Transarterial Chemoembolization Using 100-μm Drug-Eluting Microspheres in Patients with Hepatocellular Carcinoma: A Prospective Study and Midterm Follow-up

PurposeThe purpose of this study was to assess the safety and efficacy of drug-eluting embolic (DEE) transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients who are ineligible for curative treatment, using doxorubicin-loaded Tandem (Varian Medical) microspheres.Materials and MethodsBetween October 2015 and December 2017, 98 patients with unresectable HCC (69 males, 29 females; mean age, 60.5 ± 10.0 years of age; and American Joint Committee on Cancer [AJCC] stage ≦T3a) treated with DEE transarterial chemoembolization using 100-μm doxorubicin-loaded microspheres were enrolled prospectively. All studies were reviewed and approved by the Institutional Review Board of Chang Gung Memorial Hospital. Dynamic contrast-enhanced computed tomography or magnetic resonance imaging 1 month after treatment was used for tumor response assessment according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Outcomes included overall survival (OS), progression-free survival (PFS), and downstaging profile.ResultsMedian follow-up was 21.2 months. At follow-up examinations at 0.5-, 1-, 1.5- and 2.5-year follow-up, OS rates were 93.8%, 89.5%, 79.4%, and 77.0%, respectively. Complete response (CR), partial response, stable disease, and progressive disease were noted in 50 (51.0%), 23 (23.5%), 18 (18.4%), and 7 (7.1%) patients, respectively, with 93.9% disease control rate and 74.5% objective response rate. Mean OS was 28.7 months, and mean PFS was 19.6 months. Number of nodules >3, bilobar disease, larger tumor, and higher AJCC stage correlated with worse CR. No serious adverse events occurred after DEE transarterial chemoembolization. Successful downstage rate was 73.3% (22 of 30) and number of nodules predicting successful downstaging was 7 nodules (cutoff).ConclusionsTandem DEE transarterial chemoembolization provides safe and effective treatment for HCC and a bridge or downstage therapy for liver transplantation.     

Comparison of Drug-Eluting Embolics versus Conventional Transarterial Chemoembolization for the Treatment of Patients with Unresectable Hepatocellular Carcinoma: A Cost-Effectiveness Analysis

PurposeTo compare the cost-effectiveness of using doxorubicin-loaded drug-eluting embolic (DEE) transarterial chemoembolization versus that of using conventional transarterial chemoembolization for patients with unresectable hepatocellular carcinoma (HCC).Materials and MethodsA decision-analysis model was constructed over the lifespan of a payer’s perspective. The model simulated the clinical course, including periprocedural complications, additional transarterial chemoembolization or other treatments (ablation, radioembolization, or systemic treatment), palliative care, and death, of patients with unresectable HCC. All clinical parameters were derived from the literature. Base case calculations, probabilistic sensitivity analyses, and multiple two-way sensitivity analyses were performed.ResultsIn the base case calculations for patients with a median age of 67 years (range for conventional transarterial chemoembolization: 28–88 years, range for DEE-transarterial chemoembolization: 16–93 years), conventional transarterial chemoembolization yielded a health benefit of 2.11 quality-adjusted life years (QALY) at a cost of $125,324, whereas DEE-transarterial chemoembolization yielded 1.71 QALY for $144,816. In 10,000 Monte Carlo simulations, conventional transarterial chemoembolization continued to be a more cost-effective strategy. conventional transarterial chemoembolization was cost-effective when the complication risks for both the procedures were simultaneously varied from 0% to 30%. DEE-transarterial chemoembolization became cost-effective if the conventional transarterial chemoembolization mortality exceeded that of DEE-transarterial chemoembolization by 17% in absolute values. The two-way sensitivity analyses demonstrated that conventional transarterial chemoembolization was cost-effective until the risk of disease progression was >0.4% of that for DEE-transarterial chemoembolization in absolute values. Our analysis showed that DEE-transarterial chemoembolization would be more cost-effective if it offered >2.5% higher overall survival benefit than conventional transarterial chemoembolization in absolute values.ConclusionsCompared with DEE-transarterial chemoembolization, conventional transarterial chemoembolization yielded a higher number of QALY at a lower cost, making it the more cost-effective of the 2 modalities.     

Integrated Liver Inflammatory Score Predicts the Therapeutic Outcome of Patients with Hepatocellular Carcinoma after Transarterial Chemoembolization

PurposeTo evaluate the performance of the integrated liver inflammatory score (ILIS) in predicting survival in patients with hepatocellular carcinoma (HCC) who received transarterial chemoembolization, and to compare ILIS to other prognostic scoring systems and inflammatory indices.Materials and MethodsThis study included 192 patients with unresectable HCC who underwent transarterial chemoembolization from 3 medical centers. The potential risk factors of the patients’ overall survival (OS) were determined by multivariate Cox regression analysis. The predictive performances of ILIS in 1-, 2-, 3-, 4-, and 5-year survival were evaluated using receiver operating characteristic curves. The discriminatory power in the OS of ILIS and the other known scoring systems or inflammatory indices was determined by C-statistic.ResultsMultivariate regression analysis showed that high ILIS (P = .047), low lymphocyte count (P = .034), beyond up-to-seven criteria (P = .021), and nonresponse to the first transarterial chemoembolization session (P = .039) were risk factors for poor prognosis after transarterial chemoembolization. The predictive performances of ILIS for 1-, 2-, 3-, 4-, and 5-year survival were good, with area under the curve values of 0.627, 0.631, 0.621, 0.577, and 0.681, respectively. ILIS outperformed other standard scoring systems and inflammatory indices in predicting OS, with a C-statistic of 0.625.ConclusionsILIS is a powerful prognostic index for predicting the survival of patients with HCC after transarterial chemoembolization, which suggests that ILIS before treatment should be considered during the patient evaluation process.     

Hepatic Artery Infusion Chemotherapy Using Fluorouracil,Leucovorin, and Oxaliplatin versus Transarterial Chemoembolization as Initial Treatment for Locally Advanced Hepatocellular Carcinoma: A Propensity Score–Matching Analysis

PurposeTo compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with a modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) regimen with that of transarterial chemoembolization as a locoregional treatment for patients with locally advanced hepatocellular carcinoma (HCC).MethodsThis retrospective study included adult patients with locally advanced HCC who received first-line treatment with either HAIC-mFOLFOX or conventional transarterial chemoembolization monotherapy from January 2015 to December 2016. The outcomes, including tumor response rates, evaluated via imaging assessment using the modified response evaluation criteria in solid tumors; overall survival; progression-free survival; and safety, were compared. The propensity score–matching methodology was used to reduce the influence of confounding factors on the outcomes.ResultsThe study included 131 patients with locally advanced HCC who underwent transarterial chemoembolization and 101 who received HAIC-mFOLFOX as initial treatment. After propensity score matching (n = 67 in each group), patients who received HAIC-mFOLFOX had a higher objective response rate (43.3% vs 13.4%, P = .001), longer median overall survival (13.9 vs 6.0 months, P < .001), and longer median progression-free survival (6.4 vs 2.8 months, P = .001) than those who underwent transarterial chemoembolization. The survival benefit with HAIC-mFOLFOX was strengthened in patients with HCC with vascular invasion (hazard ratio: 0.379; 95% confidence interval: 0.237–0.607). HAIC-mFOLFOX was associated with lower incidences of severe adverse events (8.9% vs 22.9%) and liver toxicity than transarterial chemoembolization.ConclusionsCompared with transarterial chemoembolization, HAIC-mFOLFOX is a potentially safer and more effective locoregional therapy for patients with locally advanced HCC.     

Transarterial Chemoembolization in a Woodchuck Model of Hepatocellular Carcinoma

PurposeTo assess the feasibility of transarterial chemoembolization with drug-eluting embolic (DEE) microspheres in a woodchuck model of hepatocellular carcinoma (HCC).Materials and MethodsNine woodchucks were studied: 4 normal animals and 5 animals infected with woodchuck hepatitis virus in which HCC had developed. Three animals with HCC underwent multidetector CT. A 3-F sheath was introduced into the femoral artery, and the hepatic arteries were selectively catheterized with 2.0–2.4-F microcatheters. Normal animals underwent diagnostic angiography and bland embolization. Animals with HCC underwent DEE transarterial chemoembolization with 70–150-μm radiopaque microspheres loaded with 37.5 mg doxorubicin per milliliter. Cone-beam CT and multidetector CT were performed. Following euthanasia, explanted livers underwent micro-CT, histopathologic examination, and fluorescence imaging of doxorubicin.ResultsThe tumors were hypervascular and supplied by large-caliber tortuous vessels, with arteriovenous shunts present in 2 animals. There was heterogeneous enhancement on multidetector CT with areas of necrosis. Six tumors were identified. The most common location was the right medial lobe (n = 3). Mean tumor volume was 30.7 cm³ ± 12.3. DEE chemoembolization of tumors was achieved. Excluding the 2 animals with arteriovenous shunts, the mean volume of DEE microspheres injected was 0.49 mL ± 0.17. Fluorescence imaging showed diffusion of doxorubicin from the DEE microspheres into the tumor.ConclusionsWoodchuck HCC shares imaging appearances and biologic characteristics with human HCC. Selective catheterization and DEE chemoembolization may similarly be performed. Woodchucks may be used to model interventional therapies and possibly characterize radiologic–pathologic correlations.     

Transarterial Chemoembolization for the Palliation of Painful Bone Metastases Refractory to First-Line Radiotherapy

PurposeTo compare the efficacy and safety of transarterial chemoembolization for the palliation of radiotherapy (RT)-failure bone metastases (BMs) with those of re-radiotherapy (Re-RT) in achieving pain relief.Materials and MethodsFifty consecutive patients with RT-failure BMs who had undergone Re-RT (23 patients) and transarterial chemoembolization (27 patients) were retrospectively analyzed. The primary endpoint was clinical response, and the secondary endpoints were objective response and adverse events. Pain assessment was performed using the numerical rating scale, and tumor response was evaluated using the modified Response Evaluation Criteria in Solid Tumors. Pain relief was defined as lack of pain with no analgesic usage (complete pain response) or a decrease in pain score by ≥3 points with analgesic usage (partial pain response).ResultsThe pain relief rates in the Re-RT and transarterial chemoembolization groups were 57% and 92%, respectively (P = .006). The median pain relief duration was 2 and 3 months in the Re-RT and transarterial chemoembolization groups, respectively (P = .002). The 6-month pain-free survival rates were 30% and 51% in the Re-RT and transarterial chemoembolization groups, respectively (P = .08). The median tumor reduction rates were –4% and 9% in the Re-RT and transarterial chemoembolization groups, respectively (P < .001). The objective response rates were 0% and 11% in the Re-RT and transarterial chemoembolization groups, respectively (P = .29). No serious adverse events or complications were observed.ConclusionsTransarterial chemoembolization achieved a superior response rate and longer duration of palliation in symptomatic RT-failure BMs.     

The Safety and Effectiveness of Hepatic Transarterial Embolic Locoregional Therapy in Patients with Contraindications to Hepatectomy after Portal Vein Embolization

The safety and effectiveness of hepatic transarterial embolic locoregional therapy (LRT) was assessed, including transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), in patients who underwent portal vein embolization (PVE) before major hepatectomy in whom surgery was then contraindicated. Adverse events (AEs) were graded according to the Society of Interventional Radiology classification of AEs. Tumor response was assessed based on the Response Evaluation Criteria In Solid Tumors 1.1. Overall survival (OS) and progression-free survival (PFS) were estimated. Fifteen patients underwent 37 transarterial LRTs (25 TACEs, 11 TAREs, and 1 bland embolization), most (73%) with hepatocellular carcinoma. Eleven AEs occurred in 7 patients, including 2 Grade 3/5 (severe) and 2 Grade 4/5 (life-threatening) events. The best response was partial response in 4 (27%) and stable disease in 10 (66%) patients. The median OS and PFS were 42 (95% CI, 35–49 months) and 33 months (95% CI, 24–42 months), respectively. In conclusion, hepatic transarterial LRT can be considered as a therapeutic option in patients with contraindicated liver surgery after PVE.     

Use of a Glass Membrane Pumping Emulsification Device Improves Systemic and Tumor Pharmacokinetics in Rabbit VX2 Liver Tumor in Transarterial Chemoembolization

PurposeTo evaluate the phamacokinetics of epirubicin in conventional transarterial chemoembolization using a developed pumping emulsification device with a microporous glass membrane in VX2 rabbits.Materials and MethodsEpirubicin solution (10 mg/mL) was mixed with ethiodized oil (1:2 ratio) using the device or 3-way stopcock. Forty-eight rabbits with VX2 liver tumor implanted 2 weeks prior to transarterial chemoembolization were divided into 2 groups: a device group (n = 24) and a 3-way-stopcock group (n = 24). Next, 0.5 mL of emulsion was injected into the hepatic artery, followed by embolization using 100–300-μm microspheres. The serum epirubicin concentrations (immediately after, 5 minutes after, and 10 minutes after) and the tumor epirubicin concentrations (20 minutes after and 48 hours after) were measured after transarterial chemoembolization. Histopathologic evaluation was performed with a fluorescence microscope.ResultsThe area under the curve and maximum concentrations of epirubicin in plasma were 0.45 ± 0.18 μg min/mL and 0.13 ± 0.06 μg/mL, respectively, in the device group and 0.71 ± 0.45 μg min/mL and 0.22 ± 0.17 μg/mL, respectively, in the 3-way-stopcock group (P = .013 and P = .021, respectively). The mean epirubicin concentrations in VX2 tumors at 48 hours in the device group and the 3-way-stopcock group were 13.7 ± 6.71 and 7.72 ± 3.26 μg/g tissue, respectively (P = .013). The tumor necrosis ratios at 48 hours were 62 ± 11% in the device group and 51 ± 13% in the 3-way-stopcock group (P = .039).ConclusionsConventional transarterial chemoembolization using the pumping emulsification device significantly improved the pharmacokinetics of epirubicin compared to the current standard technique using a 3-way stopcock.     

Clinical Significance of the Initial and Best Responses after Chemoembolization in the Treatment of Intermediate-Stage Hepatocellular Carcinoma with Preserved Liver Function

PurposeTo evaluate the clinical implications of initial and best responses during repeated transarterial chemoembolization procedures for hepatocellular carcinoma (HCC).Materials and MethodsThis study included 726 patients who received a diagnosis of intermediate-stage HCC with Child-Pugh class A liver function between 2007 and 2016, and who were treated with transarterial chemoembolization as the first-line treatment. Evaluation of treatment response was based on the modified response evaluation criteria in solid tumors. Overall survival (OS) was compared between response categories after implementation of landmark analysis.ResultsOf the 726 patients, an objective response (complete response [CR] or partial response [PR]) was observed as the initial response in 78.1% of patients. Regarding the best response during the transarterial chemoembolization series, 87.2% of patients were overall responders. The median OS of initial responders (n = 483) was not significantly different from that of subsequent responders at the 1-year landmark (stable disease [SD] after first transarterial chemoembolization but CR or PR after repeated transarterial chemoembolization; n = 61; 46.2 vs 40.1 months, respectively; P = .145). Likewise, the median OS of initial CR patients (n = 326) was not significantly different from that of the subsequent CR group (n = 126) at the 1-year landmark (PR or SD after first transarterial chemoembolization but CR after repeated transarterial chemoembolization; 53.4 vs 46.3 months, respectively; P = .455). Multivariate Cox analyses showed that the objective responses, the initial responses (hazard ratio [HR], 0.638; P = .001), and the best responses (HR, 0.304; P < .001) had the significant prognostic significance for OS.ConclusionsBoth the initial and best responses during repeated transarterial chemoembolization were significantly associated with OS in patients with intermediate-stage HCC and preserved liver function.     

Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies

PurposeTo assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies.Materials and MethodsThe VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7–21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging.ResultsEight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441–404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%–100%). There were no significant changes in perfusion imaging parameters after TACE.ConclusionsBTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.     

Chronic Hepatotoxicity in Patients with Metastatic Neuroendocrine Tumor: Transarterial Chemoembolization versus Transarterial Radioembolization

PurposeTo compare the manifestations of chronic liver injury following transarterial chemoembolization with those of transarterial radioembolization (TARE) in patients with neuroendocrine tumor (NET).Materials and MethodsThis study consisted of an Institutional Review Board-approved single-institution retrospective analysis of NET patients who received transarterial chemoembolization from 2006 to 2016 and TARE from 2005 to 2014 and survived at least 1 year from the initial treatment. Patients receiving only transarterial chemoembolization (n = 63) or TARE (n = 28) were evaluated for the presence or absence of durable hepatic toxicities occurring at least 6 months after initial treatment. The definitions and grades of liver injury were adapted from Common Terminology Criteria for Adverse Events version 4.0 and were characterized by the presence of laboratory or clinical toxicities of Grade 3 or above.ResultsChronic hepatic toxicity occurred in 14 of 63 transarterial chemoembolization patients (22%) with a total of 26 Grade 3-4 events, in whom elevation of bilirubin was the most common toxicity, compared to 8 of 28 TARE patients (29%) with a total of 16 Grade 3-4 and 2 Grade 5 events, in whom ascites were the most frequent toxicity. There were more laboratory toxicities in the transarterial chemoembolization group (65% vs 38%, P = .11) and fewer Grade 4–5 injuries (6% vs 27% of patients, P = .06). There was also a significantly higher number of patients who experienced intrahepatic progression of disease in the transarterial chemoembolization cohort than in the TARE patients (75% vs 43%, respectively; P = .005).ConclusionsDelayed hepatotoxicity from transarterial chemoembolization and TARE occurred in 22% and 29% of patients, respectively, from 6 months to several years following treatment. Transarterial chemoembolization-related toxicities on average were less severe and manifested primarily as laboratory derangements, compared to TARE toxicities which consisted of clinical hepatic decompensation.     

Transarterial Chemoembolization Followed by Radiofrequency Ablation for Hepatocellular Carcinoma: Impact of the Time Interval between the Two Treatments on Outcome

PurposeTo compare the efficacy of radiofrequency (RF) ablation after transarterial chemoembolization within or beyond 30 days for medium-large or multiple recurrent hepatocellular carcinomas (HCCs).Materials and MethodsIn this single-center retrospective study conducted from 2007 through 2015, 135 patients with a single recurrent HCC (>3 cm) or multiple (2–5 tumors) recurrent HCCs underwent transarterial chemoembolization plus RF ablation. A total of 62 patients underwent RF ablation after transarterial chemoembolization within 30 days (sequential group) and 73 patients underwent RF ablation after transarterial chemoembolization beyond 30 days (delayed group). Outcomes of interests included overall survival (OS), progression-free survival (PFS), and complete response (CR) rate.ResultsThe median OS and PFS were 49.8 and 38.0 months for sequential group, and 31.0 and 11.6 months for the delayed group. The sequential group experienced significantly better OS (hazard ratio [HR]: 0.517; P = .002) and PFS (HR, 0.621; P = .021). Among patients with multiple tumors or a single tumor >5 cm, the sequential group still had significantly longer OS (P = .022; P = .018, respectively) and PFS (P = 0.042; P = .036, respectively) than the delayed group, although no significant differences were observed among patients with solitary 3- to 5-cm tumors (P = .138; P = .803, respectively). The sequential group had a significantly better CR rate than the delayed group (85.4% vs. 68.5%, respectively; P = .035). Significant predictors of OS and PFS included maximum tumor size, number of tumors, and time interval between transarterial chemoembolization and RF ablation.ConclusionsTransarterial chemoembolization plus sequential RF ablation within 30 days was more effective for recurrent HCCs than transarterial chemoembolization plus delayed RF ablation. The time interval within 30 days is required for treating large or multiple HCCs but may not be necessary for solitary medium-sized HCC.     

γ-Glutamyltranspeptidase as a Prognostic Biomarker in Advanced Hepatocellular Carcinoma Treated with Transarterial Chemoembolization

PurposeTo evaluate the prognostic value of pretreatment serum γ-glutamyltransferase (GGT) level in patients with advanced hepatocellular carcinoma (HCC) receiving transarterial chemoembolization.Materials and MethodsThis retrospective study included 140 patients (123 male, 17 female; mean age, 56.9 y ± 12.0; range, 22.0–82.0 y) with Barcelona Clinic Liver Cancer class C HCC who received first-line conventional chemoembolization between December 2013 and March 2018. Patients were divided into low and high GGT groups based on a cutoff value calculated with a receiver operating characteristic curve. Overall survival (OS) was compared between groups by log-rank test. Univariate and multivariate survival analyses were performed.ResultsThe optimal cutoff values of GGT were 119.5 U/L in men and 175.0 U/L in women. The 6-, 9-, and 12-mo OS rates were 81.7%, 72.4%, and 62.9%, respectively, for patients in the low GGT group (n = 44) and 58.8%, 35.7%, and 28.8%, respectively, for patients in the high GGT group (n = 96; P < .001). Multivariable Cox regression analysis identified high pretreatment serum GGT level (hazard ratio [HR], 2.71; 95% confidence interval [CI], 1.67–4.40; P < .001), multiple tumors (HR, 3.05; 95% CI, 1.23–7.53; P = .02), and performance of target treatment (ie, sorafenib; HR, 0.41; 95% CI, 0.24–0.72; P = .002) or ablation (HR, 0.35; 95% CI, 0.18–0.66; P = .001) as independent prognostic factors for OS.ConclusionsPretreatment serum GGT level was an independent prognostic factor for OS in patients with advanced HCC treated with chemoembolization, suggesting that GGT is a useful prognostic biomarker for advanced HCC.     

A Transarterial Chemoembolization of Balloon-Occluded Alternate Infusions of Cisplatin and Gelatin Particles for Hepatocellular Carcinoma: A Phase I/II Multicenter Prospective Study of Safety and Efficacy

PurposeTo evaluate the safety and efficacy of a newly developed technique of balloon-occluded alternate infusions of cisplatin and gelatin particles in transarterial chemoembolization in hepatocellular carcinoma (HCC) and to evaluate the liver damage following the procedure.Materials and MethodsForty-three patients with HCC from 4 medical centers were enrolled in this multicenter prospective study. Of these, 41 patients were observed for 6 months following balloon-occluded alternate infusion transarterial chemoembolization. The primary endpoint was the safety of the procedure, and the secondary endpoint was the objective response rate (ORR) of the HCCs at 2 months following treatment.ResultsThree patients experienced adverse events, including 1 patient with facial swelling and skin rash, dissection of the celiac artery, and bland portal vein thrombus. No major adverse events were identified. Two (5.3%) patients regressed from a Child-Pugh classification of A to B. The balloon-occluded alternate infusion transarterial chemoembolization treatment achieved a 22.0% complete response (CR) rate and a 73.2% ORR (95% confidence interval [CI], 57.9%–84.4%). In a retrospective analysis of 23 patients with HCCs above the up-to-7 criteria, the CR rate and ORR of the balloon-occluded alternate infusion transarterial chemoembolization were 21.7% and 82.6% (95% CI, 62.3%–93.6%), respectively.ConclusionsBalloon-occluded alternate infusion transarterial chemoembolization is safe and effective for achieving a high ORR while preserving liver function.     

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

PurposeTo 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 MethodsTwelve 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.ResultsDCE 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.ConclusionsNoninvasive 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.     

Comparative Analysis of Safety and Efficacy of Transarterial Chemoembolization for the Treatment of Hepatocellular Carcinoma in Patients with and without Pre-Existing Transjugular Intrahepatic Portosystemic Shunts

PurposeTo compare the safety and efficacy of transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients with and without transjugular intrahepatic portosystemic shunts (TIPS).Materials and MethodsThis single-institution study included a retrospective review of 50 patients who underwent transarterial chemoembolization for HCC between January 2010 and April 2017. Twenty-five patients had preexisting TIPS, and 25 patients were selected to control for age, sex, and target tumor size. Baseline median Model for End-Stage Liver Disease (MELD; 13 TIPS, 9 control; P < .001) and albumin-bilirubin (ALBI; 3 TIPS, 2 control; P < .001) differed between groups. Safety was assessed on the basis of Common Terminology Criteria for Adverse Events (CTCAE) and change in MELD and ALBI grade assessed between 3 and 6 months. Efficacy was assessed by tumor response and time to progression (TTP).ResultsThere was 1 severe adverse event (CTCAE grade >2) in the TIPS group. There was no difference in the change in MELD or ALBI grade. Although there was no difference in tumor response (P = .19), more patients achieved a complete response in the control group (19/25, 76%) than in the TIPS group (13/25, 52%). There was no difference in TTP (P = .82). At 1 year, 2 patients in the control group and 3 patients in the TIPS group received a liver transplant. Seven patients died in the TIPS group.ConclusionsTransarterial chemoembolization is as safe and effective in patients with TIPS as in patients without TIPS, despite worse baseline liver function. Severe adverse events are rare and may be transient.     

Comparison of Opioid Medication Use after Conventional Chemoembolization versus Drug-Eluting Embolic Chemoembolization

PurposeTo assess the use of opioid analgesics and/or antiemetic drugs for pain and nausea following selective chemoembolization with doxorubicin-based conventional (c)-transarterial chemoembolization versus drug-eluting embolic (DEE)-transarterial chemoembolization for hepatocellular carcinoma (HCC).Materials and MethodsFrom October 2014 to 2016, 283 patients underwent 393 selective chemoembolization procedures including 188 patients (48%) who underwent c-transarterial chemoembolization and 205 (52%) who underwent DEE-transarterial chemoembolization. Medical records for all patients were retrospectively reviewed. Administration of postprocedural opioid and/or antiemetic agents were collated. Time of administration was stratified as phase 1 recovery (0–6 hours) and observation (6–24 hours). Logistic regression model was used to investigate the relationship of transarterial chemoembolization type and use of intravenous and/or oral analgesic and antiemetic medications while controlling for other clinical variables.ResultsMore patients treated with DEE-transarterial chemoembolization required intravenous analgesia in the observation (6–24 hours) phase (18.5%) than those treated with c-transarterial chemoembolization (10.6%; P = .033). Similar results were noted for oral analgesic agents (50.2% vs. 31.4%, respectively; P < .001) and antiemetics (17.1% vs. 7.5%, respectively; P = .006) during the observation period. Multivariate regression models identified DEE-transarterial chemoembolization as an independent predictor for oral analgesia (odds ratio [OR], 1.84; P = .011), for intravenous and oral analgesia in opioid-naïve patients (OR, 2.46; P = .029) and for antiemetics (OR, 2.56; P = .011).ConclusionsCompared to c-transarterial chemoembolization, DEE-transarterial chemoembolization required greater amounts of opioid analgesic and antiemetic agents 6–24 hours after the procedure. Surgical data indicate that a persistent opioid habit can develop even after minor surgeries, therefore, caution should be exercised, and a regimen of nonopiate pain medications should be considered to reduce postprocedural pain after transarterial chemoembolization.     

Spectral CT-Based Iodized Oil Quantification to Predict Tumor Response Following Chemoembolization of Hepatocellular Carcinoma

PurposeTo quantify iodized oil retention in tumors after transarterial chemoembolization using spectral computed tomography (CT) imaging in patients with hepatocellular carcinoma (HCC) and evaluate its performance in predicting 12-month tumor responses.Materials and MethodsFrom September 2017 to December 2018, 111 patients with HCC underwent initial conventional transarterial chemoembolization. Immediately after the procedure, unenhanced CT was performed using a spectral CT scanner, and the iodized oil densities in index tumors were measured. In tumor-level analyses, a threshold level of iodized oil density in the tumors was calculated using clustered receiver operating characteristic curve analyses to predict the 12-month tumor responses. In patient-level analyses, significant factors associated with a 12-month complete response, including the presence of tumors below the threshold value (ie, suspected residual tumors), were evaluated by logistic regression.ResultsForty-eight HCCs in 39 patients were included in the analyses. The lower 10th percentile of the iodine density was identified as the threshold for determining the 12-month nonviable responses. The area under the curve of the iodine density measurements in predicting the 12-month nonviable responses was 0.893 (95% confidence interval, 0.797–0.989). The threshold value of the iodine density of 10.68 mg/mL yielded a sensitivity of 82.76% and specificity of 94.74% (P < .001). In the patient-level analysis, the 12-month complete response was significantly associated with the presence of a suspected residual tumor, with an odds ratio of 72.0 (95% confidence interval, 7.273–712.770).ConclusionsSpectral CT imaging using quantitative analysis of the iodized oil retention in target HCCs can predict tumor responses after a conventional transarterial chemoembolization procedure.     

Survival Analysis Using Albumin-Bilirubin (ALBI) Grade for Patients Treated with Drug-Eluting Embolic Transarterial Chemoembolization for Hepatocellular Carcinoma

PurposeThe albumin-bilirubin (ALBI) grade has been established as an improved predictor of survival in patients with hepatocellular carcinoma (HCC) treated with conventional transarterial chemoembolization and yttrium-90 radioembolization. The purpose of the study was to investigate the utility of ALBI grade in prognosticating outcomes in patients with HCC treated with drug-eluting embolic (DEE) transarterial chemoembolization (TACE).Materials and MethodsA single-center retrospective review was performed to compare the efficacy of ALBI grade and Child-Pugh (CP) classification in predicting the survival of patients with HCC receiving DEE-TACE. A total of 303 patients with HCC were identified who had received DEE-TACE without concomitant locoregional therapy within 30 days. Survival analysis was performed using Kaplan-Meier methods and censored for curative therapy. Survival curves were stratified based on the ALBI grade, CP class, Barcelona Clinic Liver Cancer (BCLC) stage, Eastern Cooperative Oncology Group performance status, and presence of ascites. The discriminatory ability of survival curves was calculated by C-Index.ResultsKaplan-Meier survival curves stratified by the ALBI grade produced distinct, nonoverlapping curves (P < .001), showing greater discriminatory ability than the CP classification (C-index = 0.568 and 0.545, respectively). The substratification of the BCLC stage by the ALBI grade yielded greater discriminatory ability than the substratification by the CP classification (C-index = 0.573 and 0.565, respectively). For patients with BCLC stage B, the substratification by the ALBI grade yielded distinct curves, whereas the substratification by the CP classification did not (P = .011 and P = .379, respectively).ConclusionsALBI grade showed improved discriminatory ability compared with CP classification in differentiating overall survival among patients with HCC receiving DEE-TACE. Furthermore, ALBI grade was effective in substratifying survival among patients categorized as CP class A and patients with BCLC stage B, whereas CP classification was not effective.     

Safety and Efficacy of Locoregional Treatment during Immunotherapy with Nivolumab for Hepatocellular Carcinoma: A Retrospective Study of 41 Interventions in 29 Patients

PurposeTo assess the safety of locoregional treatment (LRT) combined with nivolumab for intermediate and advanced hepatocellular carcinoma (HCC).Materials and MethodsA single-center retrospective review included 29 patients undergoing 41 LRTs—transarterial chemoembolization or yttrium-90 transarterial radioembolization—60 days before or concurrently with nivolumab. Demographic, clinical, and laboratory values and adverse events were reviewed before and after nivolumab initiation and after each LRT. Treatment response and time to progression were assessed using Modified Response Evaluation Criteria in Solid Tumors. Clinical events, including nivolumab termination, death, and time of last follow-up, were assessed.ResultsOver a median nivolumab course of 8.1 months (range, 1.0–30) with a median of 14.2 2-week cycles (range, 1–53), predominantly Child–Pugh A (22/29) patients—12 Barcelona Clinic Liver Cancer (BCLC) B and 17 BCLC C—underwent 20 transarterial chemoembolization and 21 transarterial radioembolization LRTs at a median of 67 days (range, 48–609) after nivolumab initiation. Ten patients underwent multiple LRTs. During a median follow-up of 11.5 months (range, 1.8–35.1), no grade III/IV adverse events attributable to nivolumab were observed. There were five instances of grade III/IV hypoalbuminemia or hyperbilirubinemia within 3 months after LRT. There were no nivolumab-related deaths, and 30-day mortality after LRT was 0%.ConclusionsLRTs performed concurrently with nivolumab immunotherapy demonstrate an acceptable safety profile in patients with intermediate and advanced HCC.