Conversion therapy for unresectable hepatocellular carcinoma: Advances and challenges

Table 1 Hepatocellular carcinoma conversion therapy programs

Program			Definition	Applicable population	Mechanism	Advantage	Disadvantage
Local therapy	TACE		The use of iodized oil as a carrier and chemotherapeutic drugs mixed into an emulsion is injected into the blood-supplying arteries of the tumor, then the corresponding arteries are embolized with embolic agents, resulting in ischemia and necrosis of the tumor	Patients with unresectable HCC with vascular invasion	Chemotherapeutics and embolic agents are injected through the hepatic artery into the tumor-nourishing artery, providing a synergistic effect of vascular occlusion and local chemotherapy, resulting in tumor necrosis[14]	Long drug metabolism time, strong local tumor-killing effect, high reproducibility, and fewer systemic side effects[15]	Periportal inflammatory adhesions and increased risk of intraoperative bleeding
	TARE		Selective transcatheter and intra-arterial injection of micron-sized particles containing radioisotopes (mostly 90Y) to treat moderately advanced HCC[16-18]	HCC patients with less than 50% liver involvement	Tumor ischemia and necrosis are caused by blocking the tumor’s nutrient blood vessels, while local radiotherapy kills the tumor with glass microspheres containing radioactive substances	Prolongs the time to tumor progression, shrinks tumors, and promotes healthy liver proliferation	Risk of peptic ulcer and biliary injury
	HAIC		Anti-cancer drugs and embolization agents are injected directly into the tumor tissue using catheter technology to kill the tumor cells	Patients with combined arteriovenous fistula and portal vein cancer thrombus[19,20]	The continuous infusion of chemotherapeutic agents through the hepatic artery allows the chemotherapeutic agents to accumulate in high concentrations in the tumor and have a constant effect on the tumor cells	It can significantly increase the concentration of the drug in the targeted tumor, with a low incidence of adverse events and less trauma	It is less effective in patients with large and numerous tumors
	PVE		Atrophy of the embolic lobe and compensatory hyperplasia of the non-embolic lobe of the liver by selective embolization of the portal vein branches and alteration of portal blood flow	Patients who are not resectable due to lack of adequate FLR	Selective embolization of portal vein branches induces hyperplasia in the rest of the liver	It can shorten the duration of conversion therapy and has fewer postoperative complications	Residual liver hyperplasia takes a relatively long time and may increase the rate of tumor growth
	ALPPS		Liver resection was divided into two operations and two stages. In the first operation, the liver was divided into the expected resected portion and the expected preserved portion, the liver tissue between the two was isolated, and the branch of the portal vein on the expected resected side was ligated	Giant HCC with extensive tumor invasion and inadequate FLR after resection	The surgery is divided into two stages, in the first stage, the liver with invasion is isolated from the normal liver, and the affected portal vein is ligated, after the liver on the healthy side grows to a sufficient size, in the second stage, the liver on the affected side is completely resected	It rapidly induces proliferation in the rest of the liver and minimizes the risk of tumor progression	Patients have to undergo two complex and traumatic surgeries
	Radiotherapy		Treatment of localized HCC with high-energy radiation[21]	Patients with combined portal vein thrombosis or macrovascular invasion in advanced HCC	Kill tumor cells with ionizing radiation	It causes the cancerous embolus to shrink or disappear, effectively controlling the tumor and improving the long-term effect of surgical resection[22]	Limited range, high requirements for tumor sensitivity, and may cause damage to normal tissue
	Ablation therapy	Chemical ablation	A local treatment in which a chemical ablative agent is injected directly into the tumor, causing degeneration and necrosis of the tumor cells[23,24]	HCC patients with cancer foci near high-risk hilar, gallbladder, and gastrointestinal sites	Denaturing and necrotizing tumor cells using chemical ablators	Safe, minimally invasive, and fast recovery	Inability to destroy potential circulating tumor cells
		Physical ablation	Tumor tissue is heated or frozen using specific physical techniques to induce coagulation and freeze-thaw necrosis[25-28]	Patients with solitary HCC without vascular, biliary, or adjacent site involvement	The application of heat results in necrosis of the tumor tissue	The surgery is simple and less invasive, with a shorter recovery time	There is a heat sink effect that can damage surrounding tissue
		Irreversible electroporation	By disrupting cellular homeostasis with short but powerful electric fields, causing irreversible cell damage, tumor cells die naturally[29]	HCC is located where vital extracellular matrix, blood flow, and nerves need to remain	Tumor cell membranes are disrupted by electrical impulses, resulting in apoptotic cell necrosis	There is no heat sink effect, and tumors close to ducts and nerve sites can be killed without damaging blood vessels and nerves	Conductivity has a high impact on the local environment. It is susceptible to the presence of residual tumor tissue
Systemic therapy	Chemotherapy		Chemotherapy alone to treat tumors[30]	Advanced and relatively limited HCC without severe cirrhosis	Kill cancer cells by interfering with their growth and division process	Safe and tolerable	Low conversion rate
	Target therapy		Targeting of specific cancer-causing sites at the cellular molecular level[31-33]	Primary HCC with multiple liver metastases and vascular invasion	The drug enters the body and specifically selects oncogenic sites to bind to and act on, causing tumor cell-specific death	Kill tumor cells specifically without damaging surrounding normal tissue	It is necessary to find a clear therapeutic target with limited applicability
	Immunotherapy		By directly or indirectly increasing the body’s immunoreactive cells, regulating tumor immune-related signaling pathways or vascular growth factors, inhibiting angiogenesis, and delaying tumor cell proliferation[34-38]	Patients with tumors invading large blood vessels, distant metastases, poor hepatic function, and those who cannot tolerate surgery	By enhancing host immune activity and immune recognition, it strengthens the body's immune response to tumors, weakens tumor immune escape, and inhibits or kills tumor cells	Highly targeted, high specificity, and low side effects	Lengthy conversion time and immune-related hepatitis
Combination therapy	Dual therapy	Targeted combined immunotherapy	Targeted drugs and immunotherapy work together to kill cancer cells	Patients with associated portal and vena cava cancer embolism	Targeted drugs select specific tumor targets to kill tumor cells while stimulating the body's immune response and enhancing the anti-tumor immune response	Synergistic effect and high converting efficiency[39,40]	Risk of immune-mediated inflammation
		TACE combined RFA	Combination TACE with percutaneous RFA[41]	HCC with intrahepatic, portal vein, or distant metastatic disease	Based on the blockage of most of the tumor’s blood supply, the remaining small lesions are precisely ablated, resulting in the complete destruction of the tumor tissue	The high temperature generated by the radiofrequency ablation needle after embolization is more concentrated and sustained at the tumor site, and tumor tissue is more thoroughly destroyed	The presence of adjacent vessels and invasive tumor growth may result in inadequate ablation
	Triple therapy	TACE combined with ICI and TKI	Combination of TACE, targeted therapy, and immunotherapy[42]	Patients with intermediate-stage HCC (CNLC IIb stage) or multiple lesions	Positive reinforcing feedback effects on the hypoxic and immunosuppressive microenvironment	High conversion efficiency and fewer grade 3 to 4 adverse events	Low efficacy in non-viral HCC
		HAIC combined with ICI and TKI	Combination of HAIC, targeted therapy, and immunotherapy[43]	HCC patients with portal vein thrombosis	Block tumor blood vessels and competitively inhibit tumor cell proliferation	Strong synergistic effect and long-lasting anti-tumor response	Heterogeneity was high and trial data were limited

HCC: Hepatocellular carcinoma; FLR: Future liver remnant; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic artery infusion chemotherapy; PVE: Portal vein embolization; ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy; TARE: Trans-arterial radioembolization; RFA: Radiofrequency ablation; ICI: Immune checkpoint inhibitor; TKI: Tyrosine kinase inhibitor; CNLC: China liver cancer staging.