Hepatocellular carcinoma screening is associated with survival benefit in silico but needs confirmation in an in vivo analysis
Authors: Ruben Hernaez, Fasiha Kanwal, Hashem B. El‐Serag
Journal: Hepatology (2018)

Potential conflict of interest: Dr. Kanwal received grants from Merck and Gilead. Dr. El‐Serag received grants from Merck, Gilead, and Wako. SEE ARTICLE ON PAGE 78 Supported, in part, by PHS grant P30DK056338 and the Houston VA HSR&D Center of Innovations of Quality, Effectiveness and Safety (CIN 13‐413) at the Michael E. DeBakey VA Medical Center. Abbreviation CT computed tomography HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus LT liver transplant MRI magnetic resonance imaging NAFLD nonalcoholic fatty liver disease Hepatocellular carcinoma (HCC) is the fastest‐growing cause of cancer deaths in the United States. The overall prognosis of patients with HCC remains dismal except for a small subset of patients in whom HCC is detected at an early stage and who receive curative therapies, including liver transplant (LT), surgical resection, and, possibly, local ablation.1 Therefore, for patients at increased risk of HCC (i.e., primarily those with cirrhosis), clinical practice guidelines recommend regular HCC surveillance using liver ultrasound and/or α‐fetoprotein measurements to increase the likelihood of detecting early‐stage cancer. Despite these guidelines, long‐term benefits of HCC surveillance are not known. To address this evidence gap, a large randomized, controlled trial is needed to compare long‐term outcomes of screening and no‐screening arms; such a trial could take decades to complete and may even be considered by some as unethical for patients in the no‐screening arm. Under such a situation, mathematical disease modeling is a useful method for weighing the risks and benefits of cancer screening strategies and gaining insight into the main variables affecting this balance. Yang et al. performed a multistate Markov simulation model (in silico study) to evaluate the possible efficacy of HCC surveillance on both HCC‐specific as well as overall mortality. The model incorporated cirrhosis stages, progression and decompensation rates, stage of HCC at diagnosis, sensitivity of screening tests, treatment‐related complications, recurrence posttreatment, and probability of LT listing, among others.2 In a simulated cohort of 50‐year‐olds followed for up to 15 years, 68.2% of the cohort members died (25.1% from HCC and 43.6% from cirrhosis decompensation). With HCC surveillance, median survival improved from 10.4 to 11.2 years. The numbers needed to screen to avoid one death from all causes and one HCC‐specific death over 15 years were 28 and 18 patients, respectively. The researchers put these estimates in context by drawing comparison with the number needed to screen of 550 men for prostate‐specific antigen over 12 years of follow‐up, and between 233 and 746 women for mammography over lifetime. The model addresses an important issue, provides a long‐time horizon, and, at least in the sensitivity analyses, covers some of the recently changing estimates such as HCC risk in patients treated successfully for hepatitis C virus (HCV) or hepatitis B virus (HBV). Collectively, the findings offer a rather optimistic view on HCC surveillance. Some of the limitations include the already outdated estimates (e.g., 3% annual HCC risk); lack of tailored surveillance by an individual's risk based on factors such as age, comorbidity, and access to LT; and focusing solely of effectiveness without considering the harms and costs of surveillance. By targeting few, but not all, aspects of surveillance, the study was able to present a clear and insightful message about the possible efficacy of HCC surveillance; however, it is less informative for the complex effectiveness of HCC surveillance as public health intervention or as a standard clinical practice. Incidence of HCC and stability of liver disease severity had the strongest effect on the benefit of surveillance in this study. It is quite likely that most modern hepatology practices will comprise of patients with cirrhosis who already have cured HCV, adequately suppressed HBV, or nonalcoholic fatty liver disease (NAFLD) nonalcoholic steatohepatitis, where HCC risk is low (close to 1% rather than 3% in the base model).3 These groups may also see some reversal of cirrhosis/advanced fibrosis and lower risk of progression to decompensation. This outcome is already highlighted in the so‐called Model of End‐Stage Liver Disease purgatory in treated HCV among patients listed for LT. Considering these realistic near‐future scenarios where cirrhosis severity was stable with a reduction in HCC incidence, the number needed to prevent all‐cause mortality increase by 57% (from 28 to 44 patients); number needed to screen increase by 90% (from 18 to 34) to prevent HCC related mortality. Finally, the calculations of numbers needed to screen assume a constant risk throughout the follow‐up4 and in subgroups of patients based on race and age, which may not be the case for HCC especially in those with treated viral hepatitis.5 The study did not incorporate cost and harms of HCC surveillance. In a recent study, Atiq et al. found that physical harms ranging from mild (a single diagnostic computed tomography [CT] or magnetic resonance imaging [MRI] encounter without complications), moderate (underwent multiple CT and/or MRI exams), and severe (undergo invasive procedures, such as liver biopsy or angiogram) were present in 27.5% of the patient population. Taylor et al. recently published a similar analysis using a Markov model with two 1,000‐patient cohorts with well‐compensated cirrhosis and followed up to 5 years.6 Consistent with Yang et al., surveillance was beneficial where the number needed to screen to prevent one death was 77. However, for every 1,000 patients, 150 (95% confidence interval, 146‐154) had one or more false‐positive tests equating to a number needed to harm from surveillance of 7. Not addressed in either study are the associated psychological and financial harms associated with HCC screening.7 Another obstacle in the face of greater acceptance of HCC surveillance is the decidedly unattractive recommended tools (i.e., ultrasound and α‐fetoprotein). Ultrasound‐based surveillance has inadequate sensitivity, especially for early‐stage, small‐size HCC. In clinical practice, ultrasound sensitivity for detecting early‐stage HCC may be as low as only 32% compared to the model parameter estimate of 70% (60%‐80%). The rising incidence and prevalence of NAFLD may shift the predominant etiology from HCV to NAFLD in the future; ultrasound performs particularly poorly in obese patients, which may further lower its sensitivity for HCC detection.8 New biomarkers or improved current biomarkers may eventually achieve the sensitivity of 70%‐80% and render the results of this analysis relevant in years to come.9 Yang et al. provided benefits related to HCC‐related mortality, but also overall mortality. If true, this finding, which we believe is quite optimistic, would be a major achievement for HCC surveillance. Most studies of cancer screening find discrepancies in the direction or magnitude between disease‐specific and overall mortality where, despite reductions in disease‐specific mortality in the majority of studies, overall mortality was unchanged or increased.10 It is possible that these studies were underpowered to detect a small mortality benefit; this limitation would be offset by a modeling study where sample size is not an issue, as in the current analysis. In conclusion, although the findings of this in silico study may not change many minds, they offer some insights into the influential elements affecting the benefit of HCC surveillance. Those who believe in HCC surveillance would use the study as a source of comfort, while the minds of those who are skeptical because of lack of a high level of evidence for efficacy in in vivo studies, and the difficulty in achieving success in implementation in real‐life studies are unlikely to change.