- HCC usually occurs in patients with cirrhosis (with the exception of chronic HBV infection)
- Patients with cirrhosis (Child Pugh A or B or those patients with Child Pugh C who are listed for liver transplantation) should undergo HCC surveillance with ultrasound and AFP every six months.
- In the majority of cases, HCC can be diagnosed using contrast enhanced imaging (CT, MRI or CEUS) instead of biopsy.
- When selecting therapy for HCC, consider tumour extent (stage), liver function (Child Pugh score), and patient characteristics (ECOG performance status, liver transplant eligibility)
- Barcelona Clinic Liver Cancer (BCLC) staging is the preferred staging system and can link patients to therapy. The Alberta guidelines are based off of BCLC and presented below.
- All patients with HCC must be reviewed at a Multi-Disciplinary Team (MDT) meeting before selecting therapy. This approach has increased survival rates in other series. Within Alberta, this occurs in Edmonton and in Calgary.
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Who should be screened:
- Patients with cirrhosis (regardless of the etiology) who are Child Pugh A or B.
- Given limited treatment options, surveillance should only be done in Child Pugh C patients if they are eligible for liver transplantation
- The criteria for screening for HCC in the setting of Hepatitis B (without cirrhosis) can be found in relevant guidelines.
How to screen:
- Ultrasound surveillance with serum alpha-fetoprotein (AFP) every six months
- Do not use AFP alone for surveillance
- Automated radiology recall programs are preferred to increase compliance – for Alberta, please see details for these programs in the grey bar.
- In a patient at risk for HCC (cirrhosis), a diagnosis of HCC can be made non-invasively (without the need for liver biopsy) in most patients using contrast enhanced imaging
- If a biopsy is done, specific stains may help with the diagnosis of HCC.
- Alpha-fetoprotein (AFP) elevation is not required for diagnosis of HCC (40% of HCC do not make AFP), but it should be ordered if HCC is suspected as it has prognostic properties and is used for liver transplant selection.
Mass/nodule < 1cm
- If nodule size and pattern remain stable, repeat ultrasounds Q 3 monthly for 12-18 months. If unchanged go back to Q 6 monthly imaging
- If size increasing or pattern changing – obtain cross-sectional imaging with multiphasic contrast-enhanced CT or MRI.
Mass/nodule ≥1 cm
- Obtain cross-sectional imaging with multiphase contrast-enhanced CT or MRI.
- If positive or indeterminate for HCC then get the patient reviewed at Multidisciplinary liver radiology rounds to determine treatment options.
Reproduced with permission from Dr. K. Burak. Source: HepAPPtology
|Factor||1 point||2 points||3 points|
|Total Bilirubin (μmol/L)||<34||34-50||>50|
|Serum Albumin (g/L)||>35||28-35||<28|
|Ascites||None||Controlled, on diuretics||Refractory|
|Hepatic Encephalopathy||None||Controlled, on medical therapy||Refractory|
|0||Fully active and able to carry on without restrictions|
|1||Unable to carry out physically strenuous activities but ambulatory and able to complete work of a light or sedentary nature|
|2||Ambulatory and capable of all self-care but unable to complete work activities. Up and about more than 50% of waking hours|
|3||Capable of only limited self-care and/or confined to a bed or chair for more than 50% of waking hours.|
|4||Completely disabled. Unable to carry out any self-care. Totally confined to a bed or chair.|
- For BCLC stages 0 and A. Must have preserved liver function (Child Pugh A) with no significant portal hypertension (no varices, hepatic venous pressure gradient or HVPG <10 mmHg, platelets >100) and a normal bilirubin to avoid post-op liver failure
- Recurrence occurs in 70% at 5 years
- RCTs vs RFA show similar survival but fewer recurrences after surgery
- Complications include post-op infections and liver failure (2% mortality)
- For BCLC stages 0 and A. Lesions should be <3cm and there should be < 3 lesions
- Can be performed in Child Pugh A or B (those who are not candidates for surgery)
- Meta-analyses of RCTs show that RFA is better than PEI for local control & disease free survival if tumour >2cm but PEI is preferred if concerns about thermal injury to adjacent structures or proximity to blood vessels where heat-sink can be an issue with RFA
- Recurrence also 70% at 5yrs (>2.5 cm predicts recurrence)
- Complications in 2-5% ® bleeding, thermal injury, abscess, tumour seeding (1%)
- For BCLC stage A [and selected BCLC stage B]
- LT is the only therapy that treats both the HCC and underlying cirrhosis, so it can be done in Child Pugh C
- Milan criteria [single <5cm, 3 HCC <3cm] predicts low risk for recurrence (<15%)
- Extended criteria has been adopted in Canada where patients can be transplanted up to a total tumour volume (TTV) of ≤ 115cm³ (4/3*Pi*R³) as long as the alpha-fetoprotein (AFP) is ≤ 400ug/mL
- A patient can be considered for down-staging IF the TTV is ≤ 250 cm³, regardless of AFP. Following downstaging, a patient can be considered for transplantation if TTV ≤ 115 cm³ and AFP ≤400 ug/mL for 6 months.
- Patient require long-term immunosuppression, which has many complications, and organ donor shortage lead to many patients progressing beyond accepted criteria while waiting for LT
- TACE, TARE and RFA are used to prevent waitlist drop-out and bridge to LT
- For BCLC stage B (multifocal) and early stage patients who are not candidates for RFA (tumour too large or in poor location) or to bridge patients to liver transplant
- Takes advantage of the rich arterial blood supply of tumours to provide chemotherapy (usually doxorubicin) with embolic particles (induces tumour ischemia)
- Need to have good liver function (CPA or CPB7) to prevent liver failure from ischemia, and must avoid if there is a main portal vein (PV) thrombosis (chance of liver failure)
- Caution if bilirubin >50 umol/L or ascites especially if not a candidate for transplantation
- Meta-analysis of RCTs have shown a survival advantage
- Use of drug eluting beads (DEB-TACE) provides a more standardized technique and is better tolerated (but more expensive)
- Complications include post embolization syndrome (fever, nausea, vomiting) in approximately 25%, ischemic complications and rarely liver failure (2-3% mortality)
- For BCLC stages B and C (being studied with sorafenib in RCTs)
- Like TACE it should be reserved for CPA or CPB7 and MELD ≤ 12
- Yttrium90 (Y90) microspheres provide internal radiation to the tumour
- Particles are smaller and less embolic and can be used if PV thrombosis or invasion
- Cohort studies and small RCTs show higher response rates to TACE, but survival advantage is not established
- May be better than TACE for large tumours and for bridging patients to LT
- It is more expensive than TACE and requires two angiograms (first to calculate shunt fraction to lungs and to embolize collaterals) but it can be done as an outpatient as post embolization syndrome is uncommon.
- Complications include radiation damage to liver, lungs or GI tract.
- For BCLC stage C (advanced stage) due to malignant portal vein invasion (PVI), lymph node involvement (N1) or metastases (M1) or intermediate stage patients who are failing TACE or who are not candidates for TACE
- Targeted oral chemotherapy with anti-VEGF (vascular endothelial growth factor), PDGF (platelet derived growth factor), RAF kinase activity
- RCTs have shown a survival benefit over placebo in patients with preserved liver function (Child Pugh A)
- Side-effects include nausea, diarrhea, hand & foot skin reactions and hypertension
- Blocks VEGF receptors, FGF (fibroblast growth factor) receptors, PDGF receptor, RET, and KIT
- Found to be non-inferior to sorafenib in large open-label phase 3 study (median survival 14 months for levatinib vs 12 months for sorafenib) with high tumour response rates
- Side-effect profile similar to sorafenib.
Atezolizumab and Bevacizumab
- Atezolizumab (monoclonal antibody checkpoint inhibitor that blocks PD-L1) and (monoclonal antibody that blocks VEGF) showed statistically improved overall survival when compared to sorafenib (HR 0.58; 95% CI: 0.42, 0.79).
- Median OS was not reached in the patients who received atezolizumab plus bevacizumab and was 13.2 months (95% CI: 10.4, NE) in the patients on sorafenib.
- Hypertension was seen in 15% who received atezolizumab and bevacizumab
Second-line chemotherapy (failing sorafenib)
- Regorafenib improved survival from 8 months (placebo) to 11 months
- Cabozantinib improved survival from 8 months (placebo) to 10 months
- For BCLC stages A and C (being studied with sorafenib in RCTs), who aren’t candidates for other therapies but should be reserved for CPA or B
- Provides confocal external radiation in 5 fractions
- Cohort studies show good local control
- Complications include radiation damage to liver (one third have deterioration in CP score after SBRT)
Other SBRT considerations from the Cancer Institutes in Edmonton and Calgary:
- Good performance status (ECOG 0 -2)
- Life expectancy >6 months
- Limited number of metastases (<3-5)
- Limited prior overlap RT
- Patient able to tolerate RT position
- Limited tumor size (< 6 cm)
- Controlled or absent extra hepatic disease
- At least 700 cc of uninvolved liver volume
- Adequate liver function (Child Pugh A)
- Adequate hematologic function (Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3, Platelets ≥ 70,000 cells/mm3, Hemoglobin ≥ 8.0 g/dl)
- Additional contraindications to radiotherapy
- Tumor location close to radiosensitive structures like the stomach, small bowel, large bowel, kidney
- Ascites - poor reproducibility and represents poor liver reserve
- Palliative care principles should be followed in all patients with HCC – this basic/primary palliative care can be carried out by any physician involved in the patient’s circle of care (Primary care physician, Oncologist, Hepatologist) and at a minimum includes advance care planning and goals of care discussions.
- Specialist palliative care involvement (a board certified specialist or the primary care physician if they are comfortable with palliative care) should be considered with complex palliative care including refractory symptom burden or hospice referral that is not straight-forward.
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This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.
Authors: Dr. Kelly Burak, Dr. Chris Fung, Dr. Aldo Montano Loza, Dr. Puneeta Tandon
- EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):182-236 PMID 29628281
- Heimbach JK et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018 Jan;67(1):358-380 PMID 28130846
- Sherman M, Burak K et al. Multidisciplinary Canadian consensus recommendations for the management and treatment of hepatocellular carcinoma. Curr Oncol 2011; 18(5):228-240. PMID 21980250
- Burak KW, Kneteman NM. An Evidence-Based Multidisciplinary Approach to the Management of Hepatocellular Carcinoma (HCC): The Alberta HCC Algorithm. Can J Gastroenterol 2010; 24(11): 643-650. PMID 21157578.