Chemoembolization for Hepatocellular Carcinoma

doi:10.1053/j.seminoncol.2012.05.004

Seminars in Oncology

Volume 39, Issue 4, August 2012, Pages 503-509

https://doi.org/10.1053/j.seminoncol.2012.05.004 Get rights and content

Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with preserved liver function and asymptomatic, noninvasive multinodular hepatocellular carcinoma (HCC) confined to the liver. However, the survival benefit of conventional TACE—including the administration of an anticancer agent-in-oil emulsion followed by embolic agents—reported in randomized controlled trials and meta-analyses was described as modest. Various strategies to improve outcomes for this patient group have become the subject of much ongoing clinical research. The introduction of embolic, drug-eluting beads (DEB) for transarterial administration has been shown to significantly reduce liver toxicity and systemic drug exposure compared to conventional regimens. The addition of molecular targeted drugs to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between TACE and systemic treatments. Combining TACE with agents with anti-angiogenic properties represents a promising strategy, because TACE is thought to cause local hypoxia, resulting in a temporary increase in levels of vascular endothelial growth factor. Recently, a large phase II randomized, double-blind, placebo-controlled trial (the SPACE study) has shown that the concurrent administration of DEB-TACE and sorafenib has a manageable safety profile and has suggested that time to progression and time to vascular invasion or extrahepatic spread may be improved with respect to DEB-TACE alone. These data support the further evaluation of molecular targeted, systemically active agents in combination with DEB-TACE in a phase III setting.

Section snippets

Conventional TACE

HCC exhibits intense neo-angiogenic activity during its progression. The rationale for TACE is that the intra-arterial infusion of a drug such as doxorubicin or cisplatin with or without a viscous emulsion, followed by embolization of the blood vessel with gelatine sponge particles or other embolic agents, will result in a strong cytotoxic effect combined with ischemia.¹⁰ The survival benefit of transarterial embolization (TAE) or TACE has been the subject of a few randomized controlled trials

DEB-TACE

The ideal TACE scheme should allow maximum and sustained concentration of chemotherapeutic drug within the tumor with minimal systemic exposure combined with calibrated tumor vessel obstruction.¹⁰ The recent introduction of embolic microspheres that have the ability to actively sequester doxorubicin hydrochloride from solution and release it in a controlled and sustained fashion, has been shown to substantially diminish the amount of chemotherapy that reaches the systemic circulation compared

Response Assessment

Assessment of tumor response is of utmost importance in patients undergoing TACE.²⁸ Unfortunately, conventional methods for response assessment, such as the Response Evaluation Criteria In Solid Tumors (RECIST) have limited predicting value in HCC patients treated with TACE.34, 35 These criteria rely only on tumor shrinkage as a measure of antitumor activity, an assumption that is only valid with cytotoxic drugs. TACE induces direct tumor necrosis and its anticancer efficacy is not paralleled

Synergies and Combination Strategies

An important limitation of any TACE regimen is the high rate of tumor recurrence. In RCTs, a sustained response lasting more than 3–6 months was observed in only 28%–35% of the patients who received conventionl TACE, and in nonresponders no survival benefit was identified compared to best supportive care.21, 22 Even in those patients in whom initial response was achieved, the 3-year cumulative rate of intrahepatic recurrence reached 65%, with recurrent tumor showing a significantly shorter

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Cited by (84)

Periodic mesoporous organosilica-coated magnetite nanoparticles combined with lipiodol for transcatheter arterial chemoembolization to inhibit the progression of liver cancer
2021, Journal of Colloid and Interface Science
Citation Excerpt :
TACE is a collaborative treatment process based on a combination of anticancer drugs and embolic agents [9,10]. The combination of doxorubicin (Dox) and lipiodol is the most widely used drug strategy for the treatment of HCC by TACE [11–13]. However, the effectiveness of the lipiodol system is limited by its rapid drug release characteristics [14–16].
Transcatheter arterial chemoembolization (TACE) is standard locoregional therapy for hepatocellular carcinoma (HCC) that involves the injection of chemotherapeutic drugs with embolic agents into tumor tissues through intra-arterial transcatheter infusion. TACE technology using lipiodol emulsion has been most widely used in the treatment of human HCC. However, lipiodol emulsions with anticancer drugs do not stably maintain high drug concentrations at tumor sites. Herein, we developed a dual-modality imaging nanoplatform for the TACE treatment of liver cancer by integrating periodic mesoporous organosilica (PMO) with magnetite (Fe₃O₄) nanoparticles and Cy5.5 molecules (denoted as Fe₃O₄@PMO-Cy5.5). Fe₃O₄@PMO-Cy5.5 showed an excellent doxorubicin (Dox)-loading capacity, sensitive drug release behavior under acidic conditions, and good biocompatibility. Moreover, Cy5.5-mediated optical imaging showed that Dox-loaded Fe₃O₄@PMO-Cy5.5 (Fe₃O₄@PMO-Cy5.5-Dox) could enter liver cancer cells and effectively inhibit their growth. In addition, Fe₃O₄@PMO-Cy5.5-Dox was used in combination with transarterial embolization for the treatment of in situ VX2 liver tumors in rabbits. Magnetic resonance imaging (MRI) evaluation showed that Fe₃O₄@PMO-Cy5.5-Dox perfused through arteries was deposited into liver tumors, and Fe₃O₄@PMO-Cy5.5-Dox combined with lipiodol to control liver tumors yielded the optimal therapeutic effect. In addition, histological analysis showed that compared with both lipiodol embolization and traditional lipiodol combined with Dox chemoembolization, Fe₃O₄@PMO-Cy5.5-Dox combined with lipiodol chemoembolization induced more complete tumor tissue necrosis. In summary, these results indicate that the Fe₃O₄@PMO-Cy5.5-Dox platform has the potential to become an advanced tool for the transarterial treatment of unresectable liver cancer.
Thermal Ablation and Transarterial Chemoembolization are Characterized by Changing Dynamics of Circulating MicroRNAs
2021, Journal of Vascular and Interventional Radiology
To determine whether the levels of circulating microRNAs (miRNAs) are altered in patients undergoing thermal ablation and chemoembolization and whether these changes are predictive of a clinical outcome.
This prospective study consisted of 43 patients diagnosed with hepatocellular carcinoma (n = 15) and intrahepatic colorectal cancer metastases (n = 28) treated with thermal ablation (n = 23; radiofrequency [n = 6] or microwave [n = 19]), chemoembolization using drug-eluting embolics (n = 18), or both (n = 2). Four blood samples (immediately before the intervention and 60–90 minutes, 24 hours, and 7 days after the intervention) were taken to measure the plasma concentrations of miRNAs related to hypoxia (miR-21 and miR-210), liver injury (miR-122), epithelial–mesenchymal transition (miR-200a), and apoptosis (miR-34a) using miRNA-specific TaqMan assays and quantitative real-time polymerase chain reaction. Tumor burden and treatment response at 3 months were evaluated using the modified response evaluation criteria in solid tumors. The miRNA results were compared with clinical outcomes (Mann-Whitney U test, Wilcoxon matched-pair test).
Dynamic changes in the circulating miRNA levels were observed following both the interventions. For thermal ablation, significant increases in miR-21, miR-210, miR-122, miR-200a, and miR-34a concentrations peaked 60–90 minutes after the intervention (P < .01). However, for transarterial chemoembolization, maximum increases in the miRNA concentrations were observed at 24 hours after the intervention for miR-21, miR-210, miR-122, miR-200a, and miR-34a (P < .05). The increased concentrations of the circulating miRNAs were followed by a subsequent decline to baseline by 7 days. For the thermal ablation (but not chemoembolization) patients, elevations in the miR-210 and miR-200a levels were associated with early progressive disease at 3 months (P = .040 and P = .012, respectively).
Increased but dynamic levels of circulating miRNAs are present following interventional oncologic procedures and may prove useful as biomarkers for the monitoring of clinical outcomes.
In situ forming implants exposed to ultrasound enhance therapeutic efficacy in subcutaneous murine tumors
2020, Journal of Controlled Release
In situ forming implants (ISFIs) allow for a high initial intratumoral concentration and sustained release of the chemotherapeutic. However, clinical translation is impeded primarily due to limited drug penetration from the tumor/boundary interface and poor intratumoral drug retention. Therapeutic ultrasound (TUS) has become a popular approach for improving drug penetration of transdermal devices and increasing cellular uptake of nanoparticles. These effects are driven by the mechanical and thermal bioeffects associated with TUS. In this study, we characterize the released drug penetration, retention, and overall therapeutic response when exposing ISFI to the combination of the mechanical and thermal effects of TUS (C-TUS). ISFIs were intratumorally injected into subcutaneous murine tumors then exposed to C-TUS (exposure: 5 min, duty factor: 0.33, frequency: 3 MHz, intensity: 2.2 W/cm², pulse duration: 2 ms, pulse repetition frequency: 165 Hz, effective radiating area: 5 cm², energy delivered: 896 J, time average intensity: 0.88 W/cm²). Tumors treated with the combination of ISFI + C-TUS demonstrated a 2.5-fold increase in maximum drug penetration and a 3-fold increase in drug retention at 5- and 8-days post-injection, respectively, compared to ISFIs without TUS exposure. These improvements in drug penetration and retention translated into an enhanced therapeutic response. Mice treated with ISFI + C-TUS showed a 62.6% reduction in tumor progression, a 50.0% increase in median survival time, and a 26.6% increase in necrotic percentage compared to ISFIs without TUS exposure. Combining intratumoral ISFIs with TUS may be beneficial for addressing some long-standing challenges with local drug delivery in cancer treatment and may serve as a viable noninvasive method to improve the poor clinical success of local drug delivery systems.
The blooming intersection of transcatheter hepatic artery chemoembolization and nanomedicine
2020, Chinese Chemical Letters
Transcatheter hepatic artery chemoembolization (TACE) is a universal treatment for patients with hepatocellular carcinoma (HCC) that inhibits tumor growth by cutting off the blood supply and provides chemotherapeutics locally to the tumor. The strategy of combining TACE formulation with image-guided ablation holds tremendous potential, but patient tolerance and undesired toxicity/immunosuppression remains a challenge. The application of nanotechnology in TACE opens new doors for the treatment of HCC. Strikingly, nanomaterials or nano-drugs dispersed in the TACE formulation can effectively improve the delivery efficiency of drugs by achieving both controlled and continuous release. In addition, the utilization of multifunctional nanoparticles can provide guidance and monitoring for various advanced imaging methods for TACE treatment, and can realize the combination therapy of thermal ablation, microwave ablation, in situ radiotherapy, and other therapies, greatly expanding the therapeutic strategies available for HCC treatment. Here, the current exploration of nanotechnology in TACE of HCC is briefly summarized and the challenges of TACE with nanoformulations for clinical translation are comprehensively discussed.
Predicting pharmacokinetic behaviour of drug release from drug-eluting embolization beads using in vitro elution methods
2019, European Journal of Pharmaceutical Sciences
Citation Excerpt :
More recently, we have described an open-loop flow through system which under the right conditions can be representative of the long-term release that has been observed for doxorubicin in explanted tissues (Swaine et al., 2016). None of these methods however, are particularly applicable to the initial 24 h post-delivery of the beads, where the peak plasma concentrations (Cmax) can be a predictor of the levels of systemic toxicity that might be experienced by the patient (Song & Kim, 2017; Lencioni, 2012). The reason for this lack of correlation is because established in vitro tests usually begin with a “pre-occluded system” in which the beads have already been placed into a situation that represents a post-administration occlusive mass (Caine et al., 2017a).
Drug-eluting Embolic Bead - Transarterial Chemoembolisation (DEB-TACE) is a minimally invasive embolising treatment for liver tumours that allows local release of chemotherapeutic drugs via ion exchange, following delivery into hepatic arterial vasculature. Thus far, no single in vitro model has been able to accurately predict the complete kinetics of drug release from DEB, due to heterogeneity of rate-controlling mechanisms throughout the process of DEB delivery. In this study, we describe two in vitro models capable of distinguishing between early phase and late phase drug release by mimicking in vivo features of each phase. First, a vascular flow system (VFS) was used to simulate the early phase by delivering DEB into a silicon vascular cast under high pulsatile flow. This yielded a burst release profile of drugs from DEB which related to the dose adjusted C_max observed in pharmacokinetic plasma profiles from a preclinical swine model. Second, an open loop flow-through cell system was used to model late phase drug release by packing beads in a column with an ultra-low flow rate. DEB loaded with doxorubicin, irinotecan and vandetanib showed differential drug release rates due to their varying chemical properties and unique drug-bead interactions. Using more representative in vitro models to map discrete phases of DEB drug release will provide a better capability to predict the pharmacokinetics of developmental formulations, which has implications for treatment safety and efficacy.
Prognostic Factors for Survival After Transarterial Chemoembolization Combined with Sorafenib in the Treatment of BCLC Stage B and C Hepatocellular Carcinomas
2018, Academic Radiology
Citation Excerpt :
The rationale of TACE was based on the fact that tumor growth mostly depends on the blood supply from hepatic artery in HCC patients (26). However, previous studies had shown that the incomplete necrosis rate of the target tumor after the TACE procedure had reached 80%–90% (27–29). The overexpression of hypoxia inducible factor-1 after TACE treatment can obviously enhance the expression level of VEGF and finally results in the proliferation of tumor cells (30,31).
The objective of this study was to analyze prognostic factors for survival after transarterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stages B and C.
Clinical data of 198 patients with BCLC stage B and C HCCs who underwent TACE combined with sorafenib between June 2012 and January 2017 were retrospectively collected and analyzed. Survival curves were detected using log-rank test. Univariate analysis was performed using log-rank test with respect to 11 prognostic factors potentially affecting survival. All statistically significant prognostic factors identified by univariate analysis were entered into a Cox proportion hazards regression model to identify independent predictors of survival. P values were two-sided and P < 0.05 was considered statistically significant.
By the end of this study, the median follow-up duration was 43.6 months. The median overall survival (OS) of the patients was 21.0 months (95% confidence interval [CI]: 16.94–25.05), and the 1-, 2-, 3- and 5-year OS rates were 72%, 43%, 28%, and 4%, respectively. Tumor size (χ² = 33.607, P < 0.0001), tumor number (χ² = 4.084, P = 0.043), Child-Pugh class (χ² = 33.187, P < 0.0001), BCLC stage (χ² = 50.224, P < 0.0001), portal vein tumor thrombus (χ² = 88.905, P < 0.0001), Eastern Cooperative Oncology Group (ECOG) performance status (χ² = 98.007, P < 0.0001), extrahepatic spread (χ² = 34.980, P < 0.0001), TACE times (χ² = 8.350, P = 0.015), and sorafenib treatment strategy (χ² = 81.593, P < 0.0001) were found to be significantly associated with OS by univariate analysis. Multivariate analysis showed that BCLC stage (95% CI: 1.133–3.982, P = 0.019), extrahepatic spread (95% CI: 1.136–2.774, P = 0.012), and sorafenib treatment duration (95% CI: 0.352–0.574, P = 0.000) were independent prognostic factors associated with OS. There were no serious treatment-related adverse events.
This study showed that extrahepatic spread was a risk factor, and sorafenib treatment and superior BCLC stage were protective factors. Therefore, the study indicated that TACE combined with sorafenib was an effective and safe treatment for patients with BCLC stage B HCC without extrahepatic spread.

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: Conflicts of interest: none.

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New perspectives in hepatocellular carcinomaChemoembolization for Hepatocellular Carcinoma

Section snippets

Conventional TACE

DEB-TACE

Response Assessment

Synergies and Combination Strategies

Gastroenterology

J Hepatol

Gastroenterology

J Hepatol

J Hepatol

Hepatology

Lancet

Hepatology

J Vasc Interv Radiol

Cancer Treat Rev

J Vasc Interv Radiol

J Hepatol

J Hepatol

Lancet Oncol

J Vasc Interv Radiol

J Hepatol

Global cancer statistics, 2002

CA Cancer J Clin

Cancer mortality in the United Kingdom: projections to the year 2025

Br J Cancer

Aging of the hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression

Gastroenterology

Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma

Cancer

Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population

Ann Surg Oncol

; Panel of Experts in HCC-Design Clinical TrialsDesign and endpoints of clinical trials in hepatocellular carcinoma

J Natl Cancer Inst

Management of hepatocellular carcinoma: an update

Hepatology

EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma

J Hepatol

New perspectives in hepatocellular carcinoma
Chemoembolization for Hepatocellular Carcinoma