eUpdate – Hepatocellular Carcinoma Treatment Recommendations

Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines

Published: 05 March 2021. Authors: ESMO Guidelines Committee

Note: This eUpdate replaces all previous eUpdates published for these guidelines.

The following ESMO Clinical Practice Guideline has been recently updated with new treatment recommendations for hepatocellular carcinoma:

Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [1] 

Acknowledgements

The ESMO Guidelines Committee would like to thank the authors who drafted and reviewed the eUpdate before it was approved by the ESMO Guidelines Committee: A. Vogel, A. Cervantes, I. Chau, B. Daniele, J. M. Llovet, T. Meyer, J.-C. Nault, U. Neumann, J. Ricke, B. Sangro, P. Schirmacher, C. Verslype, C. J. Zech, D. Arnold & E. Martinelli.

Staging and risk assessment

The original Table 4 is updated.

Table 4. BCLC staging and treatment options according to level of evidence and approval status

AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; BSC, best supportive care; ECOG, Eastern Cooperative Oncology Group; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Benefit Scale; HDR, high dose rate; PS, performance status; SBRT, stereotactic body radiotherapy; SIRT, selective internal radiotherapy; TACE, transarterial chemoembolisation; TKI, tyrosine kinase inhibitor.

^a Non-inferiority to sorafenib established; no evaluable benefit.
^b Regorafenib is not recommended in TKI-naïve patients.
^c Ramucirumab is only recommended in patients with an AFP level ≥400 ng/ml.

Section

Management of early and intermediate hepatocellular carcinoma (HCC), Selective internal radiotherapy

The text has been updated to include a level of evidence and grade of recommendation for selective internal radiotherapy (SIRT):

Thus, in exceptional circumstances, for patients with liver-confined disease and good liver function in whom neither transarterial chemoembolisation (TACE) nor systemic therapy is possible, SIRT may be considered [III, C].

Section

Management of advanced disease, Systemic therapies for advanced HCC

New text to replace sub-sections ‘Targeted first-line therapies’ and ‘Targeted second-line therapies’:

Treatment sequencing

In recent years, several first- and second-line treatment options have been approved for advanced HCC and recommended in ESMO Clinical Practice Guidelines. Exploratory analyses of the reported first- and second-line trials indicate that a cumulative median overall survival (OS) of >20 months can be reached in patients with maintained liver function, and sequential systemic therapy is therefore strongly recommended.

Atezolizumab plus bevacizumab is the first treatment to demonstrate a significant OS benefit compared with sorafenib with a hazard ratio for death of 0.66 [95% confidence interval (CI) 0.52-0.85; P=0.0009], data reported from a recent abstract [2]. Consequently, atezolizumab plus bevacizumab will become the standard of care in first-line systemic therapy in HCC. However, 20% of patients do not respond to atezolizumab plus bevacizumab and the median progression-free survival (PFS) is only 6.8 months, raising the need to define options for second-line therapy [3]. Drugs in the second-line setting have so far only been tested after sorafenib failure/intolerance and there are currently no phase III trial data to inform the choice of second-line therapy in HCC patients that received alternative front-line therapies. There is, however, a clear rationale for offering a multikinase inhibitor given the existing evidence for efficacy in first and second line. See ESMO-Magnitude of Clinical Benefit Scale (MCBS) (Table 8). As there is no evidence for any drug in particular, it is recommended that all the currently approved first- and second-line agents could be considered as second-line therapy (see Figure 1; efficacy data are summarised in a new Table 9).

Current evidence base:

• Sorafenib: sorafenib has only been evaluated in the first-line setting. Phase-IV/observational studies have not revealed new safety signals in patients with Child–Pugh B cirrhosis [4] [I, A; ESMO-MCBS v1.1 score:4].
• Lenvatinib: lenvatinib has only been evaluated in the first-line setting. The drug has shown a higher response rate compared with other tyrosine kinase inhibitors (TKIs) and ramucirumab in HCC [5] [I, A], with non-inferiority to sorafenib established and no evaluable benefit.
• Regorafenib: regorafenib has only been evaluated in the second-line setting after progression on sorafenib. One main inclusion criterion for the RESORCE study was the tolerance to sorafenib, therefore the drug is preferably recommended in patients that have tolerated sorafenib and not in TKI-naïve patients [6] [I, A; ESMO-MCBS v1.1 score: 4].
• Cabozantinib: cabozantinib has been evaluated in the second- and third-line (28% of patients in the CELESTIAL trial) setting after intolerance to or progression under sorafenib treatment. Efficacy and safety of cabozantinib is independent of the duration of sorafenib pretreatment [7] [I, A; ESMO-MCBS v1.1 score: 3].
• Ramucirumab: ramucirumab has only been evaluated in the second-line setting after intolerance to/progression under sorafenib treatment. Ramucirumab has only shown efficacy in patients with an α-fetoprotein (AFP) level ≥400 ng/ml [8] [I, A; ESMO-MCBS v1.1 score: 1].

The majority of ESMO Guideline authors recommend considering all approved agents (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) in the second-line setting after atezolizumab plus bevacizumab. A minority of the authors (3/14) recommended that only sorafenib or lenvatinib should be used in second line after atezolizumab plus bevacizumab and that regorafenib, cabozantinib and ramucirumab should be used in third line.

The ESMO-MCBS Table 8 is updated to include scores for ramucirumab and atezolizumab plus bevacizumab.

Table 8. ESMO-MCBS table for new therapies/indications in HCC^a

AFP, α-fetoprotein; CI, confidence interval; EMA, European Medicines Agency; ESMO-MCBS, Magnitude of Clinical Benefit Scale; HR, hazard ratio; OS, overall survival; PE, point estimate; PFS, progression-free survival; QoL, quality of life; TKI, tyrosine kinase inhibitor.

^a EMA approvals since January 2016.
^b ESMO-MCBS version 1.1 [12]. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee.
^c Estimation of gain based on the PE HR 0.58.

Management of advanced disease, immunotherapies

The text has been updated:

Atezolizumab plus bevacizumab, which showed superior efficacy compared with sorafenib, is recommended as standard of care in first-line therapy of patients with advanced HCC and received European Medicines Agency (EMA) approval in late 2020 [3, 9] [ESMO-MCBS v1.1 score: 5].

Immunotherapy in the form of monotherapy has been evaluated in patients in two phase III studies. The first-line phase III CheckMate 459 trial, comparing sorafenib with nivolumab as a first-line treatment option, failed to meet the primary endpoint of overall survival (OS) [10]. The second-line phase III KEYNOTE-240 trial of pembrolizumab versus placebo also failed to meet its co-primary endpoints of OS and PFS [11]. Neither drug has received EMA approval and they are not recommended as monotherapy for the treatment of advanced HCC.

New Table 9. Summary of efficacy data for HCC

Albi, albumin–bilirubin score; CI, confidence interval; CR, complete response; DCR, disease control rate; HCC, hepatocellular carcinoma; HR, hazard ratio; mOS, median overall survival; NA, not available; NR, not reached; ORR, overall response rate; OS, overall survival: PD, progressive disease; PFS,  progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease. 

^a Pooled data.
^b Response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).
^c Modified RECIST.

References

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