints for standard non-compartmental analysis of peak concentrations (Cmax) and area under the curve (AUC) with dose normalization (DN). Imaging markers included Lipiodol distribution on post-cTACE CT for patient stratification into 1 segment (n = 10), ≥ 2 segments (n = 10), and lobar cTACE (n = 10), and baseline enhancing tumor volume (ETV). Adverse events (AEs) and tumor response on MRI were recorded 3-4 weeks post-cTACE. Statistics included repeated measurement ANOVA (RM-ANOVA), Mann-Whitney, Kruskal-Wallis, Fisher's exact test, and Pearson correlation. RESULTS: Hepatocellular (n = 26), cholangiocarcinoma (n = 1), and neuroendocrine metastases (n = 3) were included. Stratified according to Lipiodol distribution, DOX-Cmax increased from 1 segment (DOX-Cmax, 83.94 ± 75.09 ng/mL; DN-DOX-Cmax, 2.67 ± 2.02 ng/mL/mg) to ≥ 2 segments (DOX-Cmax, 139.66 ± 117.73 ng/mL; DN-DOX-Cmax, 3.68 ± 4.20 ng/mL/mg) to lobar distribution (DOX-Cmax, 334.35 ± 215.18 ng/mL; DN-DOX-Cmax, 7.11 ± 4.24 ng/mL/mg; p = 0.036). While differences in DN-DOX-AUC remained insignificant, RM-ANOVA revealed significant separation of time concentration curves for DOX (p = 0.023) and DOXOL (p = 0.041) comparing 1, ≥ 2 segments, and lobar cTACE. Additional indicators of higher DN-DOX-Cmax were high ETV (p = 0.047) and Child-Pugh B (p = 0.009). High ETV and tumoral Lipiodol coverage also correlated with tumor response. AE occurred less frequently after segmental cTACE. CONCLUSIONS: This prospective clinical trial provides updated PK data revealing Lipiodol distribution as an imaging marker predictive of DOX-Cmax and tumor response after cTACE in liver cancer. KEY POINTS: • Prospective pharmacokinetic analysis after conventional TACE revealed Lipiodol distribution (1 vs. ≥ 2 segments vs. lobar) as an imaging marker predictive of doxorubicin peak concentrations (Cmax). • Child-Pugh B class and tumor hypervascularization, measurable as enhancing tumor volume (ETV) at baseline, were identified as additional predictors for higher dose-normalized doxorubicin Cmax after conventional TACE. • ETV at baseline and tumoral Lipiodol coverage can serve as predictors of volumetric tumor response after conventional TACE according to quantitative European Association for the Study of the Liver (qEASL) criteria.

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.

Predicting Treatment Response to Intra-arterial Therapies for Hepatocellular Carcinoma with the Use of Supervised Machine Learning-An Artificial Intelligence Concept.

PURPOSE: To use magnetic resonance (MR) imaging and clinical patient data to create an artificial intelligence (AI) framework for the prediction of therapeutic outcomes of transarterial chemoembolization by applying machine learning (ML) techniques. MATERIALS AND METHODS: This study included 36 patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization. The cohort (age 62 ± 8.9 years; 31 men; 13 white; 24 Eastern Cooperative Oncology Group performance status 0, 10 status 1, 2 status 2; 31 Child-Pugh stage A, 4 stage B, 1 stage C; 1 Barcelona Clinic Liver Cancer stage 0, 12 stage A, 10 stage B, 13 stage C; tumor size 5.2 ± 3.0 cm; number of tumors 2.6 ± 1.1; and 30 conventional transarterial chemoembolization, 6 with drug-eluting embolic agents). MR imaging was obtained before and 1 month after transarterial chemoembolization. Image-based tumor response to transarterial chemoembolization was assessed with the use of the 3D quantitative European Association for the Study of the Liver (qEASL) criterion. Clinical information, baseline imaging, and therapeutic features were used to train logistic regression (LR) and random forest (RF) models to predict patients as treatment responders or nonresponders under the qEASL response criterion. The performance of each model was validated using leave-one-out cross-validation. RESULTS: Both LR and RF models predicted transarterial chemoembolization treatment response with an overall accuracy of 78% (sensitivity 62.5%, specificity 82.1%, positive predictive value 50.0%, negative predictive value 88.5%). The strongest predictors of treatment response included a clinical variable (presence of cirrhosis) and an imaging variable (relative tumor signal intensity >27.0). CONCLUSIONS: Transarterial chemoembolization outcomes in patients with HCC may be predicted before procedures by combining clinical patient data and baseline MR imaging with the use of AI and ML techniques.

Sorafenib use for recurrent hepatocellular cancer after resection or transplantation: Observations from a US regional analysis of the GIDEON registry.

Treatment of unresectable recurrent hepatocellular carcinoma (HCC) in patients who recur after resection or orthotopic liver transplantation (OLT) remains a clinical challenge. One option is sorafenib, although little is known about its safety and tolerance in this unique patient population; therefore, we analyzed patients who underwent prior surgical resection and/or OLT and were treated with sorafenib in US cohort of GIDEON registry. In US, 645 patients were enrolled; 553 for intent to treat and 563 for safety. Data were analyzed in the safety population of 479 patients no surgery and 56 for resection or OLT. Forty-one patients underwent resection prior to the initiation of sorafenib, 15 patients had previously received an OLT, and 6 patients had both resection and OLT. Initial low starting doses (400 mg/day) were observed for more patients with prior OLT (71%) than prior resection (36%), resection and OLT (50%), concomitant OLT (25%), and no surgery (36%). Most AEs occurred in the first 4 weeks of treatment. Drug-related AEs were higher in patients with prior resection (87%), prior OLT (100%), or both (100%) than in patients with concomitant OLT (63%) or no surgery (70%). However, incidence of AEs resulting in permanent discontinuation were similar in all groups (19-38%).

Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer.

PURPOSE: To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intra-arterial therapy (HAIAT) with evofosfamide in a rabbit model. EXPERIMENTAL DESIGN: VX2-tumor-bearing rabbits were assigned to 4 intra-arterial therapy (IAT) groups (n = 7/group): (i) saline (control); (ii) evofosfamide (Evo); (iii) doxorubicin-lipiodol emulsion followed by embolization with 100-300 µm beads (conventional, cTACE); or (iv) cTACE and evofosfamide (cTACE + Evo). Blood samples were collected pre-IAT and 1, 2, 7, and 14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole-slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia, and metabolism were quantified (γ-H2AX, Annexin V, caspase-3, Ki-67, HIF1α, VEGF, GAPDH, MCT4, and LDH). RESULTS: cTACE + Evo showed a similar profile of liver enzymes elevation and pathologic scores compared with cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE + Evo demonstrated smaller tumor volumes, lower tumor growth rates, and higher necrotic fractions compared with cTACE. cTACE + Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE + Evo promoted antitumor effects as evidenced by increased expression of γ-H2AX, apoptotic biomarkers, and decreased cell proliferation. Increased HIF1α/VEGF expression and tumor glycolysis supported HAIAT. CONCLUSIONS: HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer. Clin Cancer Res; 23(2); 536-48. ©2016 AACR.

Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study.

BACKGROUND & AIMS: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction. METHODS: Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up. RESULTS: In the overall safety population (n=3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n=3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8-14.7]) compared with Child-Pugh B patients (5.2 [4.6-6.3]). CONCLUSIONS: In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions. LAY SUMMARY: The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment.

Regional differences in sorafenib-treated patients with hepatocellular carcinoma: GIDEON observational study.

BACKGROUND & AIMS: Treatment approaches for hepatocellular carcinoma (HCC) vary across countries, but these differences and their potential impact on outcomes have not been comprehensively assessed. Data from the multinational GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) registry evaluated differences in patient characteristics, practice patterns and outcomes in HCC across geographical regions in patients who received sorafenib. METHODS: GIDEON is a non-randomised, observational registry study conducted in 39 countries across five global regions. HCC patients in whom a decision to treat with sorafenib was made in clinical practice and according to local practices were included. RESULTS: 3202 patients were evaluable for safety analysis: Asia-Pacific (n = 928), Japan (n = 508), Europe (n = 1113), USA (n = 563) and Latin America (n = 90). Patients in Japan had earlier-stage disease at initial diagnosis compared with patients in other regions (Barcelona Clinic Liver Cancer stage A; 43.7% vs 9.1-24.3%). Use of locoregional therapies before sorafenib, including transarterial chemoembolisation, was more common in Japan (84.4%) and Asia-Pacific (67.2%) compared with the USA (49.4%) and Europe (43.5%). Treatment patterns with respect to sorafenib also differed, with a shorter duration of treatment reported in the USA and Asia-Pacific. Time from initial diagnosis to death was longer in Japan compared with other regions (median, 79.6 months vs 14.8-25.0 months). CONCLUSIONS: Data from GIDEON highlight regional variations in the management of HCC and patient outcomes. Greater standardisation of management may help optimise outcomes for HCC patients.

TACE Treatment in Patients with Sorafenib-treated Unresectable Hepatocellular Carcinoma in Clinical Practice: Final Analysis of GIDEON.

PURPOSE: To evaluate transarterial chemoembolization (TACE) use prior to and concomitantly with sorafenib in patients with unresectable hepatocellular carcinoma (HCC) across different global regions. MATERIALS AND METHODS: GIDEON is an observational registry study of more than 3000 HCC patients. Patients with histologically, cytologically, or radiographically diagnosed HCC, and for whom a decision had been made to treat with sorafenib, were eligible. Patients were enrolled into the registry from 39 countries beginning in January 2009, with the last patient follow-up in April 2012. Detailed data on treatment history, treatment patterns, adverse events, and outcomes were collected. All treatment decisions were at the discretion of the treating physicians. Documented approval from local ethics committees was obtained, and all patients provided signed informed consent. Descriptive statistics, including minimum, median, and maximum, were calculated for metric data, and frequency tables for categorical data. Kaplan-Meier estimates with 95% confidence intervals were calculated for survival end points. RESULTS: A total of 3202 patients were eligible for safety analysis, of whom 2631 (82.2%) were male. Median age was 62 years (range, 15-98 years). A total of 1511 (47.2%) patients underwent TACE prior to sorafenib; 325 (10.1%) underwent TACE concomitantly. TACE prior to sorafenib was more common in Japan and Asia-Pacific compared with all other regions (362 [71.3%] and 560 [60.3%] vs 12-209 [13.3%-37.1%]). Adverse events were reported in 2732 (85.3%) patients overall, with no notable differences in the incidence of adverse events, regardless of TACE treatment history. Overall survival was 12.7 months in prior-TACE patients, 9.2 months in non-prior-TACE patients, 21.6 months in concomitant-TACE patients, and 9.7 months in non-concomitant-TACE patients. CONCLUSION: Global variation exists in TACE use in sorafenib-treated HCC patients. The combination of TACE with sorafenib appears to be a well-tolerated and viable therapeutic approach.

Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data.

UNLABELLED: Transarterial chemoembolization (TACE) using lipiodol-based regimens, including the administration of an anticancer-in-oil emulsion followed by embolic agents, is widely used in the treatment of hepatocellular carcinoma (HCC). This approach has been supported by meta-analyses of randomized, controlled trials (RCTs) performed more than a decade ago. We performed a systematic review to understand current efficacy and safety data of lipiodol TACE in treatment of HCC. A search of the literature published between January 1, 1980 and June 30, 2013 was performed using MEDLINE and EMBASE databases. All potentially relevant publications were reviewed and articles were selected based on predefined inclusion and exclusion criteria. Of a total of 1,564 articles reviewed, 101 articles, including a total of 10,108 patients treated with lipiodol TACE, were selected for the efficacy analysis. Objective response rate was 52.5% (95% confidence interval [CI]: 43.6-61.5). Overall survival (OS) was 70.3% at 1 year, 51.8% at 2 years, 40.4% at 3 years, and 32.4% at 5 years. Median OS was 19.4 months (95% CI: 16.2-22.6). A total of 217 articles presenting precise description on numbers of adverse events (AEs) were selected for the safety review: In these studies, a total of 21,461 AEs were reported in 15,351 patients. Liver enzyme abnormalities were the most commonly observed AE, followed by the symptoms associated with postembolization syndrome. Overall mortality rate was 0.6% and the most common cause of death was related to acute liver insufficiency. CONCLUSIONS: In a systematic literature review, survival figures of HCC patients undergoing lipiodol TACE appear to be in line with those reported in previous RCTs, and no new or unexpected safety concerns were identified. (Hepatology 2016;64:106-116).

A Novel Inherently Radiopaque Bead for Transarterial Embolization to Treat Liver Cancer - A Pre-clinical Study.

PURPOSE: Embolotherapy using microshperes is currently performed with soluble contrast to aid in visualization. However, administered payload visibility dimishes soon after delivery due to soluble contrast washout, leaving the radiolucent bead's location unknown. The objective of our study was to characterize inherently radiopaque beads (RO Beads) in terms of physicomechanical properties, deliverability and imaging visibility in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: RO Beads, which are based on LC Bead® platform, were compared to LC Bead. Bead size (light microscopy), equilibrium water content (EWC), density, X-ray attenuation and iodine distribution (micro-CT), suspension (settling times), deliverability and in vitro penetration were investigated. Fifteen rabbits were embolized with either LC Bead or RO Beads + soluble contrast (iodixanol-320), or RO Beads+dextrose. Appearance was evaluated with fluoroscopy, X-ray single shot, cone-beam CT (CBCT). RESULTS: Both bead types had a similar size distribution. RO Beads had lower EWC (60-72%) and higher density (1.21-1.36 g/cc) with a homogeneous iodine distribution within the bead's interior. RO Beads suspension time was shorter than LC Bead, with durable suspension (>5 min) in 100% iodixanol. RO Beads ≤300 µm were deliverable through a 2.3-Fr microcatheter. Both bead types showed similar penetration. Soluble contrast could identify target and non-target embolization on fluoroscopy during administration. However, the imaging appearance vanished quickly for LC Bead as contrast washed-out. RO Beads+contrast significantly increased visibility on X-ray single shot compared to LC Bead+contrast in target and non-target arteries (P=0.0043). Similarly, RO beads demonstrated better visibility on CBCT in target arteries (P=0.0238) with a trend in non-target arteries (P=0.0519). RO Beads+dextrose were not sufficiently visible to monitor embolization using fluoroscopy. CONCLUSION: RO Beads provide better conspicuity to determine target and non-target embolization compared to LC Bead which may improve intra-procedural monitoring and post-procedural evaluation of transarterial embolization.

Treatment of Liver Tumors with Lipiodol TACE: Technical Recommendations from Experts Opinion.

Transarterial chemoembolization with Lipiodol (Lipiodol TACE), also called conventional TACE, was developed in the early 1980s and widely adopted worldwide after randomized control trials and meta-analysis demonstrated superiority of Lipiodol TACE to best supportive care. Presently, there is no level one evidence that other TACE techniques are superior to Lipiodol TACE for intermediate stage hepatocellular carcinoma (HCC), which includes patients with preserved liver function and nonsurgical large or multinodular HCC without distant metastases. In addition, TACE is part of the treatment for progressive or symptomatic liver metastases from gastroenteropancreatic neuroendocrine tumors. When injected into the hepatic artery, Lipiodol has the unique property of selective uptake and retention in hyperarterialyzed liver tumors. Lipiodol/drug emulsion followed by particle embolization has been demonstrated to improve the pharmacokinetic of the drug and tumor response. Radio opacity of Lipiodol helps to monitor treatment delivery, with retention of Lipiodol serving as an imaging biomarker for tumor response. For 30 years, Lipiodol TACE has been inconsistently referenced in many publications with various levels of details for the method of preparation and administration, with reported progressive outcomes following improvements in the technique and the devices used to deliver the treatment and better patient selection. Consequently, there is no consensus on the standard method of TACE regarding the use of anticancer agents, embolic material, technical details, and the treatment schedule. In order to develop an internationally validated technical recommendation to standardize the Lipiodol TACE procedure, a worldwide panel of experts participated in a consensus meeting held on May 10, 2014 .

Multimodality Imaging of Ethiodized Oil-loaded Radiopaque Microspheres during Transarterial Embolization of Rabbits with VX2 Liver Tumors.

Purpose To assess the visibility of radiopaque microspheres during transarterial embolization (TAE) in the VX2 rabbit liver tumor model by using multimodality imaging, including single-snapshot radiography, cone-beam computed tomography (CT), multidetector CT, and micro-CT. Materials and Methods The study was approved by the institutional animal care and use committee. Fifteen VX2-tumor-bearing rabbits were assigned to three groups depending on the type of embolic agent injected: 70-150-µm radiopaque microspheres in saline (radiopaque microsphere group), 70-150-µm radiopaque microspheres in contrast material (radiopaque microsphere plus contrast material group), and 70-150-µm radiolucent microspheres in contrast material (nonradiopaque microsphere plus contrast material group). Rabbits were imaged with single-snapshot radiography, cone-beam CT, and multidetector CT. Three to 5 weeks after sacrifice, excised livers were imaged with micro-CT and histologic analysis was performed. The visibility of the embolic agent was assessed with all modalities before and after embolization by using a qualitative three-point scale score reading study and a quantitative assessment of the signal-to-noise ratio (SNR) change in various regions of interest, including the tumor and its feeding arteries. The Kruskal-Wallis test was used to compare the rabbit characteristics across groups, and the Wilcoxon signed rank test was used to compare SNR measurements before and after embolization. Results Radiopaque microspheres were qualitatively visualized within tumor feeding arteries and targeted tissue with all imaging modalities (P < .05), and their presence was confirmed with histologic examination. SNRs of radiopaque microsphere deposition increased after TAE on multidetector CT, cone-beam CT, and micro-CT images (P < .05). Similar results were obtained when contrast material was added to radiopaque microspheres, except for additional image attenuation due to tumor enhancement. For the group with nonradiopaque microspheres and contrast material, retained tumoral contrast remained qualitatively visible with all modalities except for micro-CT, which demonstrated soluble contrast material washout over time. Conclusion Radiopaque microspheres were visible with all imaging modalities and helped increase conspicuity of the tumor as well as its feeding arteries after TAE in a rabbit VX2 liver tumor model. (©) RSNA, 2015.

Open-Label Single-Arm Phase II Trial of Sorafenib Therapy with Drug-eluting Bead Transarterial Chemoembolization in Patients with Unresectable Hepatocellular Carcinoma: Clinical Results.

PURPOSE: To determine the efficacy of combined continuous sorafenib therapy and drug-eluting bead (DEB) transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was conducted in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent prior to enrollment. Inclusion criteria included unresectable HCC, a treatment naïve status, an Eastern Cooperative Oncology Group score of 0-1, and a Child-Pugh score of A-B7. Continuous sorafenib therapy (400 mg twice daily) was started 1 week before the first round of DEB TACE, which was performed in 6-week cycles. Up to four rounds of DEB TACE therapy were allowed on demand within 6 months. The primary end point was safety. Secondary end points were time to progression (TTP), response rate, and overall survival (OS) and were stratified by the Barcelona Clinic Liver Cancer (BCLC) stage and the duration of sorafenib therapy. OS was assessed with Kaplan-Meier estimates, and the Mantel-Cox log-rank test was used to determine differences in survival. A two-sided P value of less than .05 was considered to indicate a significant difference. The study was approved by the Johns Hopkins institutional review board and remained open from March 2009 to January 2012. RESULTS: Fifty patients--of whom 76% were male, 92% had a Child-Pugh score of A, and 62% had BCLC stage C disease--underwent a median of three cycles of therapy. The 6-month disease control rate (defined as complete response plus partial response plus stable disease) was 94% according to the response evaluation criteria in solid tumors. Median TTP and OS were 13.9 and 20.4 months, respectively, and 81% of toxicities were grades 1-2. There was one death that was possibly treatment related. CONCLUSION: Combined continuous sorafenib therapy and on-demand DEB TACE provided excellent local disease control and did not lead to multiplicative toxicities. Long-term administration of sorafenib therapy in combination with DEB TACE may have a survival benefit in patients with advanced HCC.

Intraprocedural 3D Quantification of Lipiodol Deposition on Cone-Beam CT Predicts Tumor Response After Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma.

PURPOSE: To evaluate whether intraprocedural 3D quantification of Lipiodol deposition on cone-beam computed tomography (CBCT) can predict tumor response on follow-up contrast-enhanced magnetic resonance imaging (CE-MRI) in patients with hepatocellular carcinoma (HCC) treated with conventional transarterial chemoembolization (cTACE). MATERIALS AND METHODS: This IRB approved, retrospective analysis included 36 patients with 51 HCC target lesions, who underwent cTACE with CBCT. CE-MRI was acquired at baseline and 1 month after cTACE. Overall tumor volumes as well as intratumoral Lipiodol volumes on CBCT were measured and compared with the overall and necrotic (non-enhancing) tumor volumes on CE-MRI using the paired student's t test. Tumor response on CE-MRI was assessed using modified response evaluation criteria in solid tumors (mRECIST). A linear regression model was used to correlate tumor volumes, Lipiodol volumes, and the percentage of Lipiodol deposition on CBCT with the corresponding parameters on CE-MRI. Nonparametric spearman rank-order correlation and trend test were used to correlate the percentage of Lipiodol deposition in the tumor with tumor response. RESULT: A strong correlation between overall tumor volumes on CBCT and CE-MRI was observed (R(2) = 0.986). In addition, a strong correlation was obtained between the volume of Lipiodol deposition on CBCT and tumor necrosis (in cm(3)) on CE-MRI (R(2) = 0.960), and between the percentage of Lipiodol deposition and tumor necrosis (R(2) = 0.979). Importantly, the extent of Lipiodol deposition (in percentage of total tumor volume) correlated strongly with tumor response on CE-MRI (Spearman rho = 0.84, p < 0.001). CONCLUSIONS: Intraprocedural 3D quantification of Lipiodol deposition on CBCT can be used to predict tumor response on follow-up CE-MRI.

Combination of intra-arterial therapies and sorafenib: is there a clinical benefit?

Intra-arterial therapies (IATs) play a major role in the treatment of patients with unresectable hepatocellular carcinoma. Over the last three decades, multiple loco-regional approaches such as transarterial chemoembolization or radioembolization were shown to effectively achieve local tumor control, offering significant survival benefits for selected patients with intermediate to advanced-stage disease (Barcelona Clinic Liver Cancer stage B and C). These therapies provide a dual benefit of safely delivering a highly cytotoxic payload directly to the tumor while reducing systemic toxicity. This capability maintained the advantage of IATs over conventional systemic chemotherapy. The introduction of sorafenib as a systemically applicable drug, the first of its kind to provide survival benefits by means of oral monotherapy, contributed to a paradigm change. The idea of combining this novel agent with IATs seemed intriguing, and a variety of national and international clinical trials were initiated to explore the potential benefits of this exciting new option. A plethora of preliminary data has been made available throughout the last 5 years, and the interpretation of the inhomogeneously designed protocols proved difficult. In this review, we will provide a brief state-of-the-art update on the most frequently used intra-arterial modalities and discuss the molecular mechanism, potential biomarkers as well as the safety profile of sorafenib. Furthermore, we will discuss the role of the sequence of administration in combined therapies. Finally, this review will examine the evidence for clinical outcomes for the combination of different IATs with sorafenib.

Three-dimensional evaluation of lipiodol retention in HCC after chemoembolization: a quantitative comparison between CBCT and MDCT.

RATIONALE AND OBJECTIVES: To evaluate the capability of cone-beam computed tomography (CBCT) acquired immediately after transcatheter arterial chemoembolization (TACE) in determining lipiodol retention quantitatively and volumetrically when compared to 1-day postprocedure unenhanced multidetector computed tomography (MDCT). MATERIALS AND METHODS: From June to December 2012, 15 patients met the inclusion criteria of unresectable hepatocellular carcinoma (HCC) that was treated with conventional TACE (cTACE) and had intraprocedural CBCT and 1-day post-TACE MDCT. Four patients were excluded because the lipiodol was diffuse throughout the entire liver or lipiodol deposition was not clear on both CBCT and MDCT. Eleven patients with a total of 31 target lesions were included in the analysis. A quantitative three-dimensional software was used to assess complete, localized, and diffuse lipiodol deposition. Tumor volume, lipiodol volume in the tumor, percent lipiodol retention, and lipiodol enhancement in Hounsfield units (HU) were calculated and compared between CBCT and MDCT using two-tailed Student's t test and Bland-Altman plots. RESULTS: The mean value of tumor volume, lipiodol-deposited regions, calculated average percent lipiodol retention, and HU value of CBCT were not significantly different from those of MDCT (tumor volume: 9.37 ± 11.35 cm(3) vs 9.34 ± 11.44 cm(3), P = .991; lipiodol volume: 7.84 ± 9.34 cm(3) vs 7.84 ± 9.60 cm(3), P = .998; lipiodol retention: 89.3% ± 14.7% vs. 90.2% ± 14.9%, P = .811; HU value: 307.7 ± 160.1 HU vs. 257.2 ± 120.0 HU, P = .139). Bland-Altman plots showed only minimal difference and high agreement when comparing CBCT to MDCT. CONCLUSIONS: CBCT has a similar capability, intraprocedurally, to assess lipiodol deposition in three dimensions for patients with HCC treated with cTACE when compared to MDCT.

Quantitative assessment of lipiodol deposition after chemoembolization: comparison between cone-beam CT and multidetector CT.

PURPOSE: To evaluate the ability of cone-beam computed tomography (CBCT) performed directly after transarterial chemoembolization to assess ethiodized oil (Lipiodol) deposition in hepatocellular carcinoma (HCC) and compare it with unenhanced multidetector computed tomography (CT). MATERIALS AND METHODS: Conventional transarterial chemoembolization was used to treat 15 patients with HCC, and CBCT was performed to assess Lipiodol deposition directly after transarterial chemoembolization. Unenhanced multidetector CT was performed 24 hours after transarterial chemoembolization. Four patients were excluded because the margin of tumor or area of Lipiodol deposition was unclear. The image enhancement density of the entire tumor and liver parenchyma was measured by ImageJ software, and tumor-to-liver contrast (TLC) was calculated. In addition, volumetric measurement of tumor and Lipiodol was performed by semiautomatic three-dimensional volume segmentation and compared using linear regression to evaluate consistency between the two imaging modalities. RESULTS: The mean value of TLC on CBCT was not significantly different from TLC on multidetector CT (337.7 HU ± 233.5 vs 283.0 HU ± 152.1, P = .103).The average volume of the whole tumor and of only the regions with Lipiodol deposition and the calculated average percentage of Lipiodol retention on CBCT were not significantly different compared with multidetector CT (tumor volume, 9.6 cm(3) ± 11.8 vs 10.8 cm(3) ± 14.2, P = .142; Lipiodol volume, 6.3 cm(3) ± 7.7 vs 7.0 cm(3) ± 8.1, P = .214; percentage of Lipiodol retention, 68.9% ± 24.0% vs 72.2% ± 23.1%, P = .578). Additionally, there was a high correlation in the volume of tumor and Lipiodol between CBCT and multidetector CT (R(2) = 0.919 and 0.903). CONCLUSIONS: The quantitative image enhancement and volume analyses demonstrate that CBCT is similar to multidetector CT in assessing Lipiodol deposition in HCC after transarterial chemoembolization.

Consensus recommendations and review by an International Expert Panel on Interventions in Hepatocellular Carcinoma (EPOIHCC).

Hepatocellular carcinoma (HCC) presents with a high burden of disease in East Asian countries. Intermediate-stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) staging system poses a clinical challenge as it includes a heterogeneous population of patients that can vary widely in terms of tumour burden, liver function and disease aetiology. Intermediate HCC patients often have unsatisfactory clinical outcomes with repeated transarterial chemoembolization (TACE, due to non-response of the target tumour or the development of further metastasis indicating progressive disease. In September 2011, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was convened in HK in an attempt to provide a consensus on the practice of TACE. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies. This review summarises the evidence discussed at the meeting and provides expert recommendation regarding the available therapeutic options for unresectable intermediate stage HCC. A key consensus of the Expert Panel was that in order to improve patient outcomes and long-term survival, the possibility of using TACE in combination with targeted agents given systemically should be explored. While the currently available clinical data is promising, the expected completion of several pivotal phase II and III RCTs will provide further evidence in support of the rationale for combination therapy regimens.

Lack of response after initial chemoembolization for hepatocellular carcinoma: does it predict failure of subsequent treatment?

PURPOSE: To (a) evaluate the response of hepatocellular carcinoma (HCC) to chemoembolization after initial nonresponse, as determined with European Association for the Study of the Liver (EASL) criteria and modified Response Evaluation Criteria in Solid Tumors (mRECIST), and (b) compare posttreatment survival of initial nonresponders versus that of initial responders. MATERIALS AND METHODS: The institutional review board approved this retrospective study, which was compliant with HIPAA. A total of 116 consecutive patients (96 men, 20 women; mean age, 63 years) with unresectable HCC who underwent at least two chemoembolization procedures were included. The chemoembolization mixture consisted of 100 mg of cisplatin, 50 mg of doxorubicin, and 10 mg of mitomycin C mixed 1:1 with iodized oil. Tumor response at magnetic resonance imaging was evaluated after each chemoembolization procedure according to EASL criteria and mRECIST. The survival rate in each subgroup was calculated and correlated with response. The Wilcoxon test was used to test group comparability. Kaplan-Meier estimators were used to generate survival curves and compared by using the log-rank test. RESULTS: No response to initial chemoembolization was seen in 43% and 50% of patients according to EASL criteria and mRECIST, respectively. After a second chemoembolization procedure, 44% (EASL) and 47% (mRECIST) of initial nonresponders showed a significant response. With EASL criteria, the 1-, 2-, and 3-year survival rates (±standard error of the mean) after two chemoembolization procedures were 39%±10, 14%±7, and 0%, respectively, for nonresponders and 68%±10, 50%±11, and 37%±11 for responders (P=.036, P=.006, and P<.005 at 1, 2, and 3 years). With mRECIST, the 1-, 2-, and 3-year survival rates after two chemoembolization procedures were 49%±9, 20%±8, and 7%±6 for nonresponders and 67%±9, 44%±10, and 36%±9 for responders (P=.174, P=.046, and P=.011 at 1, 2, and 3 years). CONCLUSION: Patients who underwent chemoembolization for HCC showed a response (with both EASL criteria and mRECIST) and improved survival after the second chemoembolization treatment. At least two chemoembolization procedures should be performed in the same targeted lesions before further treatment is abandoned.