Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4-9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers.

Background: Access to the liver transplant waitlist for patients with hepatocellular carcinoma (HCC) depends on tumour presentation, biology, and response to treatments. The Milan Criteria (MC) represent the benchmark for expanded criteria that incorporate additional prognostic factors. The purpose of this study was to determine the added value of skeletal muscle index (SMI) in HCC patients beyond the MC.Method: Patients with HCC that were transplanted beyond the MC were included in this retrospective multicentre study. SMI was quantified using the Computed Tomography (CT) within 3 months prior to transplantation. Cox regression models were used to identify predictors of overall survival (OS). The discriminative performance of SMI extended Metroticket 2.0 and AFP models was also assessed.Results: Out of 889 patients transplanted outside the MC, 528 had a CT scan within 3 months prior to liver transplantation (LT), of whom 176 (33%) were classified as sarcopenic. The median time between assessment of the SMI and LT was 1.8 months (IQR: 0.77–2.67). The median follow‐up period was 5.1 95% CI [4.7–5.5] years, with a total of 177 recorded deaths from any cause. In a linear regression model with SMI as the dependent variable, only male gender (8.55 95% CI [6.51–10.59], P < 0.001) and body mass index (0.74 95% CI [0.59–0.89], P < 0.001) were significant. Univariable survival analysis of patients with sarcopenia versus patients without sarcopenia showed a significant difference in OS (HR 1.44 95% CI [1.07 − 1.94], P = 0.018). Also the SMI was significant (HR 0.98 95% CI [0.96–0.99], P = 0.014). The survival difference between the lowest SMI quartile versus the highest SMI quartile was significant (log‐rank: P = 0.005) with 5 year OS of 57% and 71%, respectively. Data from 423 patients, describing 139 deaths, was used for multivariate analysis. Both sarcopenia (HR 1.45 95% CI [1.02 − 2.05], P = 0.036) and SMI were (HR 0.98 95% CI [0.95–0.99], P = 0.035) significant. On the survival scale this translates to a 5 year OS difference of 11% between sarcopenia and no sarcopenia. Whereas for SMI, this translates to a survival difference of 8% between first and third quartiles for both genders.Conclusions: Overall, we can conclude that higher muscle mass contributes to a better long‐term survival. However, for individual patients, low muscle mass should not be considered an absolute contra‐indication for LT as its discriminatory performance was limited.

Background: Patient fitness is important for guiding treatment. Muscle mass, as a reflection thereof, can be objectively measured. However, the role of East–West differences remains unclear. Therefore, we compared the impact of muscle mass on clinical outcomes after liver resection for hepatocellular carcinoma (HCC) in a Dutch [the Netherlands (NL)] and Japanese [Japan (JP)] setting and evaluated the predictive performance of different cutoff values for sarcopenia. Method: In this multicenter retrospective cohort study, patients with HCC undergoing liver resection were included. The skeletal muscle mass index (SMI) was determined on computed tomography scans obtained within 3 months before surgery. The primary outcome measure was overall survival (OS). Secondary outcome measures were: 90-day mortality, severe complications, length of stay, and recurrence-free survival. The predictive performance of several sarcopenia cutoff values was studied using the concordance index (C-index) and area under the curve. Interaction terms were used to study the geographic effect modification of muscle mass. Results: Demographics differed between NL and JP. Gender, age, and body mass index were associated with SMI. Significant effect modification between NL and JP was found for BMI. The predictive performance of sarcopenia for both short-term and long-term outcomes was higher in JP compared to NL (maximum C-index: 0.58 vs. 0.55, respectively). However, differences between cutoff values were small. For the association between sarcopenia and OS, a strong association was found in JP [hazard ratio (HR) 2.00, 95% CI [1.230–3.08], P=0.002], where this was not found in NL (0.76 [0.42–1.36], P=0.351). The interaction term confirmed that this difference was significant (HR 0.37, 95% CI [0.19–0.73], P=0.005). Conclusions: The impact of sarcopenia on survival differs between the East and West. Clinical trials and treatment guidelines using sarcopenia for risk stratification should be validated in race-dependent populations prior to clinical adoption.

For patients presenting with hepatocellular carcinoma within the Milan criteria, either liver resection or liver transplantation can be performed. However, to what extent either of these treatment options is superior in terms of long-term survival is unknown. Obviously, the comparison of these treatments is complicated by several selection processes. In this article, we comprehensively review the current literature with a focus on factors accounting for selection bias. Thus far, studies that did not perform an intention-to-treat analysis conclude that liver transplantation is superior to liver resection for early-stage hepatocellular carcinoma. In contrast, studies performing an intention-to-treat analysis state that survival is comparable between both modalities. Furthermore, all studies demonstrate that disease-free survival is longer after liver transplantation compared to liver resection. With respect to the latter, implications of recurrences for survival are rarely discussed. Heterogeneous treatment effects and logical inconsistencies indicate that studies with a higher level of evidence are needed to determine if liver transplantation offers a survival benefit over liver resection. However, randomised controlled trials, as the golden standard, are believed to be infeasible. Therefore, we suggest an alternative research design from the causal inference literature. The rationale for a regression discontinuity design that exploits the natural experiment created by the widely adopted Milan criteria will be discussed. In this type of study, the analysis is focused on liver transplantation patients just within the Milan criteria and liver resection patients just outside, hereby ensuring equal distribution of confounders.

Background: Sarcopenia is associated with increased mortality in patients awaiting liver transplant (LT), but the impact of sarcopenia on cirrhosis progression remains under‐evaluated. Aims: We aimed to explore the relationship between sarcopenia and the risk of cirrhosis progression, mortality and hospitalisation in compensated and decompensated cirrhosis. Methods: Sarcopenia was measured using the skeletal muscle index (SMI) obtained from abdominal CT imaging at the 3rd lumbar vertebra (L3). Progression of cirrhosis was defined by an increase in clinical stage from baseline using the D'Amico classification. Factors associated with progression or death, death alone and hospitalisation were evaluated with univariate and multivariate Cox regression models. Results: One thousand six hundred and twenty‐four adult patients with cirrhosis from five centres across Europe, North America and Asia were included. Mean age was 54 ± 9 years, 26% of patients were female, 31% had compensated disease and mean MELD‐Na was 15 ± 7. With separate analyses for compensated and decompensated cirrhosis, sarcopenia was independently associated with the risk of progression or death (aHR 1.43, 95% CI 1.14–1.79, p = 0.002) and death alone (aHR 1.55, 95% CI 1.19–2.03, p = 0.001) only in decompensated cirrhosis. Sarcopenia was independently associated with unplanned hospitalisation in both compensated (aHR 1.70, 95% CI 1–15‐2.51, p = 0.010) and decompensated cirrhosis (aHR 1.32, 95% CI 1.08–1.63, p = 0.007). Conclusions: Sarcopenia was independently associated with cirrhosis progression or death and death alone in decompensated cirrhosis. Future studies are needed to evaluate the possibility of slowing cirrhosis disease progression by reversing or preventing sarcopenia.

When listing for liver transplantation, one can transplant as soon as possible or introduce a test-of-time to better select patients, as the tumor's biological behavior is observed. Knowing the degree of harm caused by time itself is essential to advise patients and decide on the maximum duration of the test-of-time. Therefore, we investigated the causal effect of waiting time on post-transplant survival for patients with hepatocellular carcinoma. We analyzed the UNOS-OPTN dataset and exploited a natural experiment created by blood groups. Relations between variables and assumptions were described in a causal graph. Selection bias was addressed by inverse probability weighting. Confounding was avoided using instrumental variable analysis, with an additive hazards model in the second stage. The causal effect was evaluated by estimating the difference in 5-year overall survival if all patients waited 2 months instead of 12 months. Upper bounds of the test-of-time were evaluated for probable scenarios by means of simulation. The F-statistic of the first stage was 86.3. The effect of waiting 12 months vs. 2 months corresponded with a drop in overall survival rate of 5.07% (95% CI 0.277-9.69) and 8.33% (95% CI 0.47-15.60) at 5- and 10-years post-transplant, respectively. The median survival dropped by 3.41 years from 16.21 years (95% CI 15.98-16.60) for those waiting 2 months to 12.80 years (95% CI 10.72-15.90) for those waiting 12 months. From a patient's perspective, the choice between ablate-and-wait vs. immediate transplantation is in favor of immediate transplantation. From a policy perspective, the extra waiting time can be used to increase the utility of scarce donor livers. However, the duration of the test-of-time is bounded, and it likely should not exceed 8 months. When listing patients with liver cancer for transplantation, it is unclear whether a test-of-time or immediate transplantation offer better outcomes at the population level. In this study, we found that increased liver transplant waiting times are detrimental in patients with liver cancer. Furthermore, our simulation showed that a pre-operative observational period can be useful to ensure good donor liver allocation, but that its duration should not exceed 8 months.