Surveillance for hepatocellular carcinoma in patients with liver cirrhosis in India

Patients with liver cirrhosis of any aetiology are known to be at increased risk for developing hepatocellular carcinoma (HCC).[1,2] The risk of HCC development is particularly high in patients with chronic hepatitis B virus (HBV) or epatitis C virus (HCV) infection.[3,4,5] Diagnosis of this condition is often delayed till the tumour has become fairly large. Hence, in a majority of symptomatic patients diagnosed with HCC, no effective treatment is possible and survival is short.[6]

Existence of a well identified high-risk group and recognition that patients with HCC have a fairly long asymptomatic phase preceding the appearance of symptoms has resulted in the development of surveillance methods to detect HCC at an early stage among those with cirrhosis and/or HBV or HCV infection.[7] The issue however remains controversial, and several questions relating to efficacy and cost-effectiveness have still not been fully resolved. However, professional bodies in developed countries have issued recommendations supporting such surveillance.[8] This editorial attempts to place in perspective the role that such surveillance may have in India.

For this, it may be in order to develop the arguments sequentially as follows: (i) what is surveillance and what is its aim; (ii) what are the essential prerequisites for the use of surveillance; (iii) what are the available methods for early detection of HCC; (iv) what is the available evidence in favour of and against the use of surveillance for HCC worldwide; and finally, (iv) is the situation and experience in the Indian population any different from that elsewhere?

Screening and surveillance: definitions

Screening is traditionally defined as one-time application of a diagnostic test amongst asymptomatic individuals, in order to identify unrecognised early disease or precursors of disease. Surveillance, in comparison, refers to repeated application of such test(s) in the same person over a period of time. Screening or surveillance can be done either nonselectively in the general population (e.g. examining all newborns for congenital dislocation of hip joints, or breast self-examination or mammography in all women reaching a certain age) or in a select group that has a particularly high risk of developing a specific disease (e.g. those with family history of colon cancer and hence at increased risk of that cancer). These terms are also used for the application of a test in patients with a specific disease who are at increased risk of contracting another disease or of developing complications (e.g. in patients with colonic polyps, at risk of colon cancer).

When is surveillance useful?

The primary goal of screening or surveillance is not aimed merely at early detection of a disease condition but rather to improve outcome, such as reducing mortality, increasing survival time, improving quality of life or preventing complications, through effective early intervention. Thus, for a surveillance programme to be useful, several conditions must be met, some of which are as follows:

a) The disease or condition must be fairly frequent in the general population; alternatively, it should be possible to define a subpopulation, which is at high risk of developing the disease or complication and to which the surveillance strategy is aimed.

b) A test with high sensitivity for detection of the target disorder at an early stage must be available.

c) The test should have reasonably high specificity for the diagnosis of the target disorder; alternatively, another highly specific confirmatory test should be available.

d) The surveillance test and any follow-up tests needed for confirmation of diagnosis in those with a positive surveillance test should be fairly safe, free of serious adverse effects, and widely available.

e) The test should be able to diagnose a disease at a stagein which treatment is still possible and which is much more effective than when diagnosed in the non-surveillance population.

f) The surveillance test should be acceptable to the population at large.

Thus, for any surveillance programme to be introduced and sustained in the population, it is important that (i) the persons in whom the disease is detected early using the surveillance strategy have a better outcome using clinicallyrelevant endpoints, (ii) the monetary and resource costs of surveillance are low, (iii) that the subjects undergoing surveillance tests are not harmed physically or emotionally. Furthermore, the benefits should be demonstrable at the population level, and not merely at the individual level.

Assessment of effectiveness of a surveillance test is beset with several problems, namely, (i) referral bias (or volunteer bias; due to selective use of surveillance test by persons with a more healthy lifestyle), (ii) lead time bias, (iii) prognostic selection bias and (iv) overdiagnosis bias. Several excellent reviews have discussed these issues in detail.[9,10] These issues are also alluded to briefly below in relation to HCC.

Surveillance methods for HCC

The tests most commonly used for surveillance of HCC have included the measurement of tumour markers (such as alphafetoprotein [AFP]) in the serum and/or ultrasonography [US].7,8,11 In a systematic review of data from several published studies,12 the sensitivity rate of AFP (with a cut-off of >20 ng/mL) in patients with liver cirrhosis and small HCC ranged from 54% to 74% and specificity from 85% to 94%; the sensitivity rates of abnormal AFP were almost similar for medium and large size HCC. In comparison, sensitivity of US in detecting HCC varies with the size of the lesion, being 4-27%, 8-64% and 30-95%, for small, medium and large sized tumours, respectively. It also has much higher specificity (>90%).

Other tests such as computed tomography, and measurement of des-gamma-carboxy prothrombin and ratio of lectin-bound AFP (AFP-L3) to total AFP, have also been used for HCC surveillance; however, data on these are relatively limited.[12,13] Use of computed tomography repeated every 6-12 months for surveillance appears particularly inappropriate because of significant radiation exposure, problems related to the use of contrast medium in patients with liver cirrhosis, and high false-positive rate.[13]

The ideal surveillance interval is not known. A surveillance interval of 6-12 months has been proposed based on tumour doubling time. In the studies available till date, there is no clear evidence that surveillance at 6-month intervals is better than that at 12-month intervals.[14,15]

Effectiveness of surveillance programmes for HCC

Several initial studies showed that patients diagnosed with HCC during surveillance had smaller tumours that were more often amenable to treatment and lived longer than patients diagnosed with HCC during routine clinical care. However, such studies suffered from many types of biases, which are well recognised in screening studies. First, most of these initial studies suffered from lead-time bias, which is defined as an apparent improvement in survival due to early detection of a disease at screening/surveillance.[7] The lead-time bias arises from the fact that a significant length of time may elapse from the time a tumour becomes detectable by surveillance to it becoming symptomatic. Thus, even if surveillance has no effect on the outcome of HCC, the time period between the time of detection of HCC and death would appear to be longer in patients in whom HCC is diagnosed early due to surveillance than in those in whom it is diagnosed because of symptomatic disease, merely because the time point from which survival is measured has shifted. Second, surveillance programmes preferentially identify patients with more slowly progressive disease, who are likely to liver longer to start with (prognostic selection bias). Third, use of surveillance techniques may lead to mistaken diagnosis of HCC in some patients who do not really have this tumour (overdiagnosis bias) and thus would be expected to have better survival. Thus, the assessment of benefits of screening or surveillance programmes ideally requires large population-based randomised controlled studies.

A large randomised controlled trial of HCC surveillance using 6-monthly AFP and US has been reported from China, where incidence rates for this tumour are extremely high.[16] The study included 18,816 subjects (11,848 men; mean age 41.5 years) with history of chronic hepatitis, who were randomly allocated to ‘screening’ and ‘control’ groups (9373 and 9443 subjects, respectively) and followed for 38,444 and 41,077 person-years, respectively. Most study subjects (92%) had chronic hepatitis B. The screened group completed nearly 58% of the screening sessions offered. The group undergoing HCC surveillance was found to have a lower annual HCCrelated mortality rate of 83.2/100,000 population than the unscreened group (131.5/100,000 population), with a mortality rate ratio of 0.63 (95% confidence intervals = 0.41-0.98). However, unfortunately, the analysis did not use an intentionto-treat analysis, which is the recommended approach.

In another Chinese study, that included 5,581 men (aged 30-69 years) who were chronic hepatitis B carriers, surveillance was not associated with any reduction in mortality, despite diagnosis of a larger number of tumours at an earlier stage of disease.[17] This study used 6-monthly measurement of AFP as the screening modality. The failure to show a reduction in mortality in this study may be related either to a type II error, or to the fact that only a minority of the HCC detected at screening received effective treatment.

It must be noted that the above studies were in patients with chronic hepatitis and/or chronic hepatitis B virus infection, and not in patients with cirrhosis, the subject matter of this editorial.

Cost-effectiveness of HCC surveillance programmes

Cost-effectiveness of HCC surveillance programmes has been studied both directly and using mathematical models. In a prospective cohort study from Italy, surveillance using AFP and US at 6-month intervals was found to cost US$112,993 per life-year saved.[18] The authors concluded that their surveillance policy was too costly and did not offer commensurate survival benefit.[19,20,21] Most decision analysis models have shown surveillance for HCC to be cost-effective, often marginally, in resource-rich populations. In these analyses, incidence of HCC was one of the most important determinants of cost-effectiveness, and it is thus agreed that surveillance should be offered only if the risk of HCC in a particular group exceeds 1.5% per year.[13]

A recent systematic review has summarised the data on effectiveness, cost-effectiveness and cost-utility of surveillance of patients with cirrhosis (related to alcoholic liver disease, hepatitis B or hepatitis C), using periodic serum alphafetoprotein (AFP) testing and/or liver ultrasound examination, to detect hepatocellular carcinoma (HCC), followed by treatment with liver transplantation or resection.[12] It was estimated that surveillance using AFP and US at 6-month intervals would nearly halve the number of HCC-related deaths. However, the undiscounted lifetime cost of this surveillance strategy was 42,900 British pounds; only a small proportion of this was for the cost of screening tests, and most of it was accounted for by the cost of liver transplants and post-transplant care. The cost-effectiveness depended on the aetiology of liver cirrhosis. In a mixed aetiological disease model, even if policy-makers are prepared to pay over 60,000 pounds per QALY, offering US to those with elevated blood AFP was not cost-effective.

In the only randomised study showing significant reduction in HCC-related mortality with surveillance referred to above, the absolute reduction in annual HCC-related mortality rate was 48.3 deaths per 100,000 population.[16] This implies that more than 2000 person-years of surveillance would be needed to prevent one death due to HCC. The costs of this are likely to be enormous.

Further, one must keep in mind that cost-effectiveness data needs to be looked at in the context of a particular population. Thus, an intervention that is cost-effective in a high-income population may be out of reach of a population with limited resources.

Special issues related to HCC surveillance in India

Data on the incidence of HCC in the Indian population are quite limited. In the consolidated data from hospital-based cancer registries set up by the Indian Council of Medical Research, liver cancer was not amongst one of the top 10 sites of cancer in either gender group in any of the five sites.[22] In the data from population-based registries, the liver figured amongst the top 10 sites of cancer in men in only three and among women in none of the 6 registeries.[23] Based on such data, it has been suggested that HCC is an infrequent disease in India.[24,25]

There has been only one prospective study of the rate of occurrence of HCC in Indian patients with liver cirrhosis. In this study,[26] Paul et al enrolled 194 patients with liver cirrhosis of varied aetiology (selected from among 301 patients, after excluding those with pre-existing HCC), relatively preserved liver function (Child’s A or B) and no detectable HCC (using AFP, US and triple-phase computed tomography [TPCT]) and followed them prospectively for a mean period of 34.9 months. Each subject underwent serum alpha-fetoprotein measurement and abdominal ultrasonography every 6 months, and TPCT every year. In most patients, liver cirrhosis was related to HBV infection, HCV infection or both (36.6%, 27.8% and 6.2%, respectively). During a cumulative follow-up of 563.4 person-years, HCC was detected in 9 subjects, with an incidence rate of 1.60 (95% confidence interval 0.55-2.64) per person-year. All these 9 subjects had infection with HBV, HCV or both (4, 4 and 1, respectively). In 3 of these 9 patients, the tumour was so large at the time of the initial detection that even palliative treatment was not possible. In a related report from the same group, which is available only as an abstract,the cost per HCC diagnosed was too high for the Indian population to afford.[27]

The available data thus clearly show that the rather tenuous data on cost-effectiveness of surveillance for early detection of HCC in patients with liver cirrhosis further wither away when applied to the Indian situation. This is also likely to be true for other countries with low HCC incidence and low-income levels. Thus, there is little justification to undertake surveillance for HCC in Indian patients with cirrhosis. Our limited resources would achieve much more in terms of preventing HCC mortality if we were to use these to provide universal neonatal vaccination, an approach, which is not only highly cost-effective, but in fact money-saving in the long run.[28]

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