Table 4 and Figure 3 shows the results of TTP and OS compared between the subjects with MVI or EHS, against subjects with HBV or HCV infection. Among subjects with MVI, those with HBV infection had a significant poorer TTP (mean 2.64 vs 4.74 months, P = .019) but similar OS (mean 4.53 vs 7.00 months, P = .059) compared to those with HCV infection. On the contrary, no difference was found regarding TTP and OS between EHS patients with HBV and those with HCV.
The incidence of HCC is rising steadily and the survival rate for HCC patients is poor. Patients with HCC most often are presented at their intermediate and advanced stages, and those therapies, involving surgery or radiofrequency ablation, are no longer effective. The recommended treatment for these patients are locoregional therapies, such as transarterial chemoembolization, and systemic therapy.[9–11]
Sorafenib is currently the first-line systemic medication approved for the treatment of unresectable HCC. The approval is based on the results of a multicenter, randomized, phase III SHARP study that has demonstrated the benefit of sorafenib on OS over placebo (sorafenib vs placebo, 10.7 vs 7.9 months; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.55–0.87; P = .001). Similar benefits of sorafenib were also reported in a phase III Asia Pacific study conducted in patients from the Asia Pacific region (sorafenib vs placebo, 6.5 vs 4.2 months; HR, 0.68; 95% CI, 0.50–0.93; P = .014).
One limitation of the sorafenib treatment is that a substantial number of patients fail to respond to the medication, at a disease-control rate as high as 43%. In an exploratory subgroup analysis of the SHARP trial, patients positive for HCV show a well improved median OS of 14 months compared with 7.4 months in the placebo, and this benefit is also seen in terms of time to tumor progression (7.6 vs 2.8 months) and disease control rate (44.2% vs 29.6%).
Comparing HBV and HCV infection, HR relative to OS was 0.76 in the HBV group (95% CI, 0.38–1.50), compared to 0.50 (95% CI, 0.32–0.77) in the HCV group. This tendency appears also regarding time to progression (HR1.03 for HBV patients, and 0.43 for HCV patients. Results are consistent with another study on HBV positive-HCC patients based on subgroup analysis of the phase III AP study, where the HR for OS was 0.74 (95% CI 0.51–1.06) compared to an HR of 0.57 (0.29–1.33) for patients with other etiology.
A pooled exploratory analysis of 827 patients from the SHARP and the AP phase III studies, reported that the presence of MVI and high levels of AFP are strong prognostic factors for poorer OS. Significantly greater OS sorafenib benefit over the placebo was observed in patients with HCV infection (HR, 0.47 vs 0.81). An aggregate meta-analysis enrolling 4 clinical trials suggested that sorafenib is more efficacious for patients with HCV infection (HR 0.65, 95% CI 0.53–0.80) versus those without (HR 0.87, 95% CI 0.79–0.96).
Our present results showed findings consistent with the previous reports. Subjects with HCV infection had a better TTP and OS compared to those with HBV infection. Those with EHS also had a longer TTP and OS than those with MVI, although these differences did not reach statistical significant levels. For patients with HBV infection, the occurrence of MVI, was associated with a significantly poorer outcomes in TTP and OS when compared to the occurrence of EHS. On the contrary, such occurrence of MVI or EHS did not alter the final outcome of patients with HCV infection.
The pathogenesis of greater sorafenib efficacy to HCV-infected cases of HCC patients is not clear yet. Some in vitro studies suggested that sorafenib inhibits HCV viral replication directly.[14,15] Other reported that HCV upregulates C-RAF or enhances the expression of microRNAs, thereby influencing the sensitivity of HCC cells to sorafenib. Another probable explanation is that HCV-mediated hepatocarcinogenesis strongly mediated by type I and III IFN, through the induction of kinases phosphorylation. Therefore, in this setting, the multikinase inhibitor sorafenib could be more efficacious. Inconsistently, HBV-positive HCC patients are reportedly characterized by an interleukin-6 dependent inflammatory process, which is different from the pathogenesis sorafenib is working on.
Here are several limitations of our study. First, it is a retrospective analysis of patients treated at a single tertiary care center. Selection bias of samples cannot be ruled out. Second, we did not measure elements of patient medical history like viral hepatitis, such as nucleotide/nucleoside analogs, interferon or direct-acting antivirals. Third, neither the grade of MVI nor location of EHS, both of which might influence the treatment outcome, were recorded and analyzed. Finally, we only analyzed subjects diagnosed with cirrhosis Child-Pugh stage A and HCC BCLC stage C. Further prospective research involving analysis of more variables is needed.
In conclusion, our study showed that HCC patients with HCV infection or presence of EHS are associated with better sorafenib treatment outcomes. The HBV-positive patients with MVI showed a poorer outcome to sorafenib therapy.
Conceptualization: Shou Wu Lee.
Data curation: Shou Wu Lee.
Formal analysis: Teng-Yu Lee, Sheng-Shun Yang.
Investigation: Hong-Zen Yeh, Chi-Sen Chang.
Methodology: Shou Wu Lee, Yen-Chun Peng, Hong-Zen Yeh.
Writing – original draft: Shou Wu Lee, Teng-Yu Lee, Yen-Chun Peng, Hong-Zen Yeh, Chi-Sen Chang.
Writing – review & editing: Shou Wu Lee, Teng-Yu Lee, Sheng-Shun Yang, Chi-Sen Chang.
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Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
hepatitis B; hepatitis C; hepatocellular carcinoma; sorafenib