Objectives: Hepatic resection and liver transplant are regarded as 2 potentially curative treatments for hepatocellular carcinoma. Here, we compared both options in patients with hepatocellular carcinoma secondary to cirrhosis seen at a single center over 12 years.
Materials and Methods: We evaluated early complications and survival of patients with hepatocellular carcinoma treated with liver transplant (57 patients) or hepatic resection (36 patients) at our center between 1998 and 2010.
Results: The 34-month mean follow-up period was similar for both treatment groups. The liver transplant group had a longer hospital stay than the hepatic resection group (P < .001). Patients with Child-Turcotte-Pugh A stage were treated by hepatic resection more than by liver transplant (P < .001),with Child-Turcotte-Pugh B stage patients treated by liver transplant more than by hepatic resection (P = .03). All patients with Child-Turcotte-Pugh C stage had liver transplant. Both treatment groups had similar postoperative complications and early postoperative mortality rates, but liver transplant resulted in longer overall (P = .001) and higher event-free (P = .001) survival than hepatic resection. Among the liver transplant group, 57.8% of patients met the Milan criteria. Patients who met Milan criteria were treated by liver transplant statistically more than hepatic resection, and these patients had longer overall survival (P = .01) and higher event-free survival (P < .001) than patients who had hepatic resection. Hepatocellular carcinoma recurrence rates were higher after hepatic resection (P = .232).
Conclusions: In patients with hepatocellular carcinoma, hospital stay was longer after liver transplant, but morbidity and mortality rates for liver transplant versus hepatic resection were similar. However, overall and event-free survival rates were better after liver transplant than after hepatic resection. These results suggest that liver transplant should be considered as the primary treatment option for patients with hepatocellular carcinoma secondary to cirrhosis.
Key words : Chronic liver disease, Hepatic resection, Liver tumors, Survival
Hepatocellular carcinoma (HCC) is a primer tumor of the liver that is usually secondary to chronic liver disease. The incidence of HCC has increased in conjunction with the increased incidence of cirrhosis related with chronic hepatitis. Hepatocellular carcinoma is the fifth most common cancer worldwide and is the third worst regarding cancer-related mortality.1
The primary treatment of HCC is surgery. For patients who are inoperable, local ablative treatments can be performed. Care is required not only for the tumor but also for the underlying liver disease in HCC. Although surgical resection is curative, it is prevented due to the existence of cirrhosis in 90% of patients. Additionally, there is commonly diffuse or multiple lesions, and resection is also not appropriate for these patients. Liver transplant is a curative treatment for both the underlying chronic liver disease and HCC.2
Here, we retrospectively collected the data of patients with HCC who were treated with hepatic resection or liver transplant in our hospital and evaluated their early complications and survival.
Materials and Methods
Between January 1998 and January 2010, 113 patients were diagnosed with HCC and treated with hepatic resection or liver transplant in our hospital. Inclusion criteria were a pathologic diagnosis of HCC and cirrhosis before surgery, liver transplant or hepatic resection for HCC and cirrhosis, or incidental HCC in postoperative pathologic evaluation. Based on these criteria, 93 patients were included, with 20 patients (16.2%) excluded from study.
Hospital records of patients were evaluated retrospectively; survival data were obtained by calling patients or their relatives by telephone. Of 93 patients, 57 (61.3%) had liver transplant and 36 (38.7%) had hepatic resection.
Age, sex, cause of disease, location of tumor, size of tumor, type of surgery, date of surgery, type and grade of tumor, number of tumors, Model for End-Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) stage, biochemical test results, administered chemotherapy before or after surgery, complications, mortality, morbidity, status of recurrence, time of recurrence, chemoembolization, repeated surgery, date of death, survival, and disease-free (event-free) survival were recorded.
Parametric variables were analyzed with independent t test and Mann-Whitney U test; nonparametric variables were analyzed with chi-square or Fisher exact test. The Kaplan-Meier method was used for survival analyses. The groups were compared by log-rank test. Progression was defined as time from diagnosis to recurrence, metastasis, or death without recurrence; survival was defined as time between diagnosis and death. Cox proportional hazards model was used to evaluate the effects of multiple variables on survival. P < .05 was defined as significant.
Patients who had liver transplant were younger (55.7 vs 62.1 y; P = .02) (Table 1). Both liver transplant and hepatic resection were performed more often in male than in female patients (P = .014). The most common underlying cause of HCC was chronic hepatitis B virus (HBV), with 80.8% of patients in the liver transplant group and 63.9% of patients in the hepatic resection group having HBV infection.
According to CTP stage, 38 patients (40.9%) had stage A, 42 patients (45.2%) had stage B, and 13 patients (14.0%) had stage C (Table 1). The mean MELD score was 13.3 ± 4.5 for patients who had liver transplant and 8.8 ± 3.3 for patients who had hepatic resection, which was significantly higher (Table 1; P = .01).
Mean follow-up time for both groups was not significantly different (34.5 vs 29 months for liver transplant vs hepatic resection; P = .312). The length of hospital stay was 30.9 days after liver transplant and 17.3 days after hepatic resection, which was significantly different (P < .001). Both groups had similar complication rates (P = .749) (Table 1).
We found that total bilirubin, serum urea nitrogen, activated partial thromboplastin time, prothrombin time, and international normalized ratio were higher and albumin and creatinine levels were lower in the liver transplant group. In line with these data, liver transplant patients also had higher CTP (P = .01) and MELD scores (Table 1) (P = .01).
Forty-two patients (73%) were diagnosed with HCC before liver transplant, and 15 (27%) patients were diagnosed with HCC after evaluation of pathology materials. Among patients who had liver transplant after pathologic evaluation, the rate of multifocal tumor was 54.4%. Among patients who underwent hepatic resection, the rate of unifocal tumor was 69.4%. Patients with multiple tumors were significantly more likely to have liver transplant (73.8%, P = .024). Analysis of recurrence showed 2 patients (3.5%) in the liver transplant group and 7 patients (19.4%) in the hepatic resection group with recurrence. In the liver transplant group, 1 patient had hepatic recurrence and 1 patient had nonhepatic recurrence. In the hepatic resection group, 4 patients had hepatic recurrence and 3 patients had nonhepatic recurrence. Recurrence rates were higher after hepatic resection than after liver transplant (P = .049). In 17 patients (18.2%) with complications, 11 (19.3%) were in the liver transplant group and 6 (16.7%) were in the hepatic resection group (P = .749). Regarding Clavien classification, 9 patients (52.9%) had grade I, 5 (29.4%) had grade II, 2 (29.4%) had grade IIIa, and 1 (5%) had grade V.
In the liver transplant group, 27 patients (47.3%) had deceased-donor and 30 patients (52.7%) had living-donor transplant. Thirty-three patients (57.8%) in the liver transplant and 27 patients (75%) in hepatic resection group met Milan criteria, showing similar rates (P = .09).
Overall survival was 91.6 ± 8.2 months after liver transplant and 37.7 ± 6.0 months after hepatic resection. Event-free survival was 92.9 ± 7.8 months after liver transplant and 32.6 ± 5.4 months after hepatic resection. Both overall survival (P < .001) and event-free survival (P = .021) were significantly longer after liver transplant (Figure 1).
Among patients with CTP stage A, overall survival and event-free survival rates were 53.7 ± 4.6 and 53.3 ± 3.9 months for liver transplant patients and 45.1 ± 8.4 and 38.6 ± 7.9 months for hepatic resection patients. Both overall survival (P = .02) and event-free survival (P = .008) were significantly longer after liver transplant (Figure 2).
Among patients with CTP stage B, overall survival and event-free survival rates were 93.7 ± 10.1 and 95.2 ± 10.0 months for liver transplant patients and 26.6 ± 6.2 and 23.4 ± 6.3 months for hepatic resection patients, with both survival results significantly longer for stage B patients who had liver transplant (P < .001 and P < .001, respectively) (Figure 3).
Among patients who met the Milan criteria, mean overall survival and event-free survival rates were 114.1 ± 7.1 and 112.8 ± 6.8 months in the liver transplant group and 43.3 ± 7.7 and 37.9 ± 6.9 months in the hepatic resection group, with both overall survival and event-free survival longer after liver transplant (P < .001 and P < .001, respectively) (Figure 4).
Among patients who did not meet the Milan criteria, overall survival was 38.5 ± 5.7 months in the liver transplant group and 23.8 ± 5.0 months in hepatic resection group (P = .094). Event-free survival was significantly higher in the liver transplant group (37.9 ± 5.9 mo) than in the hepatic resection group (21.6 ± 4.5 mo) (P = .031).
One-, 3-, and 5-year survival rates were 82.3%, 77.3%, and 67.2% in the liver transplant group and 69.3%, 41.7%, and 26.0% in the hepatic resection group (Table 2).
Our univariate analysis showed no significant prognostic factors. Univariate analyses of the liver transplant group showed that meeting the Milan criteria and presence of a single tumor were factors related to overall (P = .01 and P = .06) and event-free survival (both P = .03). A single tumor and meeting Milan criteria were found to be positive prognostic factors for patients with HCC who were treated by liver transplant.
Among many methods, the only curative treatments after HCC are liver transplant and hepatic resection. Although views are not consistent, treatment of HCC is hepatic resection in patients with preserved hepatic functions and liver transplant in patients with impaired hepatic function.3 In our evaluation of 57 patients treated by liver transplant and 36 patients treated by hepatic resection who had HCC with cirrhosis, we observed the efficacy of liver transplant in patients with CTP A and B. As already known, liver transplant is the only option for patients with HCC with CTP C cirrhosis. Many studies have compared outcomes of liver transplant versus hepatic resection in patients with CTP stage A.4-7 Results mostly support liver transplant, but hepatic resection can be performed when there is difficulty finding a deceased or living donor for liver transplant. Hepatic resection is commonly performed in patients with CTP A because hepatic function allows a wide resection. However, complete resection of the liver can treat both the underlying disease and HCC.
Patients with HCC in our study had a mean age of 55.7 ± 7.3 years, which is similar to other studies from Turkey that reported mean ages at HCC diagnosis of 57, 61, and 62 years8-10 and similar to a study from Europe.11 Patients who had liver transplant were younger than those who had hepatic resection in our study (P = .02). We found that HCC was about 4 times more frequent in male than in female patients (Table 1), which is similar to a previous report12 of HCC being 2 to 8 times more frequent in male than in female patients.
Hepatitis B virus is the cause of HCC in 53% of patients worldwide.8,13 The incidence of HCC is even higher in countries where HBV is endemic. Turkey is an endemic country for HBV, with HBV infection being the most important risk factor for HCC.12-14 Regarding factors leading to HCC in our study, HBV is the main reason in 74.2%, hepatitis C virus (HCV) in 10.8%, alcoholism in 9.7%, and undetermined in 5.4% of patients (Table 1). Other studies from Turkey also reported HBV as the most common risk factor for HCC, with rates of HBV of 44.4% to 65.7% and rates of HCV of 21.3% to 28.6% in patients with HCC.8-10 In contrast, the most important risk factor of HCC is HCV in Western Europe and North America.15,16
Patients with CTP A survived longer than patients with CTP B and CTP C. Surgery and other treatment (chemoembolization, percutaneous alcohol injection) outcomes are better in patients with HCC CTP A.17 Indeed, the CTP classification is an important indicator of survival. In our study, 40.8% of patients with cirrhosis had CTP A, which is higher than previous data (29.8% to 36.7%) in our country.8-10 Significantly more patients with CTP A had hepatic resection (68.4%) than liver transplant (P = .01). Previous studies have shown a mortality rate of < 2% to 5% with hepatic resection,18,19 which matches our early mortality rate of < 5% in our center.
In our study, 19.3% of liver transplant and 16.7% of hepatic resection patients had postoperative complications (P = .749). Michel and colleagues showed rates of postoperative complications of 39% after liver transplant and 38% after hepatic resection.20 Poon and associates reported similar rates of morbidity and mortality and a longer hospital stay after liver transplant (9 vs 18 days).21 Patients in our hospital also had a longer stay after liver transplant than after hepatic resection (30.9 vs 17.3 days; P < .001). The longer hospital stay after liver transplant can be attributed to the complexity of the procedure and the time to regulation of immunosuppressive treatment.
Among the 60 patients (64.5%) who met Milan criteria, patients who had liver transplant had longer overall and event-free survival rates. The 3- and 5-year survival rates were 90.3% and 90.0% in the liver transplant group and 47.9% and 36.5% in the hepatic resection group. Similarly, Baccarani and associates reported higher overall and event-free survival rates with liver transplant versus hepatic resection when Milan criteria were considered.22 This group reported 5-year overall survival rates of 72% versus 27% and event-free survival rates of 98% versus 37% for liver transplant versus hepatic resection. In our study, mean survival and event-free survival was 38.5 and 37.9 months after liver transplant and 23.8 and 21.6 months, respectively, after hepatic resection when Milan criteria were not considered. In addition, survival rates were similar in the 2 groups. Facciuto and associates also found higher overall survival rates after liver transplant compared with hepatic resection, reporting a 5-year overall survival rate of 60% in liver transplant patients and 35% in hepatic resection patients.23
Among patients with CTP A, those who had liver transplant had better survival than those who had hepatic resection (P = .02). Survival in the liver transplant group with CTP A was significantly better than that shown in the hepatic resection group (P = 0.02). It is evident that, even in patients with early-stage cirrhosis and Milan criteria, liver transplant is a better treatment modality than hepatic resection, with longer survival rates. However, many negative factors, such as liver grafting difficulties, high cost, technical difficulties, and immunosuppression, can lead to not using liver transplant as a treatment option.
We found that the recurrence rate was 3.5% after liver transplant and 19.4% after hepatic resection (P = .049), which matches the higher rates shown in the literature after hepatic resection versus liver transplant.20,24,25 The remaining cirrhotic area after resection is considered to lead to recurrence.
We found that the 5-year survival was 67.2% and event-free survival rate was 60.6% in patients who had liver transplant at our center, which was higher than for patients who had hepatic resection. In addition, some studies have reported similar 5-year survival rates of 63%, 72%, 68%, and 59% in other centers.26 In contrast, patients who had hepatic resection had 5-year survival rate of 26% and 5-year event-free survival of 25%.27
Regarding prognostic factors, the number and size of tumors are prognostic factors in HCC treated by liver transplant or hepatic resection.25 In our study, we found that meeting Milan criteria and presence of a single tumor were positive prognostic factors.
Similar to the literature,26 our study highlighted that, compared with hepatic resection, liver transplant provides better overall and event-free survival with a similar complication rate. In contrast, Otto and associates reported no significant differences in overall and event-free survival rates.28 Other studies found similar overall survival rates but better event-free survival rates after liver transplant.29,30
In conclusion, patients with HCC who had liver transplant had better overall and event-free survival. Liver transplant resulted in more favorable outcomes than hepatic resection, even in patients who meet Milan criteria and have early-stage cirrhosis (CTP A). Our results suggest that liver transplant should be considered as a primary treatment option, especially in patients with HCC secondary to cirrhosis.
DOI : 10.6002/ect.2017.0303
From the 1Department of General Surgery, the 3Department of Oncology, and the
4Department of Pathology, Dokuz Eylul University Faculty of Medicine, İzmir,
Turkey; and the 2Department of General Surgery, Baskent University Faculty of
Medicine, Ankara, Turkey
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Suleyman Ozkan Aksoy, Dokuz Eylül University Faculty of Medicine, Department of General Surgery, Mithatpaşa Street. No: 1606, 35340 Balcova/İzmir, Turkey
Phone: +90 532 308 1292
Figure 1. Overall and Disease-Free Survival in Patients With Hepatocellular Carcinoma
Figure 2. Overall and Disease-Free Survival in Patients with Hepatocellular Carcinoma Within Child-Turcotte-Pugh A
Figure 3. Overall and Disease-Free Survival in Patients with Hepatocellular Carcinoma Within Child-Turcotte-Pugh B
Figure 4. Overall and Disease-Free Survival in Patients with Hepatocellular Carcinoma Within Milan Criteria
Table 1. Patient Characteristics in the 2 Treatment Groups
Table 2. Overall and Event-Free Survival