Editor: Young-Suk Lim, University of Ulsan College of Medicine, Korea
Primary liver cancer is one of the leading causes of cancer mortality worldwide. However, the causes of death have not been studied in detail in patients with liver cancer.
The causes of death and cause-specific mortality risks in patients with primary liver cancer, diagnosed during 2000–2016, were investigated using the nationwide population-based cancer registry data in South Korea (n=231,388). The cumulative incidence function and Fine-Gray models were used to estimate the cause-specific mortality under the competing risks. Risks of non-cancer deaths relative to the general population were compared by standardized mortality ratios (SMRs).
Among 179,921 total deaths, 92.4%, 1.7%, and 6.0% of patients died of primary liver cancer, cancer from other sites, and non-cancer illnesses, respectively. Proportionate mortality from liver cancer remained high. The 5-year competing risks probability of death from liver cancer varied by tumor stage, from 42% to 94%, and it remained high 10 years after the diagnosis (61–95%). Competing mortality from other causes has continuously increased. The most common non-cancer causes of death were underlying liver diseases (SMR, 15.6; 95% confidence interval [CI], 15.1–16.1) and viral hepatitis (SMR, 46.5; 95% CI, 43.9–49.2), which demonstrated higher mortality risks compared to the Korean general population. Higher mortality risks of suicide (SMR, 2.6; 95% CI, 2.4–2.8) was also noted.
Patients with liver cancer are most likely to die from liver cancer and related liver disease, even 10 years after the diagnosis, highlighting a need for specialized long-term follow-up care.
The present nationwide study reported that liver cancer and related liver diseases remain the most prevalent causes of death among liver cancer patients, despite the progress in liver cancer control. Long-term follow-up care is necessary, considering the high risk of liver cancer death even 10 years after the diagnosis.
Cancer is the leading cause of death (COD) worldwide; however, cancer survival rates are improving [
Primary liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer mortality worldwide [
The overall survival rate of primary liver cancer in Korea has improved over the last two decades. Five-year relative survival among patients with primary liver cancer has increased from 13.2% in patients diagnosed during 1996 through 2000 to 34.0% in patients diagnosed between 2011 and 2015. Despite this improvement, the 5-year survival rate in primary liver cancer patients is still low compared to other cancers such as colorectal, stomach, breast, or thyroid [
The study protocol was approved by the Institutional Review Board of the National Cancer Center (NCC2016-0041).
We obtained data from the Korea Central Cancer Registry (KCCR), a population-based cancer registry linked to mortality statistics. This retrospective cohort database includes patients diagnosed with primary liver and intrahepatic bile duct cancer (C22) between January 1, 2000, and December 31, 2016, and followed until December 31, 2017 (n=231,388). The KCCR is the nationally representative database covering more than 98% of cancer patients in South Korea and contains nationwide cancer incidence and survival data from 1999 onward. The registry is linked to the COD statistics provided by Statistics Korea, the national statistics office of South Korea, which provides an opportunity to study cause-specific mortality [
We defined liver and intrahepatic bile duct cancer as the International Classification of Diseases for Oncology (ICD-O; 3rd edition) codes (C220, and C221 excluding 9050-9055, 9140, 9590-9992) and further classified hepatocellular carcinoma (HCC; C220) and intrahepatic cholangiocarcinoma (ICCA; C221). The exclusion criteria for this study were as follows: 1) cases with missing COD information or death certificate only cases, 2) cases with multiple primary tumors, 3) cases lost to follow-up, and 4) patients under 20 years of age at diagnosis. Tumor stage information was available as the Surveillance, Epidemiology, and End Results (SEER) summary stage in the registry, defined as follows: 1) a localized tumor is a malignancy limited to the organ of origin, 2) a regional tumor is a tumor beyond the limits of the organ of origin, and 3) a distant tumor is a tumor that has spread to areas of the body distant or remote from the primary tumor.
We used the ICD-10 codes for underlying COD and classified the COD as follows: liver cancer, other causes including cancer at other sites, and non-cancer (i.e., a death attributed to causes other than cancer). To improve the accuracy of cause-specific survival estimation, we applied the cause-specific death classification algorithm [
Descriptive statistics on demographics, tumor characteristics, and proportion of death according to causes were calculated for liver cancer patients. We estimated the trends in proportionate mortalities over the periods studied and stratified the results by the time since cancer diagnosis. Proportionate mortalities were calculated as the proportions of COD among the total number of death. We estimated standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) to compare the mortality risks of non-cancer diseases in liver cancer patients compared to the general population. The 95% CI for the SMR was calculated using the method described by Kahn and Sempos [
A total of 231,388 patients diagnosed with primary liver cancer between 2000 and 2016 were included in this study (
The absolute number of patients diagnosed with liver cancer increased from 2000 to 2011 and remained steady (
Of the 231,388 liver patients diagnosed between 2000 and 2016, 78% (n=179,921) died. Among these decedents, 92.4%, 1.7%, and 6.0% died of primary liver cancer, cancer of other sites, and non-cancer, respectively (
Non-cancer mortality risks compared to the Korean general population matched by age, gender, and calendar year are shown in
The absolute number of deaths of patients with liver cancer increased from 2000 to 2012 (
During the first 5 years after the diagnosis, 93.4% of patients died from liver cancer; however, the proportion decreased to 67.3% for patients 10 or more years post-diagnosis (
The 5-year observed survival rates from all causes of death in liver cancer patients improved from 18.3% in 2000–2005 to 32% in 2011–2016. The survival improvement was notable for patients diagnosed with localized SEER stage (from 46.6% in 2006–2010 to 51.9 % in 2011–2016), while during the same time, survival remained steady for patients diagnosed with the distant stage cancer (3.2% to 2.6%;
The prognosis of patients with HCC was better than that of ICCA patients in the early tumor stage. For instance, the observed 5-year survival was 49.3% for patients diagnosed with localized HCC, compared to 20.6% for patients diagnosed with localized ICCA in 2011–2016 (
The results of multivariable competing risks analysis showed that males with older age and an advanced stage at diagnosis had significantly higher mortality risks under the competing risks (
The present study demonstrates trends in the COD and cause-specific mortalities in liver cancer patients. The absolute number of deaths among patients with liver cancer increased over time, and liver cancer itself was the most common COD. The proportion of deaths due to liver cancer slightly decreased; however, it remained high at 88% in 2016. The risk of liver cancer death remained high, even 10 or more years after a cancer diagnosis, in liver cancer patients. Liver and viral hepatitis diseases were the most common causes of non-liver cancer deaths. Deaths from cardiovascular and cerebrovascular diseases also became frequent in 10 or more years after a cancer diagnosis.
Liver cancer remains the predominant COD, even though the probability of death from liver cancer has declined over time. The proportionate mortality from other causes of death, including cancer of other sites and non-cancer causes, gradually increased from 3.3% in 2002 to 11.7% in 2016 for patients with liver cancer. Even when liver diseases and viral hepatitis are regarded as liver cancer death, the yearly trend of proportionate mortality demonstrated the increasing tendency of the proportions of death from other non-cancer causes and other causes (
Unlike other cancer types, such as stomach, colorectal, or lung cancers, the most common causes of non-cancer deaths for patients with liver cancer was liver disease and viral hepatitis. This finding also supports that most patients with liver cancer have underlying chronic liver disease. In South Korea, which is a hepatitis B virus-endemic area, hepatitis virus B and C account for approximately 70% and 10%, respectively, of HCC [
Other than liver and viral hepatitis, intentional self-harm was the most common cause of non-cancer death among patients aged 20–59 years. The present study demonstrated that suicide ranked high in non-cancer death of young patients with liver cancer, particularly within 5 years after the liver cancer diagnosis, even though older age at diagnosis has previously been reported to be associated with higher suicide rates [
A major strength of our study was that it was a large population-based study investigating the cause-specific mortality trends and competing causes of death in liver cancer patients. The comprehensive patterns in the causes of death and trends in competing mortality risks, including the competing risks modeling approach, in patients with liver cancer have not been investigated in depth, to the best of our knowledge. However, the present study also had several limitations. First, we could not incorporate detailed individual-level etiological and prognostic factors in the analyses. The available information was limited since the cancer registry data does not include information regarding the cause of cancer, liver function, hepatitis virus infection status, antiviral treatment received, performance status, recurrence of cancer, or response to cancer treatment. A comprehensive multivariate study incorporating the risk factors for liver cancer mortality and the associated individual patient level competing risks analysis should be performed in the future. Second, misclassification of the COD based on death certificates might exist, which could have led to underestimating deaths from non-cancer death. It is challenging to distinguish liver cancer-related death from death due to underlying liver disease in real-world practice. Many of the patients with liver cancer have underlying chronic liver disease. It might have been challenging to assign a COD as progressive liver disease (diseases of liver or viral hepatitis) or progressive liver cancer, since the two are closely associated with each other. Also, the COD might have been assumed to be liver cancer once the patients were diagnosed with liver cancer. The KCCR registry data does not include detailed information on each patient’s death. Therefore, we used the information on the COD from the death certificate obtained from Statistics Korea, where the official COD statistics is reported annually in South Korea [
In summary, our results showed that patients with liver cancer were most likely to die from liver cancer itself, even 10 years after the cancer diagnosis. The proportion of mortality from causes other than liver cancer tended to increase slightly; however, the magnitude of the increase was small. The most common non-cancer causes of death were liver diseases and viral hepatitis. These findings highlight the need for specialized, continued long-term follow-up care for patients with liver cancer.
Conception and study design: BHK, HC; Investigation and data curation: DL, KWJ, YJW, HC; Methodology and formal analysis: BHK, DL, HC; Interpretation of results: BHK, DL, HC; Writing – original draft: BHK, HC; Writing-review and editing: DL, KWJ, YJW. All authors reviewed and approved the final draft.
BHK has served in an advisory role for Eisai and Roche; received honoraria from Abbvie; and participated in research sponsored by Ono-BMS and Hanmi. The other authors have no conflicts to disclose.
This study was supported by the National Cancer Center, Korea (grant number: NCC-1710300-3, NCC-2110450, and NCC2010162). The funding source had no role in the study design, data curation, or the analysis and interpretation of data.
The authors thank the staff of the Korea Central Cancer Registry and Statistics Korea.
Data that support this study’s findings can be requested from the Korea Central Cancer Registry (
Supplementary material is available at Clinical and Molecular Hepatology website (
Patient selection. KCCR, Korea central cancer registry; DCO, death certificate only.
Trends in proportionate mortality, 2000–2016. Percentages are rounded to one decimal place.
Trends in proportionate mortality by age group, 2000–2016. Percentages are rounded to one decimal place.
Trends in proportionate mortalities in liver cancer patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma, 2000–2016. (A) Hepatocellular carcinoma. (B) Intrahepatic cholangiocarcinoma. –, less than 10 cases. Percentages are rounded to one decimal place.
Competing risks probabilities of death from liver cancer and other causes by tumor stage and period of diagnosis. (A) By tumor stage, 2006–2016. (B) By period of diagnosis, 2000–2016. Tumor stage information was available from 2006. The probability of death was estimated by the cumulative incidence function.
Five-year survival and cause-specific competing risks probability of death of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma, 2000–2016. (A) Hepatocellular carcinoma. (B) Intrahepatic cholangiocarcinoma. Tumor stage information was available from 2006. The probability of death was estimated by the cumulative incidence function. Percentages are rounded to one decimal place.
Mean and standard deviation of age at death by sex, year of death, and cause of death
Distribution of non-cancer cause of death by age group
Distribution of non-cancer cause of death in liver cancer patients by time since cancer diagnosis
cumulative incidence function
confidence intervals
cause of death
hepatocellular carcinoma
intrahepatic cholangiocarcinoma
International Statistical Classification of Diseases and Related Health Problems
International Classification of Diseases for Oncology
Korea central cancer registry
Surveillance
standardized mortality ratios
World Health Organization
Distribution of age and tumor stage at liver cancer diagnosis, 2000–2016. (A) By age group. (b) By tumor stage. Tumor stage information was available from 2006. Percentages are rounded to one decimal place.
Trends in proportionate mortalities in liver cancer patients, 2000–2016. (A) By the year of death. (B) By time since diagnosis. Percentages are rounded to one decimal place.
Survival and cause-specific competing risks probability of death, 2000–2016. (A) Five-year all-cause survival and cause-specific competing risks probability of death by tumor stage and year of diagnosis. (B) Competing risks probability of death from liver cancer and other-causes by age at diagnosis. Tumor stage information was available from 2006. The probability of death was estimated by the cumulative incidence function. Percentages are rounded to one decimal place.
Demographics of patients diagnosed with primary liver cancer diagnosed between 2000 and 2016
Characteristic | Total (n=231,388) | Male (n=174,638) | Female (n=56,750) |
---|---|---|---|
Age at diagnosis (years) | 60.9±12.1 | 59.5±11.5 | 65.4±12.5 |
20–39 |
7,109 (3.1) | 5,589 (3.2) | 1,520 (2.7) |
40–49 | 34,601 (15.0) | 29,658 (17.0) | 4,943 (8.7) |
50–59 | 66,578 (28.8) | 55,510 (31.8) | 11,068 (19.5) |
60–69 | 63,813 (27.6) | 47,588 (27.3) | 16,225 (28.6) |
70–79 | 44,262 (19.1) | 28,518 (16.3) | 15,744 (27.7) |
≥80 | 15,025 (6.5) | 7,775 (4.5) | 7,250 (12.8) |
Alive |
51,467 (22.2) | 38,772 (22.2) | 12,695 (22.4) |
Death |
179,921 (77.8) | 135,866 (77.8) | 44,055 (77.6) |
Cause of death |
|||
Liver cancer | 166,167 (92.4) | 125,530 (92.4) | 40,637 (92.2) |
Cancer of other sites | 3,007 (1.7) | 2,136 (1.6) | 871 (2.0) |
Non-cancer causes | 10,747 (6.0) | 8,200 (6.0) | 2,547 (5.8) |
Tumor type |
|||
HCC | 191,334 (82.7) | 150,371 (86.1) | 40,963 (72.2) |
ICCA | 40,054 (17.3) | 24,267 (13.9) | 15,787 (27.8) |
Tumor stage |
|||
Localized | 70,244 (30.4) | 52,813 (30.2) | 17,431 (30.7) |
Regional | 36,450 (15.8) | 28,310 (16.2) | 8,140 (14.3) |
Distant | 23,269 (10.1) | 17,390 (10.0) | 5,879 (10.4) |
Unknown/NA | 101,425 (43.8) | 76,125 (43.6) | 25,300 (44.6) |
Values are presented as mean±standard deviation or number (%).
HCC, hepatocellular carcinoma; ICCA, intrahepatic cholangiocarcinoma; NA, not available.
Patients diagnosed with primary liver cancer from January 1, 2000 to December 31, 2016 who were followed up to December 31, 2017. Patients aged under 20 years at diagnosis were excluded. Tumor stage information was available only for 156,300 patients diagnosed with cancer from January 1, 2006 to December 31, 2016, among which 26,337 patients had unknown tumor stage (16.9%).
Percentage among total number of patients (all sex, male, or female) is presented.
Percentage among total number of deaths.
Standard mortality ratios of non-cancer causes of death among liver cancer patients
Rank | Total |
Male |
Female |
||||||
---|---|---|---|---|---|---|---|---|---|
Cause of death | Count |
SMR |
Cause of death | Count |
SMR |
Cause of death | Count |
SMR |
|
1 | Diseases of liver |
3,707 (34.5) | 15.6 (15.1–16.1) | Diseases of liver |
2,905 (35.4) | 9.7 (9.4–10.1) | Diseases of liver |
802 (31.5) | 28.2 (26.2–30.1) |
2 | Viral hepatitis |
1,148 (10.7) | 46.5 (43.9–49.2) | Viral hepatitis |
847 (10.3) | 40.2 (37.5–42.9) | Viral hepatitis |
301 (11.8) | 50.3 (44.6–56.0) |
3 | Cerebrovascular disease | 802 (7.5) | 0.7 (0.7–0.8) | Intentional self-harm | 656 (8.0) | 2.1 (1.9–2.2) | Cerebrovascular disease | 225 (8.8) | 0.7 (0.6–0.8) |
4 | Intentional self-harm | 713 (6.6) | 2.6 (2.4–2.8) | Cerebrovascular disease | 577 (7.0) | 0.6 (0.6–0.7) | Heart diseases | 202 (7.9) | 0.9 (0.8–1.0) |
5 | Heart diseases | 665 (6.2) | 0.8 (0.8–0.9) | Heart diseases | 463 (5.6) | 0.7 (0.6–0.7) | Diabetes mellitus | 123 (4.8) | 1.0 (0.8–1.2) |
Values are presented as number (%) unless otherwise indicated.
SMR, standard mortality ratio; CI, confidence interval.
Patients diagnosed with primary liver cancer from January 1, 2000 to December 31, 2016 who were followed up to December 31, 2017. Patients aged under 20 years at diagnosis were excluded.
SMR of intentional self-harm among female patients=1.4 (95% CI, 1.0–1.8).
Percentage among non-cancer deaths.
SMRs for the specific cause of death were calculated as the average ratio of observed deaths in cancer patients from 2000 to 2017 to the expected deaths in the general population from 2000 to 2017.
Second highest SMR among non-cancer cause of death (COD).
Highest SMR among non-cancer COD.
A multivariable analysis estimating hazard of death from liver cancer under the presence of competing risks using the Fine-Gray model
Characteristic | Coefficient | sHR (95% CI) | |
---|---|---|---|
Sex | |||
Female | Reference | ||
Male | 0.12 | 1.13 (1.11–1.15) | <0.0001 |
Age at diagnosis (years) | |||
20–39 | Reference | ||
40–49 | 0.06 | 1.07 (1.02–1.12) | 0.0049 |
50–59 | 0.01 | 1.02 (0.97–1.06) | 0.4964 |
60–69 | 0.11 | 1.11 (1.07–1.16) | <0.0001 |
70–79 | 0.39 | 1.48 (1.42–1.55) | <0.0001 |
≥80 | 0.82 | 2.27 (2.16–2.39) | <0.0001 |
Tumor type | |||
HCC | Reference | ||
ICCA | 0.18 | 1.20 (1.17–1.22) | <0.0001 |
Stage | |||
Localized | Reference | ||
Regional | 0.88 | 2.42 (2.38–2.46) | <0.0001 |
Distant | 1.49 | 4.45 (4.36–4.54) | <0.0001 |
Year of diagnosis | |||
2006–2010 | Reference | ||
2011–2016 | -0.23 | 0.80 (0.79–0.81) | <0.0001 |
CI, confidence interval; HCC, hepatocellular carcinoma; ICCA, intrahepatic cholangiocarcinoma.
Patients diagnosed with primary liver cancer from January 1, 2006 to December 31, 2016, followed up to December 31, 2017, with tumor stage information available were included in the model. Patients who were aged under 20 years at diagnosis were excluded.