Hepatocellular Carcinoma: Locoregional Therapies and Multidisciplinary Strategies

Abstract

Hepatocellular carcinoma (HCC) is an increasingly common malignancy worldwide. Transarterial chemoembolization (TACE) is a procedure that was developed to treat HCC patients deemed unsuitable candidates for surgical resection or transplantation and has shown a survival benefit for patients with unresectable HCC. Similarly, radiofrequency ablation (RFA) and microwave ablation (MWA) have been shown to treat HCC successfully, although the rates of success are size-dependent. Head-to-head studies of TACE vs. RFA have shown some superiority of ablation vs. TACE in prolonging survival, with the greatest survival benefit conferred to individuals undergoing dual TACE and ablation therapy. The chapter will discuss the merits of combination treatment vs. monotherapy.

1. Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver tumor worldwide and a major component of cancer-related mortality. It is a major health concern worldwide, particularly in regions with high rates of hepatitis B and C infections. Surgical treatment, including either liver resection or liver transplantation, has long been considered the standard of care for early hepatocellular carcinoma; when applied in carefully selected patients, it can offer five-year survival rates in the range of 60–80% with minimal postoperative morbidity and mortality. When planning a surgical resection, tumor size, multifocality, liver function, and patients’ performance status should all be taken into account. Liver transplantation has consistently been the treatment strategy leading to the highest cure rates. It combines treatment of both the malignant tumor and the underlying cirrhosis. Traditional indications include the presence of tumor not amenable to resection but within the Milan criteria. Furthermore, patients initially beyond the Milan criteria can ultimately be considered for transplantation after downstaging within appropriate protocols.

Advances in the field of surgery and continuous refinements of surgical techniques, along with breakthroughs in locoregional therapies and systematic therapies, have paved the way toward a multidisciplinary and individualized approach in treating patients with HCC. Treatment allocation commonly follows the Barcelona Clinic Liver Cancer (BCLC) staging system, which not only provides prognostic information but also makes treatment recommendations by integrating factors such as tumor status, liver function, and health status. According to that rather simplified but non-exhaustive scheme, ablative techniques are indicated for very early and early-stage HCC (stage 0-A), while chemoembolization is the standard treatment applied in intermediate-stage HCC (stage B). Advanced disease stage (stage C) calls for systematic treatment. We herein discuss the most widely used locoregional techniques, as well as a combination of multidisciplinary strategies that can benefit especially the patient who is not a resection nor a transplantation candidate.

2. Local ablation

Ablation therapy for HCC is a minimally invasive treatment aimed at destroying cancer cells within the liver. It is particularly effective for small, localized tumors and offers several advantages, including preserving healthy liver tissue and providing a curative option for patients who are not candidates for surgery or liver transplantation. Advantages include a minimally invasive procedure with reduced recovery time compared to surgery, which is often performed in the outpatient setting with local anesthesia and some sedation. This procedure can be repeated if new tumors develop, and they tend to preserve more healthy liver tissue. Disadvantages include a modality that is in general limited to smaller tumors, as there is a risk of incomplete ablation or recurrence, particularly with larger or poorly defined tumors.

The broad category of local ablation includes hyperthermic techniques, such as radiofrequency ablation (RFA) and microwave ablation (MWA), cryoablation (which is based on the cooling effect), and non-thermal techniques (percutaneous ethanol injection and irreversible electroporation).

Radiofrequency ablation (RFA) is perhaps the most widely used ablative treatment for hepatocellular carcinoma (HCC), especially for patients with small, localized tumors who are not candidates for surgical resection or liver transplantation. RFA uses high-frequency electrical currents to generate heat, which destroys cancer cells. The mechanism of action for RFA involves the use of an electrode probe (which may be a needle-like probe with multiple prongs) that is inserted into the tumor under imaging guidance (usually ultrasound). High-frequency electrical currents pass through the probe, creating thermal energy that heats the tumor tissue to temperatures of 60–100°C, resulting in coagulative necrosis of cancer cells.

Thermal Coagulation occurs when the generated heat increases the temperature of the tumor tissue to between 60 and 100°C. At these temperatures, protein denaturation and coagulative necrosis occur. The high temperatures induce cell death by protein denaturation (proteins within the cancer cells are denatured and lose their functional and structural integrity), cell membrane disruption (the heat damages cell membranes, causing loss of cell homeostasis and subsequent cell death) and ultimately coagulative necrosis (cells die alas retain their architectural outline for some time before being resorbed local macrophages).

Possible limitations include: increasing size of the tumor, neighboring vascular structures, and inaccessible location of the tumor within the hepatic parenchyma. In general, a tumor threshold of 2 cm defines optimal results with RFA; efficacy is reduced beyond that limit, likely because malignant microsatellites are more frequent with larger tumors. Lesions in proximity to large vascular structures may also reduce the efficacy of RFA, due to a phenomenon called “heat-sink” effect, which transfers heat energy toward the blood flow and might, therefore, reduce the size of the thermal ablation zone. Lastly, tumor locations close to the gallbladder or concealed by adhesions (e.g., due to previous laparotomies) or bowel loops may render the technique unfeasible. Currently, RFA is considered the treatment of choice for single tumors less than 2 cm in favorable locations and patients with preserved liver function and good performance status (very early-stage HCC – BCLC 0). In early resectable HCC (BCLC A, encompassing either a single tumor or paucinodular disease <3 cm for each nodule, in patients with preserved liver function and good performance status), a meta-analysis comparing surgery versus RFA involving 574 patients did not reveal any significant differences in terms of mortality; however, recurrences were significantly more common after RFA [1]. A cost-effective analysis concluded that surgery for single large HCCs (3-5 cm) is the best treatment strategy [2]. RFA for paucinodular disease <3 cm remains an alternative option to surgical resection in appropriately selected candidates.

Microwave ablation (MWA) is a more effective treatment option for hepatocellular carcinoma (HCC), utilizing electromagnetic waves to generate heat and destroy cancer cells. It offers several advantages over other thermal ablation techniques, particularly in terms of speed, the size of the ablation zone, and reduced sensitivity to the heat-sink effect. Nonetheless, a phase II European randomized controlled trial (RCT) failed to identify any difference in efficacy compared to RFA for small HCCs [3]. A trend toward better performance of MWA has been observed in tumors larger than 3 cm, albeit at the cost of more complications.

A microwave antenna (probe) is inserted into the tumor under imaging guidance (ultrasound, CT). The microwave antenna emits electromagnetic waves that heat the surrounding tissue, creating a zone of thermal necrosis. This microwave energy (typically in the range of 900–2450 MHz) generates an oscillating electromagnetic field, which causes water molecules within the tumor tissue to oscillate, producing frictional heat. This heat raises the temperature of the tissue to levels (60–150°C) that cause coagulative necrosis of cancer cells. The size of this zone depends on the power and duration of the ablation.

In general, MWA can produce larger ablation zones than radiofrequency ablation (RFA), making it more effective for larger tumors. It also MWA heats tissue more rapidly, reducing procedure time. Most importantly, MWA is less affected by the heat-sink effect caused by nearby blood vessels, allowing for more consistent and effective ablation near vascular structures; therefore, MWA can achieve higher temperatures than RFA, potentially leading to more complete tumor destruction.

Cryoablation is an effective treatment for hepatocellular carcinoma (HCC), using extreme cold to destroy cancer cells. This technique has unique advantages, especially for tumors located in difficult-to-reach areas or near critical structures. Cryoablation involves the use of cryoprobes, which circulate a cryogen (usually liquid nitrogen or argon gas) to create extremely low temperatures, often as low as −160°C. The cryoprobes are inserted into the tumor under imaging guidance. The extreme cold leads to the rapid formation of ice crystals both inside and outside the cancer cells. Ice crystal formation causes mechanical disruption of cell membranes and intracellular structures, leading to cell death. Additionally, the freezing process disrupts blood flow to the tumor, causing further ischemic injury and cell death. After freezing, the tissue is allowed to thaw, which causes further cellular damage due to osmotic shifts and microvascular injury. This freeze-thaw cycle is often repeated to enhance tumor destruction.

An advantage of cryoablation is that the ablation zone can be precisely controlled and monitored using real-time imaging (ultrasound, CT), minimizing damage to surrounding healthy tissue. In addition, cryoablation is not affected by the heat-sink effect, making it suitable for tumors near large blood vessels. Monitoring can be easier with cryoablation, since the formation of the ice ball during the procedure is easily visible on imaging, allowing precise targeting and real-time monitoring. Lastly, patients often experience less post-procedural pain compared to heat-based ablation techniques.

Irreversible electroporation (IRE) is a relatively new, non-thermal ablation technique used for the treatment of hepatocellular carcinoma (HCC). IRE uses electrical pulses (typically in the range of 1500 to 3000 volts) delivered via needle electrodes placed in and around the tumor, to create permanent nanopores in cell membranes, leading to cell death while sparing the surrounding extracellular matrix and critical structures such as blood vessels and bile ducts. The disruption of the cell membrane homeostasis leads to irreversible cell injury and death. The process does not rely on heat, thereby minimizing thermal damage to the surrounding tissue. The extracellular matrix, including the collagen framework, remains intact. This preservation is crucial for maintaining the structural integrity of blood vessels, bile ducts, and other critical structures.

An important advantage of IRE is that it does not rely on thermal energy; thus, it avoids the complications associated with thermal ablation techniques, such as damage to blood vessels and bile ducts. The electrical fields can be precisely controlled, making it suitable for tumors located near vital structures. In addition, unlike thermal ablation methods, IRE is not affected by the heat-sink effect, making it effective for tumors adjacent to large blood vessels. Lastly, IRE can be safely repeated if necessary. However, there is a paucity of long-term data regarding the long-term efficacy of patients who undergo IRE for HCC.

3. Embolization techniques

In embolization procedures, a catheter is inserted into the branch(es) of the hepatic artery that supplies the tumor in the liver. Then, embolic agents, and occasionally chemotherapy, or both, are injected directly into the blood vessels to block or reduce the blood flow to the tumor. This deprives the tumor of oxygen and nutrients, leading to its shrinkage or destruction.

Transarterial embolization (TAE), or bland embolization, involves blocking the blood vessels feeding the tumor with embolic agents. Transarterial chemoembolization (TACE) combines the infusion of chemotherapy drugs with the embolization process. The choice between TACE and TAE depends on various factors, including the size and location of the tumor, liver function, and overall health of the patient.

Transarterial chemoembolization (TACE) is the predominant option for embolization techniques. It delivers chemotherapeutic regimens and embolization material to the arterial network, feeding the primary liver tumor. Following the publication of two landmark trials, TACE has been established as the first-line treatment for patients with intermediate-stage HCC (BCLC B) who suffer from unresectable liver-confined disease with no evidence of vascular invasion, preserved liver function, and good performance status [4, 5]. Conventional TACE (cTACE) uses a mixture of chemotherapeutic drugs and lipiodol, while drug-eluting beads TACE (DEB-TACE) uses embolic microspheres, which release the cytotoxic agents in a controlled manner. They are both equivalent in terms of survival, tumor response, and safety profile. Transarterial chemoembolization can also be offered in patients with earlier-stage HCC who are not candidates for surgical or ablative treatments. Furthermore, for patients on the waiting list to receive a liver transplant, TACE has successfully been used as a bridge to transplantation, reducing the drop-out rates.

Transarterial radioembolization (TARE), also known as selective internal radiation therapy (SIRT), is another embolization option for HCC. TARE involves the delivery of radiation directly to the tumor in the liver using tiny radioactive particles called microspheres, such as Yttrium-90 (Y-90), which can emit high-energy radiation to the tumor. One of the main advantages is the fact that it can be used in patients with malignant portal vein thrombosis due to its minimal embolic effect. Yet, it carries the limitations of restricted availability and technically demanding procedures. It has been investigated in the setting of early, intermediate and advanced HCC. In early-intermediate-stage tumors, it has been suggested that TARE may lead to acceptable response rates or even serve as an effective downstaging strategy. Even though largely controversial, it may be an option in the context of multidisciplinary decisions for select patients. Future trials will explore the efficacy of intensive dosimetry TARE in this scenario. For advanced HCC, three RCTs have failed to provide any conclusive evidence of the survival advantage of TARE when compared to sorafenib; hence, TARE is not currently recommended in this setting [6, 7, 8].

3.1 Combination of ablative and embolization modalities

Combination of both techniques is feasible, albeit not universally incorporated in existing guidelines. TACE has the inert ability to reduce the “heat-sink” effect, which is the major drawback in the use of RFA, by embolizing the feeding arterial tumor vessels. It can also enhance the RFA-induced ablation zone and synergistically eradicate any micrometastatic satellite deposits. Sequential application of cTACE and RFA has been shown to improve the survival of patients with recurrent HCC lesions of less than 5 cm in diameter.

An important study from Winer et al. [9] evaluated all patients diagnosed with HCC (1998–2013) at New York University/Bellevue Hospital Center in New York City. Patients were retrospectively analyzed for date of diagnosis, treatment type, length of follow-up, and survival. Patients were excluded if they did not undergo TACE or RFA/MWA or underwent other treatments, such as surgery. The primary outcome was all-cause mortality 5 years after diagnosis. Of 509 patients diagnosed with HCC, 109 (21.4%) met inclusion criteria. Sixty were treated with TACE alone, 30 with ablation alone, and 19 were treated with both, either concomitantly or in sequence. Median follow-up and overall median survival were 15.5, 19, and 52 months for TACE, ablation, and dual therapy, respectively. Survival at 5 years was 11.9, 13.3, and 42.1% for TACE, ablation, and combination groups, respectively. Kaplan Meier analysis revealed a significant increase in survival in the combination therapy group vs. RFA or TACE alone at 5 years (p = 0.0006). However, there was no significant difference in survival when comparing TACE vs. RFA/MWA at 5 years (HR = 1.18, p = 0.48). The authors concluded that patients treated with combination embolization/ablation (TACE plus RFA/MWA) versus either modality alone benefited a longer survival.

A recently published long-term outcomes of a phase III RCT demonstrated that combinational treatment (TACE plus RFA) for patients with early-stage HCC achieved improved overall and recurrence-free survival over the RFA monotherapy, and the effect was specifically important for tumors larger than 3 cm [10].

3.2 Combination of locoregional therapies with systematic treatment

The concept relies on the fact that local thermal ablation or chemoembolization of primary liver tumors can change the tumor microenvironment and potentially reveal novel molecular targets, including the vascular endothelial growth factor receptor (VEGFR), the programmed death-1 cell surface receptor (PD-1) and its ligand (PD-L1). Local ablation can release various inflammatory cytokines and enhance the tumor’s immunogenicity by sequestration of antigen-presenting cells and tumor-specific T-cells. On the other hand, transarterial chemoembolization induces, by definition, a local ischemic environment, which upregulates the expression of VEGFR, further promoting angiogenesis and local tumor recurrences. VEGF signaling per se has also been associated with immunomodulatory effects. Thereby, it has been suggested that the use of tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) alone, in combination with each other, or with locoregional therapies, can provide significant benefits.

The phase III IMbrave 050 trial was the first to demonstrate positive results for adjuvant treatment in HCC [11]. It was reported that a combination of atezolizumab and bevacizumab significantly increased recurrence-free survival when compared to active surveillance in high-risk patients after resection or ablation with curative intent. Several other trials investigating the potential use of immunotherapy before or after local ablation are still ongoing.

As already mentioned, TACE is expected to exert a potentially synergistic effect in combination with TKIs by inhibiting angiogenesis and tumor proliferation. However, results from multiple RCTs have failed to confirm the expectations. TACTICS was the only trial to meet its primary endpoint for the treatment of intermediate HCC [12]. This RCT from Japan included 156 patients and compared the efficacy of cTACE plus sorafenib versus cTACE monotherapy. The median progression-free survival was 25.2 months in the combination treatment arm versus 13.5 months in the cTACE monotherapy arm (HR 0.59; 95% CI 0.41–0.87; P = 0.006). However, updated final outcomes of the same study failed to demonstrate a significant overall survival benefit. Lenvatinib is a multi-kinase inhibitor that has been approved as a first-line treatment option that is non-inferior to sorafenib in advanced HCC cases. An RCT recruiting 338 patients with advanced HCC reported significantly improved overall survival in patients receiving a combination of TACE with lenvatinib versus lenvatinib alone (median overall survival of 17.8 months versus 11.5 months; HR 0.45; p < 0.001) [13]. Alternative strategies, including the combination of PD-1/PDL-1 inhibitors with TACE are being investigated with increasing interest, and results are eagerly awaited.

Transarterial radioembolization combined with sorafenib was evaluated in the SORAMIC trial [8]. Yet, no overall survival benefit was observed. The potentially beneficial effects stemming from a combination of TARE with ICIs, even though initially encouraging, warrant further research.

4. Conclusion

The treatment of hepatocellular carcinoma (HCC), the most common type of primary liver cancer, depends on factors such as the stage and extent of the cancer, the patient’s overall health and liver function, and the availability of resources and expertise. Treatment plans are often individualized based on a multidisciplinary approach. Herein, we have presented the available options and have concluded that a combination of treatments is beneficial to the patient with HCC who is not a candidate for resection or transplantation.