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 64 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

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

Survival Benefit of Liver Transplantation Versus Resection for Hepatocellular Carcinoma: Impact of MELD Score

We sought to measure the impact of model for end stage liver disease (MELD) score, tumor staging, and microvascular invasion (MVI) on the relative survival benefit of liver transplantation (LT) versus liver resection (LR) for hepatocellular carcinoma (HCC). The study population comprised 1,106 HCC patients with cirrhosis undergoing LR from one Eastern (n = 424) and two Western (n = 682) surgical units. Exclusion criteria were very large (> 10 cm) tumors, macrovascular invasion, and metastases. We identified three tumor stages: stage I (within Milan, n = 806), stage II (beyond Milan within Up-to-7, n = 123), and stage III (beyond Milan and Up-to-7, n = 177). Patient survival after LR was compared to that predicted after LT by the Metroticket calculator in relationship with staging, MVI, and MELD score using Monte Carlo simulation. Two hundred eighty-three patients (26 %) with a MELD score of a parts per thousand yen10 had an acceptable 5-year survival after LR of 47 %, while that of patients with a low MELD score was 67 % (p < 0.0001). Mean 5-year LT benefit was -4.50 months (95 % confidence interval [CI] -4.73 to -4.27) for patients with a MELD score of < 10, and 0.81 months (95 % CI 0.58 to 1.04) for those with a MELD score of a parts per thousand yen10. MELD score and MVI were the strongest predictors of transplant survival benefit. LT reached a survival benefit, versus LR only in HCC patients with a MELD score of a parts per thousand yen10 and without MVI (3.08 months, 95 % CI 2.78 to 3.39), whatever the tumor stage. LT proved to be harmful in patients with resectable HCC with a low MELD score (< 10) or with aggressive tumors (with MVI). As a result of a shortage of donors, only selected resectable tumors with a MELD score of a parts per thousand yen10 should be considered for transplantatio

Prognostic role of noninvasive liver reserve markers in patients with hepatocellular carcinoma undergoing transarterial chemoembolization

Background Various noninvasive liver reserve markers were proposed to indicate the severity of liver damage. However, the role and feasibility of these markers to predict the prognosis of patients with hepatocellular carcinoma (HCC) are unknown. We aimed to identify the prognostic role of the 8 currently used hepatic reserve markers in patients with HCC undergoing transarterial chemoembolization (TACE). Methods Between 2002 and 2013, a total of 881 patients with HCC undergoing TACE were prospectively identified and retrospectively analyzed. The baseline characteristics, tumor status and noninvasive markers were collected. Homogeneity and corrected Akaike information criteria (AICc) were compared between these markers. The Cox proportional hazards model was used to identify independent predictors of survival. Results Significant differences in survival distribution were found for albumin-bilirubin (ALBI) grade, Child-Turcotte-Pugh (CTP) class, Lok index, fibrosis index based on 4 factors (FIB-4), Go E teborg University cirrhosis index (GUCI), cirrhosis discriminant index (CDI) and model for endstage liver disease (MELD) score (all p values <0.05). Among these markers, the ALBI grade showed the highest homogeneity and lowest AICc value, indicating a better prognostic performance. Cox multivariate analysis confirmed that ALBI grade 2, ascites, serum alkaline phosphatase and alpha-fetoprotein level, tumor diameter, vascular invasion and performance status were significant independent prognostic predictors. The distribution of the ALBI score well correlated with baseline CTP and MLED scores. Conclusions Our data suggest that among the currently used liver reserve markers, ALBI grade may serve as an objective and feasible surrogate to predict the prognosis of HCC patients undergoing TACE

Expected versus observed survival in the external validation cohort.

<p>Patients were divided into quartiles at the 25th, 50th, and 75th percentiles of the risk score. Quartile 1 coincided with ITA.LI.CA score ≤ 1, quartile 2 with score 2–3, quartile 3 with score 4–5, quartile 4 with score > 5.</p

Patient characteristics of the three groups.

<p>Patient characteristics of the three groups.</p

Expected versus observed survival in the internal validation cohort.

<p>Patients were divided into quartiles at the 25th, 50th, and 75th percentiles of the risk score. Quartile 1 coincided with ITA.LI.CA score ≤ 1, quartile 2 with score 2–3, quartile 3 with score 4–5, quartile 4 with score > 5.</p

Discrimination ability of the integrated ITA.LI.CA prognostic system and comparison with other staging systems in the training and internal validation cohorts (<i>n</i> = 5,183) stratified based on study period.

<p>Discrimination ability of the integrated ITA.LI.CA prognostic system and comparison with other staging systems in the training and internal validation cohorts (<i>n</i> = 5,183) stratified based on study period.</p

Expected versus observed survival in the training cohort.

<p>Patients were divided into quartiles at the 25th, 50th, and 75th percentiles of the risk score. Quartile 1 coincided with ITA.LI.CA score ≤ 1, quartile 2 with score 2–3, quartile 3 with score 4–5, quartile 4 with score >5.</p