Anna Giacomin

Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness.

OBJECTIVE:Although transcatheter arterial chemoembolization (TACE) is effective in hepatocellular carcinoma (HCC), it is not considered a curative procedure. Among the factors potentially interfering with its effectiveness is a hypothetical neoangiogenic reaction due to ischemia. In our study, we evaluated the changes in the levels of two angiogenic factors (vascular endothelial growth factor [VEGF] and basic fibroblast growth factor [b-FGF]) and one parameter of invasiveness (urokinase-type plasminogen activator [uPA]) in patients treated with TACE.METHODS:Three blood samples were provided from 71 HCC patients undergoing TACE: before TACE (t0), after 3 days (t1), and after 4 wk, when they had spiral computed tomography (sCT) scanning (t2). The referring radiologists blindly evaluated tumor burden and vascularization at t0 and residual activity at t2. The choice of TACE as treatment was based on the American Association for the Study of Liver Diseases (AASLD) guidelines.RESULTS:Complete response at sCT was recorded in 27% of patients; mean survival was 35 months (confidence interval [CI] 31–40) and the 4-yr survival was 57%. VEGF levels were significantly correlated with the number of nodes and were higher in nonresponders at t2 (P = 0.01); below-median VEGF levels predicted a longer survival (P = 0.008). b-FGF correlated with VEGF, tumor size, vascularization, and residual activity, showing a borderline correlation with survival. uPA correlated with tumor size and VEGF. VEGF was singled out in the Cox multivariate analysis as an independent predictor of survival.CONCLUSIONS:When TACE is not totally effective, it may induce a significant neoangiogenetic reaction, as suggested by an increase in VEGF and b-FGF following treatment; this affects patient survival. VEGF emerges as the most reliable prognostic parameter, so it could be measured for judging TACE efficacy. Finally, antiangiogenic drugs may be indicated in TACE-treated HCC.

Is female sex a significant favorable prognostic factor in hepatocellular carcinoma

Objective As sex favorably modulates the natural history of chronic liver diseases and the risk for neoplastic evolution, our study aimed to ascertain whether female hepatocellular carcinoma (HCC) patients are also characterized by better prognosis. Methods The ITA.LI.CA (Italian Liver Cancer) database was used, including 1834 HCC patients (482 females, 1352 males) that were consecutively diagnosed. The following variables were considered: age, etiology, modality of diagnosis, earlier interferon treatment, bilirubin, &agr;-fetoprotein levels, constitutional syndrome, portal thrombosis, metastasis, number and size of nodules, grading, Child–Pugh class, tumor–nodes–metastases and Cancer of the Liver Italian Program staging, and treatment. Results Female HCC patients were characterized by older age (P=0.0001), higher prevalence of HCV infection (P=0.0001), diagnosis more frequently by surveillance (P=0.003), higher &agr;-fetoprotein levels (P=0.0055), lower prevalence of constitutional syndrome (P=0.03), portal thrombosis (P=0.04), and metastasis (P=0.0001). HCC in females was more frequently unifocal (P=0.0001), smaller (P=0.001), well differentiated (P=0.001), and of lower Cancer of the Liver Italian Program and tumor–nodes–metastases stage (P=0.0001 and 0.0001). However, females underwent curative treatments (transplantation, resection, percutaneous ablation) in the same percentage of cases as males. Finally, females had a significantly longer survival (median 29 [95% confidence interval (CI): 24–33] vs. 24 (22–25) months, P=0.0001). The difference was sharper [median 36 (CI: 31–41] vs. 17 (CI: 15–19)] when females undergoing surveillance were compared with males diagnosed incidentally or for symptoms. The Cox model also identified sex as an independent predictor of survival. When only patients undergoing surveillance were considered, no significant difference was observed. Conclusion HCC in females has better prognosis, but this is possibly more because of higher compliance with surveillance than to real biological differences.

Development and Validation of a New Prognostic System for Patients with Hepatocellular Carcinoma

Background Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. Methods and Findings Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child–Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26–106 mo) and 39 mo for Taiwanese patients (interquartile range, 12–61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score ≤ 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2–3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4–5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score’s prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups. Conclusions The ITA.LI.CA prognostic system includes both a tumor staging—stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)—and a prognostic score—integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations.

Diagnostic and prognostic role of SCCA-IgM serum levels in hepatocellular carcinoma (HCC).

The serpin squamous cell carcinoma antigen complexed with IgM (SCCA‐IgM) has been reported as a promising serological marker for hepatocellular carcinoma (HCC). We aimed to further evaluate SCCA‐IgM diagnostic accuracy and to determine its prognostic role.

BCLC stage B hepatocellular carcinoma and transcatheter arterial chemoembolization: a 20-year survey by the Italian Liver Cancer group

Significant proportion of Hepatocellular Carcinoma (HCC) cases are diagnosed in stage B of Barcelona Clinic Liver Cancer (BCLC) algorithm, in which the standard of care is Transcatheter Arterial ChemoEmbolization (TACE). We aimed to ascertain adherence to current guidelines, survival and prognostic factors in BCLC stage B patients.

Liver transplantation for hepatocellular carcinoma in clinical practice: the lesson from a 20-year multicentre experience in Italy.

Introduction Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but the selection criteria and priority are still debated. Aims To ascertain the number and features of patients with HCC who undergo transplantation in a Western country, the number of patients eligible for LT according to the American Association for the Study of Liver Diseases (AASLD) guidelines, the number of patients who actually undergo transplantation and whether adherence affects survival. Methods This is a retrospective analysis from a multicentre Italian database of 2042 cases of HCC, recruited prospectively and consecutively. Kaplan–Meier (log rank) and Cox multivariate analysis estimated survival. Results Patients who had undergone transplantation (50, 2.5%, with no change over time) had a median survival of 133 months, significantly influenced by the number of lesions and alpha-fetoprotein levels, which were found to be independent predictors of survival on multivariate analysis. Milan criteria were fulfilled in 68%, impacting on survival, whereas 48% fulfilled AASLD guidelines, without such an impact. Two hundred and twenty-eight (11%) patients were eligible for LT according to AASLD; in this group, alpha-fetoprotein levels and Child–Pugh class were independent predictors of survival. Conclusion Among patients with HCC, those undergoing LT represent a small minority; even fewer (1%) are those who undergo transplantation according to AASLD guidelines, adherence to which only marginally affects survival. Overall, LT impact on HCC patients’ treatment is very limited.

TACE treatment in hepatocellular carcinoma: What should we do now?

To the Editor: We read with much interest the comment by Forner et al. [1] on the recently published Cochrane review on Transcatheter Arterial (Chemo) Embolization (TACE/TAE) treatment in hepatocellular carcinoma by Oliveri et al. [2]. The debate on the effectiveness of TACE in patients with intermediate stage hepatocellular carcinoma (HCC) is still open, indeed. On the one hand, as summarized in the updated American Association for the Study of Liver Diseases (AASLD) guidelines, there is no doubt that the level of evidence on the efficacy of TACE in the treatment of intermediate stage HCC is strong (IA, according to the standard evaluation [3], with a consequently strong grade of recommendation [Grade A]). On the other hand, there is also no doubt that this strength lies basically on the results of two randomized prospective studies [4,5] that deeply condition the two meta-analyses published on the topic [6,7]. Nevertheless, TACE is also supported by the fact that it is used in the everyday clinical practice of every center involved in the management of HCC, a very low level (IV), but still important, evidence. Dr. Forner correctly underlines that one of the papers quoted in Olivieri’s meta-analysis, the Doffoel’s randomized prospective trial of TACE vs. tamoxifen [8], presents many biases and includes patients that may have been ‘‘sub-optimally staged, selected and/ or treated’’. In several French studies, indeed (see also the two Pelletier’s articles [9,10]), the survival after TACE is so short that being affected by an intermediate stage HCC in France at the end of the last century would have suggested to move to other countries for treatment. Indeed, the reported 1-year survival (ranging from 25% to 50%) was not considered acceptable elsewhere and in past years those two studies heavily conditioned the clinical evaluation of TACE as a treatment for patients with multinodular HCC. The Cochrane review in any case casts new doubts on the topic, doubts that induce to wonder what to do in patients with intermediate stage HCC, if one accepts the conclusions of the review. In our experience, based on the data (prospectively collected over 20 years) of the ITA.LI.CA database, patients with intermediate stage HCC treated by TACE present a median survival of 35 months (42 months in those treated in the last decade), with 1and 5-year survivals of 80% and 18%, respectively. Having said this, it is worth noting that only a fraction of patients with an intermediate stage HCC were treated by TACE, while in the other cases, the treatment options vary from surgery or percutaneous treatments to best supportive care, depending on a number of factors not considered in the Barcelona Clinic Liver Cancer (BCLC) algorithm, such as age, co-morbidities, patient’s decision, and local expertise, particularly, as far as the availability of highly experienced surgical teams is concerned. Interestingly enough, patients with intermediate stage HCC who can be treated more aggressively tend to survive longer than those treated by

Sorafenib use in the transplant setting

Liver transplantation (LT) is an established treatment for hepatocellular carcinoma (HCC), and sorafenib (SFN) is a validated treatment for patients harboring advanced tumors. It is still not clear whether the combination of the 2 treatments, with SFN used in the neoadjuvant, adjuvant, or recurrence setting, is useful and cost‐effective. This article summarizes the present evidence in favor of and against the use of SFN in the setting of LT for HCC, and it also includes the problem of toxicity, particularly when mammalian target of rapamycin inhibitors, which play a central role in regulating cellular growth and proliferation, are used as immunosuppressants. Overall, the data do not support the use of SFN in the pre‐ or post‐LT setting as adjuvant therapy, and additional studies are needed to reach sound conclusions on the topic. Liver Transpl 20:1021–1028, 2014.

Megestrol and embryonic extracts in the treatment of advanced hepatocellular carcinoma : A prospective randomized trial in the pre-sorafenib era

Background:  Patients with advanced hepatocellular carcinoma (HCC) achieved significant results by the new treatment with sorafenib (a multi‐tyrosine kinase inhibitor), but, because it has been tested mainly in Child A cirrhosis, patients with impaired liver function are not eligible for the treatment.

External validation of the ITA.LI.CA prognostic system for patients with hepatocellular carcinoma: A multicenter cohort study

Several staging systems for hepatocellular carcinoma (HCC) have been developed. The Barcelona Clinic Liver Cancer staging system is considered the best in predicting survival, although limitations have emerged. Recently, the Italian Liver Cancer (ITA.LI.CA) prognostic system, integrating ITA.LI.CA tumor staging (stages 0, A, B1‐3, C) with the Child‐Turcotte‐Pugh score, Eastern Cooperative Oncology Group performance status, and alpha‐fetoprotein with a strong ability to predict survival, was proposed. The aim of our study was to provide an external validation of the ITA.LI.CA system in an independent real‐life occidental cohort of HCCs. From September 2008 to April 2016, 1,508 patients with cirrhosis and incident HCC were consecutively enrolled in 27 Italian institutions. Clinical, tumor, and treatment‐related variables were collected, and patients were stratified according to scores of the Barcelona Clinic Liver Cancer system, ITA.LI.CA prognostic system, Hong Kong Liver Cancer system, Cancer of the Liver Italian Program, Japanese Integrated System, and model to estimate survival in ambulatory patients with hepatocellular carcinoma. Harrells C‐index, Akaike information criterion, and likelihood‐ratio test were used to compare the predictive ability of the different systems. A subgroup analysis for treatment category (curative versus palliative) was performed. Median follow‐up was 44 months (interquartile range, 23‐63 months), and median overall survival was 34 months (interquartile range, 13‐82 months). Median age was 71 years, and patients were mainly male individuals and hepatitis C virus carriers. According to ITA.LI.CA tumor staging, 246 patients were in stage 0, 472 were in stage A, 657 were in stages B1/3, and 133 were in stage C. The ITA.LI.CA prognostic system showed the best discriminatory ability (C‐index = 0.77) and monotonicity of gradients compared to other systems, and its superiority was also confirmed after stratification for treatment strategy. Conclusion: This is the first study that independently validated the ITA.LI.CA prognostic system in a large cohort of Western patients with incident HCCs. The ITA.LI.CA system performed better than other multidimensional prognostic systems, even after stratification by curative or palliative treatment. This new system appears to be particularly useful for predicting individual HCC prognosis in clinical practice. (Hepatology 2018;67:2215‐2225)