Prevention |
1. All newborns (A1) and seronegative (negative for all of HBsAg, anti-HBs, and anti-HBc) children and adults should be vaccinated against HBV (B1) to prevent HCC. |
2. General HCC preventive measures include the following: prevention of HBV/HCV transmission (A1); avoidance of alcohol abuse; and control of metabolic disorders, such as obesity and diabetes (C1). |
3. Antiviral therapy as a secondary prevention of HCC should follow the KASL guidelines for the management of chronic hepatitis B or C (A1). |
4. The risk of HCC can be reduced if HBV replication is persistently suppressed in patients with chronic hepatitis B (A1), and if an SVR is achieved by interferon therapy (A2) or DAA therapy (B1) in patients with chronic hepatitis C. |
5. Among patients with chronic liver disease, the risk of developing HCC is lower in patients receiving statin therapy for the management of dyslipidemia compared to those undergoing no treatment (B1). |
6. Among patients with chronic liver disease, the risk of developing HCC is lower in patients receiving aspirin therapy for the purpose of preventing cardiovascular complications or managing pain and inflammation compared to those undergoing no treatment. However, the administration of aspirin for patients with liver cirrhosis should be considered with caution as the risk of gastrointestinal bleeding may increase (B2). |
7. Coffee consumption in patients with chronic liver disease can lower the risk of HCC (B1). |
8. After curative treatment of HBV-associated HCC, antiviral therapy should be considered to reduce the risk of HCC recurrence in patients with detectable serum HBV DNA (B1). |
9. After curative treatment of HCV-associated HCC, the association of DAA therapy with the risk or prevention of HCC recurrence remains unclear (C1). |
Surveillance |
1. Surveillance for HCC should be performed in high-risk groups; patients with chronic hepatitis B (A1), chronic hepatitis C (B1), and liver cirrhosis (A1). |
2. Surveillance test for HCC should be performed with liver US plus serum AFP measurement every 6 months (A1). |
3. When liver US cannot be performed adequately, dynamic contrast-enhanced CT or dynamic contrast-enhanced MRI can be performed as an alternative (C1) |
Diagnosis |
1. The diagnosis of HCC can be made pathologically or using the typical hallmarks of HCC obtained by non-invasive imaging in high-risk groups (chronic hepatitis B [A1], chronic hepatitis C [B1], or cirrhosis [A1]). |
2. For a new liver nodule ≥1 cm detected by surveillance tests in high-risk patients, multiphasic CT, or multiphasic MRI (extracellular contrast agents or hepatocyte-specific contrast agents) should be performed as a first-line imaging study for the diagnosis of HCC (A1). If first-line imaging study is inconclusive for the diagnosis of HCC, second-line imaging study including multiphasic CT, multiphasic MRI (extracellular contrast agents or hepatocyte- specific contrast agents), and contrast-enhanced US (blood-pool contrast agents or Kupffer cell-specific contrast agents) can be applied (B1). |
3. Imaging diagnosis of “definite” HCC can be made for the nodule ≥1 cm detected by surveillance tests in high-risk patients based on the following radiological hallmarks: |
(1) the radiological hallmarks in multiphasic CT or MRI with extracellular contrast agents are APHE with washout appearance in the portal venous or delayed phases (A1). |
(2) The radiological hallmarks in multiphasic MRI with hepatocyte-specific contrast agents are APHE with washout appearance in the portal venous, delayed, or hepatobiliary phases; these criteria should be applied only to a lesion which does not show either marked T2 hyperintensity or targetoid appearances on diffusion-weighted images or contrast-enhanced images (B1). |
(3) The radiological hallmarks in contrast-enhanced US (blood-pool contrast agents or Kupffer cell-specific contrast agents) performed as a second-line imaging study are APHE with late (≥60 seconds) and mild washout or washout appearance in the Kupffer phase; these criteria should be applied only to a lesion which does not show either rim or peripheral globular enhancement on arterial phase (B1). |
4. In nodules ≥1 cm that do not meet the radiologic diagnosis criteria of “definite” HCC, a diagnosis of “probable” HCC can be assigned by applying ancillary imaging features of HCC (B1). There are two categories of ancillary imaging features including imaging features favoring malignancy in general (mild-to-moderate T2 hyperintensity, restricted diffusion, threshold growth) and those favoring HCC in particular (enhancing or non-enhancing capsule, mosaic architecture, nodule-in-nodule appearance, fat or blood products in the mass). For nodules without APHE, “probable” HCC can be assigned only when the lesion fulfills at least one item from each of the two categories of ancillary imaging features. For nodules with APHE but without washout appearance, “probable” HCC can be assigned when the lesion fulfills at least one of the aforementioned ancillary imaging features. |
5. For “probable” HCC, follow-up imaging study within 3 months or biopsy should be considered (C1). For “indeterminate” nodules that cannot be diagnosed as “definite” or “probable” HCC by imaging, follow-up imaging study within 6 months or biopsy should be considered (B1). Follow-up study should be performed using one of the first-line imaging modalities. |
6. For subcentimeter nodules newly detected on HCC surveillance in high-risk patients, follow-up surveillance test within 6 months is recommended (C1). |
7. Newly detected or growing nodules in the follow-up study of patients with a history of prior HCC can be diagnosed as recurrent HCC regardless of size if they show the radiological hallmarks of HCC or ancillary imaging features with an increase in size (C1). |
8. Although it is not recommended to strictly limit the radiation dose for the diagnosis and follow-up evaluation of HCC, unnecessary CT examinations should be avoided. To optimize radiation exposure, the use of dose reduction techniques as well as alternative imaging modalities should to be considered in HCC patients (C1). |
Staging |
1. This guideline adopts the mUICC stages as the primary staging system, with the BCLC staging system and the AJCC/UICC TNM staging system serving as complementary systems (B1). |
2. FDG PET-CT can be utilized for staging prior to treatments with curative intent, such as hepatic resection or LT (C1). |
3. Chest CT, pelvis CT, and bone scan can be used for HCC staging workup if extrahepatic metastasis of HCC is suspected (C1). |
Hepatic resection |
1. Hepatic resection is the primary treatment modality for single HCC limited to the liver in Child-Pugh grade A patients without portal hypertension and hyperbilirubinemia (A1). |
2. Limited hepatic resection can be selectively performed for Child-Pugh A or B7 single HCC with mild portal hypertension or hyperbilirubinemia (C1). |
3. Hepatic resection may be considered even in the cases of HCC with invasion to the portal vein, hepatic vein, or bile duct if the main portal trunk is not invaded in patients with well-preserved liver function (C2). |
4. Hepatic resection may be considered for three or less multiple HCCs in patients with well-preserved liver function (C2). |
5. LLR for HCC located in the left lateral section and anterolateral segments can be selectively performed (B2). |
6. LLR for HCC located in the posterosuperior segments or caudate lobe can be selectively performed depending on the location and size of the tumor (C2). |
7. For recurrent HCC after being cured by hepatic resection, the retreatment method can be selected considering the timing of recurrence, remnant liver function, performance status, and the size, location, number of recurrent tumors (C1). |
Liver transplantation |
1. LT is the primary treatment modality for patients with HCC unsuitable for resection but within the Milan criteria (a single tumor ≤5 cm or small multinodular tumors [≤3 nodules, ≤3 cm]) (A1). |
2. In LT candidates with HCC, loco-regional therapies or TACE are recommended if the timing of transplantation is unpredictable (B1). |
3. If the HCC tumor stage is downgraded to meet the Milan criteria by loco-regional therapies, including TACE and RFA, in patients initially exceeding the Milan criteria, LT shows superior outcomes compared to other treatments (B1). |
4. Expanded indications beyond the Milan criteria for LT may be considered in limited cases without definitive vascular invasion or extrahepatic spread if other effective treatment options are not applicable (C2). |
5. Salvage transplantation can be indicated for recurrent HCC after resection according to the same criteria as for first-line transplantation (B1). |
6. For recurrent HCC after being cured by LT, the retreatment method can be selected considering the time to recurrence, liver function, performance status, size, location, and the number of recurrent tumors (C1). |
Local ablation therapies |
1. RFA has an equivalent survival rate, a higher LTP rate, and a lower complication rate compared to hepatic resection in patients with a single nodular HCC ≤3 cm in diameter (A1). |
2. Combined therapy with TACE and RFA or microwave ablation increases the survival rate in patients with 3–5 cm HCCs that are not amenable to hepatic resection compared to RFA or microwave ablation alone (A2). |
3. In the treatment of HCC, microwave ablation and cryoablation are expected to produce comparable rates of survival, recurrence, and complications to those of RFA (B2). |
4. Contrast-enhanced US and fusion imaging improve the detection rate and the technical success rate of local ablation therapy for HCCs ≤2 cm (B1). |
TACE and radioembolization |
1. cTACE is recommended for HCC patients with a good performance status without major vascular invasion or extrahepatic spread who are ineligible for hepatic resection, LT, or local ablation therapies (A1). |
2. cTACE should be performed through tumor-feeding arteries using selective/superselective techniques to maximize antitumor activity and minimize hepatic damage (B1). |
3. In cases of HCC with portal vein invasion, cTACE alone (B2) or cTACE combined with external beam radiation therapy (EBRT) (B1) can be considered for patients with intrahepatic localized tumors and well-preserved liver function. |
4. Compared with cTACE, DEB-TACE has similar clinical outcomes in ≥3 cm HCCs; therefore, it can be considered as an alternative treatment to cTACE (A2). |
5. Compared with cTACE, TARE results in a better quality of life and lower occurrence of PES; therefore, it can be considered an alternative treatment to cTACE when the remnant liver function is expected to be sufficient after the TARE treatment (B2). |
6. When developing one or more of the following conditions after two or more sessions of on-demand TACE within 6 months from the first TACE, a switch to other treatments should be considered: (1) absence of objective response, (2) new appearance of vascular invasion (3) the new appearance of extrahepatic spread (C1). |
External beam radiation therapy |
1. EBRT is recommended for patients with HCC unsuitable for hepatic resection, transplantation, local ablation treatments, or TACE (C1). |
2. EBRT is performed when the liver function is Child-Pugh grade A or B7 and when the volume to be irradiated with ≤30 Gy is ≥40% of the total liver volume in the computerized treatment plan (B1). |
3. EBRT can be combined for HCCs that are expected to have an incomplete response after TACE (B2). |
4. EBRT can be performed for the treatment of HCC with portal vein invasion (B2). |
5. EBRT can be combined with systemic therapy for HCC treatment (C2). |
6. EBRT is recommended for palliating symptoms of HCC (B1). |
7. PBT is not inferior in the local control rate and shows no difference in survival and toxicity rates compared to RFA in treating recurrent or residual HCCs ≤3 cm in size (A2); SBRT may not be inferior in the local control rate compared to RFA for the treatment of HCCs ≤3 cm in size (C2). |
Systemic therapies |
First-line therapies |
1. Atezolizumab plus bevacizumab or durvalumab plus tremelimumab is recommended for systemic treatment-naïve patients with locally advanced unresectable or metastatic HCC not amenable to curative or loco-regional therapy who have Child-Pugh class A and ECOG performance status 0–1 (A1). If these two combination therapies cannot be applied, sorafenib or lenvatinib is recommended (A1). |
2. Sorafenib is considered for patients with HCC who have Child-Pugh class B7 (B1) or B8–9 (B2) if other conditions listed in Recommendation 1 are met. |
[Second-line therapies] |
1. Regorafenib is recommended for patients with progressive HCC after at least 3 weeks of sorafenib (≥400 mg/day) treatment and with Child-Pugh class A and good performance status (ECOG score 0–1) (A1). |
2. Cabozantinib is recommended for patients with progressive HCC after first-line sorafenib or second-line systemic treatment and with Child-Pugh class A and good performance status (ECOG score 0–1) (A1). |
3. Ramucirumab is recommended for patients with progressive HCC after sorafenib or intolerance to sorafenib and with Child-Pugh class A, good performance status (ECOG score 0–1), and serum AFP level ≥400 ng/mL (A1). |
4. Pembrolizumab is recommended for patients with progressive HCC after sorafenib or intolerance to sorafenib and with Child-Pugh class A and good performance status (ECOG score 0–1) (B1). |
5. Either nivolumab plus ipilimumab combination therapy (B1) or nivolumab monotherapy (C1) can be considered for patients with progressive HCC after sorafenib or intolerance to sorafenib and with Child-Pugh class A and good performance status (ECOG score 0–1). |
Sorafenib, regorafenib, cabozantinib, ramucirumab (if serum AFP level ≥400 ng/mL), atezolizumab-bevacizumab, durvalumab-tremelimumab, pembrolizumab, nivolumab-ipilimumab, or nivolumab treatment can be tried for patients with progressive HCC after lenvatinib (D1). |
7. Sorafenib, lenvatinib, regorafenib, cabozantinib, durvalumab-tremelimumab, or nivolumab-ipilimumab can be tried for patients with progressive HCC after combination therapy with atezolizumab plus bevacizumab (D1). |
8. Sorafenib, lenvatinib, regorafenib, cabozantinib, ramucirumab (if serum AFP level ≥400 ng/mL), or atezolizumabbevacizumab can be tried for patients with progressive HCC after combination therapy with durvalumab plus tremelimumab (D1). |
[Cytotoxic chemotherapy and hepatic arterial infusion chemotherapy] |
1. HAIC may be considered for advanced HCC patients with preserved liver function and portal vein invasion without extrahepatic spread for whom first-line or second-line systemic therapies, such as atezolizumab-bevacizumab, durvalumab-tremelimumab, sorafenib, lenvatinib, regorafenib, cabozantinib, ramucirumab, nivolumab-ipilimumab, or pembrolizumab, have failed or cannot be used (C2). |
Adjuvant therapy |
1. Adjuvant immunotherapy with CIK cells can be considered after curative treatment (resection, RFA, or PEI) in patients with HCC ≤2 cm without lymph node or distant metastasis (A2). |
2. Adjuvant therapy with TACE, sorafenib, or cytotoxic chemotherapy is not recommended for patients with HCC after curative treatment (B1). |
Preventive antiviral therapy |
1. HCC Patients should be tested for hepatitis B surface antigen before starting HCC treatment (A1). |
2. In HCC patients with HBV, antiviral therapy should be initiated if serum HBV DNA is detected (A1). |
3. In HBsAg-positive HCC patients with undetectable serum HBV DNA, preventive antiviral therapy is recommended before cytotoxic chemotherapy (A1), TACE (A2), HAIC (A2), hepatic resection (A2), EBRT (B1), RFA (C1), tyrosine kinase inhibitor, or immune checkpoint inhibitor (C1) treatment. |
4. Antiviral agents for the prevention of HBV reactivation should be selected based on the KASL clinical practice guidelines for management of chronic hepatitis B (A1). |
5. There is still no evidence to recommend preventive antiviral therapy with DAAs for HCC patients who are HCV RNA positive (C1). |
Drug treatment for cancer pain in HCC |
1. In HCC patients, pain control using drugs requires a careful approach with consideration of the underlying liver disease, and type of the drug, dose, and interval of administration should be determined according to liver function (C1). |
2. In patients with HCC accompanied by chronic liver disease, a reduced dose of acetaminophen should be considered (C1), and NSAIDs should be used with caution (B1). |
3. In patients with HCC accompanied by chronic liver disease, the selection of opioid analgesics, and adjustments in the dosage and interval of administration should be carefully considered based on drug metabolism and liver function (C1). |
Assessment of tumor response and post-treatment follow-up |
1. Assessment of tumor response to treatment should be done using the RECIST v.1.1 according to the change in tumor size and the mRECIST according to the change in viable tumor by dynamic contrast-enhanced CT or MRI (B1). |
Management of patients with HCC during COVID-19 pandemic |
1. Even during the COVID-19 pandemic, the management of chronic liver disease, the surveillance of at-risk patients, and the treatment of HCC should be continued (D1). |
2. COVID-19 vaccination is recommended in patients with HCC, as the benefits of vaccination outweigh the risks (C1). Meanwhile, it is necessary to monitor the occurrence of adverse events after vaccination. |
3. Patients with chronic liver disease and HCC should strictly adhere to the infection precautionary measures even after COVID-19 vaccination since they may have a low antibody titer (D1). |