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Liver

Liver Primary - Hepatocellular carcinoma (HCC)

These guidelines are current as of May 2014. Every effort will be made to update them to reflect changes in practice.

Patients with HCC often have underlying liver  dysfunction, and co-morbidities. Optimal management requires multidisciplinary input including hepatobiliary surgeons (including liver transplant teams), diagnostic and interventional radiologists, hepatologists, gastroenterologists, and oncologists.​

1. Screening

  • ​Patients with cirrhosis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) have an annual risk of developing HCC of approximately 5%. However, all patients with cirrhosis are at increased risk for developing HCC
  • Patients with HBV infection without cirrhosis have a 0.5% annual risk of HCC that rises with age
  • Patients with cirrhosis, and some carriers of HBV without cirrhosis, are recommended to undergo surveillance with liver ultrasound every 6 months. Nodules <1cm should be evaluated q3 (should this be 6 months?) months with ultrasound. Nodules >1cm should be investigated with dynamic phase imaging, either 4 phase CT or contrast-enhanced MRI (see section 9.2 below)
  • Serum alpha-fetoprotein (AFP) as a screening tool has a high false-positive rate in patients with active hepatitis and typically begins to rise with vascular invasion making it less sensitive for detection of early lesions at a curable stage

2. Diagnostic Work-Up

  • ​Multiphasic CT scan of the abdomen with 4 phases (unenhanced, arterial, portal venous, and delayed venous) or contrast-enhanced MRI is recommended to assess extent of intra-hepatic disease, exclude extra-hepatic disease and/or tumour thrombi within the hepatic vein, inferior vena cava or portal vein. The hallmark of an HCC is arterial enhancement followed by washout on venous and/or delayed images
  • American Association for the Study of Liver Disease (AASLD) 2010 algorithm for evaluation of liver nodules in a cirrhotic liver:
    • Nodules > 1 cm, demonstrating typical imaging characteristics of an HCC (arterial enhancement AND delayed washout) are diagnostic of HCC 
      • If the nodule does not display typical imaging characteristics, then a biopsy is recommended 
      • The European Association for the Study of the Liver (EASL) recommends a single imaging modality in experienced, high-volume HCC centres (such as VGH), and both CT and MRI evaluation in other centres
    • Nodules less than 1 cm should be followed up with ultrasound imaging q3 months (every 6 months?)
  • Additional Work-up 
    • Chest x-ray or CT scan of the chest and bone scan (if bone-related symptoms) to rule out distant metastases. Baseline AFP
    • Blood work to establish Child-Pugh score: total bilirubin, serum albumin, INR
    • Hepatitis B, C serologies if not previously done
    • Liver function should be assessed by the Child-Turcotte-Pugh score or Model for End-Stage Liver Disease (MELD) score
Child-Turcotte-Pugh classification of liver disease:

4. Pathology

​(per College of American Pathologists 2012)

  • Specimen: specify 
    • Type
    • Procedure 
  • Tumour: specify 
    • Size
    • Tumour focality
    • Histologic type
    • Histologic grade
    • Microscopic tumour extension
    • Margins: parenchymal, other
    • Lymph-Vascular invasion
    • Perineural invasion
    • pTNM
      • Lymph nodes: number examined, number involved
  • Additional pathologic findings
    • Fibrosis score

5. Treatment Modalities in HCC

Primary Surgical Therapies

  • Patients with early stage disease (solitary HCC nodule or up to 3 nodules ≤3cm, Child-Pugh A or B) should be identified and evaluated for curative-intent therapies (resection, liver transplant, RFA) by a multidisciplinary team
  • Pre-operative evaluation to:
    • determine the likelihood that disease is confined to the liver, and
    • determine if size/location of tumour and patient’s hepatic function permit resection
    • determine liver volumes including the Future Liver Remnant
  • Pre-operative portal vein embolization (PVE)
    • May be used as an adjunct to major liver resection
    • initiates hypertrophy of the anticipated future liver remnant to enable an extended resection
  • Liver resection:
    • potentially curative
    • optimal treatment for HCC in patients with adequate liver function
    • ideal patient: solitary HCC (or up to 3 lesions up to 3cm), confined to the liver, no radiographic evidence of invasion of hepatic vasculature, no portal hypertension, well-preserved hepatic function
    • anatomic resection preferred but non-anatomic resection may be necessary in patients with cirrhosis to preserve hepatic function
    • TNM stage IIIB, IIIC, IVA or IVB are considered incurable by resection
  • Tumour rupture:
    • embolization or emergency surgery may be used to control bleeding.
    • following staging, some patients may have long-term benefit from resection
  • Liver transplantation:
    • The Milan criteria are used to select patients with cirrhosis and HCC for liver transplantation
    • single lesion ≤5 cm
    • up to 3 lesions with a diameter ≤3 cm
    • no extrahepatic involvement
    • no major vessel involvement

Loco-Regional Liver Directed Therapies

  • Provides tumour control pending transplantation or as an adjunct or alternative to resection in patients with liver-limited disease
  • Selection of the appropriate therapy is best done through review at multi-disciplinary conference including input from interventional radiology, hepatobiliary surgery and medical oncology
  • Radiofrequency Ablation (RFA):
    • Best outcomes when used with single tumours are centrally located, measure under 3 cm, and are distant from blood vessels (“heat sinks”) and major bile ducts. 
    • For larger tumours, RFA is preferable to PEI.
    • RFA may be performed percutaneously (ultrasound, CT) or operatively (laparoscopic, open)
  • Percutaneous Ethanol Injection (PEI)
    • Minimally invasive procedure that involves direct injection of small tumours with ethanol
    • Less effective than RFA
    • May be used when RFA cannot be performed (eg tumours in a subcapsular location or adjacent to blood vessels)
  • Transarterial Chemoembolization (TACE):
    • Used for large unresectable tumours not amenable to other local therapy
    • Involves injection of a chemotherapeutic agent with or without lipiodol into the hepatic artery  
    • Drug-eluting microspheres can also be used with potentially less toxicity and equal efficacy
    • Contraindicated in patients with portal vein thrombosis, decompensated cirrhosis (encephalopathy, jaundice, refractory ascites, or hepatorenal syndrome), extensive bilateral tumour burden, creatinine >180. Relative contraindications: platelets < 75, cardiac or lung disease, untreated varices, biliary occlusion, or tumour >10cm
    • TACE can be repeated, generally after prior response to TACE, to an area with progression
    • Bland partial embolization (i.e. without chemotherapy) can also be performed
    • Typically requires 2-3 days hospitalization. Post chemoembolization syndrome occurs in 80-90% of patients, characterized by self-limited fever, abdominal pain, nausea and vomiting, and elevated liver function tests 
    • Follow-up to assess response: generally >=4-8 weeks post TACE with multiphasic CT or MRI liver.
  • Transarterial Radioembolization (TARE)
    • lnvolves selective delivery of radioactive isotopes (eg yttrium-90 [90Y]-tagged glass microspheres) to the tumour via the hepatic artery
    • For inoperable HCC
    • An alternative treatment for patients with contraindications to TACE, particularly portal venous thrombosis
  • Stereotatic Ablative Radiotherapy (SABR) aka SBRT:
    • Radiotherapy technique in which a limited number of high dose radiation fractions are delivered to a small, precisely-defined target
    • May be useful in patients with portal vein thrombus
    • Requires consultation with Radiation Oncologist experienced with SBRT

System Therapy

  • Systemic therapy is palliative-intent therapy indicated for patients with sufficient hepatic reserve and PS but no longer eligible for surgical or liver-directed therapies
  • Sorafenib
    • First-line standard of care based upon the 3 month median survival benefit demonstrated in the SHARP trial
    • oral multikinase inhibitor, used in patients with Child-Pugh A hepatic reserve, with ECOG PS 0-2. Not indicated for patients with Child Pugh B7 or worse hepatic reserve
    • Common adverse effects include diarrhea, hand-foot syndrome, fatigue, and weight loss
  • Doxorubicin
    • May be an options in patients ieligible for sorafenib or after sorafenib failure
  • No proven role for systemic therapy in the neoadjuvant or adjuvant setting

6. Treatment Options by Stage

The Barcelona Clinic Liver Cancer (BCLC) staging system is a widely recognized staging system to help determine the appropriate treatments for patients with any stage of HCC.



Very Early Stage

  • Patients must have ECOG Performance Status 0 and Child-Pugh A liver function
  • Tumours must be less than 2 cm and confined to one lobe of the liver, with absence of vascular invasion and extra-hepatic disease, and complete removal of the tumour with a margin of greater than 1 cm is anticipated
  • Recommended treatment is ablation or resection if ablation is not possible (see above)
  • There is no role adjuvant chemotherapy or radiotherapy

Early Stage

  • Patients must have ECOG Performance Status 0 and Child-Pugh A liver function
  • Tumours must be confined to one lobe of the liver or up to three nodules all less than 3 cm, with absence of vascular invasion and extra-hepatic disease, and complete removal of the tumour with a margin of greater than 1 cm is anticipated 
  • A solitary tumour of any size may be considered for resection provided the liver function is satisfactory and there is an adequate future liver remnant
  • Recommended treatment is surgical with resection or in certain circumstances liver transplantation. Alternatively, local treatment with radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI) can be used for patients with tumours less than 3 cm that are not surgical/transplant candidates or refuse surgery 

Intermediate Stage

  • Patients must have ECOG Performance Status 0, Child-Pugh A liver function or selected patients with Child-Pugh B liver function and have adequate renal (liver?) function
  • Tumours are multinodular with absence of extra-hepatic disease, with patency of the main portal vein
  • Recommended treatment is locoregional with trans-arterial chemo-embolization (TACE) or trans-arterial radio-embolization (TARE - see UGIYTT)
  • Stereotactic Ablative Radiotherapy (SABR) is also an option
  • No role for adjuvant chemotherapy, although clinical trials are underway

Advanced Stage

  • Patients being considered for systemic treatment must have ECOG Performance Status 0, 1 or 2 and Child-Pugh A liver function
  • These patients with HCC are ineligible for, or have progressed after, surgical or locoregional therapy
  • Palliative systemic therapy may be given to help improve symptoms and quality of life, and extend survival in appropriately selected patients
  • Currently approved systemic agents for HCC include: sorafenib (see UGISORAF) and doxorubicin (see GIA
  • Consider treatment on a clinical trial, if available
  • Palliative radiotherapy for pain control
  • Symptom management, best supportive care, and involvement of palliative care services as indicated by patient’s clinical status

Terminal Stage

  • Patients with ECOG Performance Status greater than 2 and/or Child-Pugh C liver function
  • Palliative chemotherapy may adversely affect outcome
  • Palliative radiotherapy for pain control
  • Symptom management, best supportive care, and involvement of palliative care services highly recommended

7. Fibrolamellar Carcinoma

  • ​Fibrolamellar carcinoma is a rare form of primary liver cancer which has traditionally been considered to be a distinct variant of HCC
  • Not associated underlying liver inflammation, cirrhosis or fibrosis
  • Affects mainly Caucasians; males and females equally affected
  • Median age of diagnosis is 33 years; 
    • Conventional HCC is still more common in young patients than fibrolamellar carcinoma
  • Most common presenting symptoms are: abdominal pain, weight loss and malaise
  • AFP levels often normal. Liver enzymes may be slightly elevated or normal.
  • Usually presents as a hypoattenuated, well-defined solitary liver mass on a non-enhanced CT scan, sometimes with a central scar, in an otherwise normal appearing liver (i.e. usually no cirrhosis)
  • Fine-needle aspiration should not be performed in patients with resectable tumours. Referral to a hepatobiliary surgeon is indicated
  • Surgical resection or transplantation is the standard of care for eligible patients. Subsequent recurrences or development of metastatic disease occurs in more than half of patients. Median time to recurrence is reported to be between 10 and 33 months
  • TACE may be useful for patients with unresectable liver-limited disease
  • Chemotherapy for patients with metastatic disease is not well defined. There have been reports of partial responses to platinum-based regimens

8. Follow-up

  • ​Patients who have undergone curative resection should be followed every 3 to 6 months with AFP and liver imaging for about two years
  • Patients should then continue with annual lifelong screening as they remain at risk for developing recurrent disease
  • Ideally, patients with hepatitis B infection should be evaluated by a gastroenterologist for anti-viral therapy as reduction of HBV-DNA levels to undetectable levels reduces the risk of recurrence
  • Transplanted patients should be followed in specialized transplant centres
  • Relapse following resection or transplantation should be evaluated for treatment by a multidisciplinary HPB team
SOURCE: Liver ( )
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