Trends of surgery and liver resection on HCC
The number of patients and patients undergoing surgery increased with time from 1998 to 2015. However, the number of patients undergoing liver resection remained essentially constant (Additional File Fig. 1). The trends of surgery rate increased in all patients (P = 0.016), and patients with localized tumor (P < 0.001) increased but declined in the regional (P < 0.001) and the distant group (P < 0.001). The trends of surgery rate did not change with time in the unknown group (P = 0.360) (Fig. 1A). For liver resection, the frequencies and trends in localized (P < 0.001), regional (P = 0.004), distant (P = 0.014), and unknown groups (P = 0.007) declined with time (Fig. 1B). In the localized group, for stage A, stage B, and stage C, the frequencies and trends of surgery and liver resection declined with time (P < 0.001 for stage A, B and C) (Fig. 2A-2B).
Median Overall Survival (mOS) in all patients and the subgroups
After PSM, the mOS of patients in the liver resection group (71 months, 95%CI: 67.4,74.6) was longer than in the other groups (surgery group (47 months, 95%CI; 45.5,48.5), non-surgery group (15 months, 95%CI: 14.6,15.4), and all patients (26 months, 95%CI: 25.4,26.6), P < 0.001) (Additional File Fig. 2). The mOS of patients in localized group who with liver resection (85 months, 95%CI: 80,90) was longer than patients with surgery (56 months, 95%CI: 53.9,8.1) and non-surgery (19 months, 95%CI: 18.4, 19.6, P < 0.001) (Fig. 3A). Similar results were presented in regional, distant and unknown stage groups. In reginal group, the mOS of patients with liver resection (43 months, 95%CI: 38.9,47.1) was longer than patients with surgery (29 months, 95%CI: 27,31) and non-surgery (9 months, 95%CI: 8.4,9.6, P < 0.001) (Fig. 3B). In distant group, the mOS of patients with liver resection (13 months, 95%CI: 8.5,17.5) was longer than patients with surgery (10 months, 95%CI: 8.5,11.5) and non-surgery (3 months, 95%CI: 4.7,7.3, P < 0.001) (Fig. 3C). In the subgroups analysis, the patients in the stage A group who with liver resection (115 months, 95%CI: 105,125) had better survival than patients with surgery (65 months, 95%CI: 61.9,68.1) and non-surgery (23 months, 22.2,23.8, P < 0.001) (Fig. 4A). In stage B group, patients with liver resection (54 months, 95%CI:49.6,58.4) had also better survival than patients with surgery (42 months, 95%CI: 39.7,44.3) and non-surgery (10 months, 95%CI: 9.4,10.6, P < 0.001) (Fig. 4B).In stage C group, the mOS of patients with liver resection (51 months, 95%CI: 46.2,55.8) was longer than patients with surgery (39 months, 95%CI: 36,42) and non-surgery (9 months, 95%CI: 8.4,9.6, P < 0.001) (Fig. 4C). To further evaluate the effect of surgery and liver resection in patients with tumor size larger than 5 cm, the stage C was divided into four groups: group 1 (tumor size 5-7cm), group 2 (7–9 cm), group 3 (9–11 cm) and group 4 (> 11 cm.). The survival curve for the stage C group showed that the survival of patients with liver resection was longer in group 1 (61months, 95%CI:51.9,70.1) than in group 2 (46months, 95%CI:32.8,59.2), group 3 (41 months, 95%CI:29.5,52.5), and group 4 (38months, 95%CI:31.5,44.5) (P < 0.001) (Additional File Fig. 3).
Predictors of OS in all patients and the liver resection group
Cox proportional hazards models were used to identify independent predictors for OS in all patients (n = 31120) who received surgery (n = 15560) or non-surgical treatment (n = 15560) after PSM. The female patients were more likely to survive longer (Hazard Ratio: 0.923, 95%CI: 0.893,0.953P < 0.001). The black patients were more likely to have the worst survival (HR:1.057, 95%CI: 1.011,1.106, P = 0.015) than white patients and patients of other races. The younger patients had longer survival time (age 45–54 years: HR: 1.213, 95%CI: 1.092,1.347, P = 0.001; 55–64 years: HR:1.307, 95%CI: 1.180,1.449, P < 0.001; age > 65 years: HR:1.652, 95%CI: 1.492,1.831, P < 0.001) and patients with early diagnosis of HCC might had worse survival (diagnosis period 2002–2005, HR: 0.935, 95%CI: 0.887,0.986, P = 0.012; 2010–2015, HR:0.800, 95%CI: 0.760,0.842, P < 0.001; 2010–2015: HR:0.674, 95%CI: 0.641,0.709, P < 0.001). A similar result was obtained for patients with larger tumor size. Patients undergoing surgery experienced better survival than non-surgically treated patients (non-surgery: HR: 2.544, 95%CI: 2.474,2.616, P < 0.001). Married patients had better survival than single patients (single: HR:1.200, 95%CI: 1.166,1.235, P < 0.001). However, patients with severaltumors had longer survival (two tumors: HR: 0.915, 95%CI: 0.879,0.951, P < 0.001; three tumors: HR:0.894, 95%CI:0.804,0.994, P = 0.038) (Table 2).
Table 2
Multivariate regression analysis for overall survival of all patients
Characteristics | No (%) | | Multivariate |
| 31120 (100) | | HR (95%CI) | P |
Gender | | | | |
Male | 23830 (76.6) | | Reference | |
Female | 7290 (23.4) | | 0.923 (0.893,0.953) | < 0.001 |
Ethnicity | | | | |
White | 21468 (69) | | Reference | |
Black | 3210 (10.3) | | 1.057 (1.011,1.106) | 0.015 |
other | 6442 (20.7) | | 0.783 (0.756,0.811) | < 0.001 |
Age of diagnosis | | | | |
35–44 | 617 (2) | | Reference | |
45–54 | 5629 (18.1) | | 1.213 (1.092,1.347) | 0.001 |
55–64 | 12052 (38.7) | | 1.307 (1.180,1.449) | < 0.001 |
≥ 65 | 12822 (41.2) | | 1.652 (1.492,1.831) | < 0.001 |
Year of diagnosis | | | | |
1998–2001 | 2248 (7.2) | | Reference | |
2002–2005 | 5276 (17) | | 0.935 (0.887,0.986) | 0.012 |
2006–2009 | 7648 (24.6) | | 0.800 (0.760,0.842) | < 0.001 |
2010–2015 | 15948 (51.2) | | 0.674 (0.641,0.709) | < 0.001 |
Tumor status | | | | |
Localized | 22970 (73.8) | | Reference | |
Regional | 6363 (20.4) | | 1.524 (1.475,1.574) | < 0.001 |
Distant | 958 (3.1) | | 2.556 (2.383,2.741) | < 0.001 |
Unknown/Unstaged | 829 (2.7) | | 1.236 (1.133,1.349) | < 0.001 |
Tumor size | | | | |
≤ 3 cm | 12429 (39.9) | | Reference | |
3-5cm | 8349 (26.8) | | 1.375 (1.328,1.424) | < 0.001 |
5-7cm | 3505 (11.3) | | 1.680 (1.606,1.757) | < 0.001 |
7-9cm | 1612 (5.2) | | 1.842 (1.734,1.956) | < 0.001 |
9-11cm | 927 (3) | | 2.128 (1.973,2.296) | < 0.001 |
> 11 cm | 1995 (6.4) | | 2.351 (2.226,2.484) | < 0.001 |
Unknown | 2303 (7.4) | | 1.930 (1.822,2.044) | < 0.001 |
Tumor numbers | | | | |
1 | 26236 (84.3) | | Reference | |
2 | 4271 (13.7) | | 0.915 (0.879,0.951) | < 0.001 |
3 | 512 (1.7) | | 0.894 (0.804,0.994) | 0.038 |
> 3 | 101 (0.3) | | 0.996 (0.787,1.261) | 0.974 |
Marital status | | | | |
Married | 18213 (58.5) | | Reference | |
Single | 11887 (38.2) | | 1.200 (1.166,1.235) | < 0.001 |
Other | 1020 (3.3) | | 1.028 (0.947,1.116) | 0.509 |
Surgery | | | | |
Yes | 11560 (50) | | Reference | |
not | 15560 (50) | | 2.544 (2.474,2.616) | < 0.001 |
In the localized group, patients with liver resection, the multivariate analysis yielded similar results: gender, ethnicity, age, year of diagnosis, tumor stage, tumor size and marital status affected the length of survival. However, the higher number of tumors was not did not improve OS in liver resection patients (Table 3).
Table 3
Multivariate regression analysis for overall survival of patients in the localized group who with liver resection
Characteristic | No (%) | | Multivariate |
| 8652 (100) | | HR (95%CI) | P |
Gender | | | | |
Male | 6568 (75.9) | | Reference | |
Female | 2084 (24.1) | | 0.847 (0.776,0.924) | < 0.001 |
Ethnicity | | | | |
White | 5832 (67.4) | | Reference | |
Black | 907 (10.5) | | 1.411 (1.255,1.587) | < 0.001 |
other | 1913 (22.1) | | 0.852 (0.775,0.936) | 0.001 |
Age of diagnosis | | | | |
35–44 | 217 (2.5) | | Reference | |
45–54 | 1675 (19.4) | | 1.448 (1.073,1.955) | 0.015 |
55–64 | 3320 (38.3) | | 1.682 (1.252,2.258) | 0.001 |
≥ 65 | 3440 (39.8) | | 2.530 (1.886,3.393) | < 0.001 |
Year of diagnosis | | | | |
1998–2001 | 722 (8.3) | | Reference | |
2002–2005 | 1490 (17.2) | | 0.809 (0.715,0.916) | 0.001 |
2006–2009 | 2151 (24.9) | | 0.687 (0.608,0.776) | < 0.001 |
2010–2015 | 4289 (49.6) | | 0.509 (0.449,0.576) | < 0.001 |
Tumor size | | | | |
≤ 3 cm | 3071 (35.4) | | Reference | |
3-5cm | 2298 (26.6) | | 1.412 (1.283,1.555) | < 0.001 |
5-7cm | 1161 (13.4) | | 1.646 (1.466,1.849) | < 0.001 |
7-9cm | 587 (6.8) | | 1.911 (1.652,2.210) | < 0.001 |
9-11cm | 354 (4.1) | | 2.118 (1.767,2.540) | < 0.001 |
> 11 cm | 793 (9.2) | | 2.310 (2.009,2.655) | < 0.001 |
Unknown | 388 (4.5) | | 1.344 (1.099,1.644) | 0.004 |
Tumor numbers | | | | |
1 | 7305 (84.4) | | Reference | |
2 | 1181 (13.7) | | 1.011 (0.913,1.120) | 0.830 |
3 | 137 (1.6) | | 1.101 (0.850,1.426) | 0.464 |
> 3 | 29 (0.3) | | 0.965 (0.558,1.669) | 0.898 |
Marital status | | | | |
Married | 5425 (62.7) | | Reference | |
Single | 2976 (34.4) | | 1.294 (1.196,1.399) | < 0.001 |
Other | 251 (2.9) | | 0.928 (0.716,1.203) | 0.574 |