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.

Idarubicin-Loaded ONCOZENE Drug-Eluting Bead Chemoembolization in a Rabbit Liver Tumor Model: Investigating Safety, Therapeutic Efficacy, and Effects on Tumor Microenvironment.

PURPOSE: To investigate toxicity, efficacy, and microenvironmental effects of idarubicin-loaded 40-µm and 100-µm drug-eluting embolic (DEE) transarterial chemoembolization in a rabbit liver tumor model. MATERIALS AND METHODS: Twelve male New Zealand White rabbits with orthotopically implanted VX2 liver tumors were assigned to DEE chemoembolization with 40-µm (n = 5) or 100-µm (n = 4) ONCOZENE microspheres or no treatment (control; n = 3). At 24-72 hours postprocedurally, multiparametric magnetic resonance (MR) imaging including dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), and biosensor imaging of redundant deviation in shifts (BIRDS) was performed to assess extracellular pH (pHe), followed by immediate euthanasia. Laboratory parameters and histopathologic ex vivo analysis included fluorescence confocal microscopy and immunohistochemistry. RESULTS: DCE MR imaging demonstrated a similar degree of devascularization of embolized tumors for both microsphere sizes (mean arterial enhancement, 8% ± 12 vs 36% ± 51 in controls; P = .07). Similarly, DWI showed postprocedural increases in diffusion across the entire lesion (apparent diffusion coefficient, 1.89 × 10-3 mm2/s ± 0.18 vs 2.34 × 10-3 mm2/s ± 0.18 in liver; P = .002). BIRDS demonstrated profound tumor acidosis at baseline (mean pHe, 6.79 ± 0.08 in tumor vs 7.13 ± 0.08 in liver; P = .02) and after chemoembolization (6.8 ± 0.06 in tumor vs 7.1 ± 0.04 in liver; P = .007). Laboratory and ex vivo analyses showed central tumor core penetration and greater increase in liver enzymes for 40-µm vs 100-µm microspheres. Inhibition of cell proliferation, intratumoral hypoxia, and limited idarubicin elution were equally observed with both sphere sizes. CONCLUSIONS: Noninvasive multiparametric MR imaging visualized chemoembolic effects in tumor and tumor microenvironment following DEE chemoembolization. Devascularization, increased hypoxia, coagulative necrosis, tumor acidosis, and limited idarubicin elution suggest ischemia as the predominant therapeutic mechanism. Substantial size-dependent differences indicate greater toxicity with the smaller microsphere diameter.

Science to Practice: Decrypting the Enigma of Ablation-induced Off-Target Effects-Is Network Pathway Analysis the Final Piece of the Puzzle?

As part of the ongoing effort to better understand and mitigate pro-oncogenic off-target effects of imaging-guided radiofrequency ablation (RFA), Kumar et al ( 1 ) used gene expression and network pathway analysis to examine the gene activation profiles in the peri-ablational zone after RFA in a breast adenocarcinoma liver metastasis animal model. Their analysis identified STAT3 (signal transducer and activator of transcription 3) as a key transcription factor upregulated in many signaling pathways in the peri-ablational zone after RFA. Consequently, the authors successfully used two STAT3 inhibitors to reduce distant tumor growth after treatment with RFA. By demonstrating that judicious and appropriate adjuvant therapy helped contain distant tumor growth caused by ablation, Kumar et al have managed to pave the road ahead for the definitive success of ablation.

Irinotecan-Eluting 75-150-µm Embolics Lobar Chemoembolization in Patients with Colorectal Cancer Liver Metastases: A Prospective Single-Center Phase I Study.

PURPOSE: The primary end point of this trial was to determine the feasibility and safety of transarterial chemoembolization with the use of 75-150-µm drug-eluting embolics loaded with irinotecan (DEE-IRI) for the treatment of metastatic colorectal cancer (CRC) refractory to systemic chemotherapy. MATERIALS AND METHODS: Fourteen patients (mean age 57.9 years) with liver-dominant metastatic disease (14.3% unilobar, 85.7% bilobar), who had failed at least 1 line of chemotherapy, were enrolled and received up to 4 (mean 2.3) cycles of DEE-IRI lobar transarterial chemoembolization. Technical complications and adverse events were recorded, and response was assessed by means of imaging-based criteria. Levels of irinotecan and angiogenesis biomarkers in the serum were measured at multiple time points. RESULTS: Thirty-two DEE-IRI transarterial chemoembolizations were successfully performed, and the full dose (100 mg) was delivered in all cases. The only grade 3-4 toxicity was abdominal pain (29%). One patient had objective response according to the Response Evaluation Criteria in Solid Tumors and World Health Organization, and 3 patients had objective response according to the European Association for the Study of the Liver. The median overall survival was 18.14 months, and the 1-year survival was 65%. The average plasma Cmax of the active metabolite was 41.5 ± 26.1 ng/mL, with average Tmax of 1.3 ± 0.5 hours. The treatment significantly reduced levels of vascular endothelial growth factor receptor 1 (VEGFR1) at 24 hours. CONCLUSIONS: Lobar transarterial chemoembolization with the use of DEE-IRI is a technically feasible and well tolerated palliative treatment for patients with refractory liver-predominant CRC metastatic disease and has acceptable pharmacokinetics. VEGFR1 is a potential biomarker for predicting treatment efficacy and risk of adverse events.

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.

Validation of the Hong Kong Liver Cancer Staging System in Determining Prognosis of the North American Patients Following Intra-arterial Therapy.

BACKGROUND & AIMS: There is debate over the best way to stage hepatocellular carcinoma (HCC). We attempted to validate the prognostic and clinical utility of the recently developed Hong Kong Liver Cancer (HKLC) staging system, a hepatitis B-based model, and compared data with that from the Barcelona Clinic Liver Cancer (BCLC) staging system in a North American population that underwent intra-arterial therapy (IAT). METHODS: We performed a retrospective analysis of data from 1009 patients with HCC who underwent IAT from 2000 through 2014. Most patients had hepatitis C or unresectable tumors; all patients underwent IAT, with or without resection, transplantation, and/or systemic chemotherapy. We calculated HCC stage for each patient using 5-stage HKLC (HKLC-5) and 9-stage HKLC (HKLC-9) system classifications, and the BCLC system. Survival information was collected up until the end of 2014 at which point living or unconfirmed patients were censored. We compared performance of the BCLC, HKLC-5, and HKLC-9 systems in predicting patient outcomes using Kaplan-Meier estimates, calibration plots, C statistic, Akaike information criterion, and the likelihood ratio test. RESULTS: Median overall survival time, calculated from first IAT until date of death or censorship, for the entire cohort (all stages) was 9.8 months. The BCLC and HKLC staging systems predicted patient survival times with significance (P < .001). HKLC-5 and HKLC-9 each demonstrated good calibration. The HKLC-5 system outperformed the BCLC system in predicting patient survival times (HKLC C = 0.71, Akaike information criterion = 6242; BCLC C = 0.64, Akaike information criterion = 6320), reducing error in predicting survival time (HKLC reduced error by 14%, BCLC reduced error by 12%), and homogeneity (HKLC chi-square = 201, P < .001; BCLC chi-square = 119, P < .001) and monotonicity (HKLC linear trend chi-square = 193, P < .001; BCLC linear trend chi-square = 111, P < .001). Small proportions of patients with HCC of stages IV or V, according to the HKLC system, survived for 6 months and 4 months, respectively. CONCLUSIONS: In a retrospective analysis of patients who underwent IAT for unresectable HCC, we found the HKLC-5 staging system to have the best combination of performances in survival separation, calibration, and discrimination; it consistently outperformed the BCLC system in predicting survival times of patients. The HKLC system identified patients with HCC of stages IV and V who are unlikely to benefit from IAT.

Science to Practice: Molecular-targeted Drug Delivery in Combination with Radiofrequency Ablation of Liver Cancer: A Magic Bullet?

In an effort to improve the technical success rates and clinical outcomes of radiofrequency (RF) ablation, Yan et al validated the use of a tumor-penetrating peptide and thermosensitive doxorubicin (DOX)-loaded nanoparticles in combination with RF ablation in a hepatocellular carcinoma mouse model. By achieving higher chemotherapeutic drug concentrations in target lesions, fewer toxic effects, and improved survival end points in an animal tumor model, the authors conclude that superior tumor treatment with RF ablation is possible when combined with molecular-targeted drug delivery systems.

Science to Practice: Killing Dormant Cells-Is Targeting Autophagy the Key to Complete Tumor Response in Transarterial Chemoembolization?

In this issue of Radiology, Gade et al ( 1 ) describe a unique mechanism of hepatocellular carcinoma (HCC) cells for surviving ischemia induced by transarterial embolization (TAE)/transarterial chemoembolization (TACE) in a state of cell cycle arrest-a function that may serve as a defensive shield against conventional chemotherapeutic agents. This finding adds to our knowledge and establishes a previously poorly understood mechanism of chemoresistance in HCC. As the Achilles heel in terms of this process, a concurrent upregulation of autophagic flux as an adaptive response to TAE-like ischemia was found by the authors. This is a targetable mechanism that can potentially be exploited for combined therapeutic approaches of embolotherapy and autophagy inhibition in HCC.

Imaging Biomarkers of Tumor Response in Neuroendocrine Liver Metastases Treated with Transarterial Chemoembolization: Can Enhancing Tumor Burden of the Whole Liver Help Predict Patient Survival?

Purpose To investigate whether whole-liver enhancing tumor burden [ETB] can serve as an imaging biomarker and help predict survival better than World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) methods in patients with multifocal, bilobar neuroendocrine liver metastases (NELM) after the first transarterial chemoembolization (TACE) procedure. Materials and Methods This HIPAA-compliant, institutional review board-approved retrospective study included 51 patients (mean age, 57.8 years ± 13.2; range, 13.5-85.8 years) with multifocal, bilobar NELM treated with TACE. The largest area (WHO), longest diameter (RECIST), longest enhancing diameter (mRECIST), largest enhancing area (EASL), and largest enhancing volume (ETB) were measured at baseline and after the first TACE on contrast material-enhanced magnetic resonance images. With three-dimensional software, ETB was measured as more than 2 standard deviations the signal intensity of a region of interest in normal liver. Response was assessed with WHO, RECIST, mRECIST, and EASL methods according to their respective criteria. For ETB response, a decrease in enhancement of at least 30%, 50%, and 65% was analyzed by using the Akaike information criterion. Survival analysis included Kaplan-Meier curves and Cox regressions. Results Treatment response occurred in 5.9% (WHO criteria), 2.0% (RECIST), 25.5% (mRECIST), and 23.5% (EASL criteria) of patients. With 30%, 50%, and 65% cutoffs, ETB response was seen in 60.8%, 39.2%, and 21.6% of patients, respectively, and was the only biomarker associated with a survival difference between responders and nonresponders (45.0 months vs 10.0 months, 84.3 months vs 16.7 months, and 85.2 months vs 21.2 months, respectively; P < .01 for all). The 50% cutoff provided the best survival model (hazard ratio [HR]: 0.2; 95% confidence interval [CI]: 0.1, 0.4). At multivariate analysis, ETB response was an independent predictor of survival (HR: 0.2; 95% CI: 0.1, 0.6). Conclusion Volumetric ETB is an early treatment response biomarker and surrogate for survival in patients with multifocal, bilobar NELM after the first TACE procedure. © RSNA, 2016.

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).

Intra-arterial therapy of neuroendocrine tumour liver metastases: comparing conventional TACE, drug-eluting beads TACE and yttrium-90 radioembolisation as treatment options using a propensity score analysis model.

OBJECTIVES: To compare efficacy, survival outcome and prognostic factors of conventional transarterial chemoembolisation (cTACE), drug-eluting beads TACE (DEB-TACE) and yttrium-90 radioembolisation (Y90) for the treatment of liver metastases from gastroenteropancreatic (GEP) neuroendocrine tumours (NELM). METHODS: This retrospective analysis included 192 patients (58.6 years mean age, 56% men) with NELM treated with cTACE (N = 122), DEB-TACE (N = 26) or Y90 (N = 44) between 2000 and 2014. Radiologic response to therapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) and World Health Organization (WHO) criteria using periprocedural MR imaging. Survival analysis included propensity score analysis (PSA), median overall survival (MOS), hepatic progression-free survival, Kaplan-Meier using log-rank test and the uni- and multivariate Cox proportional hazards model (MVA). RESULTS: MOS of the entire study population was 28.8 months. As for cTACE, DEB-TACE and Y90, MOS was 33.8 months, 21.7 months and 23.6 months, respectively. According to the MVA, cTACE demonstrated a significantly longer MOS as compared to DEB-TACE (p <.01) or Y90 (p = .02). The 5-year survival rate after initial cTACE, DEB-TACE and Y90 was 28.2%, 10.3% and 18.5%, respectively. CONCLUSIONS: Upon PSA, our study suggests significant survival benefits for patients treated with cTACE as compared to DEB-TACE and Y90. This data supports the therapeutic decision for cTACE as the primary intra-arterial therapy option in patients with unresectable NELM until proven otherwise. KEY POINTS: • cTACE achieved a significantly longer overall survival in patients with unresectable NELM. • Patients treated with cTACE showed a prolonged hepatic progression-free survival. • cTACE, DEB-TACE and Y90 radioembolisation demonstrated comparable safety and toxicity profiles. • Age >70 years, extrahepatic metastases and tumour burden >50% were identified as negative predictors. • Propensity score analysis suggests the superiority of cTACE over DEB-TACE and Y90.

Advanced-stage hepatocellular carcinoma with portal vein thrombosis: conventional versus drug-eluting beads transcatheter arterial chemoembolization.

OBJECTIVES: Our study sought to compare the overall survival in patients with hepatocellular carcinoma (HCC) and portal venous thrombosis (PVT), treated with either conventional trans-arterial chemoembolization (cTACE) or drug-eluting beads (DEB) TACE. METHODS: This retrospective analysis included a total of 133 patients, treated without cross-over and compared head-to-head by means or propensity score weighting. Mortality was compared using survival analysis upon propensity score weighting. Adverse events and liver toxicity grade ≥3 were recorded and reported for each TACE. In order to compare with historical sorafenib studies, a sub-group analysis was performed and included patients who fulfilled the SHARP inclusion criteria. RESULTS: The median overall survival (MOS) of the entire cohort was 4.53 months (95 % CI, 3.63-6.03). MOS was similar across treatment arms, no significant difference between cTACE (N = 95) and DEB-TACE (N = 38) was observed (MOS of 5.0 vs. 3.33 months, respectively; p = 0.157). The most common adverse events after cTACE and DEB- TACE, respectively, were as follows: post-embolization syndrome [N = 57 (30.0 %) and N = 38 (61.3 %)], diarrhea [N = 3 (1.6 %) and N = 3 (4.8 %)], and encephalopathy [N = 11 (5.8 %) and N = 2 (3.2 %)]. CONCLUSION: Our retrospective study could not reveal a difference in toxicity and efficiency between cTACE and DEB-TACE for treatment of advanced stage HCC with PVT. KEY POINTS: • Conventional TACE (cTACE) and drug-eluting-beads TACE (DEB-TACE) demonstrated equal safety profiles. • Survival rates after TACE are similar to patients treated with sorafenib. • Child-Pugh class and tumor burden are reliable predictors of survival.

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.

A Review and Update of Treatment Options and Controversies in the Management of Hepatocellular Carcinoma.

OBJECTIVE: To review the current management, outline recent advances and address controversies in the management of hepatocellular carcinoma (HCC). SUMMARY OF BACKGROUND DATA: The treatment of HCC is multidisciplinary involving hepatologists, surgeons, medical oncologists, radiation oncologists, radiologists, interventional radiologists, and other disciplines. Each of these disciplines brings its unique perspective and differing opinions that add to controversies in the management of HCC. METHODS: A focused literature review was performed to identify recent studies on the management of HCC and thereby summarize relevant information on the various therapeutic modalities and controversies involved in the treatment of HCC. RESULTS: The main treatment algorithms continue to rely on hepatic resection or transplantation with controversies involving patients harboring early stage disease and borderline hepatic function. The other treatment strategies include locoregional therapies, radiation, and systemic therapy used alone or in combination with other treatment modalities. Recent advances in locoregional therapies, radiation, and systemic therapies have provided better therapeutic options with curative intent potential for some locoregional therapies. Further refinements in combination therapies such as algorithms consisting of locoregional therapies and systemic or radiation therapies are likely to add additional options and improve survival. CONCLUSIONS: The management of HCC has witnessed significant strides with advances in existing options and introduction of several new treatment modalities of various combinations. Further refinements in these treatment options combined with enrollment in clinical trials are essential to improve the management and outcomes of patients with HCC.

Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model.

Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis.

Science to Practice: Systemic Implications of Ablative Tumor Therapies-Reality Uncovered and Myths Exposed?

In their effort to characterize the systemic "off-target" effects of radiofrequency (RF) ablation and irreversible electroporation (IRE), Bulvik et al demonstrated substantial differences in physiologic, tumorigenic, and immunologic responses between the two ablative modalities. By establishing that IRE may in fact stimulate more robust inflammatory and systemic reactions than RF at liver ablation, the authors conclude that the selection of a given ablation energy source may alter the clinical outcome depending on the circumstance-both favorably and unfavorably.

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.

Comparison of Existing Response Criteria in Patients with Hepatocellular Carcinoma Treated with Transarterial Chemoembolization Using a 3D Quantitative Approach.

PURPOSE: To compare currently available non-three-dimensional methods (Response Evaluation Criteria in Solid Tumors [RECIST], European Association for Study of the Liver [EASL], modified RECIST [mRECIST[) with three-dimensional (3D) quantitative methods of the index tumor as early response markers in predicting patient survival after initial transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS: This was a retrospective single-institution HIPAA-compliant and institutional review board-approved study. From November 2001 to November 2008, 491 consecutive patients underwent intraarterial therapy for liver cancer with either conventional TACE or TACE with drug-eluting beads. A diagnosis of hepatocellular carcinoma (HCC) was made in 290 of these patients. The response of the index tumor on pre- and post-TACE magnetic resonance images was assessed retrospectively in 78 treatment-naïve patients with HCC (63 male; mean age, 63 years ± 11 [standard deviation]). Each response assessment method (RECIST, mRECIST, EASL, and 3D methods of volumetric RECIST [vRECIST] and quantitative EASL [qEASL]) was used to classify patients as responders or nonresponders by following standard guidelines for the uni- and bidimensional measurements and by using the formula for a sphere for the 3D measurements. The Kaplan-Meier method with the log-rank test was performed for each method to evaluate its ability to help predict survival of responders and nonresponders. Uni- and multivariate Cox proportional hazard ratio models were used to identify covariates that had significant association with survival. RESULTS: The uni- and bidimensional measurements of RECIST (hazard ratio, 0.6; 95% confidence interval [CI]: 0.3, 1.0; P = .09), mRECIST (hazard ratio, 0.6; 95% CI: 0.6, 1.0; P = .05), and EASL (hazard ratio, 1.1; 95% CI: 0.6, 2.2; P = .75) did not show a significant difference in survival between responders and nonresponders, whereas vRECIST (hazard ratio, 0.6; 95% CI: 0.3, 1.0; P = .04), qEASL (Vol) (hazard ratio, 0.5; 95% CI: 0.3, 0.9; P = .02), and qEASL (%) (hazard ratio, 0.3; 95% CI: 0.15, 0.60; P < .001) did show a significant difference between these groups. CONCLUSION: The 3D-based imaging biomarkers qEASL and vRECIST were tumor response criteria that could be used to predict patient survival early after initial TACE and enabled clear identification of nonresponders.

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.

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.