In this large cohort study, we analyzed 2316 HCC patients to identify the prognostic factors and treatments affecting OS. Our results demonstrated that the risk factors for OS were SR, cirrhosis, C-P class, and HBV infection within groups with different BCLC stages (Table 2). SR resulted in significantly higher OS rates than non-SR treatments among patients with HCC of various BCLC stages. After PSM, SR still had significantly higher OS rates than non-SR treatments among patients with HCC of various BCLC stages. As SR conferred significant survival benefits to patients with HCC of different BCLC stages, it should be considered a recommended treatment for selected HCC patients, especially patients with BCLC stage B and C disease.
SR, RFA and liver transplantation are the recommended treatment modalities for very early- and early-stage HCC [6, 7]. Several studies have shown that SR results in better long-term OS than RFA in very early- and early-stage HCC [18–20]. Consistent with previous studies [18–20], our results demonstrated that SR resulted in significantly higher OS rates when compared to non-SR treatments in patients with BCLC stage 0 and A disease.
TACE is recommended as a standard of care for the treatment of patients with BCLC stage B disease [6, 7]. Several HCC experts have proposed four substages based on the Eastern Cooperative Oncology Group (ECOG) performance, C-P class, and “up-to-7” criteria within BCLC stage B disease [21]. However, these criteria mostly indicate benefits from TACE. Based on the great improvements in surgical techniques and perioperative care, some treatments may not be suitable for patients with intermediate- and advanced-BCLC stage HCC. Our results showed that SR resulted in a significantly higher OS rate than non-SR Treatments including RFA, TACE, and other treatments in patients with BCLC stage B disease. Similarly, several studies from both Western and Eastern countries have demonstrated that SR results in higher long-term survival than non-SR treatments, even for patients with multiple tumors [9, 10, 13, 22]. Furthermore, compared with TACE, SR significantly increases survival in select patients with BCLC stage B HCC [13, 23]. SR is a safe and effective therapy for select patients with resectable multiple or large HCC lesions in the same half-liver and sufficient liver reserve. Hence, SR may be considered for select patients who fit these criteria and could be recommended for patients with BCLC stage B disease.
Patients with BCLC stage C disease have poor outcomes because of the presence of advanced HCC associated with major vascular invasion and/or extrahepatic metastasis. Sorafenib is the only recommended standard of care for advanced HCC based on the BCLC staging system. However, because of the large heterogeneity in the population with advanced-stage HCC, SR is no longer contraindicated and provides survival benefit [10, 22]. Moreover, several studies have demonstrated significantly favorable survival in HCC patients with major vascular invasion, including the portal vein, hepatic vein and inferior vena cava, after SR [24–26]. Our results also confirmed the data from previous studies [10, 22, 24] and demonstrated that SR improved OS rates in patients with advanced-stage HCC. Therefore, meticulous and accurate selection criteria (HCC is located on the left or right lobe of liver, and portal vein tumor thrombosis in the segmental branch or first branch of portal vein can be excised in the same half-liver) should be established to identify individuals, among patients with vascular invasion, who would benefit most from SR. Hence, SR may also be considered for select patients with BCLC stage C HCC.
Liver function preservation, including C-P class and cirrhosis, is an important non-oncological factor affecting OS. Poor liver function preservation decreases the efficacy of treatment and increases mortality. Our results showed that cirrhosis and C-P class significantly affect OS in patients with HCC of various BCLC stages. Patients with cirrhosis easily develop portal hypertension, liver failure, and HCC. Additionally, patients with C-P class B disease have low survival. It is important to treat liver disease using antiviral therapy and prevent liver disease progression.
Taiwan is a hyperendemic area for HBV-related liver diseases and HCC. HBV infection can result in hepatocarcinogenesis, and multiple mechanisms have been proposed, including the accumulation of genetic damage due to the induction of oxidative stress and immune-mediated hepatic inflammation. The integration of HBV DNA into the human genome occurs during the early steps of carcinogenesis and can induce alterations in cancer-related gene expression and chromosomal instability [27, 28]. Our study demonstrated that 71.6% of HCC patients had HBV infection and that HBV infection significantly reduced OS rates in patients with BCLC stage B and C disease. In Taiwan, HBV-related HCC accounted for 88% of all cases before 1990, whereas from 1990 to 2000, the proportion of HBV-related HCC decreased to 66% [29, 30]. Our study demonstrated that 71.6% of HCC patients had HBV infection, and the proportion of HBV-related HCC remained high in southern Taiwan. In addition, HBV infection significantly reduces OS rates in patients with BCLC stage B and C disease. Therefore, it is probable that HCC is caused not only by cirrhosis but also by HBV infection-induced hepatocarcinogenesis.
Our study has several limitations. First, as with all retrospective studies, there was some selection bias, including differences among patients regarding treatment decisions and the presence of incomplete data. Second, patients might receive multimodal treatments in a sequential manner, which would make direct comparison of every single treatment difficult in intermediate- and advanced-stage disease. Third, patients undergoing liver transplantation were not included because of the small sample size.
Compared with nonsurgical treatments, SR significantly promoted survival benefits not only in very early- and early-stage but also in intermediate- and advanced-BCLC stage HCC. More effort should be made to determine the proper selection criteria for SR in patients, especially in patients with intermediate- and advanced-stage disease. Additionally, the BCLC staging system should be further modified based on results from the clinic and responses to combinations of various treatment modalities.