Liver-directed therapy for hepatocellular carcinoma

Abstract

The high mortality rate for hepatocellular carcinoma (HCC) relative to its prevalence underscores the need for curative-intent therapies. Multidisciplinary treatment decisions are required to craft optimal treatment strategies considering tumor size, location and underlying liver cirrhosis. Surgical resection of anatomically limited tumors with adequate hepatic reserve provides long-term survival in more than half of patients and remains a standard first-line therapy. Eligibility for resection among newly diagnosed patients is low and recurrences in the remaining cirrhotic liver are common. Transplantation offers a higher chance of cure. Long wait times for the limited door pool require neoadjuvant loco-regional therapies to maintain transplant eligibility. Image-guided therapies such as ablation and embolization have an established role as primary or neoadjuvant preparing patients for curative treatment. Percutaneous ablation in appropriately selected patients offers long-term survival similar to resection. New and evolving techniques such as stereotactic body radiotherapy (SBRT), radiation segmentectomy and lobectomy, and combination therapies employing both trans-arterial and ablative approaches show promise for curative-intent treatment but require further prospective data before they can be integrated into treatment algorithms. For palliativeintent therapy, conventional trans-arterial chemoembolization with lipiodol-based emulsions remains the only technique supported by clinical trials. Newer platforms such as drug-eluting embolics failed to improve survival over bland embolization in randomized trials and showed increased hepatobiliary toxicity. Transarterial radioembolization offers similar overall survival (OS) to transarterial chemoembolization (TACE) and non-inferiority to sorafenib in meta-analyses. The more favorable clinical toxicity profile makes it an appealing technique for patients willing to accept the longer time to response.

Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma

“…Compared to the variability of the Lipiodol ® -based emulsions, the DEMs have been described to generate reproducible and predictable results in blood vessel blockage, and a prolonged drug release. However, the DEMs have not been proved to release the entire drug dose nor to enter the tumour, but they seem to release only parts of the drug [ 23 , 24 ] in arterioles at various distances from the tumour depending on the particle size [ 17 , 22 ]. Thus, it is unclear how much the drug adds to the anti-tumour effect or whether that is mainly caused by ischemia.…”

“…Thus, HCC is often detected in the intermediate stage [ 10 ], where transarterial chemoembolization (TACE) is the recommended first-line therapy [ 11 , 12 , 13 ], according to European and American guidelines [ 5 , 14 , 15 ]. TACE can also be used in early-stage HCC as a bridge to transplantation or when surgery is not possible, and in selected patients with advanced stage HCC [ 16 , 17 ].…”

“…In DEM-TACE, the chemotherapeutic drug (doxorubicin) is loaded into microspheres from which it is released slowly. However, the microspheres cannot cross the peribiliary capillary plexus and enter the tumour, and thus, the drug is released in the distal arterioles and distributed from there via diffusion, convection, or both [ 17 , 22 ]. The local release of the drug from the microsphere formulation to the vascular site is affected by the microsphere size and loading degree.…”

"Appraisal of Target Determination for Radiotherapeutic Management of Hepatic Tumors"

“…Although not included within the group of most common cancers, hepatic tumors comprise a leading cause of cancerrelated mortality around the globe [1][2][3][4]. Unfortunately, majority of affected patients present with advanced disease at diagnosis with high tumor burden and impaired hepatobiliary function which typically limits utilization of curative-intent management by surgery, Orthotopic Liver Transplantation (OLT) or Radiofrequency Ablation (RFA).…”

“…Within this context, patients with unresectable hepatic tumors may receive systemic therapies, arterially directed therapies, and limited to palliative management [5]. Nevertheless, revolutionary advances in the field of radiation oncology and related disciplines have paved the way for contemporary radiotherapeutic approaches aiming at cure as well as symptomatic palliation [1][2][3][4]…”