Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma

Abstract

Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.

Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study: idarubicin dose selection, tissue response and survival

“…Although TACE has been the standard of care for several decades it still has many limitations. 31 HCC is a heterogeneous cancer with a large variety of genotypes and phenotypes necessitating further research to understand the complexity of the disease and to pave the way for precision medicine. 32 33 Thus, to improve the therapeutic effect it is essential to increase the understanding of the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, metabolomics, patient and tumour heterogeneity and resistance mechanisms.…”

Transarterial Chemoembolization and Unresectable Hepatocellular Carcinoma: A Narrative Review

“…The study found that patients who were given atezolizumab combined with bevacizumab resulted in increased median overall survival (6.8 months vs. 4.3 months) and progression-free survival at 12 months (67.2% vs. 56.6%) compared to sorafenib (Table 5 ) [ 43 ]. In combination with immunotherapy, TACE is proven to be clinically beneficial [ 44 ]. Studies are currently being conducted on the usage of TACE with a combination of atezolizumab-bevacizumab in patients with HCC [ 45 ].…”

“…TACE's relative contraindications are large tumors >10 cm, co-morbidities, biliary dilation, and untreated esophageal varices related to liver cirrhosis with a high risk of bleeding [ 62 ]. Even though TACE has been utilized for many decades, little progress has been made in comprehending the complicated local pharmacology, tumor heterogeneity within the population, and resistance to mechanism [ 44 ].…”

Transient Cytolysis after Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma

“…Transarterial chemoembolization (TACE) is a minimally invasive radiological procedure which consists of infusing a chemotherapeutic agent in the main arterial supplier of the liver tumor, usually emulsion-based doxorubicin, followed by the occlusion of the involved vessel with 100–500 micron-sized embolic particles. The direct toxic effect of doxorubicin and the ischemic damage display a dual synergic tumoricidal effect which provokes cell apoptosis and immunogenic changes in the tumor microenvironment, hampering oncogenesis [ 1 ]. TACE takes advantage of the hypervascularity of hepatocellular carcinoma (HCC) which, in contrast to the normal liver parenchyma, obtains its blood supply mainly from the hepatic artery and marginally from the portal vein.…”

“…However, it is important to note that the periphery of the tumor, including the non-tumoral surrounding parenchyma, shows a more intense expression of proliferative pathways such as the mammalian target of rapamycin [ 19 ]. The ischemic effect on the tumor edge would contribute to re-program the immunological microenvironment for more efficient identification and destruction of remnant tumor cells [ 1 , 20 ]. In contrast, if the edge of the tumor is kept uninjured, HCC would be more likely to recur early after TACE and to maintain its spreading capacity [ 21 ].…”