Patients
A total of 273 patients diagnosed with HCC were included in the study, resulting with mean 7.8 patients per year. Mean number increased during the study from 3.0 to 12.9 (1983-2000 and 2001-2018). Since introduction of ethanol injections (year 1997), TACE (year 2000) and RF (year 2006) the rate of surgery has declined with corresponding rise in local ablation and other invasive treatments. (Figure 2). The median follow-up time in surgical patients was 2.3 years, interquartile range (IQR) (1.2-7.3). In local ablation group 2.2 years (IQR 0.9-3.3), in angiological group 1.0 years (IQR 0.5-2.7), and in palliative group 0.4 years (IQR 0.1-1.0). Respective follow-up times calculated only for survivors were 3.4 years (IQR 1.3-6.2), 1.4 years (IQR 0.1-3.6), 0.8 years (IQR 0.2-2.2) and 0.6 years (IQR 0.3-1.4).
Preoperative features of the study groups
Baseline characteristics of the study groups are presented in Table 1. Median age of patients who underwent surgical resection was 66.7 years (IQR 60.2-70.6). In local ablation, angiological treatment and palliative group respective median ages were 73.6, 73.0 and 72.4 years. Male dominance was observed in all groups. Median Charlson Comorbidity Index in the four groups was 1, 3, 2 and 1, respectively. Liver cirrhosis was present in 33%, 56%, 40% and 33%. According to Child Pugh Classification, class B/C was present in surgical resection group in 4.1%, in local ablation group 20%, in other invasive treatment group 4.2% and in palliative group 29.8%. Most common ASA status in all four groups was grade III, including 59% in the resection group, 80% in local ablation group, 65% in angiological group and 67% in palliative group.
Tumor features
Tumor stage I was the most common in the first three groups, including 79.6% in the resection group, 76.0% in local ablation group and 47.9% in angiological group. In palliative group 58.3% had tumor stage III or IV. Tumor size was bigger in resection group than in local ablation group (median 50 mm vs 30 mm, p<0.001). No difference in size was observed between resection and angiological group. For other parameters and between group comparisons, see Table 2.
Postoperative features
In surgical resection group, overall resection rate during the study period was 17.9%, twenty (40.8%) patients underwent major liver resection (≥ 3 segments), 29 (59.2%) minor resection (≤ 2 segments). Twenty (40.8%) patients were treated with additional postoperative chemotherapy or radiotherapy. One patient was treated with further liver transplantation. Median intraoperative bleeding was 1350 ml (IQR 575-2700) and 22 (44.9%) patients were given red blood cell transfusion intraoperatively. Postoperatively 10 (20.4%) patients needed red blood cell transfusion. Median time spent in hospital after operation was 11 days (IQR 8.0-19.5) and median time spent in ICU was 1 day (IQR 0.0-2.0). Readmission in 30 days occurred with 6 (12.2%) patients. Postoperative features are presented in Table 2.
In local ablation group the most common treatment was RF with 17 (68.0%) patients. Three (12.0%) patients underwent laser ablation and 5 (20.0%) patients PEI. One (4.0%) patient had postoperative chemotherapy. The median time spent in hospital was 3 days (IQR 2-5). Two (8.0%) patients had readmission in 30 days. Postoperative features are presented in Table 2. In angiologically treated group, 9 (18.8%) patients had postoperative chemotherapy. The median time spent in hospital was 5.5 days (IQR 3-9). Eight (16.7%) patients had readmission in 30 days. Postoperative features are presented in Table 2.
Postoperative complications
Overall complications occurred more frequently in resection group than in local ablation group (71.5% vs 32.0%, p<0.001). There was no significant difference between resection group and angiological group in number of complications (71.5% vs 58.3%, p=0.116). Significant difference between local ablation group and angiological group was noted in overall complications (32.0% vs 58.3%, p=0.033) (Table 2 and 3).
In surgical resection group, 14 (28.6%) patients suffered a major complication (ASG III or more), and minor complications (ASG grade I-II) occurred in 21 (42.9%) patients. Respective numbers in local ablation group were 2 (8.0%) and 6 (24.0%), in angiological group 13 (27.1%) and 15 (31.3%). The type and severity of complications according to ASG-criteria are presented in Table 3.
Short- and long-term outcomes
In resection group 27 (55.1%) patients had tumor recurrence during follow-up, of which 2 (4.1%) patients had local recidive. In local ablation group, 15 (60.0%) patients were diagnosed with tumor recurrence, of which local recidive occurred with 8 (32.0%) patients, of which five patients were treated with RF and three with PEI. In angiological group, 38 (79.2%) patients were diagnosed with tumor recurrence, of which local recidive occurred with 25 (52.1%) patients (Table 2).
Disease-specific survival
In disease-specific survival postoperative mortality was included. In surgical resection group disease-specific 30 and 90-day survival rates were 95.9% and 95.9%. The 1-, 3 and 5-year disease-specific survival rates were 85.1%, 63.7% and 58.2%. The median survival was 7.7 years, (IQR 1.6-non est.). The respective disease-specific survival rates in local ablation group were 100%, 100%, 90.2%, 67.4% and 36.8%, with a median survival of 3.4 years (IQR 2.7-non est). In angiological group 95.8%, 93.6%, 61.8%, 47.2% and 15.7%, median 2.7 years (IQR 0.7-4.7). In palliative group rates were 85.9%, 65.9%, 33.9%, 7.8% and 0%, median 0.5 years (IQR 0.2-4.1). Disease-specific survivals are presented in Figure 3. At 5-years, statistically significant difference was observed between resection and angiological group (p=0.010), resection and palliative treatment (p<0.001), local ablation and palliative treatment (p<0.001), and angiological group and palliative treatment (p<0.001).
Overall survival
In surgical resection group, overall 30 and 90-day survival rates were 95.9% and 95.9%. The 1-, 3 and 5-year overall survival rates were 85.1%, 59.0% and 51.2%. The median survival was 5.9 years, (IQR 1.6-9.7). The respective overall survival rates in local ablation group were 100%, 100%, 86.1%, 43.1% and 18.8%, with a median survival of 2.6 years (IQR 2.0-4.0). In angiological group 95.8%, 93.6%, 56.1%, 26.3% and 6.6%, median 1.5 years (IQR 0.7-3.3). In palliative group rates were 81.4%, 60.7%, 26.0%, 4.9% and 0%, median 0.4 years (IQR 0.1-1.1). Overall survivals are presented in Figure 4. At 5-years, statistically significant difference was observed between resection and angiological group (p<0.001), resection and palliative treatment (p<0.001), local ablation and palliative treatment (p<0.001), and angiological group and palliative treatment (p<0.001).
When palliative group was stratified between patients receiving oncological treatment (n=39) and only palliative treatment (n=112), overall survival rates at 30 and 90 days, 1-, 3- and 5- years were 100%, 84.2%, 36.8%, 3.7% and 0%, median 0.6 years (IQR 0.4-1.4) in oncological treatment group. In those who received only palliative treatment rates were 74.9%, 52.4%, 22.2%, 5.2% and 0%, median 0.3 years (IQR 0.1-0.8), p=0.050 between groups at 5-years.
In cox regression analysis adjusted for confounding factors, local ablation (HR 3.79, 95% CI 1.64-8.77) and angiological treatment (HR 3.76, 95% CI 1.74-8.13) were associated with increased risk for long-term mortality compared to resection group (Table 4).
Survival trends over time
To analyse survival trends over time, we divided groups (resection, local ablation, angiological, palliative) into further two equal sized cohorts based on year of operation. Cut-off years were 2000 for resection, 2012 for local ablation, 2011 for angiological and 2011 for palliative group. We observed no statistically significant differences over time inside any of the groups separately. If treatment groups were combined, disease-specific survival in old cohort at 1-, 3- and 5- years were 50.8%, 27.6% and 16.5%. Respective survival rates in new cohort were 58.0%, 40.6% and 37.2% (p=0.035 between groups at 5-years).