Abstract
Background: A sustained virological response (SVR) to interferon (IFN) therapy for chronic hepatitis C virus (HCV) reduces but does not eliminate the risk of hepatocellular carcinoma (HCC). The prognosis after hepatectomy for HCC in patients with SVR has not been fully clarified. Patients and Methods: Between 1998 and 2011, 494 patients with chronic hepatitis C underwent hepatic resection for HCC at four high-volume Centers in Japan. Out of these, 188 underwent IFN therapy for HCV. In 92 patients, SVR to IFN therapy had been achieved at the time of hepatectomy (SVR group) while in 96 patients, SVR had not (non-SVR group) had not been achieved. In the other 306 patients, IFN therapy had never been performed at all (no IFN group). The clinicopathological factors and long-term outcomes were retrospectively reviewed and compared among SVR, non-SVR and no IFN groups. Results: The mean time from achievement of SVR to hepatectomy for HCC was 6.2 years (range=2 months to 20 years). The preoperative serum alanine transaminase, albumin, prothrombin time, indocyanine green retention test at 15 min were significantly preserved in the SVR group. The overall survival and recurrence-free survival rates were significantly higher in the SVR group compared to patients in non-SVR and no IFN groups. Conclusion: In patients undergoing hepatectomy for HCC, those with SVR had good liver function and a more favorable long-term prognosis than those without SVR. Early detection of HCC after SVR and meticulous hepatectomy with small blood loss is important in patients with HCC after hepatectomy.
Hepatocellular carcinoma (HCC) is the fourth most common malignancy in Japan and the fifth most common worldwide, with hepatectomy being the mainstay of treatment (1, 2).
In Japan, hepatitis C virus (HCV) infection has been reported to be the most common cause of HCC, approximately 70% of all cases had on HCV antibody (3). Low disease-free survival after curative therapies, and the progression of cirrhosis and deterioration of liver function caused by chronic HCV infection are considered to be reasons for the poor prognosis of HCV-related HCC after hepatectomy (4).
Interferon (IFN) therapy has been the standard for HCV infection and 60-90% of patients with HCV achieve a sustained virological response (SVR), that is defined as no detection of HCV RNA in the serum at 24 weeks after cessation of therapy with pegylated IFN plus ribavirin (5,6). SVR is reported to reduce the risk of HCC occurrence, but does not eliminate it (7-18). The incidence of HCC after achievement of a SVR has been reported to be from 0.9% to 4.2% and its incidence increases with follow-up. Because the incidence of SVR after IFN therapy has improved based on recent advancements of HCV treatment (19), the number of patients with SVR after IFN will increase. Therefore, HCC after SVR is also expected to increase in the very near future. Nevertheless, the clinicopathological characteristics of HCC and prognosis after hepatectomy in patients with SVR have not been fully described.
Recently, we reported a preliminary study, using small number of patients in a single Center (20). Herein, we report the operative results of hepatectomy for HCC in patients with SVR after IFN therapy using retrospective data in multicenter. The purpose of the present study was to clarify the characteristics of HCC after HCV eradication, and the short- and long-term outcomes after hepatectomy.
Patients and Methods
Data of 494 patients with HCC associated with HCV, who underwent hepatectomy from 1998 to 2011, were collected from the records of the Departments of Surgery and Science, Kyushu University, Department of Surgery, Steel Memorial Yawata Hospital, Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, and Department of Surgery, Iizuka Hospital. Their clinical outcomes were retrospectively reviewed. This study was approved by the local Ethical Committee in Kyushu University (approval no. 27-115). Of 494 patients, IFN therapy for HCV hepatitis was performed in 188, including IFN before hepatectomy, and 92 of these 188 patients achieved SVR, defined as persistent disappearance of HCV RNA 21. Three hundred and six patients underwent hepatectomy for HCC and had never been treated by IFN therapy before or after hepatectomy (no IFN therapy group).
Histological evaluation of hepatic resection specimens was based on a previously reported classification system (22-25). Staging of liver fibrosis was defined as F0 (no fibrosis), F1 (fibrous portal expansion), F2 (bridging fibrosis), F3 (bridging fibrosis with architectural distortion) or F4 (cirrhosis). The extent of hepatic resection was decided by tumor location, tumor size, and the results of conventional liver function tests, including the indocyanine green retention rate at 15 min (ICG-R15). The general rules for clinical and pathological studies of primary liver cancer outlined by the Liver Cancer Study Group of Japan (26) were used for clinical and pathological descriptions.
Prognostic factors after hepatectomy by univariate and multivariate analyses were examined using Cox proportional hazard model. All statistical analyses were performed using JMP ver. 8.0 program (SAS Institute, Cary, NC, USA). Categorical data were compared using the Chi-square test and Mann–Whitney test. Survival rates were calculated by the Kaplan–Meier method and were compared using the log–rank test. A value of p<0.05 was considered statistically significant.
Results
Occurrence of HCC in patients with SVR. The mean time from achievement of SVR to HCC resection was 6.2 years (range=2 months to 20 years) (Figure 1). The peak of HCC occurrence after SVR achievement was from 2.5 to 5 years. Nevertheless, the HCC occurrence was not uncommon 5 years after SVR.
Comparison of clinicopathological background among SVR, non-SVR and no IFN therapy groups. The clinicopathological background of patients with HCC were compared among SVR, non-SVR and no IFN groups (Table I). The patients in the SVR group were significantly younger than those in non-SVR and no IFN groups (p<0.01). Males were more common in the SVR group than in the non-SVR group. Preoperative serum albumin, alanine aminotransferase (ALT), prothrombin time and ICGR15 were significantly better in the SVR group, indicating that hepatic reserve was preserved. Among tumor-related parameters, tumor diameter of HCC in the non-SVR group was significantly smaller than that in the no IFN group (p<0.05). Serum tumor marker levels, vascular invasion and stage of HCC were not significantly different between the group with SVR and the control groups. The histological grade of fibrosis in noncancerous liver tissue was significantly lower in the SVR group than in the non-SVR and no IFN groups. Of the perioperative parameters, the blood transfusion rate tended to be lower in the SVR group than the non-SVR and no IFN groups.
Interval between achievement of sustained virological response (SVR) and hepatectomy is shown. The mean period was 6.2 years (range from 2 months to 20 years).
Long-term prognosis after hepatectomy. Long-term outcomes were compared among three groups: SVR (n=92); non-SVR (n=96); and no IFN group (n=306). Recurrence-free survival (RFS) and cumulative overall survival (OS) rates after hepatectomy among three groups are shown in Figure 2 and 3. The RFS rate in the SVR group was significantly higher than in the non-SVR and no IFN groups (p=0.0020). RFS rates at 5 years after hepatectomy in the SVR, non-SVR and no IFN groups were 41.2%, 16.7%, and 18.6%, respectively. In the SVR group, recurrence of HCC rarely occurred 7 years or more after hepatectomy. The OS rates of the three groups are shown in Figure 3. The OS rate in the SVR group was significantly higher than the in non-SVR and no IFN groups (p<0.0001). The OS rates at 5 years after hepatectomy in the SVR, non-SVR and no IFN groups were 84.5%, 66.2%, and 56.2%, respectively.
Comparison in clinicopathological background among the three groups.
Recurrence-free survival rates of groups of patients with hepatocellular carcinoma (HCC) with preoperative sustained virological response (SVR) (n=92), no SVR (n=96), and no IFN therapy (n=306).
Prognostic factors after hepatectomy. Prognostic factors after hepatectomy by univariate and multivariate analyses were examined, using Cox proportional hazard model (Tables II and III). After univariate analysis, parameters in hepatic functional reserve, such as serum albumin, ICGR15, and prothrombin time, were significant prognostic factors. Serum AST, reflecting hepatic inflammation and SVR achievement, and histological fibrosis of non-cancerous liver were significant prognostic factors. Out of tumor-related factors, tumor size, multiple tumors and the presence of vascular invasion were significant prognostic factors. Out of surgical procedures, operative time, blood loss, and blood transfusion were significant prognostic factors.
Overall survival rates of groups of patients with hepatocellular carcinoma (HCC) with preoperative sustained virological response (SVR) (n=92), no SVR (n=96), and no IFN therapy (n=306).
Prognostic factors in cumulative overall survival in 494 patients by univariate analysis.
After multivariate analysis, SVR achievement, tumor size, liver cirrhosis, and blood transfusion were significant prognostic factors.
Prognostic factors after hepatectomy in the SVR group. Prognostic factors after hepatectomy in the SVR group were examined by univariate and multivariate analyses, using Cox proportional hazard model (Tables IV and V). In the SVR group, serum AST, tumor size, vascular invasion, tumor stage, serum AFP, anatomical resection, operative time and blood loss were significant prognostic factors after univariate analysis (Table IV). After multivariate analysis, tumor size, tumor stage, liver cirrhosis, and blood loss were significant prognostic factors (Table V).
Prognostic factors in cumulative overall survival in 494 patients by multivariate analysis.
Discussion
The previous reports show that HCC can occur even after HCV eradication by anti-viral therapy including IFN (6-18). Its incidence was reported to be 0.3 to 4.2% during a mean observation period of 3.3 to 8 years. The incidence increased with observation. Because of advancement in HCV anti-viral treatment, the proportion of patients with SVR is expected to increase as is the incidence of patients with HCC after SVR.
In this series, HCC occurred at a mean of 6.2 years after HCV was eradicated and the longest period was 20 years after SVR achievement. Therefore, long-term and lifelong screening for HCC might be important in patients even after SVR, especially with risk of HCC development. The risk factors for developing HCC after SVR were reported to be high age, male sex, liver fibrosis, alcohol intake, fat deposition in the liver and insulin resistance (7-18). There is no report on recommendable surveillance for HCC in these patients. In this study, tumor-related factors, such as the presence of vascular invasion and stage, were important prognostic factors after hepatectomy. Therefore, early detection of HCC by surveillance is important.
Prognostic factors in culumative overall survival in 92 patients after sustained viral response (SVR) by univariate analysis.
The prognosis, both OS and RFS, of patients in the SVR group was significantly better than that in non-SVR and no IFN therapy in this study. The good liver reserve function, reflected by serum albumin levels, prothrombin time and ICGR15 in the SVR group may be a cause of preferable outcome after hepatectomy, because good liver function is reported to be one of the most important factors in prognosis after hepatectomy in patients with HCC (27).
We found that the amount of operative blood loss was significantly lower in patients with SVR. It is suggested that improvement of coagulopathy and portal hypertension due to SVR contributed to the better results of surgery. Meticulous hepatectomy with small blood loss and without blood transfusion is important in patients, as we have shown the same in patients with HCV-related HCC who underwent hepatectomy (27).
The long-term prognosis of HCC is still relatively poor, and there is considerable room for improvement (1, 28). The overall 3- and 5-year survival rates of patients after hepatectomy for HCC have been reported to be 70.5% and 54.6%, respectively (28, 29). We compared long-term results after hepatectomy according to SVR status, and found that patients who developed HCC after SVR had a significantly higher RFS rate than patients without SVR. Late recurrence after hepatectomy of more than 6 years was rare in the SVR group. These results suggest that the recurrence was caused by intrahepatic metastases rather than multicentric disease (30). Therefore, our data suggest that radical treatment should be undertaken in patients with SVR who develop primary HCC in order to achieve better long-term outcomes and in some patients, cure of HCC might be achieved.
Prognostic factors in cumulative overall survival in 92 patients after sustained viral response (SVR) by multiivariate analysis.
In conclusion, in patients undergoing hepatectomy for HCC, those with SVR had good liver function and a more favorable long-term prognosis than those without SVR. Early detection of HCC after SVR and meticulous hepatectomy with small blood loss is important in patients after hepatectomy for HCC.
Acknowledgements
This research was partly supported by the Research Program on Hepatitis from Japan Agency for Medical Research and Development, AMED.
Footnotes
Conflicts of Interest
None.
- Received September 20, 2015.
- Revision received October 21, 2015.
- Accepted October 26, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
