Hepatocellular carcinoma

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

Barcelona Clinic Liver Cancer (BCLC) stage 0-A (very early 0 or early disease A): possible surgical candidate (good liver function)

1st line – consider resection or thermal ablation

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1st line –

consider resection or thermal ablation

Surgical resection is the optimal curative treatment for hepatocellular carcinoma (HCC) in patients with solitary HCC without vascular invasion, and normal hepatic synthetic function without evidence of portal hypertension.[59][90] The American Association for the Study of Liver Diseases (AASLD) recommends that surgical resection should be the treatment of choice for localised HCC in the absence of underlying cirrhosis.[7]

It may also be considered in patients with cirrhosis with limited tumour burden, well-compensated cirrhosis without clinically significant portal hypertension, and an adequate future liver remnant (typically >40%).[7] Hepatic resection is also the preferred option in patients with hepatitis B-induced HCC without cirrhosis.

Criteria for resection based on BCLC staging include: a solitary HCC confined to the liver; no radiographic evidence of invasion of the hepatic vasculatures; no radiographic evidence of any contiguous or distance metastasis; well-preserved hepatic function, with no portal hypertension.[90] However, emerging data and guidelines support considering resection in well-selected patients with stable Child-Turcotte-Pugh class B liver function and/or minor portal hypertension, with careful assessment of surgical risk and potential for hepatic decompensation.[2][59][91]

Establishing sufficient liver reserve before considering resection of HCC is important; there is a risk of potential liver failure after resection in cirrhotic livers. The 5-year survival rate is as high as 90% in carefully selected patients.[92]

Postoperative haemorrhage and liver failure are the most common complications after resection. These complications are more common in patients with cirrhosis and impaired functional reserve. Meta-analyses have shown laparoscopic hepatectomy is safe and feasible in selected patients with HCC; patients undergoing laparoscopic hepatectomy had less need for blood transfusions, shorter hospital stays, and fewer postoperative complications.[93][94]

Treatment of patients with comorbidities should be decided on a case-by-case basis and depends on the severity of the comorbidity and the patient's functional status.

Thermal ablation, including radiofrequency ablation (RFA) or microwave ablation (MWA), is a curative treatment option for patients with very early (BCLC-0) or early stage (BCLC-A) hepatocellular carcinoma. It is primarily recommended for patients who are ineligible for or decline surgical resection, particularly for solitary tumours ≤3 cm. For tumours 3-5 cm, or multifocal disease (≤3 nodules ≤3 cm), thermal ablation may still be appropriate in selected cases.[7][59][62] The choice between resection and ablation should be individualised based on tumour characteristics, liver function, and multidisciplinary discussion.[59]

One meta-analysis found that 5-year overall survival and recurrence rates were similar in patients with very early HCC treated with RFA, compared with patients treated with surgical resection.[95]

One Cochrane review found no evidence of a difference in all-cause mortality at maximal follow-up between surgery and RFA in people with very early- or early-stage HCC who were eligible for surgery.[96] [ ] Cancer-related mortality was lower in the surgery group compared with the RFA group (odds ratio 0.35, 95% confidence interval [CI] 0.19 to 0.65). Serious adverse events were higher in the surgery compared with the RFA group (odds ratio 17.96, 95% CI 2.28 to 141.60). Overall the quality of evidence was low, and further randomised controlled trials are recommended.[96]

MWA is less affected by heat sink effect compared with RFA, meaning that the efficacy of treatment is less affected by vessels located near the tumour.[97] To date, no good evidence favours one form of thermal ablation over the other. One meta-analysis including only randomised controlled trials found that MWA may reduce the long-term recurrence and improve the 5-year survival, compared with RFA.[98] Another meta-analysis found higher complete ablation and lower local tumour progression with MWA compared with RFA, with no difference in survival between the two modalities.[99]

Outcomes of laparoscopic and percutaneous MWA and that of MWA and RFA have been compared in patients with HCC and colorectal liver metastases with lesions <5 cm.[100][101] Albeit limited evidence, similar safety and feasibility profiles were seen for MWA and RFA, and either technique can be considered in appropriately selected patients.[101] Similar outcomes were observed with laparoscopic and percutaneous MWA.[100][101] While laparoscopic MWA had better local control, percutaneous MWA had lower complication rates, suggesting that either approach can be used depending on patient-specific factors.[101]

BCLC stage 0-A (very early 0 or early disease A): non-hepatic resection candidate

transplant candidate

1st line – liver transplantation

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1st line –

liver transplantation

Liver transplantation offers a curative treatment for hepatocellular carcinoma (HCC) by addressing both the tumour and the underlying liver disease. It is typically offered to patients with HCC within Milan criteria and advanced liver dysfunction (e.g., high model for end-stage liver disease [MELD] score).[7] The Milan criteria are a single lesion ≤5 cm or 2-3 lesions all ≤3 cm, without evidence of gross vascular invasion, without regional lymph node or distant extrahepatic metastasis, and with good activity performance status.[7][74]

Downstaging with locoregional therapies (e.g., transarterial chemoembolisation, thermal ablation) can be pursued in selected patients with HCC beyond Milan criteria.[7][62][102] If tumour burden is successfully reduced to within Milan criteria and remains stable for 3-6 months, patients may become eligible for liver transplantation.[7] Studies have shown that post-transplant survival in these downstaged patients is comparable to those initially meeting Milan criteria.[102][103] Major guidelines support this approach, which should be evaluated within a multidisciplinary transplant team setting.[7][62][102]

Many patients who are eligible for liver transplant may become ineligible due to deteriorating clinical condition (as a consequence of the prolonged waiting period on the deceased donor wait list). Therefore, living donor transplantation is an alternative. One systematic review found that living donor liver transplantation for HCC has comparable perioperative and survival outcomes to deceased donor donation.[104]

Consider – locoregional bridging or downstaging therapy

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Consider –

locoregional bridging or downstaging therapy

Additional treatment recommended for SOME patients in selected patient group

Transarterial chemoembolisation (TACE) or transarterial radioembolisation (TARE) and/or radiofrequency ablation (RFA) can be used as bridging therapy to minimise the risk of tumour progression while patients are awaiting transplantation, especially if the expected waiting time is more than 3 months.[59] Locoregional therapies such as TACE or thermal ablation may also be used as part of a downstaging strategy in carefully selected patients prior to transplantation.[7][62][102]

TACE uses gelatine to obstruct the tumour's arterial blood supply and induce ischaemic necrosis of the tumour.

TARE involves a transarterial injection of yttrium-90-labeled microspheres that emit damaging beta particles; this causes local radiation-induced cell death while minimising damage to the surrounding tissue.[97]

The basic principle in RFA is to generate heat, which induces coagulative necrosis of the tumour.

non-transplant candidate

1st line – thermal ablation

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1st line –

thermal ablation

Thermal ablation with radiofrequency ablation (RFA) or microwave ablation (MWA) is the standard of care for very early or early hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage 0-A) in patients who are not candidates for resection or transplantation.[7][59][62]

The Milan criteria for liver transplantation are: a single lesion ≤5 cm or 2-3 lesions all ≤3 cm, without evidence of gross vascular invasion, without regional lymph node or distant extrahepatic metastasis, and with good activity performance status.[7][74] However, some carefully selected patients initially beyond the Milan criteria may become eligible for transplantation if successfully downstaged; this should be evaluated within a multidisciplinary transplant team setting.[7][62][102]

RFA and MWA are considered equally effective.[7][99][105] However, MWA may be preferred over RFA when tumours are larger (>2-3 cm), near blood vessels (less heat-sink effect), faster ablation is beneficial, or favoured by the centre of expertise.[59][97]

The basic principle of thermal ablation is to generate heat, which induces coagulative necrosis of the tumour. Thermal ablation is most effective in tumours ≤3 cm, and is contraindicated in lesions at specific locations such as the liver dome, near major vessels, near the biliary tree, or near organs such as the gallbladder, because of the risk of injury to these structures.[7][59]

2nd line – transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) or percutaneous ethanol injection (PEI)

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2nd line –

transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) or percutaneous ethanol injection (PEI)

TACE may benefit selected asymptomatic patients with maintained liver function (Barcelona Clinic Liver Cancer [BCLC] stage A to early intermediate BCLC stage B) with small tumour burden, who are not amenable to surgery or local ablation.[59]

TACE uses gelatine to obstruct the tumour's arterial blood supply and induce ischaemic necrosis of the tumour.

TARE is an alternative treatment for patients with low-volume disease, with results similar to other curative intent treatment strategies such as ablation. TARE involves a transarterial injection of yttrium-90-labeled microspheres that emit damaging beta particles; this causes local radiation-induced cell death while minimising damage to the surrounding tissue.[97]

PEI is no longer routinely recommended, as thermal ablation methods (e.g., RFA, MWA) provide superior local control and survival outcomes.[59][109] However, PEI may be considered in patients with very small (<2 cm) solitary tumours when thermal ablation is contraindicated or not technically feasible.[105] This includes scenarios where tumours are near critical structures or in settings with limited access to advanced ablation technologies. The basic principle of PEI is the destruction of the tumour by chemicals. PEI may not cause enough necrosis of larger tumours because of their size and volume. One study in 282 people with early non-surgical hepatocellular carcinoma treated during a 15-year period found that 96% of patients with tumours ≤2 cm achieved complete response to PEI, compared with 78% of patients with tumours 2.1 to 3.0 cm and 56% of patients with tumours >3 cm.[110]

BCLC stage B: intermediate disease

1st line – transarterial chemoembolisation (TACE) or transarterial radioembolisation (TARE)

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1st line –

transarterial chemoembolisation (TACE) or transarterial radioembolisation (TARE)

TACE is generally the treatment for patients with multinodular hepatocellular carcinoma (HCC) without vascular invasion or extrahepatic spread and with relatively well preserved liver function (i.e., Barcelona Clinic Liver Cancer [BCLC] stage B disease).[7]

TACE has been shown to improve 2-year survival in patients with unresectable HCC with good functional status and compensated cirrhosis.[111]

TACE is based on the principle of causing tumour arterial obstruction by using gelatin through angiography to induce ischaemic necrosis of the tumour. The injection of localised chemotherapeutic agents (cisplatin, doxorubicin, or mitomycin) by TACE elevates levels of these agents within the tumour, while minimising systemic toxicity. A drug-eluting bead has been developed to enhance tumour drug delivery and reduce systemic availability.[112]

Portal vein thrombosis, decompensated liver disease, and end-stage liver cancer are contraindications to TACE.

TARE is another treatment option for patients with multifocal HCC.[7] Studies comparing TARE and TACE have shown similar survival and complication rates, with potentially less procedural pain and toxicity with TARE.[97]

Consider – percutaneous ablation

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Consider –

percutaneous ablation

Additional treatment recommended for SOME patients in selected patient group

The combination of transarterial chemoembolisation (TACE) with percutaneous ablation, which includes percutaneous ethanol injection or radiofrequency ablation, is also used in patients with hepatocellular carcinoma. One meta-analysis demonstrated that TACE combined with percutaneous ablation therapy improved overall survival 1-, 2-, and 3-years compared with monotherapy.[114]

2nd line – liver transplantation (post-downstaging)

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2nd line –

liver transplantation (post-downstaging)

Liver transplantation may be considered for carefully selected patients with intermediate (Barcelona Clinic Liver Cancer [BCLC] stage B) disease if they are successfully downstaged to within Milan criteria using locoregional therapy (e.g., transarterial chemoembolisation [TACE], ablation).[7][62] If tumour burden remains within criteria for typically at least 6 months, patients may be listed for transplant, provided they are managed within a multidisciplinary transplant team. Major guidelines, based on available data, support this approach to downstaging.[7][62][102][103]

One systematic review found that living donor liver transplantation for hepatocellular carcinoma has comparable perioperative and survival outcomes to deceased donor donation.[104]

2nd line – systemic therapy

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2nd line –

systemic therapy

Systemic therapy is an option for select patients with intermediate-stage (Barcelona Clinic Liver Cancer [BCLC] stage B) hepatocellular carcinoma (HCC) who are ineligible for or progress after locoregional treatments, as well those with intermediate-stage HCC that is refractory to locoregional treatments. In these cases, systemic therapy should follow the same principles as in advanced (BCLC stage C) disease, with treatment guided by liver function, performance status, and the presence of varices.[7][59]

2nd line – surgical resection

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2nd line –

surgical resection

Although surgical resection is generally reserved for patients with very early or early-stage hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] 0/A), it may be considered in select patients with intermediate-stage (BCLC B) disease who have multifocal but resectable tumours, preserved liver function, and good performance status.[59] One meta-analysis of 18 studies comparing surgical resection with TACE reported a significant survival benefit with resection (hazard ratio 0.56; 95% CI 0.35 to 0.90).[115] This approach should be individualised within a multidisciplinary team, as it is not yet widely endorsed as a standard of care.[7]

BCLC stage C: advanced disease

1st line – systemic therapy

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1st line –

systemic therapy

Atezolizumab plus bevacizumab is recommended as a preferred first-line treatment for patients with advanced (Barcelona Clinic Liver Cancer stage C) hepatocellular carcinoma (HCC) with Child-Turcotte-Pugh class A liver disease and Eastern Cooperative Oncology Group (ECOG) performance status 0-1, following management of oesophageal varices if present.[2][7][59][116][117][118][130] One phase 3 study (IMbrave150) in patients with locally advanced or metastatic HCC found that atezolizumab plus bevacizumab significantly increased overall and progression-free survival after 12 months, compared with sorafenib.[119][120] At a median follow-up of 15.6 months, median overall survival with combined therapy was significantly better (19.2 vs. 13.4 months, estimated hazard ratio for death 0.66, 95% CI 0.52 to 0.85).[121] Subcutaneous atezolizumab/hyaluronidase may be substituted for intravenous atezolizumab.[2]

Clinical trials of systemic therapy for HCC typically exclude patients with Child-Turcotte-Pugh class B liver disease. However, one case series demonstrated that immune checkpoint inhibitor-based immunotherapy (141 patients received atezolizumab plus bevacizumab, while 46 patients received nivolumab) significantly improves survival compared with best supportive care in patients with unresectable HCC and Child-Turcotte-Pugh class B liver dysfunction.[122]

Durvalumab plus tremelimumab is also recommended as a preferred first-line systemic therapy option for managing advanced HCC.[2][118] Positive results have been reported from one phase 3, randomised, open-label, multi-centre study which compared durvalumab plus tremelimumab, durvalumab alone, and sorafenib alone, for patients with unresectable HCC who have not received prior systemic therapy and who are ineligible for locoregional therapy.[142] Durvalumab plus tremelimumab was shown to significantly improve overall survival and patient-reported outcomes (quality of life, functioning, and symptoms) compared with sorafenib.[123][124]

Other first-line regimens that may be offered to patients with advanced HCC include durvalumab alone, lenvatinib, sorafenib, tislelizumab, pembrolizumab, or intravenous nivolumab plus ipilimumab.[2] Sorafenib may be considered in selected patients with Child-Turcotte-Pugh class B liver disease.[125] Sorafenib improves overall survival, with an acceptable toxicity profile.[125][126]

In one large multi-centre, randomised phase 3 trial, lenvatinib was non-inferior to sorafenib with respect to overall survival in patients with untreated advanced HCC.[127] Overall, adverse event rates were similar between the two groups, but hypertension was more common among patients treated with lenvatinib than with sorafenib.[127] One retrospective study identified low serum potassium, high albumin, and low albumin-bilirubin score as clinical predictors for hypertension risk during lenvatinib therapy, stressing the importance of personalised monitoring in HCC treatment.[128] In one randomised phase 3 trial, tislelizumab was non-inferior to sorafenib in terms of overall survival and associated with a lower incidence of treatment-related adverse events.[129]

In the UK, first-line options recommended by the National Institute of Health and Care Excellence (NICE) include atezolizumab plus bevacizumab (preferred), sorafenib, or lenvatinib.[105][130][131][132] All are recommended for people with untreated advanced unresectable HCC, only if they have Child-Turcotte-Pugh class A liver impairment; atezolizumab plus bevacizumab, or lenvatinib are recommended for patients with an ECOG performance status of 0-1, while sorafenib may be used for patients with a performance status of 0-2.[105][130][131][132]

Choice of second-line therapy may depend on what was used first line.

Second-line therapy with a tyrosine kinase inhibitor (i.e., sorafenib, lenvatinib, cabozantinib, or regorafenib) may be appropriate for patients who progress on first-line therapy.[2][59][118] In phase 3 trials, cabozantinib and regorafenib improved survival when prescribed second-line for patients who progressed on sorafenib.[133][134] In the UK, NICE recommends regorafenib or cabozantinib for treating advanced unresectable HCC in adults who have had sorafenib, but only if they have Child-Turcotte-Pugh class A liver impairment and an ECOG performance status of 0-1.[135][136]

The National Comprehensive Cancer Network (NCCN) suggests that any of the first-line systemic therapy options may also be considered as second-line therapy if not previously used.[2] Second-line use of immune checkpoint inhibitor-based therapy (e.g., atezolizumab plus bevacizumab, durvalumab, tislelizumab) is reserved for patients who have not previously received an immune checkpoint inhibitor due to a lack of data on their subsequent use in patients already treated with one. Similarly, second-line use of durvalumab plus tremelimumab, or nivolumab plus ipilimumab may be considered for patients who have not previously received anti-CTLA4-based combinations.[2]

Additional second-line options that may be useful in certain circumstances include nivolumab monotherapy, ramucirumab, dostarlimab, selpercatinib, entrectinib, larotrectinib, or repotrectinib.[2] Nivolumab monotherapy may be used second-line for patients not previously treated with immune checkpoint inhibitor therapy.[2] Nivolumab is available as an intravenous formulation and a subcutaneous formulation. The subcutaneous formulation (nivolumab/hyaluronidase) may be substituted for intravenous nivolumab when used as monotherapy, but it is not approved for concurrent use with intravenous ipilimumab. Ramucirumab may be used for patients with alpha fetoprotein ≥400 microgram/L (≥400 ng/mL).[2] In phase 3 trials, ramucirumab only improved survival in a sub-group of patients with alpha fetoprotein ≥400 microgram/L (≥400 ng/mL).[137][138] Dostarlimab is an option for patients with microsatellite instability-high/mismatch repair-deficient tumours who have no satisfactory alternative treatment options and have not previously received immune checkpoint inhibitor treatment.[2] Selpercatinib may be considered for RET gene fusion-positive tumours; and entrectinib, larotrectinib, or repotrectinib may be considered for NTRK gene fusion-positive tumours (which are rare in HCC)..[2]

No systemic therapy has been shown to be effective as an adjuvant therapy in HCC after resection or ablation.

See local consultant protocol for dosing guidelines.

Primary options

atezolizumab

atezolizumab/hyaluronidase

-- AND --

bevacizumab

durvalumab

and

tremelimumab

nivolumab

and

ipilimumab

durvalumab

lenvatinib

sorafenib

tislelizumab

pembrolizumab

Secondary options

cabozantinib

regorafenib

nivolumab

nivolumab/hyaluronidase

ramucirumab

dostarlimab

selpercatinib

entrectinib

larotrectinib

repotrectinib

2nd line – transarterial radioembolisation (TARE)

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2nd line –

transarterial radioembolisation (TARE)

TARE has been used in some patients with advanced disease to prolong survival. It has been shown to be safe in the presence of limited tumour invasion of the portal vein.[2]

In the UK, the National Institute for Health and Care Excellence (NICE) recommends TARE as an option for unresectable advanced disease only for patients with Child-Turcotte-Pugh grade A liver impairment when conventional transarterial therapies are inappropriate.[108][141]

Underlying liver function, performance status, and/or hepatopulmonary shunting can limit the use of this technique. Patients with multifocal disease usually require staged lobar treatment, which can increase the risk for radiation-induced liver disease.[97]

BCLC stage D: end-stage disease

1st line – best supportive care (± liver transplantation in selected candidates)

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1st line –

best supportive care (± liver transplantation in selected candidates)

Some patients with Child-Turcotte-Pugh class C cirrhosis and hepatocellular carcinoma (HCC) within Milan criteria may be candidates for liver transplantation.

Otherwise, there is no specific treatment for end-stage HCC. These patients are typically referred for palliative care.[59][105]

ONGOING

recurrence

1st line – reassessment for appropriate therapy

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1st line –

reassessment for appropriate therapy

Tumour recurrence can be due to incomplete treatment response, dissemination of the original hepatocellular carcinoma, or de novo oncogenesis resulting from underlying liver disease. Treatment of recurrence follows the same principle and guidelines as for primary disease.[7][62] In addition, underlying liver disease should be treated to reduce risk of de novo oncogenesis.

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Hepatocellular carcinoma

Treatment algorithm

Barcelona Clinic Liver Cancer (BCLC) stage 0-A (very early 0 or early disease A): possible surgical candidate (good liver function)

consider resection or thermal ablation

BCLC stage 0-A (very early 0 or early disease A): non-hepatic resection candidate

liver transplantation

locoregional bridging or downstaging therapy

thermal ablation

transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) or percutaneous ethanol injection (PEI)

BCLC stage B: intermediate disease

transarterial chemoembolisation (TACE) or transarterial radioembolisation (TARE)

percutaneous ablation

liver transplantation (post-downstaging)

systemic therapy

surgical resection

BCLC stage C: advanced disease

systemic therapy

Primary options

Secondary options

transarterial radioembolisation (TARE)

BCLC stage D: end-stage disease

best supportive care (± liver transplantation in selected candidates)

recurrence

reassessment for appropriate therapy