Surveillance for Hepatocellular Carcinoma Morris Sherman Surveillance for hepatocellular carcinoma (HCC) in pa- tients with recognized risk factors remains controver- sial. The populations for whom surveillance may be appropriate include all patients with established cirrho- sis, and hepatitis B (HBV) carriers, even in the absence of cirrhosis. However, even these risk groups can be stratified into patients with higher or lower risk. The most appropriate surveillance test is periodic ultra- sound examination, although the optimum screening interval has not been defined. Alphafetoprotein (AFP) is a poor surveillance test, lacking in sensitivity and specificity. There are no randomized controlled trials confirming that surveillance for HCC reduces disease- specific mortality. Modeling studies, however, have suggested that screening is cost-effective and reduces group mortality by a small amount. The criteria by which cancer surveillance programs in general can be judged have been described. Surveillance for HCC meets some of these criteria, but not all. In particular, more effective treatments have to be developed to improve the outcome of surveillance. Although there is no firm evidence to support the practice of surveillance for HCC, this has become common practice, forever preventing the definitive study from being performed. Nonetheless, surveillance is recommended in order to identify patients with small HCCs, who can be entered into trials of therapy of these tumors. Semin Oncol 28:450-459. Copyright 0 2001 by W.B. Sounders Company. C ANCER SURVEILLANCE remains a con- troversial topic. The efficacy of surveillance and early treatment is difficult to demonstrate for most established cancers. Breast cancer screening is a case in point. Large-scale randomized con- trolled trials of screening versus no screening have failed to show benefit.‘,2 Despite this there still are many advocates of regular mammography. Simi- larly, the efficacy of screening for prostate cancers remains uncertain.3 In contrast, screening for pre- neoplastic lesions, eg, colonic polyps, appears to be truly effective in reducing disease-specific mortal- ity.4 Screening (or more properly, surveillance) for From the University of Toronto and University Health Network, Toronto, Ontario, Canada. Address reprint requests to Morris Sherman, MBBch, PhD, FRCP(C) , Toronto General Hospital, EN9-223, 200 Elizabeth St, Toronto, Ontario M5G ZC4, Cunadu. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2805-0003$35.00/O doi:lO.J053/sonc.2001.26948 450 hepatocellular carcinoma (HCC) has become a standard feature of the management of patients with cirrhosis of various causes or who have chronic hepatitis B (HBV) infection. However, studies of surveillance for HCC so far reported have not addressed the crucial issue, which is whether surveillance decreases HCC-related mor- tality. There are no randomized controlled trials, nor are there adequate analyses of the costs, effi- cacy, and potential benefit. This article will criti- cally review the theoretical basis for undertaking surveillance for HCC, and discuss some practical aspects of HCC surveillance. CRITERIA FOR ESTABLISHING A SURVEILLANCE PROGRAM FOR HCC Prorok5 has delineated the criteria by which any screening/surveillance program can be judged. These include the following: (1) the disease must be common and have a substantial mortality and morbidity; (2) the target population must be easily identifiable, and there must be an expectation that the physicians caring for the population will ac- cept that screening is necessary and that the pop- ulation will answer the call for screening; (3) the screening test must have low morbidity, and high sensitivity and specificity; (4) there must be stan- dardized recall procedures; (5) the screening test must be acceptable to the target population; and (6) finally, and most important, there must be an acceptable and effective therapy. We will consider each of these criteria sepa- rately to determine how well surveillance for HCC adheres. We will not discuss therapy of HCC in any detail, nor will we discuss recall procedures, ie, what steps should be taken after a positive result has been found on a surveillance test. Both of these topics require separate consideration. Distinction Between Surveillance and Enhanced Follow-Up Strictly speaking, the term “surveillance” is re- served for undertaking diagnostic tests in a popu- lation at risk, but in whom there is no a priori reason to suspect the disease. In HCC surveillance the term is not appropriate for patients in whom macroregenerative nodules, particularly if they are “atypical” or dysplastic, have been identified. Seminon in Oncology, Vol 28, No 5 (October), 200 I: pp 450-459
Transcript
Surveillance for Hepatocellular Carcinoma
Morris Sherman
Surveillance for hepatocellular carcinoma (HCC) in pa-
tients with recognized risk factors remains controver-
sial. The populations for whom surveillance may be
appropriate include all patients with established cirrho-
sis, and hepatitis B (HBV) carriers, even in the absence
of cirrhosis. However, even these risk groups can be
stratified into patients with higher or lower risk. The
most appropriate surveillance test is periodic ultra-
sound examination, although the optimum screening
interval has not been defined. Alphafetoprotein (AFP)
is a poor surveillance test, lacking in sensitivity and
specificity. There are no randomized controlled trials
confirming that surveillance for HCC reduces disease-
specific mortality. Modeling studies, however, have
suggested that screening is cost-effective and reduces
group mortality by a small amount. The criteria by
which cancer surveillance programs in general can be
judged have been described. Surveillance for HCC
meets some of these criteria, but not all. In particular,
more effective treatments have to be developed to
improve the outcome of surveillance. Although there is
no firm evidence to support the practice of surveillance
for HCC, this has become common practice, forever
preventing the definitive study from being performed.
Nonetheless, surveillance is recommended in order to
identify patients with small HCCs, who can be entered
into trials of therapy of these tumors.
Semin Oncol 28:450-459. Copyright 0 2001 by W.B.
Sounders Company.
C ANCER SURVEILLANCE remains a con- troversial topic. The efficacy of surveillance
and early treatment is difficult to demonstrate for most established cancers. Breast cancer screening
is a case in point. Large-scale randomized con- trolled trials of screening versus no screening have failed to show benefit.‘,2 Despite this there still are
many advocates of regular mammography. Simi- larly, the efficacy of screening for prostate cancers remains uncertain.3 In contrast, screening for pre-
neoplastic lesions, eg, colonic polyps, appears to be truly effective in reducing disease-specific mortal-
ity.4 Screening (or more properly, surveillance) for
From the University of Toronto and University Health Network,
Toronto, Ontario, Canada.
Address reprint requests to Morris Sherman, MBBch, PhD, FRCP(C) , Toronto General Hospital, EN9-223, 200 Elizabeth St, Toronto, Ontario M5G ZC4, Cunadu.
Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2805-0003$35.00/O doi:lO.J053/sonc.2001.26948
450
hepatocellular carcinoma (HCC) has become a
standard feature of the management of patients with cirrhosis of various causes or who have chronic hepatitis B (HBV) infection. However,
studies of surveillance for HCC so far reported have not addressed the crucial issue, which is whether surveillance decreases HCC-related mor-
tality. There are no randomized controlled trials, nor are there adequate analyses of the costs, effi- cacy, and potential benefit. This article will criti- cally review the theoretical basis for undertaking surveillance for HCC, and discuss some practical
aspects of HCC surveillance.
CRITERIA FOR ESTABLISHING A
SURVEILLANCE PROGRAM FOR HCC
Prorok5 has delineated the criteria by which any screening/surveillance program can be judged. These include the following: (1) the disease must
be common and have a substantial mortality and morbidity; (2) the target population must be easily identifiable, and there must be an expectation that the physicians caring for the population will ac-
cept that screening is necessary and that the pop- ulation will answer the call for screening; (3) the screening test must have low morbidity, and high sensitivity and specificity; (4) there must be stan-
dardized recall procedures; (5) the screening test must be acceptable to the target population; and (6) finally, and most important, there must be an acceptable and effective therapy.
We will consider each of these criteria sepa- rately to determine how well surveillance for HCC adheres. We will not discuss therapy of HCC in any detail, nor will we discuss recall procedures, ie,
what steps should be taken after a positive result has been found on a surveillance test. Both of
these topics require separate consideration.
Distinction Between Surveillance and Enhanced Follow-Up
Strictly speaking, the term “surveillance” is re- served for undertaking diagnostic tests in a popu- lation at risk, but in whom there is no a priori reason to suspect the disease. In HCC surveillance the term is not appropriate for patients in whom
macroregenerative nodules, particularly if they are “atypical” or dysplastic, have been identified.
Seminon in Oncology, Vol 28, No 5 (October), 200 I: pp 450-459
SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA 451
These patients need close follow-up, although the
medical literature provides no guide as to how that follow-up should be undertaken, However, these patients should be removed from any discussion of surveillance, because they need a different sched-
ule of tests than patients in regular surveillance protocols.
The Disease Must Be Common and Must Have a Substantial Morbidity andlor Mortality
Although HCC is not a common cancer in North America, it is the fifth most common cancer in the world.6 Age-standardized incidence rates vary from 3 per 100,000 in North American men
to 80 per 100,000 in China.627 Whether these incidence rates make HCC a good candidate for surveillance can only be assessed in cost/efficacy analyses. These will be discussed later. The issues
concerning screening and surveillance will be more pertinent in Asia and Africa where HCC is common, but will also be important in North
America and Europe. HCC causes substantial morbidity and mortal-
ity. In the absence of early detection programs most subjects with HCC present late, with ad-
vanced incurable disease. The reported survival rates for untreated symptomatic HCC varies from 0% at 4 months to 1% at 2 years.s-10 The prognosis of small untreated HCC, ie, lesions which are the target of surveillance, is not well described. How-
ever 2-year survival in excess of 50% is not un- usua1.11j12
The Target Population Must Be Easily Identifiuiable
The target population for HCC screening in- cludes HBV carriers, patients with hepatitis C (HCV) and cirrhosis, as well as patients with cir- rhosis due to other forms of chronic liver disease.
It is worth considering the evidence for selection of these risk groups.
Hepatitis B. Many prospective and retrospec- tive studies have confirmed the causal relation ship between chronic HBV infections and the subsequent development of HCC. For example, a
prospective study of hepatitis reported by Beasley et a113,r4 included 3,454 male HBV carriers and 19,253 uninfected male controls. The relative risk of HCC in the HBV carriers was about lOO.ls The overall yearly incidence of HCC in the HEV sur- face antigen (HBsAg)-positive group was 0.5%, and was 1% at age 70. In cirrhotic HBV carriers,
the relative risk was 961. The incidence of HCC
in cirrhotics was 2.5% per year. Sakuma et all5 found the relative risk of HCC in male Japanese railway workers to be 50. The incidence of HCC
was 0.4% per year. Uncontrolled prospective studies have indi-
cated that the incidence of HCC in HBV carriers varies widely.i6-i9 Villeneuve et all6 found no tu-
mors in a cohort infected with HBV and followed for 16 years. McMahon et a117 reported an inci- dence of HCC of 0.26% in a study of HBV-
infected individuals in Alaska. Sherman et alus described an incidence of 0.46% in their cohort. Such widely differing results may be explained by the characteristics of the cohorts studied. The subjects reported by Villeneuve et all6 were rela-
tively young, with a mean age of only 46, com- pared to the older age of the cohorts reported in the other two groups.
Hepatitis C. Th ere are many retrospective and
prospective cohort analyses of HCV carriers. Al- most all the studies come to the same conclusion:
that there is a considerably increased risk of HCC, although the reported odds ratios vary consider- ab1y.20-22 Cirrhosis is almost a necessary precondi- tion for the development of HCC. There are no
prospective studies comparing the incidence of HCC in a population with HCV-induced cirrhosis versus noninfected individuals, so calculation of relative risk is not possible. However, retrospective
studies suggest that HCC is between 20 and 200 times more common in HCV-induced cirrhosis
than in noninfected persons. The incidence in these populations ranges from 1.3% to about 5% per year.20-22 It should be noted that these are all clinic-based studies. There are no population-
based data on the incidence of HCC in HCV carriers.
In two large recent prospective studies from
Japan in patients with cirrhosis due to viral hepa- titis, the relative risk of developing HCC was higher in patients with HCV infection compared to HBV infection.23224 The risk of HCC was also higher in cirrhotic patients coinfected with HBV and HCV compared to those infected with HBV or HCV alone.25
Cirrhosis. Cirrhosis, regardless of etiology, also appears to increase the risk of HCC. Sixty percent to 80% of patients who develop HCC have un- derlying cirrhosis. The annual risk of developing HCC in cirrhosis is between 1% and 6%.zsZz5-z9
452 MORRIS SHERMAN
Again, the wide range in reported incidence rates of HCC in cirrhosis reflects differences in age, gender, etiology, and duration of cirrhosis in the
groups studied. Other causes of cirrhosis. In cirrhosis of nonvi-
ral etiology, the link between the underlying dis ease and the development of HCC is less well established. Nonetheless, hemochromatosis,sO @I’ antitrypsin deficiency,31 and alcoholic cirrhosis32 do appear increase the risk of HCC significantly.
Several studies have shown that the risk of HCC is higher in patients with cirrhosis due to viral in- fection compared to nonviral causes,i4,16,26,27 al-
though a high rate of HCC has also been reported in patients with cirrhosis due to genetic hemo- chromatosis.30 In contrast, low incidence rates are seen in biliary cirrhosis.33
Other risk factors. Within these larger catego* ries there are subcategories in which the risk is
different than in the group as a whole. Increasing age and male sex are independent risk factors for HCC in the presence of cirrhosis.27334 The in- creased incidence of HCC with age in HBsAg
carriers shown by Beasley et alis~is has also been confirmed in several surveillance studies of HBV- positive individuals. 17219,~ In the Alaska study17 surveillance detected HCC at a rate of 0.2% per year in asymptomatic HBsAg-positive male carri-
ers less than 20 years of age, increasing to 1.1% in males aged over 50 years at the start of screening.
Similarly, the detection rate of HCC also increases with age in patients with chronic HBV infection35 and HBV-induced cirrhosis.19 No study has di- rectly addressed the question whether surveillance
for HCC could or should be restricted to individ- uals over a certain age limit, as is suggested for surveillance of colorectal carcinoma, while main-
taining the maximum benefit. Clearly, starting sur- veillance at a younger age, such as 30 years, would miss fewer tumors, but the ideal starting age that balances efficacy with cost has not been defined.
Selecting a target population. Thus, HBV carri- ers in general and HCV cirrhotics have an in- creased risk of HCC. Male gender and age at diagnosis of HBV infection increase the risk fur- ther. These factors can be used to define a target population for screening and surveillance. Cirrho-
sis may also be used as a diagnosis to further identify and refine selection of a target population
for surveillance. This presupposes that the diagno- sis of cirrhosis has been made by clinical or other
means. Unfortunately, undiagnosed cirrhosis is common in patients with viral hepatitis. One study reported that 56% of patients presenting with HCC had previously undiagnosed cirrhosis.36
Similarly, a Japanese study found that 20% of patients had previously undiagnosed cirrhosis,37
and thus would not have been recruited into a surveillance program if the presence of cirrhosis was used to define the target population. Further- more, cirrhosis may develop during follow-up and may still not be clinically apparent. Chiba et alss
showed that 44% of HCV carriers had cirrhosis at the time of recruitment.38 Seventeen percent of the patients with tumors that were diagnosed by surveillance over a median follow-up of 5 years
were not known to be cirrhotic at the time of entry into the study. The overall reported annual detec- tion rate of HCC in surveillance studies that in- cluded individuals with chronic active hepatitis in
addition to cirrhosis is 0.8% to 4.1%.26-28133239-41
The variation in incidence rates of HCC in these studies is a reflection of the varying percentage of individuals with chronic hepatitis and different etiologies between studies.
An alternate strategy has been proposed by Ganne-Carre et a1,42 who developed a scoring sys- tem to assess the risk of HCC. The method has been validated prospectively by the same group, but there are no independent reports of its efficacy.
There are also questions about whether the system is appropriate for patients with cirrhosis due to causes other than HCV or alcoholic liver disease.
Until better cost efficacy data become available the decision whether to enter a patient into sur- veillance becomes an individual decision on the part of the physician as to what level of risk is necessary to institute surveillance. For example, if
surveillance of male HBV carriers (relative risk loop is considered worthwhile, should female HBV carriers (relative risk lower, but not quanti- tated) also be subject to surveillance? In consider- ing surveillance of HBV carriers, variables to be
examined when selecting the target population also include the age at which surveillance should begin. Cirrhosis confers a much higher risk, but whether patients with hepatic decompensation should also be screened may depend on the avail- ability of liver transplantation as a form of therapy. In HCV infection one strategy may be to define all HCV carriers as the target population. Altema- tively, the target population may be defined as
SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA 453
only those with evidence of liver disease, even if
cirrhosis cannot be confirmed. A third strategy might be to restrict the target population to only those with diagnosed or suspected cirrhosis. Un- fortunately, at present there are no data regarding
either HBV or HCV to aid in the decision as to which of these groups or subgroups are most ap- propriate for surveillance.
The Screening Test Must Be Safe and Effective, and AcceI&Ie to the Target Po@ation
The most commonly used screening tests are serum alphafetoprotein (AFP) or ultrasonography.
The sensitivity and specificity of AFP as a diag nostic test, ie, when there is already a suspicion of HCC, will likely be better than when AFP is used as a screening test, ie, when there is no a priori
reason to suspect that HCC is present. In many reports of the performance characteristics of AFP and ultrasound, these tests are used as diagnostic examinations, or else the exact setting is not spec- ified, which makes it difficult to evaluate their
performance as screening tools. Since AFP levels increase with tumor growth,43 and since smaller tumors might be less likely to have diagnostic AFP levels, the performance characteristics of AFP as a
screening test are likely to be less beneficial than when used as a diagnostic test. Similar consider- ations apply to ultrasonography. Thus reports of
the performance characteristics of AFP or ultra- sonography have to be interpreted cautiously when applied to screening/surveillance.
The reported sensitivity of AFP for detecting HCC varies widely in both HBV-positive and
HBV-negative populations,ls,z6,29,40,43-45 possibly because of the confusion between diagnosis and screening. AFP is, however, not specific for HCC. Titers also rise with flares of active hepatitis. Of 44
HBV carriers with elevated AFP levels detected during surveillance, only six were found to have HCC on investigation44 and in 18 (41%) the raised AFP was associated with an exacerbation of underlying liver disease or changes in HBV repli-
cation status. DiBisceglie and Hoofnagle45 found that 25 of 29 AFP elevations in patients with chronic HBV infection were due to flares of in- flammatory activity, and only two were due to HCC.
Performance characteristics of AFP as a screen- ing test were reported in three studies.isJ9,+0 All
described the screening methodology well, and it
was clear that AFP was used for surveillance.
These studies report a sensitivity of 39% to 64%, a specificity of 76% to 91%, and a positive predic- tive value of 9% to 32%.
The poor sensitivity and specificity of AFP alone as a surveillance tool resulted in ultrasound scanning being used in addition to or in place of
AFP. The performance characteristics of ultra- sound as a screening test for HCC have been defined by Sherman et al’s in a study of healthy HBsAg carriers, and by Pateron et al29 in a sur-
veillance study of patients with cirrhosis. The sen- sitivity was 71% and 78%, respectively, and spec- ificity was 93%. The positive predictive value was
14% and 73%, respectively. It remains to be de- termined whether these performance characteris- tics make these efficient, economical tests for
HCC surveillance. Reported surveillance intervals vary from 3 to
12 months. However, reasons for choosing these intervals is often not reported. A 6-month surveil- lance interval may be a rational choice; based on
data from China in which tumor doubling time in asymptomatic HCC less than 5 cm was stud- ied.46,47 Sheu et a146 found a median tumor dou-
bling time of 117 days. AFP levels corresponded with tumor doubling time in 17 of 31 tumors studied. The most rapidly dividing tumor took 5
months to increase from 1 to 3 cm. Therefore every-&month surveillance provides a reasonable interval to reveal tumors growing from undetect- able to detectable size. It is also important to
realize that the surveillance interval is not related to the degree of HCC risk, but only to the rate of tumour growth.
There Must Be Standardized Recall Policies
Recall policies include deciding what consti- tutes a positive screening test, as well as how these
tests are to be further investigated. There is no literature to guide decision-making about which is the most appropriate way to deal with abnormal screening test results. Thus physicians undertaking
surveillance programs have to rely on their clinical judgment. The recall policies should be sensitive to the possibility of false-positive tests. For exam- ple, recall policies must minimize the use of addi- tional tests, particularly invasive ones, for patients with common nonmalignant lesions such as hem- angioma.
454 MORRIS SHERMAN
A variety of radiologic investigations have been
used to verify ultrasound findings and to confirm the diagnosis in patients with an isolated raised AFP. These include computed tomography (CT),
spiral CT, magnetic resonance imaging (MR)I, lipiodol-CT, and hepatic angiography. The overall sensitivity and specificity of contrast enhanced CT are 68% and 81%, respectively, but the sensitivity decreases for lesions less than 3 cm.48 Smaller
tumors are more efficiently detected by MRI, which has 81% sensitivity for tumors less than 2 cm.49 Spiral CT scanning is even more sensitive,
with 87% of tumors less than 1 cm being detected compared to 64% by MRI.sO Sensitivity can be improved by using more invasive radiologic tech-
niques such as lipiodol-CT scanning, where sensi- tivities of 93% to 97% have been reported.slJz Again, sensitivity decreases to 86% for tumors less than 1 cm. All of these radiologic techniques are
also subject to false-positive results. However, the literature does not provide good quantification of the rates at which false positive results occur.
The efficacy of various secondary radiologic im- aging techniques was compared in a study of 100 HCC smaller than 3 cm detected by combined
AFP and ultrasound screening. The comparative sensitivities of ultrasound, CT, angiography, and lipiodol-CT were 84%, 84% 81%, and 93%, re- spectively.52 The overall combined sensitivity and
specificity of ultrasound followed by two or more second-line radiologic imaging procedures was not addressed by this study (nor by any other studies).
The role of biopsy of hepatic lesions to confirm the diagnosis is controversial. Liver biopsy carries
a small risk of tumor spread along the needle
track.53 In addition, fine-needle aspirates of small tumors have a high false-positive rate because of the difficulty in distinguishing well-differentiated HCC cells from normal liver cells. This problem
arises most often in the differentiation of neoplas- tic nodules from macroregenerative nodules in a
cirrhotic liver, but also complicates evaluation of single nodules in noncirrhotic livers.
Adenomatous hyperplasia is a histologic diag-
nosis and has been defined as the presence of nodules containing normal hepatocytes and portal tracts (also known as a macroregenerative nodule [MRN] type 1).54 The term “atypical adenomatous hyperplasia” refers to the presence of atypical (dys- plastic) cells within the nodules and is known as a type 2 MRN.54 However, the diagnostic histologic
criteria for these two types of MRN is still contro- versial.55 MRN type 2 has been considered prema- lignant based on reports of finding microscopic HCC within such nodules56 and the coexistence of
HCC and MRN type 2 in the same liver.57 How- ever, in one study of 155 cirrhotic liver explants, 28% contained MRN. Both types of MRN were associated with an increased risk of coexistent
HCC. MRN was also found in livers not contain- ing HCC.s5 In a follow-up study of a selected group of patients posthepatectomy for HCC, seven
of 20 unresected MRN monitored for 1 to 5 years developed into HCC.58 A prospective study found that eight of 32 (25%) histologically proven MRN in 560 cirrhotics screened for HCC underwent
neoplastic transformation during follow-up.59 Al- though the development of HCC was more com- mon in MRN type 2 it was also seen in MRN type 1. It is therefore clear that MRN in some patients
appears to be premalignant, but at present it is not possible to predict which lesions will develop into tumors and thus specific therapy is probably not warranted. There are no data on how patients with
MRN, histologically proven or clinically sus- pected, should be monitored.
Screening/surveillance will result in patients re- quiring additional radiologic and other investiga- tions, incurring additional cost, to confirm the
diagnosis of HCC and to assess whether the lesion is potentially curable by surgery or other means. Unfortunately, none of the reported surveillance studies have described the additional investiga-
tions needed to confirm the presence of HCC, nor the amount of secondary imaging needed to ex- clude HCC identified by false-positive screening tests. This information is important for analyzing
cost-benefit and also determining the acceptability of surveillance to the target population. These investigations and any intervention for false-posi- tive results are associated with morbidity. These additional sources of morbidity have not been
evaluated in any of the reported surveillance stud- ies.
There Must Be Effective Therapy
For screening/surveillance to improve mortality there must be an effective therapy available. Fur* thermore, the therapy should be applicable to the majority of tumors found. This is not necessarily the case for HCC. There is no doubt that therapy
SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA 455
is effective in some, but the majority of patients
with HCC, even when found by surveillance, still die from their tumor.
Evaluation of the efficacy of different treatment modalities for HCC is difficult because of the dearth of randomized controlled trials. Potentially
curative forms of therapy include resection, liver transplantation, and ethanol injection or other forms of local ablation such a radiofrequency ab,
lation. Many of the reported studies have compared
surgical with nonsurgical therapy in groups of pa-
tients with different degrees of severity of liver disease, or tumors at different stages, or have com- pared results of resection of small tumors with results of resection of large tumors. These studies
are particularly difficult to interpret, because of lead-time bias. This is the apparent improvement in survival that is exclusively due to early detec- tion. Even if treatment in both arms were equally effective, or equally ineffective, such studies would
show improved survival in the small tumor group simply because of earlier diagnosis. The corollary of this statement is that in a nonrandomized, non-
matched study it is impossible to determine whether any improved survival in the early diag- nosis or small tumor group is due to treatment effect or to lead-time bias.
Screening Should Reduce Mortality From the Disease
Only controlled trials of surveillance versus no
surveillance can demonstrate a reduction in mor- tality from the disease. There are no randomized controlled studies of surveillance with mortality as the outcome. Few surveillance studies have re-
ported the clinical details of patients found to have HCC in sufficient detail to allow even a rough assessment of the effects of surveillance on survival. Data on the size of the tumors detected, age of the patient, degree of hepatic dysfunction, resectability of tumor, reasons for not considering
transplantation, definitive treatment, and out- come, including recurrence rates, are rarely all given. Several studies have attempted to compare
the clinical features of HCC detected by screening compared to symptomatic tumors and have shown that tumors detected through surveillance are smaller and more amenable to potentially curative therapy.cO-64 In a study from Japan 50% of tumors
detected through surveillance were less than 2 cm
in size compared to only 7% of unscreened HCC; consequently, more tumors in the screened group
were suitable for surgical resection60 Lai et aP3
also found a higher resectability rate (76%) in 17
HCC detected by screening compared to 47% in
191 symptomatic HCC. Improved survival follow-
ing surgical resection for asymptomatic HCC com-
pared to symptomatic tumor was also shown in a
study from Taiwan.62 This was again probably a
reflection of the fact that all the symptomatic
HCC were larger with a mean diameter of 10 cm
compared to 3 cm in the asymptomatic group. In a
similar report from Italy, 18 of 24 (75%) tumors
detected by surveillance were single and less than
3 cm in size compared to only 20 of 129 (15%) of
tumors not detected by surveillance.61 However,
these investigators did not say how the difference
in size affected the rate of curative therapy and
outcome. In all of these studies, the duration of
follow-up postresection was limited, 3 to 5 years,
making it difficult to ascertain if cure was
achieved. Furthermore, all are subject to lead/time
bias, again making it difficult, if not impossible, to
evaluate the results.
It is clear from looking at the outcome data from
specific surveillance studies that the tumor size at
diagnosis was not the only factor in the therapeu-
tic decision making. Unfortunately fewer than half
of the published surveillance studies report out-
come data. In a study from France only 7% of patients underwent hepatic resection, despite the
fact that 56% had small tumors.65 The overall
surgical resection rate reported in the remaining
studies was between 29% and 54%.62-64-69 The reason why hepatic resection was not undertaken
was mainly due to age, patient wishes, impaired
synthetic liver function due to cirrhosis, or a poor general medical condition.
This is another important consideration in eval-
uating the results of screening programs. Reports of
series of treated HCC do not include patients who
were not treated, ie, they are not intention-to-
treat analyses. However, the universe of HCC
detected on screening includes those treated and
not treated. Therefore it is a sine qua non that survival of patients with HCC in screening pro-
grams is going to be worse than in a reported series
of one or other form of therapy.
456 MORRIS SHERMAN
Efficacy of Published Screening and Surveillance Programs
A number of screening and surveillance pro- grams have been reported. The results range from
very optimistic, to downright pessimistic. McMa- hon et al screened 1,400 HBV carriers in Alaska, over a 5-year period, using AFP only as the screen-
ing test.‘7 AFP surveillance detected 15 tumors, 10 of which were resectable. After 5 years of follow- up, there were four recurrences (two patients had only been monitored to 2 years with no recur-
rence). In contrast, Sherman et al prospectively screened 1,069 HBV carriers for periods of 6 months to 5 years .is Over this period 14 tumors were detected. Seven were resectable, and six pa- tients actually underwent surgery. There were two postoperative recurrences and one postoperative
death. Only three patients survived beyond 2 years from diagnosis.
Two other studies have reported screening in HBV-positive individuals.35+ Both reported a higher proportion of HBV-related liver disease
than the previous studies. Lok et a144 screened 290 patients in Hong Kong (15% cirrhotic), and de- tected six tumors over a 4-year period.
A single study from China has been reported in which cluster sampling was used. Institutions were randomized to receive screening or not, and all of
the subjects within that institution were screened or not screened depending on the institution’s randomization assignment. Early results indicated no difference in the mortality between the
screened and unscreened groupJo
Modeling Outcomes
Results of modeling studies. If randomized con- trolled trials of HCC surveillance do not exist, and are unlikely to be established, how then can we
assess whether screening might be effective? In the absence of definitive studies, the best evidence for the efficacy of screening comes from examination
of disease models. Disease modeling can be per- formed by decision analysis and by Markov mod- eling, in which a theoretical cohort of subjects either remains in their current state of health, or develops a different state of health (eg, complica- tions of cirrhosis or HCC) at defined rates. These rates are derived from published studies, or ideally
from an actual cohort being followed. Modeling of this type has two outputs, efficacy of the interven-
tion, usually expressed as numbers of quality-ad- justed life years (QALYs) saved, and the cost of
the intervention, expressed as cost/QALY. Mod- eling has some advantages over experimental data, in that it can account for multiple variables,
whereas experimental studies can only deal with one or a limited number of variables before the sample size becomes unmanageable. However, the
major disadvantage of modeling is that it is depen- dent on the input data. If the input data is flawed, the model will be inaccurate+ To test plausible ranges of input data, a sensitivity analysis is con-
ducted. This identifies the factors that most se- verely affect the outcome of the analysis.
There are several published models of HCC screening. Sarasin et a171 undertook a Markov de-
cision analysis of screening a cohort of cirrhotics until the development of Child’s B cirrhosis, when screening stopped. Kang et a1T2 performed a deci- sion analysis of screening HBV carriers with AFP
and ultrasound. We have performed a Markov analysis of a HBV cohort, aged 30 years at the start of screening.73 All of these analyses found approx- imately similar results. Screening will prolong life in the cohort for about 3 months. This is seem-
ingly a trivial improvement in survival, but for a cohort of 1,000 subjects this translates to 250 years of life saved. Both Markov analyses showed that screening was always more expensive than no
screening, but that the costs per life-year gained were in the range considered cost-effective (<$50,000/1’f -y g 1 e ear ained) under basal asusmp- tions. However, several critical factors affected the
cost efficacy. If the incidence of HCC in the HBV cohort was less than 0.2%, or less than 1.3% in the cirrhotic cohort, screening became cost-ineffec-
tive. Similarly, if survival after therapy for HCC was less than about 50%, screening became cost- inefficient. Other important factors were the pro- portion of patients with small HCC who actually underwent treatment, and in the HBV cohort, the
age at onset of screening. The rate at which pa- tients accepted the call to surveillance, and the drop-out rate once entered into a surveillance pro- gram, were also important factors.
The compliance rate with surveillance has not been studied. There is no information on what proportion of an at-risk population will enter a
prospective surveillance program, but from per- sonal experience, most patients will accept screen- ing once the risks are explained. Perhaps more
SURVElLLANCE FOR HEPATOCELLULAR CARCINOMA 457
important is the drop-out rate. This too has not been well studied. However, what reports there are
suggest that the drop-out rate is lower in patient populations attending regular clinics than in the general population. For surveillance to be effec- tive, mechanisms have to be developed to ensure
long-term compliance. Modeling studies show that one critical factor
affecting the efficacy of surveillance is the inci-
dence of HCC. We can use this information to select the target population for HCC screening. Suitable populations would include all patients with HCV and male HBV carriers. Less clear is whether female HBV carriers or patients with cir-
rhosis of other etiology should also undergo sur- veillance, and at what age surveillance of HBV carriers should start. In the HCV population the
presence of cirrhosis should trigger surveillance. We have already discussed the problem of occult cirrhosis. Curley et al74 suggest that active hepa-
titis is also an additional risk factor for the devel-
opment of HCC. How this should be factored into the decision to offer surveillance is not yet clear.
Obstacles to tke Institution of an Effective Screening/Surveillance Program
Once surveillance for a disease has shown to be
effective other obstacles still need to be overcome before a successful surveillance program can be established. These obstacles relate to cost and the
acceptability of surveillance to the physician. In rural Africa and South East Asia where HCC
is common, surveillance is not readily available
largely because of general lack of facilities, and the cost involved in initiating such an program.
The literature contains scant information on the costs involved in screening for HCC. The cost analyses of HBV surveillance were based on actual
population-based studies rather than theoretical considerations.7zz75 Kang et a1T2 analyzed the cost* effectiveness of surveillance of HBV carriers for HCC and concluded that using AFP and ultra-
sound screening yearly would detect 90% of tu- mors early at a cost of US $11,800 per tumor detected. However, their study made assumptions about the size of tumors detectable through screen- ing based on presumed tumor growth rates that do not correlate with findings of surveillance studies. In a large mass screening study of 8,090 Japanese subjects, 70% of whom were at high risk with either a history of liver disease or of HBV or HCV
infection or a family history of HCC, 91 tumors were detected (1.1%) at a cost of US $25,000 per
tumor.75 However, the overall survival of the pa- tients found to have HCC was only 19% at 5 years. Thus, the cost per death prevented will be higher. Neither of these cost-benefit analyses included
postscreening diagnostic costs or reported the cost per life-year gained.
RATIONALE FOR OFFERING SURVEILLANCE
Given the uncertainty about the benefit of HCC surveillance, the question must be asked whether surveillance should be recommended at
all, particularly in this era of evidence-based med- icine. I believe there are two reasons for undertak- ing surveillance for HCC. First, we have to start
somewhere. Surveillance protocols cannot im- prove if no surveillance is being undertaken. Sec- ond, if progress in treating HCC is ever to be made
it will only come from treating small HCC, whether it be by transplantation, local ablation, chemotherapy, or some combination of treat- ments. In order to improve management of small
HCC it is essential to find small HCC and to undertake randomized controlled trials of treat- ment. Therefore one approach may be to accept
that surveillance cannot be fully evaluated, but to use the best available surveillance tools (currently ultrasound) to find small HCC, and to then deter-
mine the optimal treatment of these small tumors. This scenario would require that at-risk subjects undergo regular surveillance, but that when the small tumor is discovered subjects are entered into
randomized controlled trials of different forms of therapy. Given the low resectability rate and sur- vival after surveillance in most Western centers, this is the only way that continued surveillance
can be justified. The corollary of this statement is that if subjects do not have access to randomized controlled studies, surveillance should not be un- dertaken.
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