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.
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.
Using Italian and Taiwanese cohorts, Alessandro Vitale and colleagues develop and validate a staging system and prognostic model for hepatocellular carcinoma.
Primary liver cancer—a tumor that starts when a liver cell acquires genetic changes that allow it and its descendants to divide uncontrollably and move around the body (metastasize)—is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide. Liver cancer kills more than three-quarters of a million people every year, mostly in resource-limited countries. The risk of developing hepatocellular carcinoma (HCC; the most common type of liver cancer) is highest in eastern and southeastern Asia; among wealthier nations, the risk of HCC is particularly high in Italy. HCC can be treated by surgical removal of part of the liver, liver transplantation, ablation (which uses an electric current to destroy the cancer cells), intra-arterial therapies (which deliver drugs directly into the liver), or systemic (whole body) drug therapies. However, the symptoms of HCC, which include weight loss, tiredness, and jaundice, are vague. HCC is therefore rarely diagnosed before the cancer is advanced and has a poor prognosis (likely outcome)—fewer than 5% of patients survive for five or more years after diagnosis.
Why Was This Study Done?
Cancer staging describes the severity of a cancer based on the size and extent of the original tumor and whether the tumor has metastasized. Staging helps doctors estimate the patient’s prognosis and can help them devise a treatment plan that will, hopefully, improve patients’ quality of life and may extend their life expectancy. Several staging systems have been devised for HCC, but prognostic assessment of patients with HCC is controversial. No single prognostic model (a model that allows clinicians to obtain predictions about the likely outcomes of individual patients) has been universally adopted. An ideal model is difficult to achieve as it would need to consider tumor-related, liver-function-related, and patient-related variables, all of which have different impacts on patient prognosis. Here, the researchers use a database created by the Italian Liver Cancer (ITA.LI.CA) group that includes information on more than 5,000 Italians with HCC to develop a new prognostic model to predict individual patient outcomes based on tumor-related, liver-function-related, and patient-related variables.
What Did the Researchers Do and Find?
The researchers first defined ITA.LI.CA stages for HCC using tumor characteristics only. They then used information on 3,628 patients in the ITA.LI.CA database (the “training” set) and statistical modeling to calculate the relative prognostic value of tumor staging, Eastern Cooperative Oncology Group (ECOG) performance status (an indicator of whether patients are able to look after themselves and undertake normal daily activities), liver function (measured using the Child—Pugh score), and alpha-fetoprotein level (a liver tumor marker) in the prediction of the survival of individual patients. Based on these modeling results, they constructed an ITA.LI.CA integrated prognostic score. The researchers report that the observed and predicted median (average) survival times in the training set and in an internal validation cohort of 1,555 additional patients in the ITA.LI.CA database were similar. Moreover, although the observed and predicted survival times were lower in the Italian patients than in 2,651 patients with HCC from Taiwan, the ITA.LI.CA score had high discrimination and calibration features in this external validation cohort as well (the discrimination of a prognostic model indicates its ability to separate patients into groups with different outcomes, the calibration of a prognostic model is the degree of correspondence between predicted and observed outcomes). Finally, the prognostic ability of the new ITA.LI.CA prognostic model was significantly better than that of several other prognostic scoring systems.
What Do These Findings Mean?
These findings introduce a revised staging system for HCC and an integrated prognostic score—the ITA.LI.CA prognostic score—based on this staging system, Child—Pugh score, ECOG performance status, and alpha-fetoprotein level that has a greater ability to predict survival among Italian and Taiwanese patients than previous prognostic models. Because this study was retrospective—previously recorded data, including outcomes, were used to develop the prognostic model—a prospective trial is needed to validate the ITA.LI.CA prognostic score. That is, researchers need to enroll a group of patients, determine their ITA.LI.CA prognostic scores, and then follow the patients to determine their actual outcomes. If validated in this way and in other populations, use of the ITA.LI.CA prognostic score should allow clinicians to provide more accurate prognoses for individual patients, and may be a starting point for evaluating which treatment option is best suited to each patient presenting with HCC.
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1002006.
This study is further discussed in a PLOS Medicine
Perspective by Neehar Parikh and Amit Singal
The US National Cancer Institute provides information about all aspects of cancer, including detailed information for patients and professionals about primary liver cancer and about cancer staging (in English and Spanish)
The American Cancer Society also provides information about liver cancer (including information on support programs and services; available in several languages)
The UK National Health Service Choices website provides information about primary liver cancer (including a video about coping with cancer) and about cancer staging
Cancer Research UK (a not-for-profit organization) provides detailed information about primary liver cancer
The British Liver Trust (a not-for-profit organization) also provides information about liver cancer, including a personal story
MedlinePlus provides links to further resources about liver cancer (in English and Spanish)