hepatocellular%20carcinoma
HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma is malignancy that originates from the liver.

Physical signs are hepatomegaly and ascites. It is usually asymptomatic for much of its natural history.

Liver cancer is the second most common cause of cancer-related mortality worldwide & hepatocellular carcinoma accounts for >90% of liver cancers.

 

Pharmacotherapy

Protein Kinase Inhibitors

Sorafenib

  • An oral multikinase inhibitor that suppresses tumor cell proliferation & angiogenesis
  • Recommended in selected patients w/ Child-Pugh A & B liver function w/ disease characterized as:
    • Unresectable (confined in the liver) & 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
  • Recommended for the 1st-line treatment of advanced-stage patients (macrovascular invasion or extrahepatic metastasis) who are not suitable for locoregional therapy & who have Child-Pugh class A liver function
  • Results from 2 randomized, placebo-controlled, phase III trials (SHARP & Asia-Pacific trials) suggested that Sorafenib may be an effective treatment in patients w/ advanced hepatocellular carcinoma irrespective of the baseline ECOG performance status (0-2), tumor burden (w/ or without macrovascular invasion &/or extrahepatic spread), presence or absence of either lung or lymph node metastasis, tumor stage, prior therapy & disease etiology (alcholol-related or HCV-related hepatocellular carcinoma)
    • The studies also showed that Sorafenib is an effective treatment irrespective of serum concentrations of ALT/AST/AFP & 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 w/ unresectable hepatocellular carcinoma treated w/ Sorafenib & it should be used w/ caution in patients w/ Child-Pugh class B
  • Sorafenib following arterial directed therapies may be appropriate in patients w/ adequate liver function once bilirubin returns to baseline, if there is evidence of residual or recurrent tumor not amenable to additional locoregional therapy
Lenvatinib
  • A VEGF inhibitor recently approved by US FDA as one of the 1st line treatment of patients w/ unresectable hepatocellular carcinoma
  • 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 progress-free survival w/ Lenvatinib as compared to Sorafenib

Regorafenib

  • A novel multikinase inhibitor that has potent inhibitory activities against multiple angiogenic pathways
  • Approved for use in patients w/ hepatocellular carcinoma who progressed on or after Sorafenib & w/ Child-Pugh A liver function
Cabozantinib
  • A tyrosine kinase inhibitor that is recommended in patients w/ Child-Pugh A liver function w/ hepatocellular carcinoma that progressed on or after Sorafenib therapy

Investigational Therapies

  • Axitinib showed potential activity in patients w/ intermediate to advanced Child-Pugh Class A disease when given after Sorafenib therapy

Immunotherapy

  • Nivolumab is recommended as 2nd-line therapy for hepatocellular carcinoma patients w/ disease progression during or post-Sorafenib therapy
    • Also recommended for patients w/ Child-Pugh Class A or B7 
  • A systematic review showed that immunotherapy may prevent recurrence in resected hepatocellular carcinoma
  • Various clinical trials are being conducted to prove the use of other monoclonal antibodies in hepatocellular carcinoma
    • Improvement in median progression-free survival & time-to-tumor progression were seen in patients w/ advanced hepatocellular carcinoma given Ramucirumab after Sorafenib treatment
    • Other investigational agents include Tremelimumab, Bevacizumab, Metuximab, & Pembrolizumab 

Antiviral Therapy

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

Locoregional Therapies

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 & 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 between 3 & 5 cm can be treated w/ a combination of ablation & arterially directed therapies to prolong survival, as long as the tumor location is amenable to ablation
    • For patients w/ unresectable tumor > 5 cm, treatment using arterially directed therapies or pharmacological therapy should be considered 
  • All hepatocellular carcinoma tumors, w/ 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
  • Stereotactic body radiation therapy (SBRT) can be considered as an alternative to ablation &/or embolization techniques or when these therapies have failed or are contraindicated
  • External beam radiation therapy (EBRT) is an alternative when the patient is neither suitable for radiofrequency ablation (RFA) or transplantation
  • Palliative EBRT is appropriate for symptom control &/or prevention of complications from metastatic hepatocellular carcinoma 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 w/ early stage hepatocellular carcinoma should be based on tumor size & 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 & major vessels/bile ducts 
  • Radiofrequency ablation (RFA) & percutaneous ethanol injection (PEI) are commonly used ablation therapies
    • Both are associated w/ relatively low complication rates
    • RFA has greater complete response rate & local recurrence rate than PEI
    • RFA has significantly lower tumor progression rates than PEI 
  • RFA is the treatment of choice in hepatocellular carcinoma 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 & widely used as an image-guided percutaneous ablation technique 
  • Percutaneous ablation therapies should be performed in hepatocellular carcinoma patients w/ Child-Pugh A or B class that have ≤3 tumors each measuring ≤3 cm in diameter
  • Ethanol injection is only recommended in cases in which RFA cannot be performed safely because of either enterobiliary reflux, adhesion between the tumor & the gastrointestinal tract, or other reasons
  • In percutaneous microwave ablation the cancer tissue is ablated by dielectric heat produced by microwave energy emitted from the inserted bipolar-type electrode
  • Irreversible electroporation (IRE) is a nonthermal tumor ablation technique that uses elecric pulses to induce cell death, while preserving the structural integrity of the bile ducts & vessels; seems to 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
    • Also, hepatocellular carcinoma 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 w/ drug-eluting beads (DEB-TACE) & transarterial radioembolization (TARE) w/ yttrium-90 microspheres
  • TAE's principle is 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 & polyacrylamide microspheres
    • It has been shown to be an effective treatment option for patients w/ unresectable hepatocellular carcinoma 
  • TACE's goal is to deliver a highly concentrated dose of chemotherapy to tumor cells, prolong the contact time between the chemotherapeuitc agents & the cancer cells & minimize systemic toxicity of chemotherapy
    • TACE is recommended as first-line, non-curative therapy in hepatocellular carcinoma patients w/ unresectable, large/multifocal hepatocellular carcinomas without vascular invasion or extrahepatic spread
    • Randomized clinical trials showed a survival benefit for TACE compared w/ supportive care in patients w/ unresectable hepatocellular carcinoma 
  • Complications common to TAE & TACE are non-target embolization, liver failure, pancreatitis, & cholecystitis
  • 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 w/ yttrium-90, an emitter of beta radiation
    • There is a growing body of literature which suggests that radioembolization might be an effective treatment option for patients w/ liver-limited, unresectable disease, though additional randomized clinical trials are need to determine the harms & benefits of TARE w/ yttrium-90 microspheres in patients w/ unresectable hepatocellular carcinoma
    • TARE w/ yttrium-90-loaded resin/glass beads may be used as an alternative locoregional treatment for unresectable hepatocellular carcinoma
    • Reported complications are cholecystitis/bilirubin toxicity, gastrointestinal ulceration, radiation-induced liver disease & abscess formation

External Beam Radiation Therapy (EBRT)

  • 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 w/ unresectable or inoperable hepatocellular carcinoma
  • EBRT can be used to control pain in patients w/ bone metastases
    Advances in EBRT, such as intensity-modulated radiation therapy (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
  • There is growing evidence (primarily from non-RCTs) supporting the usefulness of SBRT for patients w/ unresectable, locally advanced or recurrent hepatocellular carcinoma
  • All tumors, irrespective of their location, may be amenable to SBRT, IMRT or 3D conformal radiation therapy
  • SBRT is often used for patients w/ 1-3 tumors w/ minimal or no extrahepatic disease
  • There is no strict size limit, so SBRT may be used for larger lesions if there is sufficient uninvolved liver & liver radiation dose constraints can be respected
  • Although SBRT & 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 w/ hepatocellular carcinoma
    • However RT may be considered for symptomatic bony metastases
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