Gastroenterologie
a hepatologie

Surveillance of hepatocellular carcinoma in Slovakia

Svetlana Adamcová-Selčanová¹, Ľubomír Skladaný ^{Orcid.org  1}, Jana Čiefová¹, Sylvia Dražilová², Tomáš Koller ^{Orcid.org  3}, Peter Jarčuška ^{Orcid.org  4,5}, Miroslav Žigrai⁵

+ Affiliation
¹ HEGITO (Division of Hepatology, Gastroenterology and Liver Transplantation), Department of Internal Medicine II, Slovak Medical University, F. D. Roosevelt University Hospital, Banska Bystrica, Slovak Republic
² Oddelenie vnútorného lekárstva s JIS metabolickou, Nemocnica Poprad, a. s., Slovenská republika
³ Gastroenterologické a hepatologické oddelenie, V. interná klinika LF UK a UN Bratislava
⁴ I. interná klinika LF UPJŠ a UN L. Pasteura Košice, Slovenská republika
⁵ The working party of the Slovak Society of Hepatology

Summary

Background:
Certain trials have demonstrated that surveillance of hepatocellular carcinoma (HCC) lowers mortality via earlier dia­gnosis and therapy. We aimed to analyse surveillance performance in order to define targets for improvement.
Methods:
We retrospectively analysed consecutive patients (pts) ELIGIBLE for surveillance between January 2001 and December 2010, with three questions: 1. How many have had surveillance RECOMMENDED and 2. PERFORMED, and by which method and 3. with what outcome. We divided the pts into three groups by dia­gnosis of cirrhosis or HBV infection (ELIGIBLE), written recommendation for surveillance (RECOMMENDED) and ≥ 2 US or alpha-fetoprotein (AFP) exams six months apart (PERFORMED). We recorded the demographics, liver disease characteristics, ultrasound (US), AFP, new lesions, their size and mortality. We excluded patients without data for analysis.
Results:
We identified 445 and excluded 52 of the ELIGIBLE pts. The remaining 393 pts formed the RECOMMENDED group: 334 (85%) with cirrhosis, 59 (15%) with HBV infection. The median age was 55 years, 34% were females. The most prevalent aetiologies were alcohol-related liver disease (ALD, 46%), non-alcoholic steatohepatitis (NASH, 17%) and hepatitis C virus (HCV, 12%). Surveillance was PERFORMED in 322 (82%) of the RECOMMENDED pts by US only in 1%, AFP in 40% and US with AFP in 31% of the pts, respectively. New lesions were detected in 2.2% of the pts, aged 63.5 years (53–79), with diameter of 31.5 mm (9–120) in 8 surveillance pts and 75 mm (35–115) in 2 pts without surveillance (p = 0.296).
Conclusion:
This quality control study has shown that the uptake of HCC surveillance in pts with valid indication was suboptimal, the methods used deviated considerably from the guidelines and the diameter of newly-detected lesions was larger than would be required for surveillance to be effective.

Keywords

surveillance, abdominal ultrasound, hepatocellular carcinoma, alpha-fetoprotein

Introduction

Hepatocellular carcinoma (HCC) is the most frequent (90%) primary liver tumour and 16^th most common cause of death [1,2]. Among cancers, HCC ranks fifth in frequency, second or third as a global cause of death and first in the rate of increase in mortality, especially in the West and very probably in Slovakia (SK) – mostly due to its association with non-alcoholic fatty liver diseases (NAFLD) and alcohol-related liver disease (ALD) [3–5].
Slovakia belongs amongst the medium-incidence countries with 3 to 30 new cases per 100,000 inhabitants and is among those countries where incidence is on the rise [2,3,6–11]. In unresectable HCCs, five-year survival is less than 5% [12]. Finding HCC early is therefore crucial, while small, localised and early-stage tumours are amenable to better treatment options with better prognosis [13–16]. Although detection at an early stage remains the most important prognostic factor, less than 20% of the patients are dia­gnosed at a stage eligible for curative treatment options [17]. The method of choice to make the HCC dia­gnosis early is surveillance (SUR). Most scientific societies such as AASLD, EASL, APASL and Vete­ran Affairs, as well as the Slovak Society of Hepatology recommend surveillance in their guidelines [13,15,18–20]. While screening is defined as a one-time application of a test that allows the detection of a disease at a stage when intervention may improve the natural course and outcome, SUR is the repeated application of such a test over time [13]. The objective of both is to reduce disease-specific mortality [21,22]. Surveillance of HCC is a public health approach to i) a well-defined group of pts ii) at increased risk of HCC, by means of iii) a widely available and acceptable dia­gnostic method – abdominal ultrasound (US). Despite continuing debate, alpha-fetoprotein (AFP) has been discarded as a tool recommended for surveillance due to its small added value to the sensitivity of the US-only approach, its controversial impact on specificity and incremental cost [13,19,23,24]. The 6-month interval between US examinations is based on the data on the tumour doubling time and the cost effectiveness of US exam frequency [25,26]. According to valid guidelines operative during the interval of our study, the group at risk (ELIGIBLE) consisted of pts with i) liver cirrhosis of any aetiology and with ii) hepatitis B virus (HBV) infection plus additional characteristics [18].
In our previous study, we found that only 24% of 207 pts with HCC had been dia­gnosed by means of SUR [11]. These patients had smaller tumours (5.05 vs. 8.6 cm) and more favourable BCLC sta­ging (BCLC A 31% vs. 9%, p = 0.0002), than their counterparts with HCC dia­gnosed by other means [11]. However, the dia­meter of lesions discovered in the SUR group was still larger than that required for SUR to be fully effective [11,21,22].

Aim

We aimed to determine the downstream cascade of care from SUR eligibility to SUR effection to SUR quality in order to determine:

1. What proportion of pts fulfilling the indication criteria (ELIGIBLE) have actual­­ly received a written recommendation for SUR (RECOMMENDED).
2. What proportion had SUR actually PERFORMED).
3. Which modality of SUR was used – US, AFP or both.

Methods

At the liver unit (LU) of the tertiary referral centre serving the region with about 6 × 105 inhabitants we performed a retrospective study among SUR-ELIGIBLE pts to determine the PERFORMED-to-ELI­GIBLE ratio. Our standard practice at the LU has been to provide a written recommendation for SUR to all pts with a valid indication, with a clear note to use semi-annual US. We do not issue any remarks as to where/by whom SUR should be performed. We have followed up our patients at intervals determined mainly by the stage of cirrhosis, but at least once a year. We have conceived this study as a quality control procedure of the SUR process [18].
The study was carried out in accordance with the proceedings of the Declaration of Helsinki. All the patients have signed an informed consent. The study has a retrospective design, the data were anonymised in the database. The dataset for this observational study is available from the authors upon request.
One of the authors (JČ) performed the search of the institutional electronic database – Care Center® (NIS – CC), which was followed by a manual search of retrieved medical records. We included patients with liver cirrhosis of any aetiology and with chronic HBV infection without cirrhosis but with added characteristics according to the guidelines [15]. We used these two indications as key words for a search of the electronic database. We excluded patients with insufficient data and patients who were lost to follow-up. We enrolled patients for whom the first recommendation for surveillance fell in the 10-year interval between 1 January 2001 and 31 December 2010.
We accepted the dia­gnosis of liver cirrhosis as stated in the medical record when it was clearly established by an experienced hepatologist from the LU. The only prerequisite for the dia­gnosis of HBV infection was HBsAg positivity; we did not take into account bio­chemical, virological or histological activities. We defined SUR as at least two US and/or AFP exams performed 6 months apart. With the help of these definitions, we have created three groups which have enabled us to evaluate the process:

1. ELIGIBLE group (dia­gnosis of liver cir­rhosis or HBV infection with a clear indication for surveillance).
2. RECOMMENDED group (written recommendation for SUR in the medical records of ELIGIBLE patients). The recom­mendation usually read ’We recommend… performing surveillance at 6-month intervals by US’.
3. PERFORMED group (at least two surveillance procedures performed six months apart).

The variables included in the analysis were age, gender, aetiology of liver cirrhosis, Child Pugh class, US and AFP exams, newly detected HCC lesions, their size and mortality.

Results

We identified four hundred and forty- -five (445) pts with an indication for SUR (ELIGIBLE). In fifty-two of the ELIGIBLE patients (12%), we did not find a written recommendation for SUR in the medical records. The remaining 393 formed the RECOMMENDED group, of whom 334 (85%) had liver cirrhosis (22 caused by HBV infection) and 59 (15%) had chronic HBV infection without cirrhosis. The median age of the patients was 55 years (in a range of 22–83 years), females represented 34%. The primary aetiology of liver cirrhosis was ALD in 153 pts (46%), followed by NASH in 58 pts (17%), HCV infection in 39 pts (12%), autoimmune hepatitis in 25 pts (7%), HBV infection in 22 pts (7%), primary sclerosing cholangitis in 13 pts (4%), cryptogenic in 10 pts (3%), primary biliary cholangitis in 7 pts (2%) and other aetiologies in 7 pts (2%).
Despite written recommendations, SUR was not performed in 71 pts (18%) from the RECOMMENDED group (18%). Of the remaining 322 pts in whom SUR had been performed (which formed the PERFORMED group), the modalities of SUR were as follows: US only in 4 pts (1%), AFP only in 179 pts (40%) and US together with AFP in 139 pts (31%). Du­ring the follow-up period of 66 months (12–120), new lesions were detected in 10 of 393 pts from the RECOMMENDED group (2.2%); their median age was 63.5 years (53–79) (Tab. 1, Graphs 1, 2). The median diameter of newly detected lesions was 31.5 mm (9–120) in eight surveillance pts and 75 mm (35–115) in two pts without SUR (p = 0.296). Six of these 10 patients died during the study interval (Tab. 2).

Discussion

To the best of our knowledge, this is the first study on the performance of SUR from Central Europe. It shows that hepatologists at the tertiary referral centre had not been recommending surveillance in 12% (52 of 445) of the ELIGIBLE patients. Moreover, we found that SUR was not performed in 18% (71 out of 393) of the patients for whom it was recommended. Together, one in three eligible patients did not reach the process of surveillance. Of the remaining two-thirds, an inappropriate modality of surveillance (out of the guidelines) was used in almost three-quarters (71%) of the pts (AFP alone in 40% [179 of 322] and US plus AFP in 31% [139 of 322] of the pts). Moreover, the resultant size of newly detected lesions (31.5 mm) was beyond the threshold required for effective recall policy to be applied. Taken together, we consider the results of this quality control study as proof of the suboptimal performance of SUR as a public health measure. Indirect support of this notion comes from the single-centre analysis of the HCC cohort in which only 24% of the patients were dia­gnosed by SUR and the diameter of the newly  detected lesions in this group was more than 5 cm [11]. If left unnoticed, SUR will not be able to translate to its main aims: to dia­gnose HCC at an early stage, to increase uptake of radical therapies and to improve survival. On the other hand, experience from Italy and Japan shows a decreasing diameter of newly detected lesions by SUR over time [27]. Our results do not allow for deeper analysis of the reasons for the suboptimal performance of SUR [28,29], but it brings to light the main domains to work with in the region: to increase the awareness of SUR on the part of hepatologists, to increase the uptake of SUR after recommendation on the part of pts and to increase the sensitivity (detection rate) of US on the part of performing physicians.
There was a significant overuse of AFP either as the single dia­gnostic moda­lity (in 40% [179 out of 322]) or in combination with the US (in 31% [139 out of 322]). Whereas the second approach can be accepted, although it has been more expensive and falsely positive than US alone, the first is entirely unacceptable due to its low sensitivity and specificity (30). Although the cohort is small for this purpose, the number of newly detected lesions (2.5% [10 of 393 patients]) over the study period of 66 months (12–120) would support the allocation of Slovakia amongst low-medium incidence countries [9,10]. The median diameter of lesions (31.5 mm [9–120] [p = 0.296]) testifies to room for improvement in this segment of the process. In Slovakia, the US for SUR is performed by radiologists, ultrasound specialists, gastroenterologists and hepatologists, largely without specific training in liver cirrhosis and in SUR. Whether there is a difference in the detection rate between these specialties remains to be elucidated.
Our study has several limitations. It is a single-centre study with a limited follow-up period and a limited number of patients. For these reasons, we were unable to look in more detail at the relationships between age, sex, risk factors for HCC, aetiology of liver cirrhosis and outcome [31]. We think, however, that these limitations do not preclude the main conclusions.
The strength of our study lies in the fact that it is the first on the performance of SUR in the Central European region, and could serve as both a quality control measure and a pragmatic study.
Since SUR is considered a public health approach to increasing incidence disease with a long-term subclinical phase during which curative therapy and improved survival are possible, its performance is a matter of much interrest [32,33]. Moreover, if enlarged, our cohort can serve as the basis for the calculation of incidence-based cost effectiveness of SUR in our region; in lite­rature, the threshold incidence for SUR is controversial, depending on the aetiology of the liver disease and population studied, and varies from 0.5% to 2.6% [34]. Without more data on this subject, one cannot hope for more region-specific and personalised SUR recommendations [33,35–37].
Although reports on the underutilisation of SUR similar to ours are not exceptional, we have to study the barriers to effective SUR locally, for they are known to be region-, and population--specific [38,39]. Our study has already addressed one of the most frequently cited barriers – the lack of knowledge about SUR on the part of caregivers and patients [40].

Conclusions

The uptake of SUR in patients with valid indications is suboptimal. The met­hods used deviate considerably from the guidelines operative at the time of the study, and the diameter of newly-detected lesions is larger than required for SUR to be fully effective.

Acknowledgment

We would like to thank Professor Amit Singal for his kind review of the paper.

Submitted/Doručené: 22. 9. 2020
Accepted/Prijaté: 5. 10. 2020
 
Svetlana Adamcová Selčanová, MD, PhD.
HEGITO (Division of Hepatology,  Gastroenterology and Liver  Transplantation) of the Department  of Internal Medicine II,  Faculty of Medicine, Slovak Medical  University, FD Roosevelt Hospital,  Banska Bystrica
Ludvika Svobodu 1
974 01 Banska Bystrica
Slovakia
sselcanova@gmail.com

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