World Gastroenterology Organisation Global Guidelines
Peter Ferenci (chair) (Austria)
Michael Fried (Switzerland)
Douglas Labrecque (USA)
J. Bruix (Spain)
M. Sherman (Canada)
M. Omata (Japan)
J. Heathcote (Canada)
T. Piratsivuth (Thailand)
Mike Kew (South Africa)
Jesse A. Otegbayo (Nigeria)
S.S. Zheng (China)
S. Sarin (India)
S. Hamid (Pakistan)
Salma Barakat Modawi (Sudan)
Wolfgang Fleig (Germany)
Suliman Fedail (Sudan)
Alan Thomson (Canada)
Aamir Khan (Pakistan)
Peter Malfertheiner (Germany)
George Lau (Hong Kong)
F.J. Carillo (Brazil)
Justus Krabshuis (France)
Anton Le Mair (The Netherlands)
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More than 600,000 people die from hepatocellular carcinoma (HCC) each year. Worldwide research on the disease needs to be intensified in both the medical and pharmaceutical fields, especially with a focus on providing help to areas where resources are limited.
Treatment approaches depend on the stage of the disease at diagnosis and on access to complex treatment regimens. However, advanced disease is not curable, and management of advanced disease is expensive and only marginally effective in increasing quality-adjusted life-years.
The delivery of health-care services for HCC can be improved by developing centers of excellence. Concentrating medical care in this way can lead to an increased level of expertise, so that resections are performed by surgeons who understand liver disease and the limitations of resection and other relevant procedures.
Promising new agents are beyond the reach of those who would benefit most: in low-resource countries, sorafenib is out of the question for general use. For example, “snapshot” cost indications of monthly pharmacy prices for sorafenib are: $7300 in China, $5400 in the USA, $5000 in Brazil, €3562 in France, and $1400 in Korea (source: N Engl J Med 2008;359:378–90; PMID 18650519).
From a global perspective, therefore, the most urgent task is to prevent the occurrence of HCC. The only effective strategy is primary prevention of viral hepatitis, and in most countries this is already in place in the form of hepatitis B vaccination of newborns. Prevention of alcohol abuse and preventing the spread of hepatitis C virus (HCV) and metabolic syndrome are also relevant. Another important task is to prevent aflatoxin formation through proper care of crops and food storage. The next best approach is to increase awareness among the health-care community in order to promote surveillance of patients who are at risk and achieve earlier diagnosis and resection or ablation of small lesions.
Global prevalence and incidence
HCC is the sixth most common malignancy worldwide. It is the fifth most common malignant disease in men and the eighth most common in women. It is the third most common cause of death from cancer, after lung and stomach cancer.
HCC is the most common malignant disease in several regions of Africa and Asia. At least 300,000 of the 600,000 deaths worldwide occur in China alone, and the majority of the other 300,000 deaths occur in resource-challenged countries in sub-Saharan Africa. These devastating figures are most likely due to:
Other important factors include poor compliance, with inadequate or absent attendance in surveillance programs and thus late presentation of patients with large tumors; low awareness of the benefits of HCC treatment and ways of preventing underlying liver disease; and a negative opinion among some physicians about screening. In Japan, the United States, Latin America, and Europe, hepatitis C is the major cause of HCC. The incidence of HCC is 2–8% per year in patients with chronic hepatitis C and established cirrhosis. In Japan, the mortality from HCC has more than tripled since the mid-1970s. HCV infection is responsible for 75–80% of cases and hepatitis B virus (HBV) for 10–15% of cases. HCV-related HCC has been linked to blood transfusions in the 1950s and 1960s, intravenous drug use, and the reuse of syringes and needles. In many (but not all) countries, the spread of HCV is declining, but due to migration the disease burden has not changed.
In Asia, Africa, and in some eastern European countries, chronic hepatitis B is the prime cause of HCC, far outweighing the impact of chronic hepatitis C (Fig. 1). There are 300 million people infected with HBV, 120 million of whom are Chinese. In China and Africa, hepatitis B is the major cause of HCC; approximately 75% of HCC patients have hepatitis B.
Fig. 1 The worldwide geographic distribution of chronic hepatitis B virus infection
(source: Centers for Disease Control, 2006)
HCC is associated with liver disease independently of the specific cause of the disease:
The major risk factors for HCC are:
The risk of developing HCC in patients infected with HBV increases with:
The risk of developing HCC in patients infected with HCV and cirrhosis increases in combination with:
Signs that should raise a suspicion of HCC in patients with previously compensated cirrhosis:
Patients with late-stage HCC may present with:
Follow-up to assess the patient after therapy—to be performed every 3–6 months:
Referring for a specialist evaluation may help in:
Initial patient evaluation:
Ascitic fluid cytology may also be considered, despite its low sensitivity—it is simple and practicable in Africa.
Diagnostic tests (Table 1). Sufficient to establish a diagnosis of HCC is a combined finding of: the classic appearance on one of the imaging modalities—i.e., a large and/or multifocal hepatic mass with arterial hypervascularity; and elevated serum AFP, against a background of chronic (generally asymptomatic), generally cirrhotic-stage liver disease.
Table 1 Tests used to diagnose hepatocellular carcinoma
AFP, alpha fetoprotein; CT, computed tomography; MRI, magnetic resonance imaging.
Ultrasound imaging, CT, or MRI. Radiology and/or biopsy are the definitive diagnostic tools. Contrast-enhanced ultrasound may produce false-positive findings for HCC in patients with intrahepatic cholangiocarcinoma. AFP is an adjunctive diagnostic tool. A persistent AFP level of more than 400 ng/mL or a rapid increase in the AFP level may be a useful diagnostic criterion. In patients with lower AFP levels when radiology is not available, the diagnosis of HCC can only be made by clinical judgment. Even if options for treating HCC are absent or very limited, AFP testing and ultrasound imaging may be available.
A “cascade” is a hierarchical set of diagnostic, therapeutic, and management options for dealing with risk and disease, ranked by the resources locally available.
A gold-standard approach is feasible in regions and countries where liver transplantation is available for the treatment of HCC. Elsewhere, resection and/or local ablation are available, but not liver transplantation. What is it still possible to do in the various settings in which transplantation or resection and/or local ablation are available?
To answer this question, this guideline is structured on the basis of resource-sensitive cascades: for minimal-resource and medium-resource areas, the guideline discusses primary and secondary prevention, patient evaluation, and treatment options. For high-resource regions and countries, the guideline published by the American Association for the Study of Liver Diseases (AASLD) should be consulted.
Particularly when potentially curative treatment is unavailable, primary prevention is very important in reducing the risk of HCC (Table 2).
Table 2 Options for primary prevention of hepatocellular carcinoma
HBeAg, hepatitis B e antigen; HBIG, hepatitis B immune globulin.
* Deciding which individuals infected with hepatitis B or C require treatment is a complex issue that goes beyond the scope of this document.
Screening should be encouraged in regions in which it is possible to offer curative treatment for HCC. There is little point in carrying out mass screening of a population if the resources for further investigation and treatment are lacking. Screening should only be undertaken if at least one of these management options is available: liver transplantation, resection, transarterial chemoembolization (TACE), or ablation techniques. Treatment with acetic acid (vinegar) is used in some places.
One of the starting-points for screening is to identify asymptomatic patients with HCC. If patients have cancer symptoms at diagnosis, the outcome is not good and treatment is not likely to be cost-effective.
Appropriate treatment options that may or may not be beyond the scope of local medical facilities include:
Traditional chemotherapy has no place in the management of HCC. Patients should be offered symptomatic treatment when it is needed and possible.
When resection and/or local ablation are available for the treatment of HCC, there should be an emphasis on surveillance.
Primary prevention—i.e., hepatitis B vaccination of youngsters—is optimal in reducing the risk of HCC. Early diagnosis and treatment are essential for improving survival, but preventing recurrent HCC is still a major challenge.
HCC surveillance may improve early detection of the disease. Generally, treatment options are broader when HCC is detected at an earlier stage.
Screening for early detection of HCC is recommended for the groups of high-risk patients listed in Table 3.
Table 3 Criteria for hepatocellular carcinoma screening
Surveillance involves establishing screening tests, screening intervals, diagnostic criteria, and recall procedures (Table 4).
Table 4 Surveillance techniques
See the “Cautionary notes” under “Diagnosis” above.
Recurrent HCC may result from multicentric carcinogenesis or inadequate initial treatment. Prevention of HCC recurrence requires early diagnosis and complete removal of primary HCC lesions.
Currently, there is no proof of the efficacy of tertiary prevention of HCC with any agent, including chemotherapy, HBV and HCV therapy, or interferon (IFN).
The management of HCC is changing. In the developed countries, HCC patients are increasingly being evaluated and managed in specialized centers by multidisciplinary pathologists.
The Barcelona Clinic Liver Cancer (BCLC) staging system takes into account variables related to tumor stage, liver function, physical status, and cancer-related symptoms, and links these with treatment options and life expectancy. On the basis of the BCLC staging system, patients may classified as having:
After a diagnosis of HCC has been confirmed, liver function is one of the main factors in the treatment selection process; performance status and comorbid conditions need to be established.
Important aspects in assessing liver function are:
Treatment options largely depend on liver function, tumor size, and the presence or absence of metastatic lesions or vascular invasion. In most cases, curative treatments such as resection, radiofrequency ablation, or liver transplantation are not feasible, limiting the options to palliation. Screening of at-risk populations is therefore the only way of detecting tumors at a stage at which they are capable of being treated. Most of the treatment options are expensive and/or require specialized centers. Resection and local ablation are the treatment options most likely to be used in patients with HCC identified during surveillance in developing countries.
Both resection and ablation can allow a cure in small tumors.
Table 5 presents a recent description of treatments, their benefits in HCC, and levels of evidence, developed by an AASLD expert panel.
Table 5 American Association for the Study of Liver Diseases (AASLD) expert panel description of treatments, benefits, and levels of evidence in hepatocellular carcinoma
Source: Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698–711.
* Classification of evidence adapted from National Cancer Institute: www.cancer.gov. Study design: randomized controlled trial, meta-analysis = 1 (double-blinded 1i; nonblinded 1ii). Nonrandomized controlled trials = 2. Case series = 3 (population-based 3i; non–population-based, consecutive 3ii; non–population-based, nonconsecutive 3iii). End points: survival (A), cause-specific mortality (B), quality of life (C). Indirect surrogates (D): disease-free survival (Di), progression-free survival (Dii), tumor response (Diii).
† Although sorafenib may be unavailable for treatment in low-resource regions and countries, and perhaps even medium-resource ones, it has a proven impact that is as good as, or better than, many systemic cancer treatment options for other cancers.