We reviewed data of 67,637 HCC patients. The majority of them were aged ≥ 50 years at diagnosis (61,203; 90.5%) and were males (52,212; 77.2%). Most patients were White (45,530; 67.3%) and were diagnosed at a localized disease stage (35,420; 52.4%). Most patients had chemotherapy (42,279; 62.5%), but a minority of patients had radiotherapy (4,935; 7.3%) or underwent surgery (17,373; 25.7%). During the follow-up period, 50,571 patients died (74.77%). Table 1 shows the characters of the included patients.
Table 1
Baseline characteristics of hepatocellular carcinoma patients.
Characteristic | Total | Observed deaths | Percentage |
Overall | 67,637 | 50,571 | 74.77 |
Age | | | |
< 50 | 6,434 | 4,628 | 71.93 |
≥ 50 | 61,203 | 45,943 | 75.07 |
Sex | | | |
Male | 52,212 | 39,374 | 75.41 |
Female | 15,425 | 11,197 | 72.59 |
Race | | | |
White | 45,530 | 34,408 | 75.57 |
Black | 9,280 | 7,363 | 79.34 |
Othera | 12,827 | 8,800 | 68.61 |
Stage | | | |
Localized | 35,420 | 22,767 | 64.28 |
Regional | 20,602 | 17,073 | 82.87 |
Distant | 11,615 | 10,731 | 92.39 |
Grade | | | |
Grade 1 | 7,679 | 5,260 | 68.5 |
Grade 2 | 10,552 | 6,976 | 66.11 |
Grade 3 | 5,379 | 4,302 | 79.98 |
Grade 4 | 539 | 449 | 83.3 |
Unknown | 43,488 | | 0 |
Surgery | | | |
Yes | 17,373 | 8,879 | 51.11 |
No | 50,264 | 41,692 | 82.95 |
Chemotherapy | | | |
Yes | 42,279 | 32,850 | 77.7 |
No | 25,358 | 17,721 | 69.88 |
Radiotherapy | | | |
Yes | 4,935 | 3,503 | 70.98 |
No | 62,702 | 47,068 | 75.07 |
a Asian or Pacific Islander and Indian American/Alaska Native females. |
Totally, 50,571 patients died during the follow-up period. The majority of deaths were attributed to HCC (35,535 deaths, 70.3%) and other cancers (3,983 deaths, 7.9%). Leading causes of non-cancer mortality, with higher mortality risk than the general population, included infectious and parasitic diseases (including human retrovirus (HIV)) (2,823 deaths, SMR = 105.68, 95% CI: 101.82-109.65), followed by chronic liver disease (2,719 deaths, SMR = 76.56, 95% CI: 73.71,79.5), and heart diseases (1,265 deaths, SMR = 2.26, 95% CI: 2.14–2.39).
Causes of Death During the first Year After HCC Diagnosis
During the first year after the HCC diagnosis, a total of 33,775 patients died. Among these patients, 24,547 died from HCC, and 2,621 died from other cancers. During this period, the first non-cancer cause of death was chronic liver disease and cirrhosis, accounting for 1,814 deaths, with a significantly higher risk in HCC patients than in the general population (SMR = 147.50, 95% CI; 140.79-154.45). This was followed by other infectious and parasitic diseases including HIV, accounting for 1,699 deaths, (SMR = 177.22, 95% CI: 168.89-185.85), and then heart diseases, accounting for 723 deaths, (SMR = 3.61, 95% CI: 3.35–3.88) (See Table 2).
Table 2
Standardized mortality ratios for each cause of death categorized by timing of deaths after hepatocellular carcinoma diagnosis.
Cause of death | > 1 year | | 1–5 years | | 5–10 years | | > 10 years | | Total |
Observed | SMR (95% CI) | | Observed | SMR (95% CI) | | Observed | SMR (95% CI) | | Observed | SMR (95% CI) | | Observed | SMR (95% CI) |
All causes | 33,775 | 59.72 (59.09–60.36)* | | 14,780 | 25.60 (25.19–26.02)* | | 1,755 | 15.64 (14.92–16.39)* | | 261 | 17.33 (15.29–19.56)* | | 50,571 | 40.19 (39.84–40.55)* |
Hepatocellular carcinoma | 24,547 | 62.43 (61.65–63.22)* | | 10,036 | 29.42 (28.84-30)* | | 882 | 19.06 (17.83–20.36)* | | 70 | 20.02 (15.61–25.29) | | 35,535 | 45.32 (44.85–45.79)* |
Other cancers | 2,621 | 56.68 (54.53–58.89)* | | 1,118 | 22.60 (21.3-293.97)* | | 200 | 14.39 (12.46–16.53)* | | 44 | 26.12 (18.98–35.06)* | | 3,983 | 35.79 (34.69–36.92)* |
Non-cancer causes | | | | | | | | | | | | | | |
In situ, benign or unknown behavior neoplasm | 92 | 19.70 (15.88–24.17)* | | 15 | 2.45 (1.37–4.05)* | | 5 | 2.35 (0.76–5.49) | | 0 | 0 (0-6.25) | | 112 | 8.30 (6.83–9.98)* |
Tuberculosis | 6 | 15.99 (5.87–34.81)* | | 3 | 5.68 (1.17–16.6)* | | 0 | 0 (0-19.44) | | 0 | 0 (0-73.19) | | 9 | 7.87 (3.6-14.94)* |
Syphilis | 0 | 0 (0-231.59) | | 0 | 0 (0-183.89) | | 0 | 0 (0-596.15) | | 0 | 0 (0-2481.55) | | 0 | 0 (0-84.49) |
Septicemia | 141 | 12.47 (10.5–14.7)* | | 83 | 5.65 (4.5–7.01)* | | 16 | 3.23 (1.84–5.24)* | | 6 | 4.53 (1.66–9.85)* | | 246 | 7.62 (6.7–8.64)* |
Other Infectious and Parasitic Diseases including HIV | 1,699 | 177.22 (168.89-185.85)* | | 967 | 78.83 (73.94–83.96)* | | 137 | 34.89 (29.29–41.24)* | | 20 | 21.46 (13.11–33.15)* | | 2,823 | 105.68 (101.82-109.65)* |
Diabetes Mellitus | 139 | 5.09 (4.28–6.01)* | | 92 | 2.55 (2.05–3.12)* | | 28 | 2.26 (1.5–3.27)* | | 11 | 3.36 (1.68–6.02)* | | 270 | 3.41 (3.02–3.85)* |
Alzheimer's (ICD-9 and 10 only) | 13 | 0.77 (0.41–1.31) | | 14 | 0.64 (0.35–1.07) | | 4 | 0.51 (0.14–1.31) | | 2 | 0.79 (0.1–2.85) | | 33 | 0.67 (0.46–0.94)* |
Diseases of Heart | 723 | 3.61 (3.35–3.88)* | | 407 | 1.60 (1.45–1.77)* | | 114 | 1.37 (1.13–1.64)* | | 21 | 0.96 (0.59–1.46) | | 1,265 | 2.26 (2.14–2.39)* |
Hypertension without Heart Disease | 43 | 5.21 (3.77–7.02)* | | 24 | 2.18 (1.4–3.25)* | | 8 | 2.06 (0.89–4.06) | | 3 | 2.78 (0.57–8.12) | | 78 | 3.22 (2.55–4.02)* |
Cerebrovascular Diseases | 120 | 2.91 (2.41–3.48)* | | 112 | 2.14 (1.76–2.57)* | | 32 | 1.84 (1.26–2.6)* | | 9 | 1.88 (0.86–3.56) | | 273 | 2.36 (2.09–2.65)* |
Atherosclerosis | 12 | 5.67 (2.93–9.9)* | | 4 | 1.62 (0.44–4.14) | | 1 | 1.34 (0.03–7.45) | | 0 | 0 (0-19.09) | | 17 | 3.07 (1.79–4.92)* |
Aortic Aneurysm and Dissection | 6 | 1.43 (0.52–3.1) | | 3 | 0.58 (0.12–1.69) | | 1 | 0.61 (0.02–3.4) | | 0 | 0 (0-8.96) | | 10 | 0.87 (0.42–1.61) |
Other Diseases of Arteries, Arterioles, Capillaries | 5 | 1.8 (0.58–4.2) | | 9 | 2.57 (1.17–4.87)* | | 2 | 1.73 (0.21–6.25) | | 1 | 3.21 (0.08–17.89) | | 17 | 2.19 (1.28–3.51)* |
Pneumonia and Influenza | 60 | 3.57 (2.72–4.59)* | | 45 | 2.09 (1.52–2.79)* | | 12 | 1.61 (0.83–2.82) | | 4 | 1.98 (0.54–5.07) | | 121 | 2.53 (2.1–3.02)* |
Chronic Obstructive Pulmonary Disease and Allied Cond | 122 | 2.78 (2.31–3.32)* | | 69 | 1.22 (0.95–1.54) | | 26 | 1.32 (0.87–1.94) | | 8 | 1.46 (0.63–2.88) | | 225 | 1.79 (1.56–2.04)* |
Stomach and Duodenal Ulcers | 23 | 20.38 (12.92–30.57)* | | 7 | 4.88 (1.96–10.05)* | | 1 | 2.09 (0.05–11.66) | | 0 | 0 (0-29.28) | | 31 | 9.78 (6.65–13.89)* |
Chronic Liver Disease and Cirrhosis | 1,814 | 147.50 (140.79-154.45)* | | 809 | 49.40 (46.05–52.92)* | | 80 | 14.50 (11.5-18.05)* | | 16 | 12.12 (6.93–19.67)* | | 2,719 | 76.56 (73.71–79.5)* |
Nephritis, Nephrotic Syndrome and Nephrosis | 93 | 6.13 (4.95–7.51)* | | 71 | 3.60 (2.81–4.54)* | | 25 | 3.75 (2.43–5.53)* | | 9 | 5.04 (2.3–9.56)* | | 198 | 4.57 (3.95–5.25)* |
Complications of Pregnancy, Childbirth, Puerperium | 2 | 227.03 (27.49-820.11)* | | 0 | 0 (0-275.25) | | 0 | 0 (0-745.93) | | 0 | 0 (0-2793.63) | | 2 | 70.23 (8.51–253.7)* |
Congenital Anomalies | 6 | 6.83 (2.5-14.86)* | | 6 | 5.21 (1.91–11.34)* | | 0 | 0 (0-9.75) | | 0 | 0 (0-40.79) | | 12 | 4.80 (2.48–8.39)* |
Certain Conditions Originating in Perinatal Period | 1 | 93.87 (2.38-523.04)* | | 0 | 0 (0-211.08) | | 0 | 0 (0-2258.56) | | 0 | 0 (0-11169.99) | | 1 | 33.23 (0.84-185.15) |
Symptoms, Signs and Ill-Defined Conditions | 92 | 12.56 (10.13–15.41)* | | 44 | 4.69 (3.41–6.3)* | | 7 | 2.24 (0.9–4.61) | | 2 | 2.44 (0.3–8.82) | | 145 | 7.02 (5.93–8.27)* |
Accidents and Adverse Effects | 116 | 4.44 (3.66–5.32)* | | 118 | 3.45 (2.85–4.13)* | | 32 | 2.79 (1.91–3.94)* | | 3 | 1.03 (0.21-3) | | 269 | 3.60 (3.18–4.05)* |
Suicide and Self-Inflicted Injury | 16 | 1.95 (1.12–3.17)* | | 23 | 2.12 (1.35–3.19)* | | 5 | 1.39 (0.45–3.25) | | 0 | 0 (0-4.41) | | 44 | 1.88 (1.36–2.52)* |
Homicide and Legal Intervention | 8 | 4.53 (1.96–8.92)* | | 1 | 0.47 (0.01–2.6) | | 1 | 1.58 (0.04–8.79) | | 1 | 7.56 (0.19–42.1) | | 11 | 2.35 (1.18–4.21)* |
Other Cause of Death | 1,255 | 12.47 (11.79–13.17)* | | 700 | 5.27 (4.89–5.67)* | | 136 | 2.92 (2.45–3.45)* | | 31 | 2.34 (1.59–3.33)* | | 2,122 | 7.23 (6.93–7.55)* |
SMR, standardized mortality ratio. *P < 0.05. |
Infectious and parasitic diseases (including HIV) was the commonest cause of non-cancer mortality in various patients' subgroups such as patients less than 50 years old, females, Blacks, other races, patients with distant tumor stage, patients with grade II or IV tumor, and patients who underwent chemotherapy, radiotherapy or surgery. However, the difference between it and chronic liver disease and cirrhosis was generally small. (See supplementary tables 1 to 13).
Causes of Death Within 1 to 5 Years After HCC Diagnosis
A total of 14,780 patients died during this period, of whom, 10,036 died from HCC, and 1,118 died from other cancers. During this interval, the first non-cancer mortality cause was infectious and parasitic diseases (including HIV), accounting for 967 deaths with significant mortality risk in HCC patients compared with the general population (SMR = 78.83, 95% CI: 73.94–83.96). Other significant non-cancer causes of death included chronic liver disease and cirrhosis (809 patients, SMR = 49.40, 95% CI: 46.05–52.92), heart diseases (407 patients, SMR = 1.60, 95% CI: 1.45–1.77), accidents and adverse effects (118 patients, SMR = 3.45, 95% CI: 2.85–4.13), and cerebrovascular diseases (112 patients, SMR = 2.14, 95% CI: 1.76–2.57). There was no reported death from syphilis, complications of pregnancy, labor, or puerperium, or from conditions related to the perinatal period (See Table 2).
The leading cause of non-cancer mortality in most patients' subgroups was also infectious and parasitic diseases (including HIV). However, in patients with distant disease stage, and in patients with grade I or III at diagnosis, chronic liver disease and cirrhosis was the first cause of non-cancer mortality (See supplementary tables 1 to 13).
Causes of Death Within 5 to 10 Years After HCC Diagnosis
A total of 1,755 patients died during this period, of whom, 882 died from HCC, and 200 died from other cancers. During this period, the first cause of non-cancer mortality was infectious and parasitic diseases (including HIV), that had a high risk of mortality in HCC patients than the US general population (137 deaths, SMR = 34.89, 95% CI: 29.29–41.24), followed by heart diseases (114 deaths, SMR = 1.37, 95% CI: 1.13–1.64), and chronic liver disease and cirrhosis (80 deaths, SMR = 14.50, 95% CI: 11.5-18.05). There was no reported death from syphilis, tuberculosis, congenital anomalies, complications of pregnancy, labor, or puerperium, or from c conditions related to the perinatal period (See Table 2).
Infectious and parasitic diseases was the leading cause of non-cancer mortality in different patients' demographic and pathological subgroups. But in patients with grade I or II tumor at diagnosis, heart diseases was the leading cause of non-cancer mortality (See supplementary tables 1 to 13).
Causes of Death after more than 10 Years Following HCC Diagnosis
A total of 261 patients died during this period, of whom, 70 died from HCC, and 44 died from other cancers. During this period, the first cause of non-cancer mortality was heart diseases, but its mortality risk in HCC patients was similar to that in the general population (21 deaths, SMR = 0.96, 95% CI: 0.59–1.46). Other common causes of death included other infectious and parasitic diseases including HIV (20 patients, SMR = 21.46, 95% CI: 13.11–33.15), and chronic liver disease and cirrhosis (16 patients, SMR = 12.12, 95% CI: 6.93–19.67). There was no reported death from syphilis, tuberculosis, suicide and self-inflicted injury, stomach and duodenal ulcers, non-invading neoplasm, aortic aneurysm and dissection, atherosclerosis, complications of pregnancy or puerperium, and congenital anomalies (See Table 2). The category "other cause of death" was accounted for more deaths than heart diseases with high SMR (31 patients, SMR = 2.34, 95% CI: 1.59–3.33), but the causes of death included in this category was not defined by the SEER database.
Heart diseases was the leading cause of non-cancer death in most patients' subgroups. But infectious and parasitic diseases (including HIV) was the leading cause of non-cancer mortality in many subgroups, including patients with localized tumor or with grade III tumor at diagnosis and patients treated with chemotherapy or surgery. Chronic liver disease and cirrhosis was the leading cause of non-cancer mortality in patients < 50 years at diagnosis, and in females. In blacks, it was cerebrovascular diseases. In other races, both infectious and parasitic diseases (including HIV) and chronic liver disease and cirrhosis were the leading causes of non-cancer mortality.