Reply
Authors: Annalisa Berzigotti, Maria Reig, Jordi Bruix
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. We were pleased to see the attention raised by our article about the relevant role of portal pressure assessment in the outcome prediction in patients considered for surgical resection of hepatocellular carcinoma (HCC).1 The value of this parameter in predicting outcome has been a very controversial issue in the surgical domain, and the fact that three independent metanalysis1 are concordant reinforces the clinical value of the portal pressure assessment. Cucchetti et al. expose limitations of metanalytical studies, as compared to single‐center cohort data, allowing regression assessment or propensity score matching. Though the concept is correct, the higher hierarchic value does not exist. Regression of retrospective data collection is also at risk of suboptimal strength, and propensity score analysis may just delete from the cohort those individuals with an outlier profile that is captured by that use of the parameter that is aimed to be tested, as is the case for portal hypertension in the prediction of prognosis in patients considered for surgical resection. Furthermore, in the absence of a direct measurement of portal pressure in their study,4 their definition of portal hypertension may have overestimated its presence and prompted a flaw. In their study, 20% of the patients were registered as portal hypertensive because of esophageal varices, but did not have splenomegaly and low platelet count.4 This combination is uncommon; we wonder whether, in their retrospective analysis, the registration of varices may indeed be a false positive of endoscopy that could have been performed elsewhere. This misclassification would benefit the high‐risk subgroup. Excluding patients who underwent transplantation because of liver failure is another relevant concern for their propensity analysis. Finally, a 5% postoperative mortality rate currently exceeds the expected ratio5 and suggests that several factors in addition to portal hypertension have to be factored in their analysis. Ultimately, if presence and degree of portal hypertension is a powerful predictor for survival in patients with cirrhosis even if compensated, there is no reason to expect that this value would disappear in patients diagnosed with HCC.7 We have to thank Cucchetti et al. for allowing us to detect a mistake in Table 3 of our article despite our intense revision. The correct values (3‐ and 5‐year overall survival [OS] in patients with portal hypertension: 62.4% and 51.5%; 3‐ and 5‐year OS in patients without portal hypertension: 72.8% and 61.8%) were used for the analysis that has been again redone to eliminate any concern, and we have submitted a "corrigendum" to Hepatology. Table 3 - 3‐ and 5‐Year Overall Survival (OS) in the Studies Included in the Analysis of the Primary Endpoint (n=8) Number of Child A Single 3‐ Year OS 5‐ Year OS Study Patients (n) (%) Nodule (%) Without CSPH With CSPH Without CSPH With CSPH Capussotti, 2006 217 82.0 76.0 62.1; Child A 64.8 44.8; Child A 59.9 39.8; Child A 41.5 28.9; Child A 40.8 Cucchetti, 2009 241 94.6 83.8 72.8 62.4 61.8 51.5 Giannini, 2013 152 100% 79.7% 69.8 71.7 45.1 47.7 Hidaka, 2012 177 90.4 73.5 72.0 49.0 63.7 31.0 Ishizawa, 2008 434 (386 with cirrhosis) 83.8 29.1 Child A 81.0 Child B 62.0 Child A 71.0 Child B 59.0 Child A 71.0 Child B 31.0 Child A 56.0 Child B 41.0 Llovet, 1999 77 96.1 100 87.0 TotBil <=1 mg/dl 59; TotBil >1 mg/dl 39 74.0 TotBil <=1 mg/dl 50; TotBil >1 mg/dl 25 Ruzzenente, 2011 135 81.5 71.9 68.4 48.7 61.2 44.9 Santambrogio, 2013 223 96.0 NR 80.0 66.0 65.0 48.0 In our study, we analyzed both the short‐ and the long‐term results in terms of survival. Of note, date of death is a clear‐cut parameter in all studies, whereas morbidity and recurrence may be affected by the methods and timing used to register any event. Furthermore, long‐term survival is the endpoint that patients consider the most valued, together with preserved quality of life. Therefore, initial cancer removal or recurrence‐free survival are less informative given that it is preferable to be alive with recurrence than free of disease for some time, but dying at an earlier time point because of progressive liver failure. As Yang et al. mention, the survival prediction after adequate preoperative evaluation should be compared against the outcome that may be achieved by other options with accepted efficacy in HCC patients (i.e., liver transplant, ablation, transarterial chemoembolization, or sorafenib8). This is the critical role of expert physicians who blend evidence‐based data as exposed in guidelines5 with the refined assessment of the specific profile of the individual patient as corresponds to so‐called "personalized" or "stratified" medicine. Finally, as Yang et al. mention, if there is evidence of significant portal hypertension (esophageal varices or ascites), the evaluation of portal pressure is not needed. However, it should be noted that absence of varices or ascites does not at all indicate absence of portal hypertension, which should be confirmed by specific investigations. In that sense, we have recently shown that elastography may confirm or rule out clinically significant portal hypertension in a substantial proportion of patients.9 Also, in some cases, the combination of ultrasonographic findings with low platelet count may also provide proper confirmation of the risky profile.10 As a whole, assessment of portal pressure should be a cornerstone of the evaluation of potential candidates for surgical resection. Though key in conventional clinical practice, it is also of utmost importance in research studies. If any clinical or molecular parameter is aimed to correlate with the outcome of the patients and portal pressure consideration is not in place, the value of the findings is at risk of significant bias.