Surveillance for Hepatocellular Carcinoma in Patients With Cirrhosis

Ju Dong Yang; W. Ray Kim


Clin Gastroenterol Hepatol. 2012;10:16-21. 

In This Article

Areas of Uncertainty

Is Serum Alpha-Fetoprotein Beneficial?

There is broad agreement that serum AFP alone is inadequate as an independent tool for HCC surveillance and must not be used. For example, investigators of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial serially measured the serum AFP every 3 months before the diagnosis of HCC and reported that serum AFP has inadequate efficacy as a surveillance test. Many other studies investigating the performance of AFP were in the setting of diagnosis rather than surveillance, where pretest probabilities are higher and the performance of the test is overestimated. The biggest limitation of serum AFP, when used alone, is its low sensitivity. Whereas the test might be made sufficiently specific if a high cutoff value is used, modest elevations might be seen in patients with viral hepatitis especially hepatitis C, pregnant women, and in those with tumors other than HCC, most notably gonadal tumors. Thus, depending on the cutoff value, serum AFP has suboptimal sensitivity and/or specificity. More recent serum markers such as des-carboxy prothrombin and the ratio of lecithinbound AFP to total AFP are even less sensitive than AFP for the detection of early-stage HCCs and have not been shown to be useful for surveillance.

Compared with US alone, the combination of US and serum AFP might slightly enhance the sensitivity to detect an HCC lesion. A study from China showed that the combination of US and serum AFP increases the liver cancer detection rate by 9%. However, the combination was associated with a 2.4-fold increase in false positivity and a 2.2-fold decrease in the positive predictive value. A cost-effectiveness analysis performed in the United States showed abdominal US is most cost-effective, and addition of AFP to US in HCC surveillance provides a small gain at a significant increase in cost. This increase in cost stems not only from adding the cost of AFP testing but also from the expenses needed to investigate false-positive results. For this reason, the AASLD guideline recommends the use of US alone for the surveillance of HCC.

Despite these limitations of serum AFP, a recent study that used the Surveillance Epidemiology and End Results-Medicare database reported that the combination of serum AFP and US, followed by serum AFP alone, is most commonly used for HCC surveillance in the United States. The reality in practice is that AFP is widely available and inexpensive. Proponents point out that given the poor adherence to US-based surveillance, even a suboptimal test might still be better than complete lack of any surveillance. This might be more relevant in settings with limited health care access and resources, such as in Alaskan natives with chronic HBV infection in whom serum AFP was found to be beneficial.

How Often Should Tests be Repeated?

Most guidelines recommend surveillance to be conducted every 6 months. The principle for determining the interval for surveillance is that it should not be based on the anticipated incidence of HCC, but on the rate of tumor growth. Even if the incidence is high, if all of the tumors grow slowly, infrequent surveillance would be sufficient. On the other hand, if many tumors grow fast, frequent surveillance is needed for any hope of early diagnosis to exist. Thus, the absolute risk (incidence) of HCC determines whether surveillance should be performed, whereas the rate of tumor growth dictates the interval for surveillance.

It is currently uncertain whether surveillance every 6 months is superior to every 12 months in decreasing HCC mortality and improving patient survival ( Table 3 ). Several retrospective studies showed that there is no difference in survival between 6-month and 12-month surveillance intervals. However, the most recent study showed that surveillance every 6 months improved patient survival compared with that every 12 months. In short, to date, there is no robust evidence from a randomized controlled trial to determine the optimal surveillance interval. Most hepatologists tend to err on being more conservative with frequent (ie, semiannual) surveillance.


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