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.


RESULTS
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.
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
Fabio
F
Farinati
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
Alessandro
A
Vitale
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
Gaya
G
Spolverato
Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland, United States of America.
Timothy M
TM
Pawlik
National Yang-Ming University, Taipei City, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan.
Teh-la
TL
Huo
National Yang-Ming University, Taipei City, Taiwan.|Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan.
Yun-Hsuan
YH
Lee
Biostatistics Unit, University of Padua, Padua, Italy.
Anna Chiara
AC
Frigo
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
Anna
A
Giacomin
Gastroenterology Unit, Department of Internal Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino IST, University of Genoa, Genoa, Italy.
Edoardo G
EG
Giannini
Division of Surgery, San Marco Hospital, Zingonia, Italy.
Francesca
F
Ciccarese
Division of Internal Medicine, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Fabio
F
Piscaglia
Division of Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Università Cattolica del Sacro Cuore, Rome, Italy.
Gian Lodovico
GL
Rapaccini
Division of Medicine, Bolognini Hospital, Seriate, Italy.
Mariella
http://orcid.org/0000-0002-4648-3365
M
Di Marco
Division of Gastroenterology, Belcolle Hospital, Viterbo, Italy.
Eugenio
E
Caturelli
Division of Internal Medicine, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Marco
M
Zoli
Division of Radiology, Department of Medicine, Fatebenefratelli Hospital, Milan, Italy.
Franco
F
Borzio
Division of Gastroenterology, Biomedical Department of Internal and Specialistic Medicine, University of Palermo, Palermo, Italy.
Giuseppe
G
Cabibbo
Division of Gastroenterology, Bolzano Regional Hospital, Bolzano, Italy.
Martina
http://orcid.org/0000-0002-9697-5843
M
Felder
Division of Gastroenterology and Metabolic Diseases, University Hospital of Pisa, Pisa, Italy.
Rodolfo
R
Sacco
Division of Gastroenterology, Department of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
Filomena
F
Morisco
Division of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Elisabetta
E
Biasini
Department of Internal Medicine, Ospedale per gli Infermi di Faenza, Faenza, Italy.
Francesco Giuseppe
FG
Foschi
Division of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Roma, Italy.
Antonio
A
Gasbarrini
Division of Gastroenterology, Polytechnic University of Marche, Ancona, Italy.
Gianluca
G
Svegliati Baroni
Division of Internal Medicine 2, Ospedali Riuniti Villa Sofia Cervello, Palermo, Italy.
Roberto
R
Virdone
Gastroenterology Unit, Ospedale Sacro Cuore Don Calabria, Negrar, Italy.
Alberto
http://orcid.org/0000-0002-0496-1461
A
Masotto
Division of Semeiotics, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Franco
F
Trevisani
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
Umberto
U
Cillo
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000401:mortality / Q000556:secondary*; D016208:Databases, Factual; D003661:Decision Support Techniques; D005260:Female; D006801:Humans; D007558:Italy; D008113:Liver Neoplasms / Q000097:blood* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging / Q000379:methods*; D009378:Neoplasms, Multiple Primary; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013624:Taiwan; D013997:Time Factors; D047368:Tumor Burden; D000509:alpha-Fetoproteins / Q000032:analysis*
C097353:AFP protein, human; D000509:alpha-Fetoproteins