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Page 4 of 17 Chen et al. Hepatoma Res 2019;5:12 I http://dx.doi.org/10.20517/2394-5079.2019.03

Assuming that any disease or the carcinogenic process started at T , and developed before the time T , this
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evolution process (T - T) is undetectable. After the point T , the disease (cancer) is asymptomatic but can
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be detected, until the point T , when symptoms occur. This length of time (T - T) is called lead time, or
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“detectable preclinical phase” (DPP), and also “sojourn time”. In the absence of any screening test, a patient may
be diagnosed as an outpatient due to symptoms and/or signs, and then experiences a natural disease course
accompanying the process of healing and rehabilitation until the end of life (T - T). Obviously, screening cases
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will survive with “cancer” for an additional time (lead time: T - T); therefore, their full survival time will be
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(T - T) + (T - T) = T - T, which is “longer” than the survival time (T - T) of the outpatient cases. This “increase”
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in time essentially has no clinical significance for the patient, but it is artificially diagnosed earlier as a cancer.
However, the real purpose of screening is to enable timely treatment of cases that are diagnosed early, and hence
to prolong the time (T - T) benefit from the prompt treatment, whose increment is assumed to be Tx. Thus,
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the survival time of the cases after actual screening is (T - T) + (T - T) + Tx, or, T - T + Tx, where Tx is the
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patient’s real extension of survival length due to early detection and treatment.
MeANs Of sCReeNINg IMPleMeNTATION
It is possible to achieve the intended purpose of screening by mastering the principles of screening,
identifying the target population for screening, using appropriate tests/examination or diagnostic tools,
and relying on reliable and effective treatment. In terms of liver cancer screening, the evidence supporting
feasible means of screening in populations at-risk or of specific individuals are summarized as follows.
Major risk factors should be point of focus
Epidemiological studies have confirmed the main risk factors for liver cancer in China, and high-risk
areas as well as high-risk groups (populations) of liver cancer can be defined scientifically [5,16,19,41-44] . In
accord with recent understanding, the risk factors for primary liver cancer may be categorized into 3
groups [41,45] : (1) established factors: chronic HBV infection, chronic HCV infection, alcoholic cirrhosis,
dietary aflatoxins, tobacco smoking; (2) likely factors: diabetes mellitus, inherited metabolic disorders-α-
antitrypsin deficiency, hemochromatosis, porphyria cutanea tarda, cirrhosis of any etiology, obesity; and (3)
possible factors: decreased consumption of vegetables, oral contraceptives, high parity, ionizing radiation,
organic trichloroethylene solvent, clonorchis sinensis infection. However, as a population screening strategy,
it is impossible to consider all of these etiological factors or risk factors. Moreover, some characteristics
of disease or risk factors need to be confirmed in advance by specific test methods; in addition, factors
that are considered “established” and “likely” in some areas may only be “possible”, or even “not possible”
in other regions. For instance, liver fluke infection may be a “very likely” important risk factor for
cholangiocarcinoma (CC) in Southeast Asia and Guangdong-Guangxi regions [46,47] ; Hepatitis C virus (HCV)
is considered to be the established factors in many countries [48-50] , but these factors seem “impossible” in the
etiology of liver cancer in some regions such in Qidong, Jiangsu [41,51] . The other example is the nonalcoholic
fatty liver disease (NAFLD), which is becoming an increasingly important health issue nowadays in China,
[52]
with an overall pooled prevalence of 20.09% (17.95%-22.31%) . It is considered as an alarming important
[53]
risk factor of HCC development . Therefore, population screening in high-incidence areas should be
implemented in conjunction with the major local risk factors that can be easily identified within the general
population.

AFP could be used as a useful marker
AFP has been shown to be a sensitive and specific marker for screening [17,18,54-57] . In the early stage of liver
cancer, abnormal levels (> 20 μg/L) can be detected in serum, which can ensure that most patients with liver
cancer have a long enough DPP characterized with positive AFP even 2 years before the clinical presentation
[58]
of liver cancer . When an AFP cut-off of 20 μg/L is used, the sensitivity and specificity of AFP for HCC
were in the range of 41%-65% and 80%-95%, respectively [56,59-61] ; and the sensitivity and specificity of AFP
would be changed if the cut-off value is modified [56,62] . In Qidong’s screening program the sensitivity and