Cirrhosis represents a diffuse liver disease characterized by structurally abnormal nodules of liver cells surrounded by fibrosis. 1 It results from chronic liver injury and regeneration secondary to chronic viral hepatitis, alcoholic liver disease, metabolic liver diseases (e.g. hemochromatosis, Wilson's disease, 1-antitrypsin deficiency, non-alcoholic steatohepatitis), and autoimmune diseases (e.g. autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis). Cirrhosis is associated with an annual incidence of hepatocellular carcinoma of 3 to 5 percent.
Hepatocarcinogenesis represents a multi-step process in which both genetic abnormalities and epigenetic alterations encourage the malignant transformation of hepatocytes. Hepatocellular carcinomas are associated with up-regulated signal transduction through multiple pathways (e.g. mitogen-activated protein kinase, vascular endothelial growth factor receptor).
Prognosis depends upon the extent of hepatic replacement by the tumour, the -fetoprotein (AFP) level, the patient's performance status (see Appendix B), the tumour's histologic subtype (e.g.: fibrolamellar variant), and the degree of liver dysfunction (as assessed by the Child-Pugh classification system, see Appendix C).

# Guideline Questions
- What are the goals of therapy and recommendations for the treatment of adult patients with: o very early stage hepatocellular carcinoma? o early stage hepatocellular carcinoma? o intermediate stage hepatocellular carcinoma? o advanced stage hepatocellular carcinoma? o terminal stage hepatocellular carcinoma?

# Search Strategy
This guideline was developed to promote evidence-based practice in Alberta. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data. The 2021 update did not necessitate a full literature review; recommendations were modified based on a consensus discussion at the 2020 Annual Gastrointestinal Tumour Team Meeting.

# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with hepatocellular carcinoma (HCC). Different principles may apply to pediatric patients.
The American Association for the Study of Liver Disease (AASLD) promotes routine HCC surveillance for all adult patients with Child-Pugh A or B cirrhosis. 2 Screening and surveillance using liver ultrasound, with or without -fetoprotein (AFP), is recommended every six months. Patients with Child-Pugh C cirrhosis are not recommended for surveillance due to low anticipated survival unless these patients are on a liver transplant waiting list (see Appendix C for details on Child-Pugh score).
Patients with hepatitis B are also considered at risk; screening is recommended starting at age 40 for Asian males, age 50 for Asian females and age 20 for those of African descent. 2 The American College of Radiology (ACR) has created the Ultrasound Liver Imaging Reporting and Data System (US LI-RADS) algorithm for interpretation and reporting of ultrasound exam results. 3 The US LI-RADS is composed of 3 observational categories and 3 visualization scores, which are summarized in Table 1. An AFP value that exceeds 20 ng/mL is considered positive, while anything lower is considered negative. 3 Noninvasive diagnosis with a multiphase CT scan or a multiphase MRI is recommended by the AASLD. 2 The results should be interpreted and reported through the CT/MRI Liver Imaging Reporting and Data System (CT/MRI LI-RADS) algorithm developed by the ACR. This algorithm allows definitive diagnosis of HCC in high risk patients without pathologic confirmation. 5 The CT/MRI LI-RADS outlines eight diagnostic categories summarized in Table 2. The key imaging features include size  1 cm, arterial phase hyperenhancement (APHE), and a combination of washout, threshold growth and capsule appearance. 6 If these features are not present but HCC is suspected, then a liver biopsy should be considered. A biopsy should also be considered in patients with a liver mass that is atypical of HCC on contrast-enhanced imaging 2. If high-grade dysplasia and HCC are not disguisable by routine histology alone, tumour markers glypican-3 (GPC3), heat-shock protein 70 (HSP70) and glutamine synthetase (GS) can be assessed.

# Goals and Recommendations
To define and provide optimal care to a patient with HCC, a multidisciplinary team (MDT) is required.
It should be composed of hepatobiliary surgeons, diagnostic and interventional radiologists, hepatologists/gastroenterologists, and oncologists. Consideration is given to patient factors (e.g. functional status, co-morbidities, liver function) and tumour factors (e.g. size, number, location, vascular invasion).
The Barcelona Clinic Liver Cancer (BCLC) staging system (Table 3) provides a system to define the care for patients with HCC. 7,8 It links the TNM staging system (see Appendix A), the patient's ECOG performance status (see Appendix B), and the patient's liver function (see Appendix C) to treatment options. An algorithm for management of HCC according to the updated AHS clinical practice guideline recommendations is provided (Figure 1).
Consider treatment on a clinical trial, if available.   - Well-compensated liver function (Child-Pugh class A). Tumour Requirements: - Solitary tumour (< 2 cm) confined to one lobe of the liver.
- Absence of vascular invasion and extra-hepatic disease.
- Complete removal of the tumour with a margin of  1 cm anticipated.
- To render patient free of disease and to delay or prevent recurrence. Recommendation:
- Resection. 10 Resection: - In carefully selected patients, five-year survivals of 50 to 70% are anticipated.
- Comparative genomic hybridization reveals that 60 to 70% of recurrences are intra-hepatic metastases and that 30 to 40% are de novo tumour development. - Abnormal bilirubin and portal hypertension (as suggested by thrombocytopenia with platelet count under 100, varices, ascites, and/or splenomegaly) predict for failure to benefit from resection. 11 - If extra-hepatic disease is confirmed at laparotomy, resection is not pursued.
- Intra-operative ultrasound and bi-manual palpation assessment for other intra-hepatic lesions. Intraoperative or subsequent radiofrequency ablation or percutaneous ethanol injection 12,13 can be considered for multicentric disease. - No clear benefit has been established for adjuvant therapy post-resection. In fact, adjuvant chemotherapy may adversely affect the outcome, especially in cirrhotic patients. 14,15 Sorafenib was of no benefit as adjuvant therapy following curative intent resection or radiofrequency ablation (STORM study). 16 - In patients who are not candidates for surgical resection, radiofrequency ablation (see below) can offer a 97% complete response for tumours  2 cm with long-term survival similar to what has been reported in patients who have undergone resection. 17 - Three randomized controlled trials comparing surgical resection to RFA have been performed in China.
Although the studies had methodological flaws (cross-over between groups), similar outcomes were reported in two studies 18,19 whereas one study demonstrated improved recurrence-free and overall survival in the surgical resection group. 20 Follow-Up: To identify recurrence, obtain a contrast enhanced CT scan, MR, or ultrasound of the abdomen every three months for two years and then every six months thereafter. Obtain an AFP every three months for two years and then every six months thereafter. 21

# Early Stage HCC
- Good performance status (ECOG 0).
- Well-compensated liver function (Child-Pugh class A). Tumour Requirements: - Solitary tumour confined to one lobe of liver or three nodules (all  3 cm)
- Absence of vascular invasion and extra-hepatic disease.
- Complete removal of the tumour(s) with a margin of  1 cm anticipated. Goals:
- To render patient free of disease and to delay or prevent recurrence. Recommendations:
- Resection (see above), liver transplantation (see below), or ablation 12 (see below). Liver Transplantation:
Removes the cancer and corrects the underlying "field defect" (cirrhosis) but subjects the patient to the potential complications of long-term immunosuppression. - Offers a five-year disease-free survival of up to 70% and a short-term mortality of up to 10%.
- In Alberta, transplantation is contraindicated if the total tumour volume (TTV) exceeds 115 cm 3 the alphafetoprotein exceeds 400 ng/mL, vascular invasion and/or extra-hepatic disease exist, or significant comorbidities exist. - Patients may be considered for liver transplantation after being "down-staged" if their initial total tumour volume was under 250 cm 3 and both the total tumour volume and the AFP remain under 115 cm 3 and 400 ng/mL, respectively, for more than six months. 22,23

# Radiofrequency Ablation (RFA) or Percutaneous Ethanol Injection (PEI):
- Provides tumour control pending transplantation or as an adjunct or alternative to resection.
- Recent series of radiofrequency ablation report local recurrence rates under 5% and five-year survivals equal to resection. Radiofrequency ablation requires fewer sessions to ablate tumours and results in improved survival when compared to percutaneous ethanol injection. 24 - Survival rates with radiofrequency ablation may be similar to surgical resection; 18 however, two-year recurrence rates are higher following percutaneous ethanol injection and radiofrequency ablation than with resection. 25 - Best outcomes are achieved from radiofrequency ablation when tumours are centrally located, measure under 3 cm, and are distant from "heat sinks" (blood vessels). 11 Consider percutaneous ethanol injection or transarterial chemo-embolization (TACE) when tumours are in a subcapsular location, exceed 4 cm, or are located adjacent to blood vessels. - Hepatocellular carcinomas are considered "treated" only if the imaging study demonstrates complete tumour necrosis (without contrast enhancement to suggest residual disease).

# Intermediate Stage HCC

# Patient Requirements:
- Good performance status (ECOG 0-1).
- Well-compensated liver function (Child-Pugh class A) and only select patients with impaired liver function (Child-Pugh class B 7). Tumour Requirements:
- Multinodular disease.
- Absence of extra-hepatic disease.
- Patency of the main portal vein (as assessed by ultrasound Doppler or MR angiography) for TACE.
- Adequate renal function.
- To maintain or to improve the patient's quality of life (to control or to delay the onset of tumour-related symptoms, possibly while awaiting transplant).
- To prolong life, if possible. Recommendations:
- Transarterial chemo-embolization  or transarterial radioembolization.  Consider palliative care if not an LT candidate.

# Transarterial Chemo-Embolization (TACE):
- Blood supply to hepatocellular carcinomas is preferentially derived from the hepatic artery rather than the portal vein. - Involves placement of an intravascular catheter into the hepatic artery (inserted percutaneously in the femoral artery and advanced through the abdominal aorta and celiac trunk). Injection of chemotherapy (with or without the oily contrast agent, Lipiodol) followed by embolic agents (e.g.: gelatin-sponge particles, Embosphere  occludes the relevant branch of the hepatic artery and localizes the chemotherapy. Metaanalyses of randomized controlled trials demonstrate a survival benefit of TACE. 35,36 Drug-eluting beads (DEBs) decrease the systemic exposure to doxorubicin. 37 Although DEBs have not been shown to be superior to conventional TACE, they offer a more standardized technique and are better tolerated with fewer complications. 29 Recent cohort studies are demonstrating median survival of 4 years after TACE with DEBs in carefully selected patients. 30 Transarterial Radioembolization (TARE):
- TARE or selective internal radiotherapy (SIRT) uses microspheres loaded with yttrium-90 (Y 90 to deliver radiation directly into the tumour via the hepatic artery. Unlike TACE it is done as an outpatient. Prior to the TARE, the patient requires a staging angiogram to calculate the liver-to-lung shunt fraction in Nuclear Medicine using technicium-99 macro-aggregated albumin (Tc 99 MAA). At the same time selective embolization of the gastroduodenal arteries is carried out to prevent delivery of radiation to the stomach and duodenum. The procedure may be repeated depending upon response.
- A meta-analysis 38 and large cohort studies from Europe 31 and the USA 32 have shown similar survival to TACE in BCLC stage B patients. However, a separate meta-analysis showed superior survival with TACE in unresectable patients. 39 - TARE, unlike TACE, can be performed safely in patients with portal vein thrombosis, as the microspheres used in TARE are smaller and less embolic. 31,32 - TARE may be considered for patients who have progressive disease after TACE, who cannot tolerate doxorubicin or who are likely to fail TACE (large HCC).
- TARE may also be more effective than TACE in bridging or down-staging patients to liver transplantation. 33,35 
Outcomes following TARE are best in patients with preserved liver function (Child-Pugh score <8 or MELD score <13). 34 Patients should be selected for TARE at MDT meetings.
- As there remains uncertainty about TARE efficacy compared to TACE (intermediate stage) or sorafenib (advanced stage), clinical trials are encouraged.

# Advanced Stage HCC
- Good performance status (ECOG 0 or 1).
- Well-compensated liver function (Child-Pugh class A). Tumour Requirements:
- Disease ineligible for, or that progressed after, surgical or locoregional therapy. Goals:
- To maintain or to improve the patient's quality of life (to control or to delay the onset of tumour-related symptoms). - To prolong life, if possible.
- First-line treatment: Atezolizumab-Bevacizumab or participation in a clinical trial 36  First-Line Systemic Therapy:
Atezolizumab-Bevacizumab (Preferred, Type of recommendation: evidence based, benefits outweigh harms; Evidence quality: moderate to high; Strength of recommendation: strong) 42 - Atezolizumab-bevacizumab was compared to sorafenib in the open-label phase 3 IMbrave150 trial. 43 Hazard ratio for death was 0.58 (95%CI: 0.42-0.79; p<0.001) in favor of atezolizumab-bevacizumab. Last revision: August, 2021
Additionally, hazard ratio for disease progression or death was superior in the atezolizumab-bevacizumab arm (HR: 0.59; 95%CI: 0.47-0.76; p20 kPa or if the platelet count is <150. 46 Patients with incompletely treated varices should not be treated with this combination. - Atezolizumab-Bevacizumab is not currently funded in Alberta
In those patients where Atezolizumab-Bevacizumab is not appropriate/contraindicated: Lenvatinib (Type of recommendation: evidence based, benefits outweigh harms; Evidence quality: moderate to high; Strength of recommendation: strong) - Lenvatinib was shown to be non-inferior to sorafenib for overall survival in an open-label, phase 3, multicenter, non-inferiority trial in patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease (median OS 13.6m lenvatinib vs 12.3m sorafenib, respectively, HR: 0.92, 95%CI: 0.79-1.06). Patients had Child Pugh A liver function, and ECOG 0-1. 47 - It is worth noting that lenvatinib was superior to sorafenib in terms of progression-free survival (7.4m vs 3.7m, respectively, HR: 0.66, 95%CI: 0.57-0.77, p<0.001). Objective response rates were also higher in the lenvatinib group (24.1% vs. 9.2%, respectively, p<0.001). - Treatment-related adverse events of grade 3 or higher occurred in 57% of patients treated with lenvatinib and 49% with sorafenib. Rates of hand-foot syndrome are lower in the lenvatinib arm compared to sorafenib arm. In the lenvatinib arm, the most common any-grade adverse events included hypertension (42%), diarrhea (39%), decreased appetite (34%), and decreased weight (31% - Hypothyroidism develops in 18% of patients within two to four months of starting Sorafenib. Obtain a baseline TSH and then monitor levels every six weeks. 35,50 - Increases the incidence of arterial thromboembolic events (1.4%, RR 3.03, p = 0.015). 36 Second-Line Systemic Therapy:

# Lenvatinib (if not received in the first-line)
- There is no level 1 evidence to inform the most effective treatment after atezolizumab plus bevacizumab.
The most common second line therapies received by patients in the IMbrave150 trial were sorafenib (n=31)

# Stereotactic Body Radiotherapy (SBRT)
- There is growing experience with providing ionizing radiotherapy to HCC using very conformal dose distribution, with image guidance and motion management to provide high doses of radiation to the HCC while minimizing exposure to the adjacent liver or other tissues. 53 - SBRT can provide good local control of HCC range (ranging from 43% to 100% at 1 year) which can depend on factors such as lesion size and number, and the delivered radiation dose. It has been used in patients with portal vein invasion 54 and to bridge patients to liver transplantation. 55 - Patients should be discussed at multidisciplinary rounds. SBRT can be considered when alternative therapies such as ablation/embolization techniques have failed or are contraindicated.
- Patients can experience worsening of liver function with SBRT 54 and tolerance to normal liver is the main dose limiting constraint. Most safety evidence is for patients with Child-Pugh class A disease. Evidence is more limited for Child-Pugh class B disease and in practice treatment dose is lowered to reduce the chance of treatment toxicities. Treatment of patients with Child-Pugh class C disease is not recommended as the safety of liver SBRT in this population has not been determined.
- Continued clinical trials in the use of liver SBRT are recommended. Studies evaluating SBRT in combination with sorafenib are currently underway. Enrollment of patients into clinical trials or investigational protocols should be encouraged.

# Terminal Stage HCC

# Patient Requirements:
- Poor performance status (ECOG > 2).
- Decompensated liver function (Child-Pugh class B and C). Goals:
- To maintain or to improve the patient's quality of life (to control tumour-related symptoms). Recommendations:
- Best supportive care.
- Palliative chemotherapy may adversely affect outcome. 56 Appendix A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.

# This guideline was originally developed in 2009.
Maintenance A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.