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Semin intervent Radiol 2024; 41(01): 084-091
DOI: 10.1055/s-0043-1778660
Clinical Corner

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

Rajangad S. Gurtatta
1   University of Illinois College of Medicine, Chicago, Illinois
,
Sydney E. Whalen
1   University of Illinois College of Medicine, Chicago, Illinois
,
Charles E. Ray Jr.
2   Department of Radiology, University of Illinois College of Medicine, Chicago, Illinois
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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.




Publication History

Article published online:
14 March 2024

© 2024. Thieme. All rights reserved.

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