Hepatocellular Carcinoma Management

Evaluation

Once the diagnosis of hepatocellular carcinoma is established, the following factors influence the workup, treatment staging and treatment options: Tumor burden; liver function and liver reserve; general health of the patient and the presence of comorbidities.  

Workup, as may be appropriate, will be based on: History and physical examination; hepatitis panel for detection of HBV and/or HCV infection; renal panel by measuring blood urea nitrogen (BUN) and creatinine; liver function tests (LFTs) by measuring serum levels of bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase; measuring prothrombin time with international normalized ratio (PT with INR) and albumin; complete blood count and platelet count; measurement of serum alpha fetoprotein; chest computed tomography scan for assessing the presence of any comorbidity or metastatic disease in the lung; bone scan, if clinically indicated; abdominal/pelvic computed tomography or magnetic resonance imaging with contrast, if not previously done or needs updating; and indocyanine green (ICG) retention test performed to assess liver function if resection is being considered in a cirrhotic patient. A referral to a hepatologist should also be considered.  

Pre-operative Imaging  

Pre-operative imaging is essential for surgical planning. Computed tomography/magnetic resonance imaging are used to facilitate characterization of the number and size of the hepatocellular carcinoma lesions in order to detect the presence of satellite nodules, extrahepatic metastasis, and tumor invasion of the portal vein or the hepatic veins/inferior vena cava, and to aid in establishing the location of the tumors with respect to vascular and biliary structures.  

Child-Pugh Score  

Child-Pugh scoring is used to estimate liver function or as a tool to rule out patients for liver resection.

Class A: 5-6 points; good operative risk
Class B: 7-9 points; moderate operative risk
Class C: 10-15 points; poor operative risk
Reference: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Hepatocellular carcinoma. Version 3.2024. Sep 2024.  

The finding of esophageal varices and/or splenomegaly with blood platelet counts of <100,000/μL suggest clinically important portal hypertension, which can also be measured by the transjugular route.  

United Network for Organ Sharing (UNOS) Criteria  

The United Network for Organ Sharing (UNOS) criteria specify that patients eligible for liver transplantation should not be candidates for liver resection: Alpha fetoprotein level ≤1,000 ng/mL and radiologic evidence of a single tumor ≥2 to ≤5 cm in diameter or; two to three tumors ≥1 to ≤3 cm in diameter; and no evidence of macrovascular involvement or extrahepatic disease.  

Milan Staging Criteria

• Early-stage hepatocellular carcinoma: Solitary tumors ≤5 cm in diameter or ≤3 multiple tumors, each measuring ≤3 cm in diameter; no macrovascular invasion; and no distant metastases shown during preoperative imaging
• Locally advanced hepatocellular carcinoma are tumors outside of the Milan criteria without any distant metastases and with or without macrovascular invasion
• Metastatic hepatocellular carcinoma

Pre-operative Assessments  

Careful patient selection should be done before liver resection with considerations on patient characteristics, as well as the characteristics of the liver and the tumor. The patient performance status (PS) assessments should also be considered before resection. The estimates of the overall liver function and the size and function of the putative future liver remnant (FLR) together with technical considerations related to tumor and liver anatomy should be taken into account before a patient can be considered to have resectable disease. The presence of significant portal hypertension should also be a part of surgical assessment.  

In general, liver resection is possible in patients with optimal liver function characterized by a Child-Pugh class A score with no evidence of portal hypertension. In highly selected cases, patients with a Child-Pugh score B may be considered for limited liver resection when liver function tests are normal and clinical signs of portal hypertension are absent. A limited resection can be feasible in cases where portal hypertension is mild. The optimal tumor characteristics for liver resection are single tumors with no major vascular invasion. Although there is no limitation on the size of tumor that is considered for liver resection, the risk of vascular invasion and dissemination increases with size. A strong predictor of hepatocellular carcinoma recurrence is the presence of macro- or microscopic vascular invasion. The evaluation of the postoperative future liver remnant volume is also an essential preoperative assessment to be done. Computed tomography is utilized to measure future liver remnant directly and estimates of total liver volume can be calculated. The ratio of future remnant/total liver volume (subtracting tumor volume) is then determined. It is recommended that the ratio be at least 20% in patients without cirrhosis and at least 30-40% in patients with chronic liver disease and a Child-Pugh A score. Preoperative portal vein embolization (PVE) should be considered in patients with an estimated future liver remnant/total liver volume ratio below recommended values who are otherwise suitable candidates for liver resection. Preoperative portal vein embolization is a procedure that redirects blood flow toward the portion of the liver that will remain following surgery. It is safe and effective. Hypertrophy is induced in these segments of the liver while the embolized portion of the liver undergoes atrophy. The presence of extrahepatic metastasis is contraindicated for resection.  

Pre-arterial Directed Therapies Assessments  

Prior to the initiation of arterially directed therapy, an evaluation of the arterial anatomy of the liver, patient's performance status, and liver function is essential. General patient selection criteria for arterially directed therapy include tumors that are unresectable or inoperable and not amenable to ablation therapy only, and large volume extrahepatic disease is not present. Arterially directed therapies are relatively contraindicated in patients with >3 mg/dL bilirubin levels unless segmental treatment can be performed and in patients with main portal vein thrombosis. It is not recommended in patients with Child-Pugh class C.  

Extrahepatic Staging  

The most common sites of extrahepatic metastases are lung, bone, and lymph node; rarely, adrenals and peritoneum. Chest computed tomography, contrast-enhanced computed tomography/magnetic resonance imaging of the abdomen and pelvis, and bone scan (if skeletal symptoms are present) are recommended at initial diagnosis of hepatocellular carcinoma and are used to assess response during or after treatment. Intranodular arterial vascularity of residual/recurrent tumor is a reliable feature to assess response after treatment.  

STAGING OF HEPATOCELLULAR CARCINOMA  

There are several staging systems that have been devised for patients with hepatocellular carcinoma that each include variables to evaluate any of the following factors that affect the prognosis of hepatocellular carcinoma patients: Clinical stage; aggressiveness and growth rate of the tumor; general health of the patient; liver function of the patient; and the treatments administered.  

Barcelona Clinic Liver Cancer (BCLC) Staging System  

Barcelona Clinic Liver Cancer (BCLC) staging system is widely accepted in clinical practice and trials as a basis for appropriate treatment modalities depending on the disease's Okuda system stage and other tumor characteristics, measurements of liver function, and the patient's Eastern Cooperative Oncology Group (ECOG) performance status (PS). 

• Stage 0 (very early HCC): ≤2 cm single nodule, ECOG PS 0, preserved liver function, Child-Pugh A; may benefit from curative therapies
• Stage A (early HCC): Single nodule of any size or ≤3 cm x ≤3 nodules, ECOG PS 0, preserved liver function Child-Pugh A-B; may benefit from curative therapies
• Stage B (intermediate HCC): Multiple nodules, ECOG PS 0, preserved liver function Child-Pugh A-B; may benefit from palliative treatments
• Stage C (advanced HCC): With portal invasion and/or extrahepatic metastases, ECOG PS 1 or 2, preserved liver function, Child-Pugh A/B, N1 or M1; may benefit from palliative treatments
• Stage D (terminal HCC): ECOG PS 3 or 4, end stage liver function, Child-Pugh C, any T, N or M; patients with very poor life expectancy

American Joint Commission on Cancer (AJCC) Staging System

The American Joint Commission on Cancer (AJCC) staging system gives information about the pathologic characteristics of the resected specimens only while the Okuda staging system incorporates aspects of liver function and tumor characteristics.  

Primary Tumor

• Tx - Primary tumor cannot be assessed
• T0 - Absence of evidence of primary tumor
• T1 - Single tumor ≤2 cm or >2 cm with no vascular invasion
• T1a - Single tumor ≤2 cm
• T1b - Single tumor >2 cm with no vascular invasion
• T2 - Single tumor >2 cm with vascular invasion, or multiple tumors but none measuring >5 cm
• T3 - Several tumors with at least one of which is measuring >5 cm
• T4 - Single or multiple tumors of any size that involve any branch of the portal vein or hepatic vein, or tumor(s) with direct invasions of adjacent organs other than the gallbladder or with perforation of visceral peritoneum

Regional Lymph Node (LN)

• Nx - Regional LN cannot be assessed
• N0 - Absence of regional LN metastasis
• N1 - Presence of regional LN metastasis

Distant Metastasis

• M0 - No distant metastasis
• M1 - Distant metastasis present

Histologic Grade (G)

• Gx - Grade cannot be assessed
• G1 - Well differentiated
• G2 - Moderately differentiated
• G3 - Poorly differentiated
• G4 - Undifferentiated

Anatomic Staging

• Stage IA - T1a N0 M0
• Stage IB - T1b N0 M0
• Stage II - T2 N0 M0
• Stage IIIA - T3 N0 M0
• Stage IIIB - T4 N0 M0
• Stage IVA - Any T N1 M0
• Stage IVB - Any T Any N M1

Fibrosis Score

• F0 - None to moderate fibrosis
• F1 - Severe fibrosis or cirrhosis

National Comprehensive Cancer Network (NCCN) Disease Stratification

• Potentially resectable or transplantable by tumor burden, operable by performance status or comorbidity
• Liver-confined, unresectable disease and not eligible for transplant
• Extrahepatic/metastatic disease and not eligible for resection, transplant or locoregional therapy

Principles of Therapy

Surgery  

If the patient has good liver function (Child-Pugh A or early B, good ICG retention at 15 minutes), adequate liver remnant and good general health, he/she is a good candidate for liver resection. Some patients with unresectable disease but with a good response to systemic therapy may be considered for surgery. Consultation with a medical oncologist, interventional radiologist and a multidisciplinary team is recommended to determine the timing of surgery after systemic therapy.  

Liver transplantation can be considered in selected patients with early hepatocellular carcinoma with good liver function after multidisciplinary assessment (eg when future liver remnant is marginally adequate or where vascular margins are close). The initial treatment with either partial hepatectomy/liver resection or transplantation should be considered in patients with liver function characterized by a Child-Pugh class A score, lack of portal hypertension and who fit the UNOS criteria. The patient should also have an operable disease on the basis of performance status and comorbidity. Minimally invasive approaches to surgery have been proven safe and effective.  

Locoregional Therapy  

Locoregional therapy is the preferred treatment approach for patients in whom surgery or liver transplantation is not possible or is contraindicated. This should be considered as a part of a strategy to bridge patients for other curative therapies to control tumor growth and reduce the risk of waitlist dropout. All tumors should be amenable to ablation such that the tumor and a margin of normal tissue are treated. Tumors must be in a location accessible for laparoscopic, percutaneous or open approaches. Ablation alone may be a curative treatment for tumors ≤3 cm. Tumors measuring 3-5 cm can be treated with a combination of ablation and arterially directed therapies to prolong survival, as long as the tumor location is amenable to ablation. For patients with unresectable tumor >5 cm, treatment using arterially directed therapies, radiation therapy (RT) or pharmacological therapy should be considered. All hepatocellular carcinoma tumors, with no consideration of the location in the liver, may be amenable to arterially directed therapies, as long as the arterial blood supply to the tumor may be isolated.  

Radiation therapy and stereotactic body radiation therapy (SBRT) can be considered as an alternative to ablation and/or embolization techniques or when these therapies have failed or are contraindicated. Radiation therapy is an alternative when the patient is neither suitable for radiofrequency ablation (RFA) or transplantation. Palliative radiation therapy is appropriate for symptom control and/or prevention of complications from metastatic hepatocellular carcinoma lesions in bone or brain and extensive liver tumor burden.  

Systemic Therapy  

Systemic therapy is often a last resort for a small percentage of patients with advanced hepatocellular carcinoma eligible for curative therapies. This is a recommended option for patients with: Unresectable, liver-confined disease but inoperable by performance status, comorbidity or with minimal or uncertain extrahepatic disease, metastatic disease or extensive liver tumor burden; advanced disease especially patients progressing on locoregional therapies and those with extrahepatic metastatic disease; and recurrence of disease after a curative procedure. The first-line systemic therapy options may be used as a subsequent-line agent.

Pharmacological therapy

Protein Kinase Inhibitors  

Cabozantinib  

Cabozantinib is a tyrosine kinase inhibitor recommended as subsequent-line therapy in patients with Child-Pugh A liver function with hepatocellular carcinoma that progressed on or after treatment with first-line regimens. This showed significantly greater median overall survival, disease control rate, overall response rate (ORR) and progression-free survival (PFS) in the phase III randomized CELESTIAL trial when compared to placebo.  

Entrectinib

Hepatocellular Carcinoma_Management 1

Hepatocellular Carcinoma_Management 2

Nonpharmacological

LOCOREGIONAL THERAPIES  

Ablation Therapies  

Ablation therapies are treatment options for patients with potentially resectable or transplantable tumor and operable performance status or comorbidity who meet resection criteria regardless if transplant criteria are met. These are treatment options in patients with liver-confined, unresectable tumors who are not eligible for transplant due to inadequate liver reserve, tumor location or extent of disease. Tumor necrosis can be induced either by chemical ablation, thermal ablation, or cryoablation that can be performed by laparoscopic, percutaneous or open approaches. Available evidence suggests that the choice of ablative therapy for patients with early-stage hepatocellular carcinoma should be based on the tumor size and location, as well as the underlying liver function. Ablative therapies are most effective for tumors ≤3 cm that are in an appropriate location away from other organs and major vessels/bile ducts. Adjuvant therapies post-ablation has not been proven to have added benefits. Radiofrequency ablation, cryoablation, microwave ablation (MWA) and percutaneous ethanol injection (PEI) are the commonly used ablation therapies. This is associated with relatively low complication rates. Percutaneous ablation therapies should be performed in hepatocellular carcinoma patients with Child-Pugh A or B class that have ≤3 tumors each measuring ≤3 cm in diameter.  

Ablation (Microwave Ablation [MWA])  

Ablation is considered as an emerging alternative to radiofrequency ablation in patients with small or unresectable hepatocellular carcinoma. In percutaneous microwave ablation, the cancer tissue is ablated by dielectric heat produced by microwave energy emitted from the inserted bipolar-type electrode.  

Percutaneous Ethanol Injection (PEI)  

Ethanol injection is only recommended in cases in which radiofrequency ablation cannot be performed safely because of either enterobiliary reflux, adhesion between the tumor and the gastrointestinal tract, or other reasons. This may be considered in selected patients with hepatocellular carcinoma tumors <2 cm who are not suitable for thermal ablation.  

Radiofrequency Ablation (RFA)

Hepatocellular Carcinoma_Management 3

Hepatocellular Carcinoma_Management 4

Surgery

Liver Resection  

Liver resection involves surgical removal of functional liver parenchyma in the setting of underlying liver disease. This is a potentially curative therapy for patients with a single tumor of any size with no evidence of gross vascular invasion. This is also a potentially curative treatment option and is the preferred treatment for patients with the following disease characteristics: Adequate liver function (Child-Pugh class A and highly selected Child-Pugh class B patients with no portal hypertension); with suitable tumor location; single tumor with no major vascular invasion; and adequate liver remnant (≥20% without cirrhosis and ≥30-40% with Child-Pugh class A cirrhosis, adequate vascular and biliary inflow/outflow). This may be associated with an increased risk for tumor recurrence depending on tumor size, number of lesions and presence of microvascular invasion. This is the preferred treatment option in patients with potentially resectable or transplantable tumor and operable performance status or comorbidity who meet resection criteria regardless if transplant criteria are met.  

Liver Transplantation

Hepatocellular Carcinoma_Management 5

Radiation Therapy

Radiation Therapy (RT)  

Radiation therapy is a treatment option in patients with potentially resectable or transplantable tumors and operable performance status or comorbidity who meet resection criteria regardless if transplant criteria are met. This is a treatment option in patients with liver-confined, unresectable tumors who are not eligible for transplant due to inadequate liver reserve, tumor location or extent of disease. This is a treatment option for patients with unresectable hepatocellular carcinoma or inoperable hepatocellular carcinoma due to the presence of comorbidities. This allows focal administration of high-dose radiation to liver tumors while sparing surrounding liver tissue, thereby limiting the risk of radiation-induced liver damage in patients with unresectable or inoperable hepatocellular carcinoma. Radiation therapy can be used to control pain in patients with bone metastases and to prevent complications from metastasis and extensive liver tumor burden. Advances in radiation therapy, such as intensity-modulated radiation therapy (IMRT), have allowed for enhanced delivery of higher radiation doses to the tumor while sparing surrounding critical tissue. All tumors, irrespective of their location, may be amenable to SBRT, IMRT or 3D conformal radiation therapy. Although SBRT and proton beam (also carbon ion beam) are reasonable options for patients who have failed other local therapies, radiation therapy has not been shown to improve outcomes for patients with hepatocellular carcinoma. Radiation therapy may be considered for symptomatic bony metastases.  

Stereotactic Body Radiation Therapy (SBRT)  

Stereotactic body radiation therapy is an advanced technique of radiation therapy that delivers large ablative doses of radiation. This can be considered as an alternative for patients unresponsive to or with contraindications to ablation therapy and embolization techniques. There is growing evidence (primarily from non-RCTs) supporting the usefulness of SBRT for patients with unresectable, locally advanced or recurrent hepatocellular carcinoma.  Stereotactic body radiation therapy is often used for patients with 1-3 tumors ≤3 cm with minimal or no extrahepatic disease. The usual dose is 30-50 Gy given in 3-5 fractions depending on underlying liver function and the ability to meet normal organ constraints. There is no strict size limit, so SBRT may be used for larger lesions if there is sufficient uninvolved liver and liver radiation dose constraints can be respected. This has demonstrated to be an effective bridging therapy for hepatocellular carcinoma patients with cirrhosis awaiting liver transplant.  

Selective Internal Radiation Therapy (SIRT)  

Selective internal radiation therapy, also called TARE, is a method that involves internal delivery of high-dose beta radiation to the tumor-associated capillary bed, thereby sparing the normal liver tissue. It is accomplished through the catheter-based administration of microspheres embedded with ⁹⁰Y, an emitter of beta radiation. This may be considered in patients with BCLC stage B or C unresponsive to TACE or systemic therapy. This may also be considered as an alternative to TACE as treatment of small tumors in patients awaiting liver transplantation. Phase III studies showed no significant difference in overall survival rates but with less adverse reactions with SIRT compared to Sorafenib treatment. Reported complications are cholecystitis/bilirubin toxicity, gastrointestinal ulceration, radiation-induced liver disease and abscess formation.