Locoregional and systemic therapy for hepatocellular carcinoma

Abstract

The management of hepatocellular carcinoma (HCC) remains challenging due to late presentation and the presence of accompanying liver dysfunction. As such, most patients are not eligible for curative resection and liver transplant. Management in this scenario depends on a number of factors including hepatic function, tumor burden, patency of hepatic vasculature and patients' functional status. Based on these, patients can be offered catheter based intra-arterial therapy for intermediate stage disease and in more advanced disease, sorafenib. Given recent data, regorafenib is now an option following failure of sorafenib.Catheter directed intra-arterial therapy takes advantage of tumor hypervascularity and the unique dual blood supply of the liver, as hepatic tumors receive arterial perfusion via the hepatic artery while the rest of the liver is supplied by the portal vein. This allows selective embolization and delivery of chemotherapeutic agents to the tumor. Compared to best supportive care, intra-arterial therapy offers a survival benefit in intermediate stage HCC and is the recommended approach for treatment. None of the catheter based approaches; including bland embolization, conventional trans-arterial chemoembolization (cTACE), drug eluting bead trans-arterial chemoembolization (DEB-TACE) or trans-arterial radioembolization (TARE) offers a clear advantage over the other, although DEB-TACE may be characterized by less systemic toxicity. All of these approaches are contraindicated in patients with portal vein thrombosis (PVT). On the other hand, intraarterial, radio embolization, with Yttrium-90 (Y90) can be offered to patients with PVT. The place of this modality in management of HCC is still being investigated. The role of sorafenib in advanced HCC is not in doubt, as until recently, it was the only systemic therapy approved for the management in this setting. This is despite multiple trials evaluating other agents. The addition of sorafenib to catheter-based therapy in intermediate stage disease has also failed to show any benefit. The modest survival benefit with sorafenib and the failure of other targeted agents suggest that it is important to look beyond inhibition of angiogenesis in advanced HCC. Identification of key drivers and mediators of HCC remains paramount for successful drug development. In line with this, it is refreshing that the excitement that has followed developments in cancer immunotherapy is finding its way to HCC with early trials of anti-PD1 monoclonal antibodies showing sufficient activity that phase III trials are now ongoing for Pembrolizumab and Nivolumab in advanced HCC. Future drug development efforts will focus on defining the feasibility of combining different treatment approaches targeting multiple important modulators of HCC.

Perfusion Magnetic Resonance as a Biomarker for Sorafenib-Treated Advanced Hepatocellular Carcinoma: A Pilot Study

“…Between 70 and 90% of the HCC cases occur in patients with chronic liver disease and cirrhosis [4, 5]. Most HCC patients show advanced disease at the time of diagnosis, given the scarcity of specific symptoms in the early stages, which causes a worse prognosis [2, 5-8]. …”

“…Treatment options for HCC depend on the stage of the disease, and surgical resection, hepatic transplantation, ablation or chemoembolization are recommended in the early stages (stages A and B of the Barcelona Clinic for Liver Cancer [BCLC] classification) [5, 9, 10]. Patients with more advanced stages (stages C and D of the BCLC classification) have more limited and less effective therapeutic options [5, 9, 10].…”

“…Patients with more advanced stages (stages C and D of the BCLC classification) have more limited and less effective therapeutic options [5, 9, 10]. In recent years, there has been a breakthrough in the knowledge of the molecular pathogenesis of HCC, which has led to the development of molecular targeted therapies such as sorafenib [4, 6, 11, 12].…”

“…In recent years, there has been a breakthrough in the knowledge of the molecular pathogenesis of HCC, which has led to the development of molecular targeted therapies such as sorafenib [4, 6, 11, 12]. This drug is a multikinase inhibitor, active against the Raf-1 serine/threonine protein-kinase proto-oncogene and the B-Raf proto-oncogene, the vascular endothelial growth factor receptor cells 1–3, platelet-derived growth factor receptor β, as well as the gene fms-related tyrosine kinase 3, RET gene, c-KIT gene, stimulating apoptosis, and inhibiting the proliferation and angiogenesis of tumor cells [4, 5, 9, 13-16]. Currently, sorafenib is recommended in advanced HCC, and its effect on increasing the median overall survival of these patients has been demonstrated in approximately 3 months [5, 9, 12-15, 17].…”

Microsurgical Technique of Locoregional Injection into the Hepatic Artery in Tumor-Bearing Mice

“…Although surgical resection and liver transplant have proven effective and improve overall survival, many patients develop unresectable diseases due to late presentation and the presence of accompanying liver dysfunction [2]. These patients in intermediate or more advanced stage can be offered locoregional treatment such as intraarterial therapy [3, 4].…”