This article appears in the following Annals of Oncology issue: ESMO Clinical Recommendations [View the issue table of contents]
ESMO clinical recommendations |
Hepatocellular carcinoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up
Internal Medicine Service, Institute of Oncology and Radiology, Belgrade, Serbia
* Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations{at}esmo.org
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incidence |
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Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and eighth most common cancer in women worldwide. Its crude incidence in the European Union is 8.29/100 000. Areas such as Asia and sub-Saharan Africa with high rates of infectious hepatitis have incidences as high as 120 cases per 100 000. It is 4–8 times more common in men and usually associated with chronic liver injury (hepatitis B, hepatitis C and alcoholic cirrhosis). Chronic infection with hepatitis B virus in the setting of cirrhosis increases the risk of hepatocellular carcinoma 1000-fold. Some 5–30% of individuals with HCV infection develop chronic liver disease, about 30% progress to cirrhosis, and in these, 1–2% per year develop hepatocellular carcinoma. Co-infection with HBV further increases the risk. Alcohol abuse in the setting of chronic HCV infection doubles the risk of hepatocellular carcinoma compared with HCV infection alone. Median age at diagnosis is between 50 and 60 years. In Africa and Asia, age at diagnosis is substantially younger, occurring in the fourth and fifth decades of life, respectively.
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surveillance |
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Patients with high risk for hepatocellular carcinoma can be considered for, and offered to be entered into surveillance programs. These include all cirrhotic hepatitis B carriers; non-cirrhotic patients with high hepatitis B DNA concentration; patients with hepatitis C related or alcoholic cirrhosis, as well as patients with several more rare disorders. Surveillance should be performed using ultrasonography at 6–12 months interval, associated or not with AFP determination, in order to detect early hepatocellular carcinoma amenable to surgical treatment with curative intent (II, B). Despite correct surveillance, there are, however, still no data confirming that these advantages in detection of earlier lesions produce an improvement in long-term survival, and cirrhotic patients may have rather limited options for curative treatment.
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diagnosis |
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Tumors are multifocal in the liver in 75% of cases at diagnosis. Diagnosis is usually made by history, physical examination, imaging (ultrasound, MRI or CT scan showing a liver mass consistent with HCC) and optionally elevated serum alpha-feto protein (AFP higher than 400 ng/ml), because AFP is elevated in only 50–75% cases. A suspicious lesion on the sonogram generally requires additional imaging studies to confirm the stage of the tumor and sensitivity for detection of small nodules may be low. The addition of arterial phase imaging to conventional CT scanning increases the number of tumor nodules detected, but in nodular cirrhotic livers the sensitivity for detecting hepatocellular carcinoma is low. The overall sensitivity of MRI is similar to that of triphasic CT scan, but in patients with nodular cirrhotic livers MRI has better sensitivity and specificity. Confirmation of diagnosis is made by fine needle aspiration or biopsy. Elevation of AFP over 400 ng/ml can be used instead of fine needle cytology for diagnosis of HCC in patients with liver cirrhosis and a focal hypervascular liver lesion (>2 cm) in at least one imaging technique. Patients with potentially resectable liver mass and AFP >400 ng/ml should undergo surgery without pre-operative FNAC or biopsy. Any deterioration in liver function in a patient with known liver cirrhosis of any etiology should raise a suspicion for hepatocellular carcinoma.
The size of lesions and the presence or not of cirrhosis may influence the sequence of tests used to diagnose hepatocellular carcinoma. Suspect nodules smaller than 1 cm should be followed with ultrasound at intervals of 3–6 months; nodules between 1–2 cm in a cirrhotic liver should be investigated with at least two dynamic studies (triphasic CT scan, ultrasound, or MRI with contrast). If two techniques show a typical appearance of hepatocellular carcinoma, the nodule should be interpreted as such; if it is not the case, the lesion should be either biopsied whenever possible or extirpated at the discretion of the physician. Nodules larger than 2 cm with a typical feature of hepatocellular carcinoma on a dynamic imaging technique, as well as any nodule associated with an AFP level higher than 400 ng/ml or a rising AFP on sequential determinations need not be biopsied but should be considered as proven hepatocellular carcinoma.
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staging and risk assessment |
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Staging should include X-ray of chest (alternatively CT scan), and CT scan (alternatively MRI) of the abdomen. Imaging studies for eventual other tumor localizations should be performed as needed according to the clinical context. Tumors should be staged according to AJCC staging criteria/TNM system, although it appears to be of less predictory value than the CLIP (Cancer of the Liver Italian Program) and the BCLC staging. The fibrolamellar variant is not associated with cirrhosis of any etiology and, if resectable, has a more favorable prognosis.
For patients being considered for liver transplantation, the MELD score is also useful.
Child-Pugh grade C patients should be offered only supportive care. Child-Pugh grade A and favorable grade B should be evaluated for specific treatment options. For the fibrolamellar variant, local treatment modalities should only be considered as there is no documented chemotherapy regimen or biological agent that has shown any activity.
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treatment plan |
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This should be based on extent of disease, growth pattern of tumor, hepatic functional reserve and patient's performance status.
localized resectable tumors (T1, T2, T3 and selected T4; N0; M0)
Optimal treatment should be surgical resection (partial hepatectomy) with no adjuvant therapy, for patients without liver cirrhosis [II, A]. However resection is possible in only 5% of all diagnosed patients with hepatocellular carcinoma, and with the absence of strict criteria concerning tumor size, the cutoff tends to be fixed at 5 cm.
For patients with liver cirrhosis, surgical resection or liver transplantation may be considered depending on hepatic functional reserve, and whether donor-related supply is adequate to demand. Only about 5% of hepatocellular carcinoma patients are suitable for transplantation; these patients may have a 5-year survival greater than 75%. Liver transplantation should be performed according to standard Milan criteria and at the moment no definite recommendations can be made regarding extension of the original criteria, a topic that is being currently assessed.
localized unresectable tumors (selected T2, T3 and T4; N0; M0)
Total hepatectomy with liver transplantation should be considered [II, A]. Local ablation as further cited can be used as a separate treatment modality by itself, or as a bridge to transplantation.
Local ablation options include:
- Trans-arterial chemoembolization (TACE) for patients with adequate hepatic functional reserve and multifocal HCC that does not present vascular invasion or extrahepatic spread. TACE principle is intra-arterial injection of cytotoxic drug combinations like Doxorubicin and/or Cisplatin and/or Mitomycin into the hepatic artery, followed by Lipiodol injection, gelfoam for vessel occlusion and degradable microspheres (II, A).
- Percutaneous ethanol injection (PEI) for patients with less than 3–4 tumor nodules, maximum 5 cm in size (III, B).
- Radiofrequency ablation also for tumors less than 5 cm in size and/or less than 4 in number, its efficacy being clearly superior to PEI in larger tumors (II, B).
- Sorafenib that in a phase II study induced response in 8% and disease control in 41% of patients. In a further phase III study with patients with Child-Pugh grade A liver disease, it extended survival for 2,8 months as compared to placebo (II, A), and may be a first line option for systemic treatment.
- Inclusion in clinical trials.
- Best supportive care.
- Systemic chemotherapy should not be included in standards of care but may be discussed with and offered to selected candidates for systemic treatment if no other options are locally available. Systemic chemotherapy containing anthracyclines was reported to have a prospect of a 10% response rate and no survival benefit (if bilirubin normal and hepatic reserve adequate). Cisplatin based combinations were reported to improve response rate but again with no survival benefit as compared to supportive care alone (III, C). In the PIAF regimen (cisplatin, interferonalpha, doxorubicin and infusional 5FU) treatment-related toxicity was significant. Anthracycline/cisplatin based combination will probably become obsolete with the wide availability of Sorafenib.
Thyrosine kinase inhibitors such as Sunitinib and Erlotinib (the latter either alone or in combination with Bevacizumab) have shown activity in hepatocellular carcinoma but at the moment their use is limited to prospective clinical trials. Avoiding use of investigational agents for hepatocellular carcinoma outside clinical trials is strongly recommended.
advanced tumors (any T; N+; M1)
There is no established standard of care, and therapeutic possibilities should be decided on an individual basis. Sorafenib, inclusion in clinical trials, systemic chemotherapy (this by default only), and best supportive care could be considered. Best supportive care is the only option for patients with Child B/C liver cirrhosis.
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response assessment |
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Due to frequent multifocality of the tumor at presentation, measuring the effect of systemic treatment in individual patients may prove difficult. Clear-cut responses according to RECIST criteria are rare. Published responses of chemotherapy regimens should be interpreted with great caution. Endpoints like progression-free survival and overall survival can only be assessed in randomized trials. The assessment of response to locoregional treatments is still a matter of debate. Tumor control is an option that should be assessed both radiologically and by estimating achieved clinical benefit.
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prevention |
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Recent studies suggest that antiviral treatment of chronic HCV infections may reduce significantly the risk of hepatocellular carcinoma. It is anticipated that with implementation of worldwide vaccination, the incidence of hepatitis B-related hepatocelluar carcinoma will decrease.
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follow-up |
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Patients undergoing curative resection should be followed up 3–6 monthly with AFP determination and liver imaging (for 2 years), since curative therapy can still be offered at relapse, to a minority. The indications for antiviral/IFN therapy for patients positive for hepatitis C and hepatitis B virus should depend on degree of hepatitis and/or liver cirrhosis and viral replicative status. For other patients, follow up aims to prevent and/or treat hepatic decompensation.
Transplanted patients should be followed only in specialized transplant centers. Post transplantation treatment includes corticosteroids, cyclosporine and tacrolimus. Follow-ups should be scheduled once monthly up to 6 months, then once every 3 months up to 1 year, than twice a year up to 2 years and once a year every year thereafter. Imaging studies should be performed as needed. The follow-up is aimed at drug dosage adjustment, early diagnosis of eventual immunosupression-related infection, early detection of rejection or transplant dysfunction, and later also at detection of immunosupression-related neoplasia. Antiviral therapy should be continued if previously started.
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note |
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Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
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footnotes |
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Approved by the ESMO Guidelines Working Group: November 2007, last update December 2008. This publication supercedes the previously published version—Ann Oncol 2008; 19 (Suppl 2): ii27–ii28.
Conflict of interest: Dr Jelic has reported no conflicts of interest
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references |
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