Hepatocellular Carcinoma–Challenge and Prospect in the Early 21st Century

Zhaoyou Tang

Hepatocellular carcinoma(HCC) was the 4th cancer causing death in 1990, however in 2000 it ranked 3rd in the world (Parkin et al. 2001). In China, HCC ranked 2nd in causing cancer mortality since the 1990s. Despite of encouraging reports for HCC treatment in some research centers, the dismal outcome of HCC remains unchanged according to population–based data.

Challenge and prospects in the early 21st century will be briefly delineated.(1) Hepatitis B and C viruses (HBV and HCV), aflatoxin intake and alcohol remain the major causative factors of HCC. Primary prevention using HB vaccine has resulted in a decrease in HCC incidence in vaccinated children (Lee et al. 2003). An analysis of the literature revealed that interferon(IFN) reduced the incidence of both HBV and HCV-related HCC, but more studies are needed (Tabor et al. 2003).(2) The recent advances of HCC treatment indicate that surgery will remain of the major treatment for HCC. In the 1970s to 1980s, small HCC resection has contributed to the increase of long-term survival after HCC surgery. At the author’s institution, the analysis of 5364 inpatients (1958–2002) demonstrated that the marked increase of the 5–year survival (from 4.2%, 22.6% to 42.3% in the three consecutive periods) was well correlated to the marked increase of small HCC resection in the series (from 1.0%, 19.2% to 38.8%); moreover, of the 680 patients who survived more than 5 years, 56% of patients received small HCC resection. Screening using an assay for alpha fetoprotein in HBsAg carriers was reported to detect resectable HCC with increased survival (McMahon et al. 2000). However, small HCC resection is facing the challenge of regional cancer therapy (such as radiofrequency ablation), and particularly the biological characteristics of HCC, which remain the major obstacle for further improving the prognosis of small HCC resection. Down –staging followed by resection will probably be a new approach for treatment of a part of unresectable HCC in the new century. (3) The role of liver transplantation in the treatment of HCC will gradually increase, but it is mainly indicated for small HCC without vascular invasion and with Child B or Child C cirrhosis that is not suitable for resection. The expenses, shortage of donor organs and relapsing of viral hepatitis (particularly HCV) are problems that remain to be solved. Using living donors is one of the possible solutions. (4) The technique and concept of minimally invasive surgery will be a major influencing factor for treatment of HCC in the early 21st century. As a result of earlier diagnosis, different modes of regional cancer therapy for HCC will further develop. Three dimensional conformal radiotherapy, a kind of regional cancer therapy, will play a more important role. (5) Systemic chemotherapy has been disappointing in the past but in the future, for example, used selective chemotherapy can be promising. Biotherapy, including cytokines, differentiation inducers, anti-angiogenic agents, gene therapy and tumor vaccines will probably play a role, particularly in the prevention of tumor metastasis and recurrence. Unfortunately, based on the analysis of more than 60 randomized controlled trials, nothing has been thoroughly proved to prolong survival of patients with unresectable HCC, except transcatheter arterial chemoemobolization, which needs further study. (6) HCC invasion and metastasis will be a major target to be studied in the new century. To this end, a stepwise metastatic human–HCC model system has been established at the author’s institution. This system will be of value for studying HCC metastasis related chromosomes / genes / proteins. Monogene–based studies revealed that HCC was similar to that of other solid tumors, and biological characteristics of small HCC were only slightly better than that of large HCC. Using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), genotyping, cDNA microarrays and 2-dimensional gel electrophoresis, we have obtained some interesting results. In particular, in collaboration with NCI, NIH in the United States, we generated a molecular signature that can classify metastatic HCC patients, identified osteopontin as a lead gene in the signature, and found that genes favoring metastatic progression were initiated in the primary tumors. We also found that chromosome 8p deletion, particularly in the region of 8p23, associated with HCC metastasis. Cytokeratin 19 was identified as the only protein that appears in MHCC97H but not in MHCC97L. Experimental interventions using the highly metastatic nude mice model have provided clues for prevention of HCC metastasis. Translation from bench to bedside demonstrated that serum VEGF, microvessel density and p53 scoring may be of value for prediction of postoperative metastatic recurrence. Interferon alpha proved effective for prevention of recurrence both experimentally and clinically. In short, HCC metastasis probably initiate in the primary tumor as a multigene–involved, multistep and changing process. The further elucidation of the mechanism underlying HCC metastasis will provide a more solid basis for the prediction and prevention of metastatic recurrence of HCC.

To sum up, there are many stones yet unturned for conquering HCC in the 21st century, but the future is hopeful.