Biologics, Immunotherapies, and Cytotoxic Chemotherapy for Hepatocellular Carcinoma following Current Recommendations by the BCLC: A Review of Agents

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and among the leading causes of cancer-related deaths worldwide. ^{1 2} While early-stage HCC is amenable to curative therapy, intermediate- and late-stages require a team of hepatologists, surgeons, oncologists, and interventional radiologists to optimize treatment.

Several staging systems have been proposed in the management of HCC, the most prominent being the Barcelona Clinic Liver Cancer (BCLC) Staging System which is endorsed by leading organizations in Europe and North America. ³ According to the BCLC System, HCC stage is assessed using measures of tumor burden, performance status, and liver function. Tumor burden incorporates the size, location, and number of lesions as well as portal invasion or extrahepatic spread. Performance status is determined using the Eastern Cooperative Oncology Group (ECOG) criteria. ⁴ Finally, liver function is classified as “preserved” or “end-stage.” Measures of liver function have traditionally relied on Child–Pugh (CP) scores which stratify patients into three classes of liver function based on serum bilirubin, albumin, coagulation, and the presence or absence of ascites and hepatic encephalopathy. ⁵ The Model for End-Stage Liver Disease (MELD) scoring system, originally developed to predict outcomes of patients undergoing transjugular intrahepatic portosystemic shunt, overcomes some limitations of the CP system, namely, the subjectivity in rating ascites or encephalopathy which could inappropriately be used to benefit a patient's position on transplant lists. ⁶ New BCLC recommendations suggest incorporating α fetoprotein and albumin–bilirubin scores to accurately assess liver function in addition to these traditional measures. Tumor burden, performance status, and liver function are used in conjunction to stratify HCC into very early stage (0), early stage (A), intermediate stage (B), advanced stage (C), and terminal stage (D) ( Table 1 ).

Table 1. Barcelona Clinic Liver Cancer 2022 recommendation for the stratification of hepatocellular carcinoma.

	Tumor burden	Performance status	Liver function
Very early stage (0)	Single ≤ 2 cm	0	Preserved
Early stage (A)	Single, or ≤ 3 nodules each ≤ 3 cm	0	Preserved
Intermediate stage (B)	Multinodular	0	Preserved
Transplant-eligible	Meets extended liver transplant criteria (size, AFP levels)
TACE-eligible	Well-defined nodules, preserved portal flow, selective access	0	Preserved
Recommended for systemic therapy	Diffuse, infiltrative, extensive bilobar liver involvement
Advanced stage (C)	Portal invasions, extrahepatic spread	1–2	Preserved
Terminal stage (D)	Any tumor burden	3–4	End-stage liver function

Abbreviations: AFP, α fetoprotein; TACE, transarterial chemoembolization.

The most recent BCLC Staging System was published in 2022 and contains several changes from the 2018 iteration. For one, the 2022 version stratifies intermediate stage (B) HCC into three categories: transplant eligible, TACE eligible, or recommended for systemic therapy. ⁷ This is a change from the 2018 guidelines which recommended chemoembolization for all intermediate stage (B) lesions, drawing criticism of suboptimal recommendations for such a heterogeneous grouping of patients. ³ This stratification is considerably important for interventional radiologists to be aware of as management of stage B HCC now depends on the nature and/or extent of tumor involvement as well as patients' transplant eligibility. Furthermore, TACE and transarterial radioembolization (TARE) are now recommended as second-line treatments when transplant, ablation, or resection fails in Stage 0 or A HCC. ⁷ Notably, the recommendations for TARE are limited to lesions ≤ 8 cm based on results of the LEGACY study. ⁸

In general, it is worth noting that liver transplantation has become increasingly more prevalent in the long-term management of HCC compared with prior BCLC iterations. This is because of the high risk of recurrence of HCC of up to 70% within 5 years after ablation or surgical resection. ⁹ Liver transplantation is theoretically curative for both HCC and underlying liver disease, and demonstrates ∼50 to 70% survival within 5 years; however, a 10 to 20% reported incidence of HCC recurrence still exists in this patient population. ^{10 11} TACE and TARE can be used as bridging treatments prior to transplant, and have demonstrated effectiveness in halting tumor progression and reducing waitlist dropout rates for patients with liver cirrhosis and HCC. ^{12 13 14 15} Given the increasing prevalence of transplantation as a definitive treatment for HCC and the demonstration of TACE and TARE as effective strategies for improving access to transplantation, this approach to downstaging and bridging to transplant has been included in the 2022 iteration of the BCLC guidelines. New modifications to the role of IR interventions in HCC are summarized in Table 2 .

Table 2. Comparison of applications for IR interventions for HCC between 2018 and 2022 iterations of BCLC.

	BCLC 2018 iteration	BCLC 2022 iteration
Tumor ablation	BCLC-0 if transplant is contraindicated	BCLC-0 if transplant is contraindicated
	BCLC-A with up to 3 nodules ≤3 cm if associated comorbidities present	BCLC-A with up to 3 nodules ≤3 cm if transplant is contraindicated
	BCLC-A with solitary lesion and elevated portal pressure/bilirubin if associated comorbidities present	BCLC-A with solitary lesion and elevated portal pressure/bilirubin if transplant is contraindicated
TACE	BCLC-B	BCLC-B if well-defined nodules with preserved portal flow and tumor burden not acceptable for transplant
	N/A	Second-line for BCLC-A if transplant, resection, or ablation fails
	N/A	Bridge to transplant if successful downstaging occurs post-procedure
TARE	N/A	Second-line for BCLC-A if transplant, resection, or ablation fails and single lesion ≤8 cm
		Bridge to transplant if successful downstaging occurs post-procedure

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Notes: Broadly, liver transplantation has taken precedence over previous strategies for select groups, and modifiers have been included to subdivide the staging groups and personalize treatments. In addition, TACE and TARE are now recommended as second-line options and for bridging to transplantation.

The final change to BCLC 2022 is the inclusion of new classes of systemic agents as per recommendations from the European Association for the Study of the Liver Position Paper published in 2021. ¹⁶ New classes of systemic agents for the treatment of HCC include immune checkpoint inhibitors and anti-vascular endothelial growth factor (VEGF) antibodies, in conjunction with traditionally approved receptor tyrosine kinase (RTK) inhibitors like sorafenib. Systemic therapy is now recommended for intermediate stage (B) HCC with diffuse, infiltrative, bilobar involvement, ⁷ or as second-line treatment when TACE or TARE fails or are not feasible. New classes of systemic agents ( Table 3 ) available for the treatment of HCC are presented below to aid interventional radiologists in their discussion of treatment options with colleagues and patients.

Table 3. Systemic agents recommended by the Barcelona Clinic Liver Cancer Staging System for hepatocellular carcinoma.

	Agent	Class	ROA	Schedule
First line	Atezolizumab–bevacizumab	Immune checkpoint + anti-VEGF Ab	IV	1,200 mg–15 mg/kg Q3wks
	Durvalumab–tremelimumab	Immune checkpoint inhibitor	IV	1,500 mg Q4wks–300 mg ×1
	Sorafenib	Receptor tyrosine kinase inhibitor	PO	400 mg BID
	Durvalumab	Immune checkpoint inhibitor	IV	1,500 mg Q4wks
	Lenvatinib	Receptor tyrosine kinase inhibitor	PO	<60 kg: 8 mg Qday, ≥60 kg: 12 mg Qday
Second line	Ramucirumab	Anti-VEGF Ab	IV	8 mg/kg Q2wks
	Regorafenib	Receptor tyrosine kinase inhibitor	PO	160 mg Qday for 3wks, 1 wk off
Second or third line	Cabozantinib	Receptor tyrosine kinase inhibitor	PO	60 mg Qday (40 mg for Child–Pugh B)

Abbreviations: BID, twice a day; IV, intravenously; PO, per os (by mouth); Q2wks, every 2 weeks; Q3wks, every 3 weeks; Q4wks, every 4 weeks; Qday, every day; ROA, route of administration; VEGF, vascular endothelial growth factor.

Immune Checkpoint Inhibitors

While immune checkpoints were initially discovered in 1987, their true function was not fully realized until 1995. ^{17 18} These checkpoints play a crucial role in safeguarding the integrity of healthy cells within the body. Among the well-established immune checkpoints are the interactions between programmed cell death protein 1 (PD-1) on T-cells and its ligand (PD-1L) on non-immune or tumor cells. A second established immune checkpoint is the interaction between cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on T-cells and B7 on non-immune or tumor cells. The interaction between PD-1/PD-1L and CTLA-4/B7 effectively hinder the immune-mediated response directed at healthy cells, thus maintaining the balance between immune surveillance and self-tolerance. ¹⁸

The first immune checkpoint inhibitor, ipilimumab, was approved in 2011 to target interactions between CD28/80/86 in the treatment of melanoma, ¹⁹ and the first PD-1 immune checkpoint inhibitor was approved in 2014. ²⁰ Despite having different targets, all immune checkpoint inhibitors function by disrupting the binding interactions between established immune checkpoints such as PD-1 to PD-1L and CTLA-4 to B7 as previously described. By impeding this binding process, immune checkpoint inhibitors enable T-cell–mediated destruction of cancerous cells. ²¹ The BCLC 2022 recommendation includes immune checkpoint inhibitors as first-line agents for the treatment of HCC, namely, durvalumab–tremelimumab and atezolizumab.

Durvalumab–tremelimumab is recommended as a first-line agent in BCLC 2022 following positive results of the HIMALAYA trial. ²² Durvalumab exerts its effects by binding to PD-1L on the surface of tumor cells, thereby preventing its interaction with PD-1 on T-cells. By doing so, durvalumab inhibits the tumor cell's ability to suppress the T-cell response, allowing for enhanced immune-mediated destruction of cancerous cells. ²³ Tremelimumab has a similar effect by binding CTLA-4 on T-cells, impeding the inhibitory effects of neighboring T-cells and enabling an enhanced immune response to cancerous cells. ²⁴

Durvalumab can be employed as a standalone treatment or in combination with tremelimumab for HCC. Administration of tremelimumab involves a single intravenous dose of 300 mg, followed by 1,500 mg of durvalumab which is given intravenously every 4 weeks. The HIMALAYA trial revealed an increased overall survival rate at 36 months with tremelimumab plus durvalumab (T + D) in combination compared with durvalumab (D) or sorafenib (S) alone, ²² leading to its inclusion in BCLC 2022 recommendations. The overall survival rate at 36 months was 30.7% for T + D, 24.7% for D, and 20.2% for S, with median overall survival rates of 16.43, 16.56, and 13.77 months, respectively. It is important to note that tremelimumab plus durvalumab produced more Grade 3 or 4 adverse events (50.5%) compared with durvalumab alone (37.1%), ²² which warrants a discussion of the risk and benefits of combined therapy with respect to the patient's goals. Caution should be exercised due to the potential for infusion-related reactions to these agents. Both tremelimumab and durvalumab produce specific, immune-mediated adverse events that necessitate close monitoring during treatment. Baseline aspartate transaminase/alanine transaminase, creatinine, and thyroid function should be assessed prior to initiation to aid in the early detection of immune-mediated organ damage such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, or pancreatitis. ^{23 24} Immune-mediated hepatitis (7.5%) and hypothyroidism (8.3%) are among the most common severe adverse reactions. Durvalumab–tremelimumab is also teratogenic and contraindicated in patients with a history of hematopoietic stem cell transplantation.

Other side effects associated with immune-checkpoint inhibitors include rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. ^{23 24} As previously mentioned, the incidence of adverse reactions tends to be higher in patients undergoing durvalumab–tremelimumab combination therapy (50.5%), compared with those receiving durvalumab alone (37.1%), though both result in fewer Grade 3 or 4 adverse events when compared with sorafenib (52.4%). ²² It is crucial to consider these adverse reactions and their potential impact when determining the appropriate treatment strategy for patients receiving immune checkpoint inhibitors. The combination of an immune checkpoint inhibitor with an agent from different classes, as seen with atezolizumab–bevacizumab, may potentially reduce the occurrence of adverse events.

According to BCLC 2022, atezolizumab plus the anti-VEGF agent bevacizumab is recommended as a first-line agent in the treatment of HCC. ⁷ Atezolizumab functions by binding to PD-1L on the surface of tumor cells, thereby inhibiting its interaction with PD-1. ²⁵ This blockade prevents the tumor cells from suppressing the T-cell response, enabling enhanced immune-mediated destruction of cancer cells. Atezolizumab is reported as effective against HCC when combined with bevacizumab. This is supported by the IMbrave 150 trial of 2020, where atezolizumab–bevacizumab exhibited superior efficacy compared with sorafenib in terms of 6- and 12-month survival rates, as well as progression-free survival at 6 months. ²⁶ It is already known that anti-VEGF agents can stabilize tumor vasculature and thereby increase drug delivery to the tumor. ²⁷ Further rationale for combining the two is that VEGF promotes immunosuppression by upregulation of regulatory immune cells and downregulation of antigen-presenting cells and cytotoxic T-cells within the tumor microenvironment. An anti-VEGF agent can thus reverse this effect and work synergistically with atezolizumab to increase immune activity directed at the tumor. ²⁸ The administration of atezolizumab typically involves intravenous delivery of 1,200 mg in combination with 15 mg/kg of bevacizumab every 3 weeks. Caution should be exercised due to the risk of infusion-related reactions, and it is important to note that atezolizumab–bevacizumab, like other immune checkpoint inhibitors, can cause severe or fatal immune-mediated adverse reactions which should be closely monitored during treatment. ²⁵

Anti-VEGF Antibodies

VEGF, initially characterized in the 1990s, plays a significant role in various physiological processes, including neovascularization, hematopoiesis, and wound healing. ²⁹ In neoplastic conditions, VEGF contributes to the establishment of a positive feedback loop of increased angiogenesis and neovascularization within tumors. To counteract this process, monoclonal antibodies (mAbs) have been developed to inhibit VEGF and interfere with the formation of new blood vessels. By targeting VEGF, these mAbs can disrupt the neovascularization process, thereby limiting the blood supply to tumors and impeding their growth. Furthermore, they may normalize the tumor vasculature, decreasing microvascular density and vascular permeability which thereby improves oxygen and drug delivery to the tumor. ²⁷ The inhibition of VEGF and neovascularization through the use of mAbs represents a promising approach in cancer therapeutics that is being capitalized on for the treatment of HCC.

Anti-VEGF antibodies such as bevacizumab are established agents that have been employed for several years, with bevacizumab receiving its initial approval for the treatment of colon cancer in 2004. ³⁰ In more recent years, bevacizumab has been investigated for its potential in combination therapy for HCC. ²⁶ When compared with sorafenib, combination atezolizumab and bevacizumab improved both median survival at 6 and 12 months (84.8%, 67.2% compared with 72.2%, 54.6%). Atezolizumab–bevacizumab also improved progression-free survival (54.5%) compared with sorafenib (37.2%) with a similar incidence of adverse events. Adverse events associated with bevacizumab, including hypertension, proteinuria, and hyponatremia, cause interruption in the treatment of nearly half (46%) of patients. ³⁰ Fatal adverse reactions, most commonly caused by gastrointestinal or esophageal variceal hemorrhage or infection, occurred in 4.6% of patients. The most common serious adverse reactions included hemorrhage, infection, and pyrexia. Finally, bevacizumab treatment should be withheld at least 28 days following elective surgery due to complications of surgical wound healing and hemorrhage.

A second anti-VEGF antibody, ramucirumab, has been assessed as a second-line treatment following sorafenib in BCLC 2022 recommendations. This decision follows results of the Reach-2 Trial published in 2019. ³¹ Reach-2 sought to determine the efficacy of ramucirumab compared with placebo after sorafenib therapy was discontinued due to tumor progression or intolerance. Results indicated that ramucirumab, when used as a second-line agent, led to improved median overall survival and progression-free survival when compared with placebo. Yasui et al noted several patients who received and tolerated subsequent TACE after ramucirumab therapy. These patients, along with others receiving subsequent therapies after ramucirumab, demonstrated longer overall survival compared with those who received ramucirumab alone, ³² supporting its use in combination therapy. Ramucirumab is delivered intravenously at a dosage of 8 mg/kg every 2 weeks. ³³ It is important to consider severe adverse events associated with ramucirumab, such as ascites and pneumonia. ^{31 33} Fatal adverse events included ascites, hepatic encephalopathy, and hepatorenal syndrome, suggesting a hepatic etiology. ³³

Receptor Tyrosine Kinase Inhibitors

RTKs are a class of cell surface receptors that play a crucial role in various cellular processes. ³⁴ RTKs are primarily activated by binding to exogenous growth factors such as VEGF, platelet-derived growth factor (PDGF), epidermal growth factor, fibroblast growth factor (FGF), and hepatocyte growth factor. Upon binding and activation, RTKs initiate downstream signaling cascades that regulate cell proliferation, survival, differentiation, and migration. However, constitutive activation of RTKs has been implicated in various types of cancer, including HCC. ³⁴ Dysregulation of RTKs contributes to the uncontrolled growth and survival of cancer cells, highlighting their significance as potential therapeutic targets in cancer treatment.

RTK inhibitors (RTKis) have a history dating back to the 1990s when their safety and efficacy were initially established. Notable RTKis include trastuzumab, which was approved in 1998 for its targeting of HER2, ³⁵ and sorafenib (Nexavar), which was approved for renal cell carcinoma in 2005, and HCC in 2007. ³⁶ RTK is used in the treatment of HCC and share a common mechanism of action, inhibiting the RTK that serves as the VEGF receptor (VEGFR). By blocking VEGFR, these inhibitors effectively prevent angiogenesis, inhibit endothelial cell proliferation, and impede tumor metastasis. This targeted approach against VEGFR has demonstrated efficacy in suppressing the growth and progression of HCC, highlighting the significance of RTKis as valuable therapeutic options in the management of this particular cancer.

Sorafenib, as recommended in the BCLC 2018 guidelines, served as a first-line therapeutic agent for HCC followed by regorafenib or lenvatinib. ³⁷ In addition to inhibiting VEGFR, sorafenib is shown to inhibit the RTK, PDGF receptor (PDGFR), effectively halting angiogenesis and mitotic activity. ³⁸ Furthermore, sorafenib has demonstrated inhibitory effects on RAF-MEK signaling and soluble epoxide reductase. Apart from its approved indication for inoperable HCC, sorafenib is also indicated for the treatment of renal cell carcinoma and thyroid carcinoma. ³⁸ Sorafenib is administered 400 mg per os (PO), twice daily. Adverse events observed in the REFLECT 2018 study include palmar-plantar erythrodysesthesia (52%), diarrhea (46%), hypertension (30%), and decreased appetite (27%). ³⁹ It is important to note that sorafenib should be avoided with potent CYP3A4 inducers and monitored for serious adverse events such as interstitial lung disease, congestive heart failure, hypertensive crisis, QT prolongation, gastrointestinal perforation or hemorrhage, cerebral hemorrhage, and leukoencephalopathy. ³⁸ Sorafenib continues to be recommended as a first-line agent for the treatment of HCC in BCLC 2022, ⁷ though side effects should be discussed with the patient to select an agent that aligns with their treatment goals.

Atezolizumab + bevacizumab and durvalumab + tremelimumab are prioritized over sorafenib for exhibiting greater overall survival in the IMbrave 150 ²⁶ and HIMALAYA trials, ²² respectively.

BCLC 2022 recommendations included lenvatinib, another RTKi, as first-line treatment for HCC following results from the REFLECT trial. ³⁹ This non-inferiority trial compared the efficacy of lenvatinib to sorafenib. Both agents inhibit PDGFR, leading to the interruption of angiogenesis and mitotic activity. Additionally, lenvatinib has demonstrated inhibitory effects on FGF receptor, RET receptor, and c-KIT receptor, thereby providing a broader spectrum of targeted inhibition. ⁴⁰ It is approved for the treatment of inoperable HCC, renal cell carcinoma, and thyroid carcinoma, suggesting similar uses to sorafenib. ⁴¹ Lenvatinib is administered PO with a recommended dosage of 8 mg once daily for patients weighing less than 60 kg and 12 mg once daily for patients weighing more than 60 kg. Adverse events observed with lenvatinib include hypertension (42%), diarrhea (39%), decreased appetite (34%), and decreased weight (31%). ³⁹ The most common serious adverse events included hepatic encephalopathy, liver failure, and ascites.

Regorafenib is an additional RTKi recommended in the BCLC 2022 guidelines as a second-line therapeutic option following results from the RESOURCE trial published in 2017. ⁴² Regorafenib's mechanism of action involves the inhibition of Tie2R (TEK), an endothelium-specific RTK, effectively halting angiogenesis and impeding tumor growth. Regorafenib has also been shown to inhibit soluble epoxide reductase. It is approved for the treatment of HCC, metastatic colorectal cancer, and gastrointestinal stromal tumors. ⁴³ The delivery of regorafenib is PO following a low-fat meal with a recommended dosage of 160 mg once daily for 3 weeks, followed by a 1-week break. Adverse events observed in the RESOURCE 2017 trial include hypertension (15%) and palmar-plantar erythrodysesthesia (13%). ⁴² Regorafenib is contraindicated with CYP3A4 inducers, and patients should also be monitored for life-threatening adverse events, most notably hepatotoxicity. ⁴³

Cabozantinib is recommended as a third-line treatment option in the BCLC 2022 guidelines following the CELESTIAL trial published in 2018. ⁴⁴ Cabozantinib is specifically recommended for HCC patients who had previously received sorafenib, with dose reductions implemented to manage adverse events. Cabozantinib exerts its mechanism of action by inhibiting MET (mesenchymal–epithelial transition) and AXL, as well as TAM receptors, thereby targeting multiple pathways involved in tumor growth and progression. It is approved for the treatment of thyroid carcinoma, renal cell carcinoma, and HCC following sorafenib therapy. ⁴⁵ The standard delivery of cabozantinib is 60 mg PO once daily, with a reduced dosage of 40 mg once daily for patients with CP B liver function impairment. Adverse events associated with cabozantinib therapy include but are not limited to hypertension, diarrhea, fatigue, decreased appetite, and palmar-plantar erythrodysesthesia. Specific black box warnings are provided for severe hemorrhage, gastrointestinal perforation, and fistula formation, emphasizing the importance of diligent monitoring and management of these potential risks during treatment. ⁴⁵

Implications for the Practicing Interventionalist

An emerging concept in HCC therapy is that of curative conversion following systemic therapy. Atezolizumab + bevacizumab therapy can induce tumor shrinkage, even for poorly differentiated or multinodular HCC. This effect along with the stabilization of tumor vasculature opens the possibility for surgical resection, TACE, or ablation, which has demonstrated curative conversion in up to 30% of patients with HCC after receiving atezolizumab + bevacizumab. ⁴⁶ Sorafenib followed by TACE has demonstrated increased progression-free survival surpassing 13 months, and overall survival surpassing 11 months when compared with TACE alone in those with HCC that was initially TACE unsuitable. ⁴⁷ Furthermore, in a meta-analysis by Yang et al pooling randomized controlled trials (RCTs) with retrospective observational studies, it was found that combined sorafenib + TACE led to significantly increased overall survival and delayed progression (though not when pooling RCTs only) over TACE alone. As expected, the combination therapy also led to increased sorafenib-related adverse events including hand–foot skin reactions, hypertension, diarrhea, alopecia, desquamation, and elevated aminotransferases. ⁴⁸ However, other trials examining a similar combination did not find significant improvements in overall survival or progression-free survival. ^{49 50 51} Future research is needed to elucidate effective dosages and timings for this approach.

Lenvatinib followed by TACE is also associated with increased survival, curative conversion in a subset of patients, and preservation of liver function compared with TACE alone, again in patients with initial TACE-unsuitable HCC. ⁵² These approaches will become more relevant to the interventionalist, as several organizations have already endorsed the use of lenvatinib–TACE sequential therapy in those with intermediate-stage HCC unsuitable for TACE alone. ^{53 54 55}

A combination of TACE and anti-VEGF therapy with bevacizumab may also provide a means of synergistically promoting tumor necrosis in HCC. As TACE reduces blood flow and therefore oxygen delivery to the tumor, there is hypoxia-induced neovascularization within the local environment driven by VEGF and PDGF, promoting tumorigenesis. Concurrent administration of bevacizumab with TACE has been shown to inhibit angiogenesis and stabilize tumor vasculature. ⁵⁶ However, it is already known that TACE can lead to deterioration of liver function via hepatic devascularization in a subset of patients, ⁵⁷ and care should be taken in determining which patients should be eligible for combined locoregional and anti-VEGF therapy, as this may exacerbate liver devascularization and chronic liver dysfunction post-TACE.

The role of TARE and radiofrequency ablation (RFA) in combination with systemic therapy is less well established, though recommendations may arise as new evidence becomes available. In a 2019 study, sorafenib combined with TARE did not show increased overall survival in patients with advanced HCC. ⁵⁸ However, in a case report of HCC where portal vein thrombosis precluded the use of TACE, a combination of atezolizumab + bevacizumab followed by TARE demonstrated reduction in tumor size and delayed progression. ⁵⁹ This suggests a safe and potentially effective means of delaying progression in more advanced cases. Combination lenvatinib and RFA is a safe technique that may also lead to delayed progression and increased survival in those with preserved liver function but higher tumor burden. ⁶⁰

Though the current BCLC iteration does not recommend or incorporate combination therapies, the practicing interventionalist should be aware of the emerging evidence for curative conversion using systemic therapy followed by locoregional modalities (TACE, RFA, and TARE). Several clinical trials are underway to examine the effects of combined atezolizumab and bevacizumab along with TACE for the management of untreated BCLC-B HCC. ^{61 62} Another trial is designed to determine if systemic and locoregional combination therapy may successfully lead to downstaging of tumors beyond the Milan criteria to make liver transplantation accessible for these individuals. ⁶³ Results from these trials will influence the future management of intermediate-stage HCC and further characterize the role of interventional techniques as a curative strategy or bridge to transplant.

Conclusion

The 2022 iteration of the BCLC guidelines introduces new systemic agents and expands on the role of interventional techniques in the second-line management of BCLC-A as well as in the new subclassifications of BCLC-B HCC. It also supports a means for locoregional therapy as a bridge to liver transplantation, which has become increasingly important due to improved access and outcomes for patients as a definitive therapy. Practicing interventional radiologists should be aware of these new additions to the guidelines and continue to evolve as new recommendations exploring combination therapy with systemic agents emerge. Though BCLC 2022 does not yet incorporate these combination approaches, they will be of increasing importance as future studies better characterize the role of systemic therapy before, during, and after locoregional management.