Hepatocellular carcinoma can arise in both non-cirrhotic and cirrhotic livers. In the Orient, where hepatitis B or toxins are the most common underlying causes, HCC commonly arises in the absence of cirrhosis (80
). In the west, where hepatitis C and alcohol are the most common underlying liver diseases, HCC arises mostly in the setting of cirrhosis (81
). Prognosis is predictably worse in patients with underlying cirrhosis (81
). Even in patients with cirrhosis (without HCC), it has recently been shown that the prognostic factors, survival and causes of death differ significantly between those with compensated and decompensated cirrhosis (2
) and that these two entities should be considered separately both in clinical practice and in clinical research (85
). In fact, HCC is an independent predictor of death in patients with decompensated cirrhosis (2
Prognosis is an essential part of the assessment of patients with HCC. It allows the patient to make important decisions, both therapeutic and other and it allows for risk stratification such that different therapies can be investigated according to risk. However, prognostic studies in HCC are often unsatisfactory because patients included are heterogeneous, particularly with regard to the presence (or absence) of underlying cirrhosis, and the results are therefore not widely applicable. Because most of the cases of HCC in the USA occur in the setting of cirrhosis, it is important to determine the prognostic variables in this subset of patients with HCC. Unfortunately, many of the prognostic studies in HCC include patients with and without cirrhosis. In fact, of the 159 articles retrieved for this analysis, at least 45 (28%) were excluded because more than 20% of the patients did not have cirrhosis or the presence (or absence) of cirrhosis was not mentioned. Even within the 72 studies selected for analysis, only 22 (31%) of them clearly stated that they included only patients with cirrhosis.
One of the strengths of this systematic review is that it analysed predictors of death in HCC, specifically in studies in which ≥80% of the patients had underlying cirrhosis. Furthermore, it aimed to analyse whether the predictors differed in patients with compensated vs. decompensated cirrhosis.
Despite methodological problems in the evaluated studies (none met all quality criteria and only 21% of them met important quality criteria), this systematic review allowed for the identification of the ‘robust’ predictors of death. As could have probably been predicted, these were both tumour related (portal vein thrombosis, tumour size and AFP) and cirrhosis related (mainly, the Child–Pugh class). The strength or the robustness of a predictor is given by the ratio between the number of studies in which each variable was significant and the number of studies in which it was assessed. With a larger number of studies, a large ratio is an indirect measure of the validity as each study that confirms the predictive value of a variable provides indirect proof of its validity (2
). This robustness, which is independent of the quality of the studies, was particularly true for portal vein thrombosis, tumour size and Child–Pugh class, each of which was evaluated in more than 30 studies with a ratio >50%, i.e. more than half of the studies proved them to be among the first five most significant variables on a multivariable analysis. Importantly, the same parameters were the most frequent significant variables when only the studies in which 100% of the patients included had cirrhosis and when ‘good’ quality studies were analysed. In the analysis of good quality studies, one of the most robust predictors of death was the AFP.
Interestingly, one of the most commonly used HCC staging systems, the CLIP system (4
), includes all four of these predictors (portal vein thrombosis, tumour size, Child–Pugh class and AFP) and, in fact, the CLIP staging system itself was identified as the sixth most common predictor of mortality, being among the first five significant variables in 11/15 studies (73%). Six of the 11 studies identifying the CLIP score as an independent predictor were of Italian origin (24
). Another commonly used HCC staging system, and the one recommended in recently published guidelines (81
), is the Barcelona Clinic Liver Cancer (BCLC) system (5
), which was only evaluated in three studies, but was nevertheless found to be among the first five significant variables in two (67%) of them. This staging system also includes three of the predictors (tumour size, Child–Pugh class and portal vein thrombosis). Although it does not include AFP, the BCLC staging system has the advantage of including other parameters such as performance status (found to be an important predictor in 6/8 or 75% of the studies in which it was assessed) and, importantly, of tailoring other prognostic factors to different tumour stages (early vs. intermediate/advanced) and to Child–Pugh class. For example, portal pressure, as determined by the hepatic venous pressure gradient, which was not directly evaluated in any of the studies in this analysis, was shown to be an independent predictor of death in early stages (patients subjected to resection) (86
) and is included in the BCLC system but only in Child A patients with resectable tumours (5
). In the BCLC multivariable analysis study that was performed to identify the predictors of death in intermediate/advanced stages, an AFP of >35 ng/ml was not significant on univariate analysis (23
), whereas in the CLIP staging system an AFP of >400 ng/dl had an independent prognostic value (4
). As has been recently discussed, the prognostic utility of AFP is unclear in part due to the use of heterogeneous cut-off levels and also due to its variable sensitivity (88
). For example, in a recent study of 1158 patients (60% Child–Pugh A), even though the specificity of an AFP level >600 ng/ml in predicting survival was 93%, its sensitivity was only 23% (89
Therefore, although the BCLC model has been reported to be superior to alternate models for the prediction of survival in HCC, including the Okuda, CLIP, tumour node metastasis, Japanese Integrated System, Groupe d'Etude de Traitement du Carcinoma Hepatocellulaire and Chinese University Prognostic Index models (61
), three of which include the AFP, it would be interesting to see whether the AFP (as a continuous variable) adds to the prognostic value of the BCLC. The appropriate cut-off level and the group of patients in which the AFP may be helpful remains to be determined, although our analysis would suggest that it appears to be more useful in advanced tumour stages ().
The importance of determining prognosis at different stages of cirrhosis cannot be overemphasized (2
). We had hypothesized that in the compensated patients factors related to the tumour would be more important, whereas in the decompensated patient, both liver- and tumour-related factors would be important. However, in a subanalysis of studies including mostly patients with compensated or decompensated cirrhosis (), both tumour-related and cirrhosis-related predictors appeared to be predictive of death in both groups. However, the number of studies is too small to draw firm conclusions, particularly regarding patients with mostly decompensated cirrhosis and those with mostly non-advanced tumour stage.
Our study is limited by the design and prognostic parameters chosen in each of the studies included in this analysis as well as the heterogeneous group of patients included with both treated and untreated tumours. Furthermore, although the choice of the 66% cut-off for the definition of ‘mostly decompensated cirrhosis’ or ‘mostly non-advanced tumour’ was in part arbitrary, it can be justified because even at this cut-off there were too few studies available in the >66% non-advanced tumour or >66% decompensated cirrhosis categories to obtain definitive results.
Future studies on the prognostic indicators of HCC should include patients either with or without cirrhosis. Studies that will apply to patients with HCC seen in western countries should include only patients with cirrhosis and the prognostic variables should be assessed separately for the different stages of cirrhosis, at a minimum, separating those with compensated and those with decompensated cirrhosis. The study quality should be optimized by incorporating most, if not all, of the criteria listed in . Additionally, parameters identified by the majority of the studies included in this analysis should be included in such studies.