Hepatocellular carcinoma

Overview 
Theory 
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The management of hepatocellular carcinoma (HCC) is affected by degree of liver dysfunction and patient performance status, in addition to tumour burden.[3] Hepatic resection, liver transplantation, and ablative therapies are considered curative treatment options for HCC. [ ] Comparative data from randomised trials are limited or lacking, and decisions regarding the appropriate treatment for the individual patient are based on cure rates described in case series.

Non-curative therapies, such as transarterial chemoembolisation (TACE), transarterial radio-embolisation (TARE), and systemic chemotherapy, aim to slow tumour progression and consequently prolong survival.

For details of the Barcelona Clinic Liver Cancer (BCLC) staging system, see Diagnostic criteria.

BCLC stage 0-A (very early 0, or early disease A): possible surgical candidate (good liver function)

Surgical resection is the optimal curative treatment for HCC in patients with solitary HCC without vascular invasion, and normal hepatic synthetic function without evidence of portal hypertension.[6][7][56][84] 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.[3] 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%).[3] Hepatic resection is also the preferred option in patients with hepatitis B-induced HCC without cirrhosis. Criteria for resection based on BCLC staging include:[84]

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.

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.[85] Postoperative haemorrhage and liver failure are the most common complications after resection. These complications are more common in patients with cirrhosis and with 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.[86][87] 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.

Radiofrequency ablation (RFA) is a curative treatment that can be considered as an alternative first-line therapy for very early (BCLC-0) and early (BCLC-A) stage HCC.[3][6][7][80] 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.[88] 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.[89] [ ] 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.[89] Microwave ablation (MWA) is an alternative form of thermal ablation. 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.[90] 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 distant recurrence and improve the 5-year survival, compared with RFA.[91] 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.[92]

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.[93][94] Albeit limited evidence, similar safety and feasibility profiles were seen for MWA and RFA, and either technique can be considered in appropriately selected patients.[94] Similar outcomes were observed with laparoscopic and percutaneous MWA.[93][94] 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.[94]

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

Liver transplantation

Liver transplantation affords the potential to cure the cancer and the underlying liver disease. It is an option for those patients who have a high model for end-stage liver disease (MELD) score, with HCC within Milan criteria.

Patients are selected for liver transplantation according to the Milan criteria (adopted by the United Network for Organ Sharing):[3][69]

A single lesion between 1 and 5 cm
Or 2-3 lesions between 1 and 3 cm
Without evidence of gross vascular invasion
Without regional lymph node or distant extrahepatic metastasis, and
With good activity performance status.

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.[95]

Radiofrequency ablation (RFA)

RFA is the standard of care for very early or early HCC in patients who are not candidates for resection or transplantation.[6][7][80] RFA can also 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 3-6 months.[6][7]

The basic principle 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.[6][7]

Transarterial chemoembolisation (TACE)

TACE 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 3-6 months.[6][7]

TACE may also benefit selected asymptomatic patients with maintained liver function (BCLC A stage to early intermediate BCLC B stage) with small tumour burden, who are not amenable to surgery or local ablation.[6]

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

Transarterial radio-embolisation (TARE)

TARE (also known as selective internal radiotherapy [SIRT]) with yttrium-90 is another transarterial therapy that can be used to downstage or bridge patients prior to transplant or resection. 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.[90] In one multi-centre phase 3 trial in France, patients with inoperable locally advanced HCC (Child-Pugh class A5 to B7) randomised to TARE versus sorafenib did not differ in overall survival; however, TARE was associated with higher response rates, delay in tumour progression in the liver, and fewer adverse events.[96] Another multi-centre study in Asia reported similar results.[97]

Percutaneous ethanol injection (PEI)

PEI is a reasonable alternative for patients with BCLC stage 0-A HCC who are not candidates for surgery or thermal ablation.[80][87]

The basic principle of PEI is the destruction of the tumour by chemicals.

PEI is effective for HCC smaller than 2 cm; it may not cause enough necrosis of larger tumours because of their size and volume. It has been found that 96% of patients with tumours ≤2 cm achieve 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.[98]

BCLC stage B: intermediate disease

TACE is generally the treatment for patients with multinodular HCC without vascular invasion or extrahepatic spread and with relatively well-preserved liver function (i.e., BCLC stage B disease).[3]

Data suggest that bland embolisation is as effective as chemoembolisation.[88] TACE improved 2-year survival in patients with compensated cirrhosis and good functional status.[99] Portal vein thrombosis, decompensated liver disease, and end-stage liver cancer are contraindications to TACE.

The injection of localised chemotherapeutic agents (cisplatin, doxorubicin, or mitomycin C) by TACE elevates levels of these agents within the tumour, while minimising systemic toxicity. A drug-eluting bead (DC Bead®) has been developed to enhance tumour drug delivery and reduce systemic availability.[100] Whether drug-eluting-bead TACE is better than conventional lipoidal-based TACE is still a matter of debate, but data seem to suggest superiority and better safety profile of drug-eluting-bead TACE in patients with more advanced disease.[101]

The combination of TACE with percutaneous ablation, which includes PEI or RFA, is also used in patients with HCC. One meta-analysis found that TACE combined with percutaneous ablation therapy improved overall survival by 1-, 2-, and 3-years compared with monotherapy.[102]

TARE is another treatment option for patients with multifocal HCC.[3] Studies comparing TARE and TACE have shown similar survival and complication rates, with potentially less procedural pain and toxicity with TARE.[90]

BCLC stage C: advanced disease

First-line therapy

Atezolizumab plus bevacizumab is recommended as a preferred first-line treatment for patients with advanced HCC, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and following management of oesophageal varices, when present.[3][6][7][64][103][104][105][106] 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.[107][108] 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).[109] Subcutaneous atezolizumab/hyaluronidase may be substituted for intravenous atezolizumab.[64]

Durvalumab plus tremelimumab is also recommended as a preferred first-line systemic therapy option for managing advanced HCC.[64][106] 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.[110] Durvalumab plus tremelimumab was shown to significantly improve overall survival compared with sorafenib.[111]

Other recommended first-line regimens that may be offered to patients with advanced HCC include durvalumab alone, lenvatinib, sorafenib, tislelizumab, or pembrolizumab.[64] Sorafenib may be considered in selected patients with Child-Pugh class B liver disease.[112] Sorafenib improves overall survival, with an acceptable toxicity profile.[112][113] 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.[114] Adverse event rates were similar between the two groups, but hypertension was more common among patients treated with lenvatinib than with sorafenib.[114] Lenvatinib is recommended in the UK for patients with untreated advanced HCC only if they have Child-Pugh class A liver impairment and an ECOG performance status of 0 or 1.[115]

Advanced disease: progression despite first-line therapy

If patients progress on first-line treatment second-line therapy with a tyrosine kinase inhibitor (i.e., sorafenib, lenvatinib, cabozantinib, or regorafenib) may be appropriate.[6][7][64][106]

Pembrolizumab or intravenous nivolumab plus ipilimumab are also reasonable second-line options following progression on first-line therapy.[64][106][116] Nivolumab is available as an intravenous formulation and a subcutaneous formulation; however, the subcutaneous formulation (nivolumab/hyaluronidase) is not approved for concurrent use with intravenous ipilimumab.[64]

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

Regorafenib, nivolumab, pembrolizumab, and cabozantinib provide survival benefit when prescribed second-line for patients who progress on sorafenib.[117][118][119][120][121] In the UK, regorafenib is recommended for treating advanced unresectable HCC in adults who have had sorafenib, but only if they have Child-Pugh class A liver impairment and an ECOG performance status of 0 or 1.[122] Further, based on clinical trial evidence regarding effectiveness of cabozantinib and indirect comparison of cabozantinib with regorafenib, cabozantinib is recommended as an alternative to regorafenib for treating advanced HCC in adults who have had sorafenib, provided they have Child-Pugh grade A liver impairment and an ECOG performance status of 0 or 1.[123] No systemic therapy has been shown to be effective as an adjuvant therapy in HCC after resection or ablation.

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.[64] 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.[90]

BCLC stage D: end-stage disease

BCLC stage D patients with poor liver function but limited tumour burden within Milan criteria may be candidates for liver transplantation. Otherwise, there is no specific treatment for end-stage HCC, and these patients are typically referred for palliative care.

Recurrence

Tumour recurrence can be due to lack of complete treatment response, intrahepatic dissemination of the originally treated HCC, or de novo oncogenesis resulting from underlying liver disease.

The most important predictors of intrahepatic dissemination are vascular invasion and satellite lesions found in pathology after tumour resection. Treatment of recurrence follows similar principles and guideline recommendations as for primary disease. Response and tolerability of prior treatment should also be taken into consideration. In addition, underlying liver disease should be treated to reduce risk of de novo oncogenesis.

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