Patient Characteristics
Out of the 106,502 cases of HCC diagnosed, 34,656 were included in the current analysis. The remaining 71,846 cases were excluded for the following reasons: aged 18 years old (n = 203), diagnosed before Jan 1, 2010 (n = 39,481), not primary cancer (n = 9,231), identified only by autopsy or on death certificate (n = 1,139), unknown or borderline pretreatment AFP (n = 13,038), blank(s) in distant metastatic status of lung, bone and brain (n = 8), or survival time less than 1 month or over 60 months (n = 8,746). The study population was divided into two cohorts: the distant metastasis (DM) cohort, consisting of 3,498 (10.1%) patients, and the non-distant metastasis (Non-DM) cohort, consisting of 31,158 (89.9%) patients. The distribution of patients among 4 groups was as follows: 21,084 (60.8%) in the Non-radiation & AFP positive group, 8,449 (24.4%) in the Non-radiation & AFP negative group, 3,810 (11.0%) in the Radiation & AFP positive group, and 1,313 (3.8%) in the Radiation & AFP negative group. The DM cohort exhibited significantly higher proportions of patients in the Non-radiation & AFP positive and Radiation & AFP positive groups, while the Non-radiation & AFP negative group had a lower percentage compared to the Non-DM cohort. The demographic and tumor characteristics of the two cohorts are presented in Table 1.
Table 1
Patient characteristics in cohorts with and without distant metastasis.
| Overall | With Distant Metastasis | Without Distant Metastasis | P-value |
| (N = 34656) | (N = 3498) | (N = 31158) | |
Age Group | | | | < 0.001 |
<60 | 11468 (33.1%) | 1272 (36.4%) | 10196 (32.7%) | |
60–70 | 14059 (40.6%) | 1378 (39.4%) | 12681 (40.7%) | |
≥70 | 9129 (26.3%) | 848 (24.2%) | 8281 (26.6%) | |
Sex | | | | < 0.001 |
Male | 26913 (77.7%) | 2898 (82.8%) | 24015 (77.1%) | |
Female | 7743 (22.3%) | 600 (17.2%) | 7143 (22.9%) | |
Year of Diagnosis | | | | < 0.001 |
2010–2014 | 14359 (41.4%) | 1648 (47.1%) | 12711 (40.8%) | |
2015–2019 | 20297 (58.6%) | 1850 (52.9%) | 18447 (59.2%) | |
Tumor Size | | | | < 0.001 |
≤2cm | 4190 (12.1%) | 136 (3.9%) | 4054 (13.0%) | |
2-5cm | 13987 (40.4%) | 598 (17.1%) | 13389 (43.0%) | |
>5cm | 13184 (38.0%) | 2030 (58.0%) | 11154 (35.8%) | |
Unknown | 3295 (9.5%) | 734 (21.0%) | 2561 (8.2%) | |
Race | | | | < 0.001 |
White | 23970 (69.2%) | 2349 (67.2%) | 21621 (69.4%) | |
Black | 4554 (13.1%) | 550 (15.7%) | 4004 (12.9%) | |
Other | 5932 (17.1%) | 586 (16.8%) | 5346 (17.2%) | |
Unknown | 200 (0.6%) | 13 (0.4%) | 187 (0.6%) | |
Marital Status | | | | 0.245 |
Married | 16866 (48.7%) | 1659 (47.4%) | 15207 (48.8%) | |
Unmarried | 16328 (47.1%) | 1695 (48.5%) | 14633 (47.0%) | |
Unknown | 1462 (4.2%) | 144 (4.1%) | 1318 (4.2%) | |
Grade | | | | < 0.001 |
Well | 2500 (7.2%) | 180 (5.1%) | 2320 (7.4%) | |
Moderately | 4253 (12.3%) | 310 (8.9%) | 3943 (12.7%) | |
Poorly | 2023 (5.8%) | 314 (9.0%) | 1709 (5.5%) | |
Undifferentiated | 158 (0.5%) | 24 (0.7%) | 134 (0.4%) | |
Unknown | 25722 (74.2%) | 2670 (76.3%) | 23052 (74.0%) | |
Histologic Type | | | | < 0.001 |
Adenoma | 34326 (99.0%) | 3445 (98.5%) | 30881 (99.1%) | |
Other | 330 (1.0%) | 53 (1.5%) | 277 (0.9%) | |
Lymph Nodes Metastasis | | | | < 0.001 |
Yes | 1180 (3.4%) | 1180 (33.7%) | 0 (0%) | |
No | 32634 (94.2%) | 2289 (65.4%) | 30345 (97.4%) | |
Unknown | 842 (2.4%) | 29 (0.8%) | 813 (2.6%) | |
Lung Metastasis | | | | < 0.001 |
Yes | 1670 (4.8%) | 1670 (47.7%) | 0 (0%) | |
No | 32208 (92.9%) | 1756 (50.2%) | 30452 (97.7%) | |
Unknown | 778 (2.2%) | 72 (2.1%) | 706 (2.3%) | |
Bone Metastasis | | | | < 0.001 |
Yes | 1366 (3.9%) | 1366 (39.1%) | 0 (0%) | |
No | 32584 (94.0%) | 2085 (59.6%) | 30499 (97.9%) | |
Unknown | 706 (2.0%) | 47 (1.3%) | 659 (2.1%) | |
Brain Metastasis | | | | < 0.001 |
Yes | 91 (0.3%) | 91 (2.6%) | 0 (0%) | |
No | 33825 (97.6%) | 3316 (94.8%) | 30509 (97.9%) | |
Unknown | 740 (2.1%) | 91 (2.6%) | 649 (2.1%) | |
Chemotherapy | | | | 0.006 |
Yes | 16189 (46.7%) | 1711 (48.9%) | 14478 (46.5%) | |
None | 18467 (53.3%) | 1787 (51.1%) | 16680 (53.5%) | |
Surgery | | | | < 0.001 |
Yes | 7824 (22.6%) | 91 (2.6%) | 7733 (24.8%) | |
None | 26482 (76.4%) | 3395 (97.1%) | 23087 (74.1%) | |
Unknown | 350 (1.0%) | 12 (0.3%) | 338 (1.1%) | |
Radiation & AFP | | | | < 0.001 |
Non-radiation & AFP + | 21084 (60.8%) | 2284 (65.3%) | 18800 (60.3%) | |
Non-radiation & AFP - | 8449 (24.4%) | 394 (11.3%) | 8055 (25.9%) | |
Radiation & AFP + | 3810 (11.0%) | 708 (20.2%) | 3102 (10.0%) | |
Radiation & AFP - | 1313 (3.8%) | 112 (3.2%) | 1201 (3.9%) | |
AFP alpha-fetoprotein. |
Survival Analysis
The Kaplan-Meier analysis showed significant differences in overall survival among the Non-radiation & AFP+, Non-radiation & AF-, Radiation & AFP+, and Radiation & AFP- groups in both cohorts (Fig. 2). In the DM cohort, the median OS and 95% confidence interval (CI) for the four groups were 3 months (3–3), 4 months (3–4), 5 months (5–6) and 11 months (9–15), respectively. In the Non-DM cohort, the median OS and 95% confidence interval (CI) for the four groups were 12 months (11–12), 28 months (27–28), 15 months (15–16) and 28 months (25–32), respectively. Radiation & AFP - greatly improved OS in both cohorts and Non-radiation & AFP - significantly improved OS when compared with the reference group of Non-radiation & AFP +.
Figure 3 shows unadjusted and adjusted hazard ratios for overall survival in both cohorts. In the DM cohort, patients of the Radiation & AFP - group had the lowest HRs (unadjusted HR [95%CI]: 0.422 [0.341–0.522], adjusted HR [95%CI]: 0.497 [0.399–0.619]), in comparison with the reference group of Non-radiation & AFP + patients. Patients of the Non-radiation & AFP - and Radiation & AFP + also showed improvement in OS compared with patients in the Non-radiation & AFP + group (unadjusted HRs [95%CI]: 0.737 [0.659–0.824] and 0.670 [0.613–0.732], adjusted HRs [95%CI]: 0.791 [0.706–0.886] and 0.725 [0.657–0.801]). The multivariable model of the distant metastatic cohort was adjusted for year of diagnosis, race, tumor size, grade, surgery, chemotherapy, lung and bone distant metastases.
In the Non-DM cohort, patients of the Radiation & AFP - group still had the lowest unadjusted and adjusted HRs (unadjusted HR [95%CI]: 0.492 [0.453–0.535], adjusted HR [95%CI]: 0.405 [0.372–0.441]). Non-radiation & AFP - and Radiation & AFP + showed improved OS compared with the Non-radiation & AFP + group (unadjusted HRs [95%CI]: 0.548 [0.530–0.566] and 0.805 [0.768–0.844], adjusted HRs [95%CI]: 0.656 [0.634–0.678] and 0.630 [0.600-0.661]). Variables included in the adjusted model were sex, age, year of diagnosis, race, marital status, tumor size, grade, surgery and chemotherapy.
Figure 4 presents the median overall survival (OS) of patient subgroups categorized by their Radiation & AFP status and metastasis patterns. Patients who received radiation treatment and had negative AFP exhibited longer median OS compared to other subgroups, even in patients with complex metastatic patterns such as brain or bone metastasis.