Advertisement

We need stronger evidence for (or against) hepatocellular carcinoma surveillance

  • Peter Jepsen
    Correspondence
    Corresponding author. Address: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200, Aarhus N, Denmark. Tel.: +45 2425 2944.
    Affiliations
    Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

    Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom
    Search for articles by this author
  • Joe West
    Affiliations
    Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom

    NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom
    Search for articles by this author
Published:January 16, 2021DOI:https://doi.org/10.1016/j.jhep.2020.12.029

      Summary

      Current guidelines from EASL recommend that most patients with cirrhosis are offered surveillance for hepatocellular carcinoma (HCC), but fewer patients than expected actually receive it. The recommendation is based on observational studies and simulations, not randomised trials. In this opinion piece we argue that a randomised trial of HCC surveillance vs. no surveillance is necessary and feasible, and we believe that clinician and patient participation in HCC surveillance would be better if it were based on trial results demonstrating its value.

      Keywords

      Linked Article

      • Before we can find an evidence base for HCC surveillance, we need to define our target demographic
        Journal of HepatologyVol. 75Issue 6
        • Preview
          We read with interest the expert opinion on surveillance for hepatocellular carcinoma by Jepsen and West.1 The authors propose that a randomized control trial of HCC surveillance vs. no surveillance is necessary and feasible; they postulate that clinician and patient involvement would be improved if trial results proved its benefit.
        • Full-Text
        • PDF
      • In search of an evidence base for HCC surveillance: Purity or pragmatism?
        Journal of HepatologyVol. 74Issue 5
        • Preview
          For decades, clinicians faced by a patient with advanced hepatocellular carcinoma (HCC) have felt helpless. The cancer had developed ‘silently’, causing no symptoms until it had spread widely or overwhelmed liver function and was no longer amenable to potentially curative therapy. Despite the recent ‘revolution’ in systemic therapies, leading investigators opined in 2019 that ‘although [new systemic agents] have the potential to improve outcomes, a survival increase of 2–5 months remains poor’.1 To clinicians, the obvious answer was to detect the cancer at a treatable stage by undertaking surveillance of patients perceived to be at highest risk, namely those with chronic liver disease at the stage of cirrhosis.
        • Full-Text
        • PDF
      See Editorial, pages 1025–1027

      Introduction

      I (PJ) clearly remember my meeting with John, a 57-year-old man, in the outpatient clinic. He had been diagnosed with alcohol-related cirrhosis 5 years earlier and was doing very poorly back then, but he had managed to quit alcohol and live a stable life, and his ascites was now a thing of the past. I would have discharged him from our outpatient clinic, had he not said that he was losing weight despite maintaining his usual diet. His wife confirmed this, and so we agreed to do an ultrasound examination to “make sure that nothing was amiss”. Of course, he had a hepatocellular carcinoma (HCC). It turned out to be multifocal and not amenable to any treatment with curative intent. I talked to the couple again, and they were understandably frustrated that we had been following him for years without noticing this cancer that was now going to kill him. Oh yes, I remember this conversation. And I am convinced that many of you reading this remember similar conversations from your practice. I am equally convinced that you do not remember quite so well the many patients you have seen whose ultrasound examination did not show an HCC, just as you forget the times when the ultrasound showed something that required additional CT scans before the patient was cleared of cancer suspicion. Studies from behavioural psychology have shown that we overestimate the occurrence of events that come easily to mind, such as an HCC that we might have diagnosed earlier.
      • Tversky A.
      • Kahneman D.
      Judgment under uncertainty: heuristics and biases. Biases in judgments reveal some heuristics of thinking under uncertainty.
      This pattern may explain why many hepatologists are in favour of HCC surveillance, and equally why hepatologists may be poorly positioned to judge the value of HCC surveillance.
      Current guidelines from EASL recommend that patients with cirrhosis are offered surveillance for HCC, with some exceptions.
      European Association for the Study of the Liver
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      It is well recognised that this recommendation rests on observational studies and simulations, not randomised trials. Fewer than expected patients with cirrhosis actually receive surveillance.
      • Wolf E.
      • Rich N.E.
      • Marrero J.A.
      • Parikh N.
      • Singal A.G.
      Utilization of hepatocellular carcinoma surveillance in patients with cirrhosis: a systematic review and meta-analysis.
      One solution has been to develop models to predict the individual patient’s risk of HCC, expecting that low-risk patients can be exempted from surveillance. We believe that there is a need for a randomised trial of HCC surveillance for the reasons we expound in this opinion piece.

      The purpose of HCC surveillance

      HCC surveillance aims to prolong survival by reducing deaths from HCC whilst simultaneously improving (or at least not decreasing) quality of life; it is hoped that surveillance allows an earlier HCC diagnosis and curative treatment. Yet, a United States study found that 27.5% of cirrhosis patients experienced harms during 3 years of HCC survival.
      • Atiq O.
      • Tiro J.
      • Yopp A.C.
      • Muffler A.
      • Marrero J.A.
      • Parikh N.D.
      • et al.
      An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis.
      While none of them died from those harms, they may have suffered a decrement in their quality of life.
      Leaving aside quality of life and focusing on survival, HCC surveillance will provide the greatest benefit to those whose rate of HCC development (rate 1→2 in Fig. 1) is high compared with their rate of death without HCC (rate 1→4), such as a 50-year-old man with compensated cirrhosis due to hepatitis C who is otherwise healthy. By extension, HCC surveillance provides the least benefit to those whose rate of death without HCC is much higher than their rate of HCC development, or whose rate of death from other causes after HCC diagnosis (rate 2→4) far outweighs their rate of death from HCC (rate 2→3). This view is recognised by the EASL guidelines which state that patients’ life expectancy and ability to tolerate potentially curative treatment should be taken into consideration when offering surveillance.
      European Association for the Study of the Liver
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      Figure thumbnail gr1
      Fig. 1Disease model for HCC surveillance.
      There are 4 states and 4 transitions between them indicated by arrows. The intensity with which a transition occurs is expressed as a rate, and the probability of making a specific transition is expressed as a risk. A transition from state 2 to state 1 is possible with curative treatment (or spontaneous regression) of HCC, but it is not necessary for the discussion and therefore not in the figure. HCC, hepatocellular carcinoma.

      Problems with current evidence for HCC surveillance

      We rely on observational studies

      A well-conducted randomised trial provides an unbiased and unconfounded estimate of the average effect that we can expect from offering HCC surveillance to our patients. As a rule, regulatory bodies insist that clinical interventions are shown to be net beneficial in at least 1 well-conducted randomised clinical trial before they are adopted into clinical practice. HCC surveillance comes with benefits, harms, and costs – just like any other intervention. We are wrong to think that HCC surveillance is the default, and that the burden of proof is on those who question the benefits of surveillance.
      • Singal A.G.
      • Lok A.S.
      • Feng Z.
      • Kanwal F.
      • Parikh N.D.
      Conceptual model for the hepatocellular carcinoma screening continuum: current status and research agenda.
      ,
      • Sherman M.
      Surveillance for hepatocellular carcinoma.
      Studies without randomisation are prone to bias and uncontrolled confounding.
      • Sørensen H.T.
      • Lash T.L.
      • Rothman K.J.
      Beyond randomized controlled trials: a critical comparison of trials with nonrandomized studies.
      ,
      • Singal A.G.
      • Lampertico P.
      • Nahon P.
      Epidemiology and surveillance for hepatocellular carcinoma: new trends.
      Fortunately, randomised trials typically reach the same conclusions as the observational studies that have gone before them, but there have been notable examples where a medical practice established without a randomised trial was stopped or even reversed when a randomised trial was finally conducted.
      • Prasad V.K.
      • Cifu A.S.
      Ending medical reversal.

      We trust the ‘1.5% risk per year’ limit, but are not sure what it means

      Current guidelines for HCC surveillance and many review articles state that HCC surveillance is cost-effective if the HCC risk exceeds 1.5% per year.
      European Association for the Study of the Liver
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Marrero J.A.
      • Kulik L.M.
      • Sirlin C.B.
      • Zhu A.X.
      • Finn R.S.
      • Abecassis M.M.
      • et al.
      Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases.
      ,
      • Kanwal F.
      • Singal A.G.
      Surveillance for hepatocellular carcinoma: current best practice and future direction.
      This conclusion can be traced to a simulation study from 1996,
      • Sarasin F.P.
      • Giostra E.
      • Hadengue A.
      Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis.
      but we find the statement problematic for 2 reasons. First, the 1.5% per year statement has been repeated so many times that its perceived validity is much higher than its true validity; studies that find an HCC risk above 1.5% per year often claim that HCC surveillance is therefore beneficial in their population.
      • Ganne-Carrie N.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Nomogram for individualized prediction of hepatocellular carcinoma occurrence in hepatitis C virus cirrhosis (ANRS CO12 CirVir).
      • Ganne-Carrie N.
      • Chaffaut C.
      • Bourcier V.
      • Archambeaud I.
      • Perarnau J.M.
      • Oberti F.
      • et al.
      Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis.
      • Nilsson E.
      • Anderson H.
      • Sargenti K.
      • Lindgren S.
      • Prytz H.
      Risk and outcome of hepatocellular carcinoma in liver cirrhosis in southern Sweden: a population-based study.
      • Kanwal F.
      • Kramer J.R.
      • Asch S.M.
      • Cao Y.
      • Li L.
      • El-Serag H.B.
      Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
      Second, we have not been able to determine from the 1996 simulation study or its references whether simulations assumed an HCC risk of 1.5% per year or an HCC rate of 1.5 per 100 person-years. The latter is often presented as a “rate of 1.5%”, and because many authors use “rate” and “risk” interchangeably,
      • Kanwal F.
      • Singal A.G.
      Surveillance for hepatocellular carcinoma: current best practice and future direction.
      the true meaning is often lost. It is of crucial importance whether researchers mean “rate” (events per person-years of observation) or “risk” (probability of experiencing event), as the risk of HCC depends on the rate of HCC development and the rate of death without HCC (Fig. 1).
      • Andersen P.K.
      • Perme M.P.
      • van Houwelingen H.C.
      • Cook R.J.
      • Joly P.
      • Martinussen T.
      • et al.
      Analysis of time-to-event for observational studies: guidance to the use of intensity models.
      Table 1 uses simulations to show how the risk of HCC varies in response to changes in the rate of death without HCC when the HCC rate is held constant at 1.5 per 100 person-years.
      • Morina D.
      • Navarro A.
      Competing risks simulation with the survsim R package.
      The rate of death without HCC among patients with cirrhosis was between 10 and 18 per 100 person-years in studies from the United States, England, and Sweden.
      • Orman E.S.
      • Roberts A.
      • Ghabril M.
      • Nephew L.
      • Desai A.P.
      • Patidar K.
      • et al.
      Trends in characteristics, mortality, and other outcomes of patients with newly diagnosed cirrhosis.
      • Ratib S.
      • Fleming K.M.
      • Crooks C.J.
      • Aithal G.P.
      • West J.
      1 and 5 year survival estimates for people with cirrhosis of the liver in England, 1998-2009: a large population study.
      • Nilsson E.
      • Anderson H.
      • Sargenti K.
      • Lindgren S.
      • Prytz H.
      Clinical course and mortality by etiology of liver cirrhosis in Sweden: a population based, long-term follow-up study of 1317 patients.
      We are wrong to think that an HCC rate of 1.5 per 100 person-years therefore means that the risk of HCC is 1.5% after 1 year, 5∗1.5% = 7.5% after 5 years, etc. We must incorporate the rate of death without HCC into our computation of HCC risk, particularly when the rate of death without HCC is high (Table 1). The solution is simple: be accurate when it comes to rate or risk; do not express a rate as a percentage; and use the cumulative incidence function to compute HCC risk, not the Kaplan-Meier function.
      • Jepsen P.
      • Vilstrup H.
      • Andersen P.K.
      The clinical course of cirrhosis: the importance of multistate models and competing risks analysis.
      Table 1Results of simulation studies to demonstrate how the incidence rate of death without HCC affects the risk of HCC, assuming a constant incidence rate of HCC.
      Incidence rate of HCCIncidence rate of death without HCCCumulative risk of HCC
      After 1 yearAfter 5 yearsAfter 10 years
      1.50
      If we use the Kaplan-Meier method instead of the cumulative incidence function to compute the cumulative risk of HCC, we are by definition assuming that the incidence rate of death without HCC is zero. HCC, hepatocellular carcinoma.
      1.5%7.3%14.0%
      1.51.51.5%6.9%13.0%
      1.561.5%6.3%10.5%
      1.5151.4%5.0%7.2%
      1.5241.3%4.2%5.4%
      Incidence rates are per 100 person-years. Note that the risk of HCC goes down as the incidence rate of death without HCC goes up. If we mistakenly assume that an incidence rate of 1.5 per 100 person-years equals a risk of 1.5% per year, so that the 5-year risk is 5∗1.5% = 7.5% and the 10-year risk is 15%, we will overestimate the true risk substantially when the incidence rate of death without HCC is high.
      If we use the Kaplan-Meier method instead of the cumulative incidence function to compute the cumulative risk of HCC, we are by definition assuming that the incidence rate of death without HCC is zero. HCC, hepatocellular carcinoma.

      We do not know how HCC surveillance affects quality of life

      It is possible that HCC surveillance reduces patients’ quality of life. Maybe surveillance burdens patients with frequent reminders of a looming cancer, the need to travel to the hospital, false-positive screening tests, or futile screening examinations offered to those who would not benefit from an early HCC diagnosis. Alternatively, maybe they feel reassured by the screening examinations, and maybe the biannual hospital visits are a welcome opportunity to get help with non-HCC health issues. At present we do not know how HCC surveillance affects quality of life, and the decision to recommend HCC surveillance should be based on the effects on survival and on quality of life.
      World Health Organization
      Screening programmes: A short guide. Increase effectiveness, maximize benefits and minimize harm.
      A randomised trial could tell us both and indeed is being attempted in another situation that is similar to HCC surveillance, namely Barrett’s oesophagus.
      • Old O.
      • Moayyedi P.
      • Love S.
      • Roberts C.
      • Hapeshi J.
      • Foy C.
      • et al.
      Barrett's Oesophagus Surveillance versus endoscopy at need Study (BOSS): protocol and analysis plan for a multicentre randomized controlled trial.

      We have given up on randomisation on the basis of a single patient survey

      It has been argued that patients would not be willing to participate in a randomised trial because they insist on undergoing surveillance.
      • Kanwal F.
      • Singal A.G.
      Surveillance for hepatocellular carcinoma: current best practice and future direction.
      This argument rests on a survey of 205 Australian patients with Child-Pugh class A or B cirrhosis.
      • Poustchi H.
      • Farrell G.C.
      • Strasser S.I.
      • Lee A.U.
      • McCaughan G.W.
      • George J.
      Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.
      The participants in this study were given verbal information and a written decision aid to guide their decision to participate in a trial of HCC surveillance vs. no surveillance. As many as 204 (99.5%) said they would not participate, the vast majority because they preferred surveillance. We have 2 concerns. First, the decision aid was biased in favour of HCC surveillance. There is no mention of harm except that a figure on the second-last page mentions the possibility of “inconvenience of clinical visits, ultrasounds and other tests every 6 months” and of “anxiety from false positive result” (without explaining what a “false positive result” is). The figure is preceded by pages stating, in our view, that a survival benefit from HCC surveillance is plausible although not guaranteed.
      • Poustchi H.
      • Farrell G.C.
      • Strasser S.I.
      • Lee A.U.
      • McCaughan G.W.
      • George J.
      Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.
      The content of information leaflets has been hotly debated in other screening programmes.
      • Bewley S.
      The NHS breast screening programme needs independent review.
      Second, as a field, we must do better than giving up on a randomised trial of HCC surveillance on the basis of a single survey.

      Prediction models do not address the core question and can be hard to interpret

      Several studies have developed prediction models that stratify patients with cirrhosis by their HCC risk,
      • Ganne-Carrie N.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Nomogram for individualized prediction of hepatocellular carcinoma occurrence in hepatitis C virus cirrhosis (ANRS CO12 CirVir).
      ,
      • Sharma S.A.
      • Kowgier M.
      • Hansen B.E.
      • Brouwer W.P.
      • Maan R.
      • Wong D.
      • et al.
      Toronto HCC risk index: a validated scoring system to predict 10-year risk of HCC in patients with cirrhosis.
      • Ioannou G.N.
      • Green P.
      • Kerr K.F.
      • Berry K.
      Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.
      • Fan R.
      • Papatheodoridis G.
      • Sun J.
      • Innes H.
      • Toyoda H.
      • Xie Q.
      • et al.
      aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.
      • Audureau E.
      • Carrat F.
      • Layese R.
      • Cagnot C.
      • Asselah T.
      • Guyader D.
      • et al.
      Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status.
      but they cannot answer the question of whether the resulting high-risk group (or the low-risk group) benefits from HCC surveillance. Of course, the studies have value nonetheless, and they are indispensable in the planning stages of a randomised trial.
      Prediction models have identified several correlates of cirrhosis severity as risk factors for HCC, along with male gender and increasing age. However, most of the studies used Cox regression to identify risk factors, so they have in fact identified predictors of the rate of HCC development,
      • Ganne-Carrie N.
      • Layese R.
      • Bourcier V.
      • Cagnot C.
      • Marcellin P.
      • Guyader D.
      • et al.
      Nomogram for individualized prediction of hepatocellular carcinoma occurrence in hepatitis C virus cirrhosis (ANRS CO12 CirVir).
      ,
      • Sharma S.A.
      • Kowgier M.
      • Hansen B.E.
      • Brouwer W.P.
      • Maan R.
      • Wong D.
      • et al.
      Toronto HCC risk index: a validated scoring system to predict 10-year risk of HCC in patients with cirrhosis.
      • Ioannou G.N.
      • Green P.
      • Kerr K.F.
      • Berry K.
      Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.
      • Fan R.
      • Papatheodoridis G.
      • Sun J.
      • Innes H.
      • Toyoda H.
      • Xie Q.
      • et al.
      aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.
      not the risk.
      • Sutradhar R.
      • Austin P.C.
      Relative rates not relative risks: addressing a widespread misinterpretation of hazard ratios.
      What matters for decisions about HCC surveillance is the risk of HCC development. Again, this risk depends on the rate of HCC development and the rate of death without HCC, and prediction studies must consider both rates in their analysis.
      • Andersen P.K.
      • Perme M.P.
      • van Houwelingen H.C.
      • Cook R.J.
      • Joly P.
      • Martinussen T.
      • et al.
      Analysis of time-to-event for observational studies: guidance to the use of intensity models.
      ,
      • Jepsen P.
      • Vilstrup H.
      • Andersen P.K.
      The clinical course of cirrhosis: the importance of multistate models and competing risks analysis.
      ,
      • Austin P.C.
      • Lee D.S.
      • D'Agostino R.B.
      • Fine J.P.
      Developing points-based risk-scoring systems in the presence of competing risks.
      • Latouche A.
      • Allignol A.
      • Beyersmann J.
      • Labopin M.
      • Fine J.P.
      A competing risks analysis should report results on all cause-specific hazards and cumulative incidence functions.
      • Andersen P.K.
      • Geskus R.B.
      • de Witte T.
      • Putter H.
      Competing risks in epidemiology: possibilities and pitfalls.
      The ideal patients for HCC surveillance are those who possess a characteristic with a strong positive effect on the rate of HCC development and a negative or small effect on the rate of death without HCC. Male gender is such a characteristic.
      Table 2 shows results of simulation studies illustrating the effects of hypothetical risk factors on the rate of HCC development and on the rate of death without HCC.
      • Morina D.
      • Navarro A.
      Competing risks simulation with the survsim R package.
      One of those risk factors (#1) could be male gender, with its roughly 3-fold increase in HCC rate and null effect on death without HCC,
      • Sharma S.A.
      • Kowgier M.
      • Hansen B.E.
      • Brouwer W.P.
      • Maan R.
      • Wong D.
      • et al.
      Toronto HCC risk index: a validated scoring system to predict 10-year risk of HCC in patients with cirrhosis.
      • Ioannou G.N.
      • Green P.
      • Kerr K.F.
      • Berry K.
      Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.
      • Fan R.
      • Papatheodoridis G.
      • Sun J.
      • Innes H.
      • Toyoda H.
      • Xie Q.
      • et al.
      aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.
      others resemble increasing age or decompensation with their increasing effects on both the rate of HCC and the rate of death without HCC. Clearly, the effect of an HCC risk factor on the risk of HCC depends on the factor’s effects on both possible outcomes (HCC and death without HCC). One suggestion to facilitate the interpretation of prediction models is to use Fine & Gray regression instead of Cox regression.
      • Austin P.C.
      • Lee D.S.
      • D'Agostino R.B.
      • Fine J.P.
      Developing points-based risk-scoring systems in the presence of competing risks.
      Table 2Results of simulation studies to illustrate the effects of hypothetical risk factors that affect the hazard ratio of both competing events on the 5- and 10-year relative risks of HCC.
      Hypothetical risk factorHazard ratio of HCC development for patients with vs. without risk factorHazard ratio of death without HCC for patients with vs. without risk factor5-year relative risk of HCC for patients with vs. without risk factor10-year relative risk of HCC for patients with vs. without risk factor
      #1312.792.72
      #2322.301.91
      #3331.881.42
      #4211.901.87
      #5221.511.28
      #6231.270.96
      Risk factor #1 could be male gender, and risk factor #5 could be clinically significant portal hypertension. In these simulations the incidence rate of death without HCC is 10 per 100 person-years, and the incidence rate of HCC is 1 per 100 person-years. Note that the effect of a risk factor on the relative risk of HCC depends on that risk factor’s effect on both competing events. The relative risks are only weakly affected by the incidence rate of HCC: If it is increased from 1 to 2 per 100 person-years, the 10-year relative risk for risk factor #5 increases from 1.28 to 1.30. They are more strongly affected by a change of the incidence rate of death without HCC: If that rate is increased from 10 to 20 per 100 person-years, the 10-year relative risk for risk factor #5 decreases from 1.28 to 1.08. HCC, hepatocellular carcinoma.

      We need a randomised trial of HCC surveillance

      It is likely that some patients with cirrhosis can expect substantial benefit from HCC surveillance, while others can expect substantial harm; we just do not know which patients fall into which group. Clinical equipoise exists somewhere between these extremes, i.e. there are patients whom we would expect to have a fifty-fifty chance of experiencing net harm or net benefit. It is our hope that we can reach a consensus on who these equipoised patients are in terms of, for example, underlying chronic liver disease, severity of cirrhosis, gender, age, comorbidities, and frailty. Then we should include these patients in a randomised trial of HCC surveillance vs. no surveillance. Such a trial could give us all the information we need about benefits, harms, and costs so that an informed decision can be made by patients, clinicians and policy makers on whether or not to take up, deliver or invest in a surveillance programme. It would also avoid the complexities of rates and risks and competing outcomes, as we would simply be comparing all-cause mortality between those under surveillance and those not. There are, however, obstacles to such a trial.

      Sample size

      Recently, a randomised trial of CT-based surveillance for lung cancer in men aged 50 to 74 years with a smoking history found no effect on all-cause mortality: After 10 years of follow-up, the 13,195 participants randomised to surveillance vs. no surveillance had all-cause mortality rates of 13.93 vs. 13.76 per 1,000 person-years, for a rate ratio of 1.01 (95% CI 0.92 to 1.11). The authors’ conclusion, however, focused exclusively on the rate ratio for lung cancer-related mortality (0.76, 95% CI 0.61 to 0.94), which was the primary outcome.
      • de Koning H.J.
      • van der Aalst C.M.
      • de Jong P.A.
      • Scholten E.T.
      • Nackaerts K.
      • Heuvelmans M.A.
      • et al.
      Reduced lung-cancer mortality with volume CT screening in a randomized trial.
      A randomised trial of HCC surveillance must study all-cause mortality as the primary outcome; it is far more relevant to the patient than HCC-related mortality. Moreover, it can be difficult to determine whether a patient died from HCC or from cirrhosis. Algorithms to define HCC-related death exist,
      • Moon A.M.
      • Weiss N.S.
      • Beste L.A.
      • Su F.
      • Ho S.B.
      • Jin G.Y.
      • et al.
      No association between screening for hepatocellular carcinoma and reduced cancer-related mortality in patients with cirrhosis.
      but they could never be good enough for a trial of an intervention that possibly has a small effect.
      An HCC surveillance trial designed to compare all-cause mortality after, say, 5 years between patients randomised to HCC surveillance or no surveillance will need to include several thousand patients (Table 3). Note that if we argue that a trial would require an unrealistically large number of patients, we are at the same time arguing that the effect of surveillance will be very small.
      Table 3Sample size estimations depending on all-cause mortality and its components and the hypothesised effect of surveillance on deaths from HCC-related causes.
      Standard-of-care armSurveillance armNumber of patients to randomise
      All-cause 5-year mortalityDeaths from HCC, % of all deaths5-year HCC-related mortality (Fig. 1: state 3)5-year mortality from non-HCC causes (Fig. 1: state 4)Proportion of deaths from HCC averted by HCC surveillanceAll-cause 5-year mortality
      30%5%1.5%28.5%50%29.3%90,730
      40%5%2.0%38.0%50%39.0%57,878
      50%5%2.5%47.5%50%48.8%38,074
      40%10%4.0%36.0%50%38.0%14,418
      40%15%6.0%34.0%50%37.0%6,386
      50%20%10.0%40.0%50%45.0%2,390
      40%25%10.0%30.0%50%35.0%2,282
      30%25%7.5%22.5%50%26.2%3,530
      30%25%7.5%22.5%25%28.1%14,368
      40%5%2.0%38.0%25%39.5%231,912
      40%5%2.0%38.0%75%38.5%25,678
      40%5%2.0%38.0%100%38.0%14,418
      All-cause mortality comprises HCC-related causes (Fig. 1: state 3) and other causes (Fig. 1: state 4). The hypothetical trial has all-cause 5-year mortality as the primary outcome and employs 1:1 randomisation, a power of 80%, a significance level of 5%, and a one-sided test of statistical significance (null hypothesis: surveillance has no effect or reduces survival; alternative hypothesis: surveillance improves survival). HCC, hepatocellular carcinoma.

      Generalisability of trial results

      In a randomised trial of HCC surveillance, the patients randomised to ‘no surveillance’ should receive the standard-of-care except HCC surveillance. That standard may differ between countries. For example, in some places those patients would be followed as outpatients, in others they would not. It will be important to have prespecified subgroup analyses by standard-of-care, because some of the benefit of HCC surveillance may come from the outpatient visits that accompany ultrasound examinations, not from a reduction in HCC-related mortality.
      Another source of regional variation is the access to liver transplantation. The benefit of HCC surveillance is likely greater if all patients with unresectable HCC within the Milan criteria can be offered a liver transplantation. That will not be possible in all countries,
      • Trotter J.F.
      • Cardenas A.
      Liver transplantation around the world.
      and that is a threat to the generalisability of trial results. One solution is to conduct prespecified subgroup analyses by ‘standard practice for liver transplantation for HCC’.

      Screening tools

      Abdominal ultrasound (with or without alpha-fetoprotein) is the standard screening tool and has been for many years. Newer imaging tools have been examined, but none are in widespread use and neither are biomarker panels. It has been argued that “the promise of HCC screening in reducing HCC-related mortality cannot be fulfilled with currently available tests.”
      • Singal A.G.
      • Lok A.S.
      • Feng Z.
      • Kanwal F.
      • Parikh N.D.
      Conceptual model for the hepatocellular carcinoma screening continuum: current status and research agenda.
      It is true that more sensitive and specific screening tests could greatly increase the benefits and reduce the harms of HCC surveillance, but for now ultrasound is the standard that we think must be tested in a randomised trial.

      Conclusion

      Currently there is insufficient evidence to recommend HCC surveillance in clinical practice. We believe that healthcare systems, clinicians, and patients would be much more likely to participate in HCC surveillance if it were based on randomised trial results showing it is of value.

      Financial support

      PJ was supported by a grant from the Novo Nordisk Foundation ( NNF18OC0054612 ). The funding organization was not involved in the conception, the writing, or the decision to submit the manuscript for publication.

      Authors’ contributions

      Peter Jepsen drafted the manuscript. Both authors revised and edited the manuscript for content.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      References

        • Tversky A.
        • Kahneman D.
        Judgment under uncertainty: heuristics and biases. Biases in judgments reveal some heuristics of thinking under uncertainty.
        Science. 1974; 185: 1124-1131
        • European Association for the Study of the Liver
        EASL clinical practice guidelines: management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Wolf E.
        • Rich N.E.
        • Marrero J.A.
        • Parikh N.
        • Singal A.G.
        Utilization of hepatocellular carcinoma surveillance in patients with cirrhosis: a systematic review and meta-analysis.
        Hepatology. 2020; https://doi.org/10.1002/hep.31309
        • Atiq O.
        • Tiro J.
        • Yopp A.C.
        • Muffler A.
        • Marrero J.A.
        • Parikh N.D.
        • et al.
        An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis.
        Hepatology. 2017; 65: 1196-1205
        • Singal A.G.
        • Lok A.S.
        • Feng Z.
        • Kanwal F.
        • Parikh N.D.
        Conceptual model for the hepatocellular carcinoma screening continuum: current status and research agenda.
        Clin Gastroenterol Hepatol. 2020; https://doi.org/10.1016/j.cgh.2020.09.036
        • Sherman M.
        Surveillance for hepatocellular carcinoma.
        Best Pract Res Clin Gastroenterol. 2014; 28: 783-793
        • Sørensen H.T.
        • Lash T.L.
        • Rothman K.J.
        Beyond randomized controlled trials: a critical comparison of trials with nonrandomized studies.
        Hepatology. 2006; 44: 1075-1082
        • Singal A.G.
        • Lampertico P.
        • Nahon P.
        Epidemiology and surveillance for hepatocellular carcinoma: new trends.
        J Hepatol. 2020; 72: 250-261
        • Prasad V.K.
        • Cifu A.S.
        Ending medical reversal.
        Johns Hopkins University Press, 2015
        • Marrero J.A.
        • Kulik L.M.
        • Sirlin C.B.
        • Zhu A.X.
        • Finn R.S.
        • Abecassis M.M.
        • et al.
        Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases.
        Hepatology. 2018; 68: 723-750
        • Kanwal F.
        • Singal A.G.
        Surveillance for hepatocellular carcinoma: current best practice and future direction.
        Gastroenterology. 2019; 157: 54-64
        • Sarasin F.P.
        • Giostra E.
        • Hadengue A.
        Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis.
        Am J Med. 1996; 101: 422-434
        • Ganne-Carrie N.
        • Layese R.
        • Bourcier V.
        • Cagnot C.
        • Marcellin P.
        • Guyader D.
        • et al.
        Nomogram for individualized prediction of hepatocellular carcinoma occurrence in hepatitis C virus cirrhosis (ANRS CO12 CirVir).
        Hepatology. 2016; 64: 1136-1147
        • Ganne-Carrie N.
        • Chaffaut C.
        • Bourcier V.
        • Archambeaud I.
        • Perarnau J.M.
        • Oberti F.
        • et al.
        Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis.
        J Hepatol. 2018; 69: 1274-1283
        • Nilsson E.
        • Anderson H.
        • Sargenti K.
        • Lindgren S.
        • Prytz H.
        Risk and outcome of hepatocellular carcinoma in liver cirrhosis in southern Sweden: a population-based study.
        Scand J Gastroenterol. 2019; 54: 1027-1032
        • Kanwal F.
        • Kramer J.R.
        • Asch S.M.
        • Cao Y.
        • Li L.
        • El-Serag H.B.
        Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
        Hepatology. 2020; 71: 44-55
        • Andersen P.K.
        • Perme M.P.
        • van Houwelingen H.C.
        • Cook R.J.
        • Joly P.
        • Martinussen T.
        • et al.
        Analysis of time-to-event for observational studies: guidance to the use of intensity models.
        Stat Med. 2021; 40: 185-211
        • Morina D.
        • Navarro A.
        Competing risks simulation with the survsim R package.
        Commun Stat - Simulation Comput. 2017; 46: 5712-5722
        • Orman E.S.
        • Roberts A.
        • Ghabril M.
        • Nephew L.
        • Desai A.P.
        • Patidar K.
        • et al.
        Trends in characteristics, mortality, and other outcomes of patients with newly diagnosed cirrhosis.
        JAMA Netw Open. 2019; 2e196412
        • Ratib S.
        • Fleming K.M.
        • Crooks C.J.
        • Aithal G.P.
        • West J.
        1 and 5 year survival estimates for people with cirrhosis of the liver in England, 1998-2009: a large population study.
        J Hepatol. 2014; 60: 282-289
        • Nilsson E.
        • Anderson H.
        • Sargenti K.
        • Lindgren S.
        • Prytz H.
        Clinical course and mortality by etiology of liver cirrhosis in Sweden: a population based, long-term follow-up study of 1317 patients.
        Aliment Pharmacol Ther. 2019; 49: 1421-1430
        • Jepsen P.
        • Vilstrup H.
        • Andersen P.K.
        The clinical course of cirrhosis: the importance of multistate models and competing risks analysis.
        Hepatology. 2015; 62: 292-302
        • World Health Organization
        Screening programmes: A short guide. Increase effectiveness, maximize benefits and minimize harm.
        WHO Regional Office for Europe, Copenhagen2020
        • Old O.
        • Moayyedi P.
        • Love S.
        • Roberts C.
        • Hapeshi J.
        • Foy C.
        • et al.
        Barrett's Oesophagus Surveillance versus endoscopy at need Study (BOSS): protocol and analysis plan for a multicentre randomized controlled trial.
        J Med Screen. 2015; 22: 158-164
        • Poustchi H.
        • Farrell G.C.
        • Strasser S.I.
        • Lee A.U.
        • McCaughan G.W.
        • George J.
        Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.
        Hepatology. 2011; 54: 1998-2004
        • Bewley S.
        The NHS breast screening programme needs independent review.
        BMJ. 2011; 343: d6894
        • Sharma S.A.
        • Kowgier M.
        • Hansen B.E.
        • Brouwer W.P.
        • Maan R.
        • Wong D.
        • et al.
        Toronto HCC risk index: a validated scoring system to predict 10-year risk of HCC in patients with cirrhosis.
        J Hepatol. 2017; 68: 92-99
        • Ioannou G.N.
        • Green P.
        • Kerr K.F.
        • Berry K.
        Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification.
        J Hepatol. 2019; 71: 523-533
        • Fan R.
        • Papatheodoridis G.
        • Sun J.
        • Innes H.
        • Toyoda H.
        • Xie Q.
        • et al.
        aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.
        J Hepatol. 2020; 73: 1368-1378
        • Audureau E.
        • Carrat F.
        • Layese R.
        • Cagnot C.
        • Asselah T.
        • Guyader D.
        • et al.
        Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status.
        J Hepatol. 2020; 73: 1434-1445
        • Sutradhar R.
        • Austin P.C.
        Relative rates not relative risks: addressing a widespread misinterpretation of hazard ratios.
        Ann Epidemiol. 2018; 28: 54-57
        • Austin P.C.
        • Lee D.S.
        • D'Agostino R.B.
        • Fine J.P.
        Developing points-based risk-scoring systems in the presence of competing risks.
        Stat Med. 2016; 35: 4056-4072
        • Latouche A.
        • Allignol A.
        • Beyersmann J.
        • Labopin M.
        • Fine J.P.
        A competing risks analysis should report results on all cause-specific hazards and cumulative incidence functions.
        J Clin Epidemiol. 2013; 66: 648-653
        • Andersen P.K.
        • Geskus R.B.
        • de Witte T.
        • Putter H.
        Competing risks in epidemiology: possibilities and pitfalls.
        Int J Epidemiol. 2012; 41: 861-870
        • de Koning H.J.
        • van der Aalst C.M.
        • de Jong P.A.
        • Scholten E.T.
        • Nackaerts K.
        • Heuvelmans M.A.
        • et al.
        Reduced lung-cancer mortality with volume CT screening in a randomized trial.
        N Engl J Med. 2020; 382: 503-513
        • Moon A.M.
        • Weiss N.S.
        • Beste L.A.
        • Su F.
        • Ho S.B.
        • Jin G.Y.
        • et al.
        No association between screening for hepatocellular carcinoma and reduced cancer-related mortality in patients with cirrhosis.
        Gastroenterology. 2018; 155: 1128-1139
        • Trotter J.F.
        • Cardenas A.
        Liver transplantation around the world.
        Liver Transpl. 2016; 22: 1059-1061