Hepatocellular%20carcinoma Treatment

Protein Kinase Inhibitors

Cabozantinib

• A tyrosine kinase inhibitor that is recommended in patients with Child-Pugh A liver function with HCC that progressed on or after treatment with 1st-line regimens
• Showed significantly greater median OS, disease control rate, overall response rate (ORR) and progression-free survival (PFS) in the phase III randomized CELESTIAL trial when compared to placebo

Entrectinib

• A tropomyosin receptor kinase (TRK) inhibitor used as a treatment option for patients with neurotrophic tropomyosin receptor kinase (NTRK) gene fusion-positive HCC

Larotrectinib

• A TRK inhibitor used as a treatment option for patients with NTRK gene fusion-positive HCC

Lenvatinib

• An oral multikinase inhibitor recently approved as one of the 1st line treatment of patients with unresectable HCC with Child-Pugh class A liver function without macrovascular invasion
• May also be used as subsequent-line treatment in patients with unresectable or advanced HCC with Child-Pugh class A liver function with disease progression after treatment with Sorafenib or Atezolizumab/Bevacizumab combination therapy 
• An international, multicenter, randomized, open-label, non-inferior but not statistically superior to Sorafenib for overall survival
  • The trial also showed that there is a statistically significant improvement in PFS, time-to-progression(TTP) and ORR with Lenvatinib as compared to Sorafenib

Regorafenib

• A novel multikinase inhibitor that has potent inhibitory activities against multiple angiogenic pathways
• Approved for use in patients with HCC who progressed on or after treatment with 1st-line regimens and with Child-Pugh A liver function
• Improvements in OS, PFS, TTP, objective response and disease control rate were seen in patients given Regorafenib compared to patients given placebo in the randomized, double-blind, placebo-controlled, international phase III RESOURCE trial

Sorafenib

• An oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis
• Recommended as one of the 1st-line treatment of advanced-stage patients (macrovascular invasion or extrahepatic metastasis) with Child-Pugh A liver function and those with intermediate stage HCC (BCLC stage B) not eligible for, or with disease progression after locoregional therapy 
• Recommended in selected patients with Child-Pugh A and B liver function with disease characterized as:
• Unresectable (confined in the liver) and extensive/not suitable for liver transplantation
• Local disease only in patients who are not operable due to performance status or comorbidity
• Metastatic disease
• Biopsy should be considered to confirm metastatic disease prior to initiation of treatment

• Sorafenib following arterially directed therapies may be appropriate in patients with adequate liver function once bilirubin returns to baseline, if there is evidence of residual or recurrent tumor not amenable to additional locoregional therapy
• Sorafenib may also be used as subsequent therapy in patients with disease progression on or after 1st-line therapy with Lenvatinib 
• Results from 2 randomized, placebo-controlled, phase III trials (SHARP and Asia-Pacific trials) suggested that Sorafenib may be an effective treatment in patients with advanced HCC irrespective of the baseline ECOG performance status (0-2), tumor burden (with or without macrovascular invasion and/or extrahepatic spread), presence or absence of either lung or lymph node metastasis, tumor stage, prior therapy and disease etiology (alcohol-related or HCV-related HCC)
  
  • The studies also showed that Sorafenib is an effective treatment irrespective of serum concentrations of ALT/AST/AFP and total bilirubin levels 

• While more mature results from ongoing studies are needed to recommend Sorafenib for Child-Pugh B or C patients, available evidence so far suggests that the Child-Pugh status is a strong predictor for patients with unresectable HCC treated with Sorafenib and it should be used with caution in patients with Child-Pugh class B
• Studies have shown that Sorafenib may be more beneficial in HCV patients compared with patients with HBV

Cancer Immunotherapy/Immunomodulating Agents

• A systematic review showed that immunotherapy may prevent recurrence in resected HCC

Dostarlimab-gxly

• Indicated for patients with high microsatellite instability (MSI-H)/mismatch repair deficient (dMMR)-positive recurrent or advanced tumors with disease progression on previous treatment and with no alternative treatment options

Durvalumab

• A human immunoglobulin monoclonal antibody that may be considered as a treatment option for patients with unresectable or metastatic HCC or patients with extensive liver tumor burden

Nivolumab

• An anti-programmed cell death protein (PD-1) antibody, recommended as subsequent-line therapy for HCC patients with disease progression during or post-1st-line therapy or other anti-angiogenic agents
  
  • Also recommended for patients with Child-Pugh Class A or B7 

Pembrolizumab

• An anti-PD-1 antibody that may be considered as subsequent-line treatment in patients, with or without MSI-H/dMMR, who showed signs of disease progression or those intolerant to 1st-line treatment regimens
• Based on the results from the phase II and III KEYNOTE-224 study, patients given Pembrolizumab showed improvement in OS, PFS and objective response rate in both phases when compared to placebo, although was deemed not statistically significant in phase III 

Ramucirumab

• A human immunoglobulin G1 (IgG1) monoclonal antibody that may be considered as subsequent-line treatment in patients with AFP ≥400 ng/mL with Child-Pugh class A liver function and with disease progression following treatment with 1st-line regimens
• Significant improvements in median PFS and OS were seen in patients given Ramucirumab compared to those given placebo in the REACH-2 phase III study

Combination Regimen

Atezolizumab + Bevacizumab

• Atezolizumab is a programmed death-ligand 1 (PD-L1) inhibitor and Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor 
• Recommended as the preferred 1st-line regimen of patients with unresectable advanced HCC with Child-Pugh class A liver function
• IMbrave 150 study has demonstrated clinically significant improvements in OS and PFS in patients with unresectable HCC who have not received previous systemic treatment and treated with combination of Atezolizumab and Bevacizumab

Infusional Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX)

• May be considered in patients with advanced HCC with microinvasion and/or extrahepatic metastasis when multikinase inhibitors are unavailable

Nivolumab + Ipilimumab

• May be used as subsequent-line regimen in patients with unresectable advanced HCC with Child-Pugh class A liver function with progressive disease after treatment with 1st-line systemic agents
• CheckMate 040 study has demonstrated clinically significant results and acceptable safety profile of Nivolumab with Ipilimumab in patients with advanced HCC and previously treated with Sorafenib

Investigational Agents

• Axitinib showed potential activity in patients with intermediate to advanced Child-Pugh Class A disease when given after Sorafenib therapy
• Various clinical trials are being conducted to prove the use of other agents in HCC, including Tremelimumab, Linifanib and Tivantinib

Antiviral Therapy

• Antiviral therapy in a postoperative setting may improve outcomes especially in HCC patients with HBV-related infection
• It has been shown in a randomized trial that those treated with antiviral therapy (eg Lamivudine, Adefovir, Dipivoxil or Entecavir) have significantly decreased HCC recurrence and HCC-related death, improved liver function and improved liver function at 6 months after surgery

Principles of Therapy

• Locoregional therapy is the preferred treatment approach for patient in whom surgery or liver transplantation is not possible or contraindicated
• 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, external beam radiation therapy (EBRT) or pharmacological therapy should be considered 

• All HCC 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
• EBRT 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
• EBRT is an alternative when the patient is neither suitable for radiofrequency ablation (RFA) or transplantation
• Palliative EBRT is appropriate for symptom control and/or prevention of complications from metastatic HCC lesions in bone or brain

Ablation Therapies

• 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 HCC should be based on tumor size and location, as well as underlying liver function
  
  • Ablative therapies are most effective for tumors ≤3 cm that are in an appropriate locations away from other organs and major vessels/bile ducts

• Radiofrequency ablation (RFA) cryoablation, microwave ablation (MWA) and percutaneous ethanol injection (PEI) are commonly used ablation therapies
  
  • Associated with relatively low complication rates
• Percutaneous ablation therapies should be performed in HCC patients with Child-Pugh A or B class that have ≤3 tumors each measuring ≤3 cm in diameter

Microwave Ablation (MWA)

• Considered as an emerging alternative to RFA in patients with small or unresectable HCC
  • In percutaneous MWA, 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 RFA cannot be performed safely because of either enterobiliary reflux, adhesion between the tumor and the gastrointestinal tract, or other reasons

Radiofrequency Ablation

• Treatment of choice in HCC that is ≤2 cm in Child-Pugh A or B class patients
  
  • An alternative option to resection for HCC ≤3 cm in diameter in Child-Pugh A or B class patients
  • In RFA, radiofrequency energy emitted from the exposed portion of the electrode is converted into heat that causes necrosis of the tumor
  • It is recommended and widely used as an image-guided percutaneous ablation technique 

• Greater complete response rate and local recurrence rate than PEI
• Significantly lower tumor progression rates than PEI 

Other Ablation Therapy

Irreversible Electroporation (IRE)

• A nonthermal tumor ablation technique that uses high-voltage electric pulses to induce cell death, while preserving the structural integrity of the bile ducts and vessels
• May be useful for tumors near a major Glisson's sheath

Arterially Directed Therapies

• Involves the selective catheter-based infusion of particles targeted to the arterial branch of the hepatic artery feeding the portion of the liver in which the tumor is located
• This is made possible by the dual blood supply to the liver; whereas the majority of the blood supply to normal liver tissue comes from the portal vein, blood flow to liver tumors is mainly from the hepatic artery
  • HCC tumors are hypervascular resulting from increased blood flow to tumor relative to normal liver tissue
• Currently in use therapies are transarterial bland embolization (TAE), transarterial chemoembolization (TACE), TACE with drug-eluting beads (DEB-TACE) and transarterial radioembolization (TARE) with yttrium-90 (⁹⁰Y) microspheres
• Complications common to TAE and TACE are non-target embolization, liver failure, pancreatitis, and cholecystitis
• Hepatic arterial infusion chemotherapy (HAIC) is being studied in clinical trials to prove its superiority against Sorafenib treatment and other locoregional strategies for the management of HCC
• All arterially directed therapies are relatively contraindicated in patients with bilirubin >3 mg/dL (>2 mg/dL if with TARE with ⁹⁰Y microspheres)

Hepatic Arterial Infusion Chemotherapy (HAIC)

• May be used in advanced, nonmetastatic HCC with macrovascular invasion
• The most recent arterially directed management strategy being proposed to be the 1st-line treatment for large stage A-B HCC with macroscopic invasion
• Several studies showed that patients given HAIC plus Sorafenib versus Sorafenib monotherapy showed better overall survival (OS) rates

Selective Internal Radiation Therapy (SIRT)

• 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
• May be considered in patients with BCLC stage B or C unresponsive to TACE or systemic therapy
• 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 on 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

Transarterial Bland Embolization (TAE)

• Aims to reduce or eliminate blood flow to the tumor resulting in tumor ischemia followed by tumor necrosis
• Used to block arterial flow are gelatin sponge particles, polyvinyl alcohol particles and polyacrylamide microspheres
• It has been shown to be an effective treatment option for patients with unresectable HCC 

Transarterial Chemoembolization (TACE)

• The goal is to deliver a highly concentrated dose of chemotherapy to tumor cells, prolong the contact time between the chemotherapeutic agents and the cancer cells, and minimize systemic toxicity of chemotherapy
• Recommended as 1st-line, non-curative therapy in HCC patients with unresectable, large/multifocal HCC without vascular invasion or extrahepatic spread, and patients with ECOG PS 0, preserved liver function and single nodule ≤3 cm
• Randomized clinical trials showed a survival benefit for TACE compared with supportive care in patients with unresectable HCC 
• Not recommended in patients with liver function characterized as Child-Pugh class C but is safe for use in highly selected patients with limited tumor invasion of the portal vein

Radiation Therapy

• All tumors, irrespective of their location, may be amenable to SBRT, intensity-modulated radiation therapy (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, radiotherapy (RT) has not been shown to improve outcomes for patients with HCC
  • RT may be considered for symptomatic bony metastases

External Beam Radiation Therapy (EBRT)

• Treatment option for patients with unresectable HCC or inoperable HCC due to presence of comorbidities 
• 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 HCC
• EBRT can be used to control pain in patients with bone metastases and to prevent complications from metastasis and extensive liver tumor burden
• Advances in EBRT, such as IMRT, have allowed for enhanced delivery of higher radiation doses to the tumor while sparing surrounding critical tissue

Stereotactic Body Radiation Therapy (SBRT)

• An advanced technique of EBRT that delivers large ablative doses of radiation
• Can be considered as an alternative to or in patients unresponsive or with contraindication 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 HCC
• SBRT is often used for patients with 1-3 tumors ≤3 cm with minimal or no extrahepatic disease
• 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
• Has demonstrated to be an effective bridging therapy for HCC patients with cirrhosis and awaiting liver transplant