key: cord-1021411-kkvkatjq
authors: Chen, Chongfa; Jiang, Yi; Yang, Fang; Cai, Qiucheng; Liu, Jianyong; Wu, Yushen; Lin, Huapeng
title: Risk factors associated with suicide among hepatocellular carcinoma patients: A surveillance, epidemiology, and end results analysis
date: 2020-10-07
journal: Eur J Surg Oncol
DOI: 10.1016/j.ejso.2020.10.001
sha: f8a73e2bdf43983661155effe6737b0a0649fab0
doc_id: 1021411
cord_uid: kkvkatjq

BACKGROUND: Throughout the world, hepatocellular carcinoma (HCC) remains the primary type of liver cancer. The suicide risk was higher among patients with HCC than the general population. Hence, the purpose of this study was to confirm the suicide rates, standardized mortality ratios (SMRs), and the potential risk factors associated with suicide among HCC patients. METHODS: HCC patients were collected from the Surveillance, Epidemiology, and End Results (SEER) database during 1975–2016. Suicide rates and SMRs among these patients were calculated, and the general population of the United States (U.S.) during 1975–2016 was used as a reference. Univariable and multivariable Cox regression were taken to find out the underlying risk factors of suicide in HCC patients. RESULTS: There were 70 suicides identified among 102,567 individuals with HCC observed for 160,500.88 person years. The suicide rate was 43.61 per 100,000 person-years, and SMR was 2.26 (95% CI: 1.78–2.84). On Cox regression, year of diagnosis (1975–1988 vs. 2003–2016, HR: 3.00, 95% CI: 1.01–8.89, P = 0.047; 1989–2002 vs. 2003–2016, HR: 1.92, 95% CI: 1.10–3.34, P = 0.021), gender (male vs. female, HR: 8.72, 95% CI: 2.73–27.81, P < 0.001), age at diagnosis (63–105 years old vs. 0–55 years old, HR: 2.28, 95% CI: 1.21–4.31, P = 0.011), race (white race vs. American Indian/Alaska Native, Asian/Pacific Islander, HR: 3.02, 95% CI: 1.35–6.76, P = 0.007) were independent risk factors of suicide among HCC patients. CONCLUSIONS: Diagnosed in the early years (1975–2002), male sex, the older age (63–105 years old), white race, survival months (＜2 months) were significantly associated with suicide among HCC patients. For the sake of preventing suicide behaviors, the government, clinicians, and family members should take adequate measures to decrease the rate of suicide, especially in patients with high-risk factors of suicide.

Suicide is a global public health problem, a complex behavior influenced by physical, 2 psychological, social, environmental, and cultural factors. 1 Additionally, suicide is the leading 3 cause of death worldwide among persons 15 to 24 years of age and the 10 th leading cause of death 4 in North America. 2 Globally, 817,000 persons died of suicide in 2016, comprising 1.49% of total 5 deaths. 3 The World Health Organization (WHO) estimated that the suicide rate in 2016 was 10.6 6 suicides per 100,000 people, of which 80% occurred in low-and middle-income countries. 4 7

Although suicide rates had an approximate 18% reduction from 2000 to 2016 in most WHO 8 regions, 2 the United States (U.S.) had a suicide rate increasing annually by 1.5% since 2000. 5 9

Besides, the data from Centers for Disease Control and Prevention had released that the suicide 10 rate for men aged 45 to 64 had increased from 21 suicides among 100,000 in 1999 to 30 suicides 11 among 100,000 in 2017. 6 12

In recent years, studies have reported a significant correlation between depression and suicide, and 13 the suicide rate of depression patients is much higher than that of the average population. 7-9 14 Furthermore, during the COVID-19 outbreak and the outcomes of isolation and quarantine, a 15 rapidly increasing in suicide ideation and behavior may be witnessed among at-risk populations, 16 such as the unemployed, 10 the bereaved, 11 the debtor. 12 Many previous proofs also indicated that 17 patients with poor prognosis diseases (especially cancer) are more likely to feel desperate, suffer 18 from depression and subsequently commit suicide. [13] [14] [15] [16] Additionally, some evidence from 19 systematic reviews has also shown an increased risk of suicide among patients with cancer. 17-19 20 Surprisingly in the U.S., the suicide rate of patients with cancer was almost twice than that of the 21 general population. 20 Moreover, one of the most recent studies conducted by Zaorsky et al. 22 showed that the standardized mortality rate (SMR) of suicide among cancer patients is 4.44 23 compared to the general population. 21 Since suicidal behavior is potentially recognizable and 24 preventable, identifying patients with high-risk factors for suicide is particularly important. 22 25

Similarly, primary liver cancer is the 7 th most common cancer in the world and the second leading 26 cause of cancer mortality. 23 Throughout the world, hepatocellular carcinoma (HCC) was the 27 primary type of liver cancer, accounting for nearly 75% of the total, 24 and prognosis of HCC were 28 inferior. 25 In 2019, Chelsea Anderson et al. reported that the suicide rate of patients with digestive 29 system cancer was higher than that of the general population. The SMR of the liver and 30 intrahepatic bile duct was 2.14 (95% CI: 1.58-2.85) relative to the general U.S. population 2014), with adjustment for age, sex, and race. 26 However, risk factors and SMR for suicide in 32 patients with HCC were not involved in the study. 33

To our knowledge, a comprehensive study of suicide rates in patients with liver cancer has not 34 been investigated before. Additionally, few studies explored the risk factors for suicide in patients 35

with HCC based on a large representative sample. J o u r n a l P r e -p r o o f and treatment (e.g., surgery, radiation therapy, and chemotherapy). 27 The Public Use version of 1 data collected from the SEER18 registries from 1975 to 2016 was used for this study. 28 The data 2 of the total U.S. population, including the cause of death, was obtained by the National Center for 3

Health Statistics spanning 1975 to 2016 and accessed through the SEER program. 29,30 The  4 permission to access the database was achieved after we signed and submitted a SEER Research 5 Data Agreement form through email. Moreover, it is unnecessary to ask for the patient's informed 6 consent because the data of patients in the SEER database were anonymized and de-identified 7 before release. The SEER database can be accessed publicly available, and this study was 8 exempted from seeking informed consent by the institutional research committee of the Dongfang 9

Hospital, Xiamen University. 10

The SMRs according to survival months (< 2 months, 2 months -11months, 12 months -59 months, ≥ 42 60 months), selecting the initial 2-month cutoff as our best estimate of a reasonable window 43 between diagnosis and the start of cancer treatment, this period which we hypothesized would be 44 J o u r n a l P r e -p r o o f associated with the highest suicide rates. Univariable and multivariable Cox regression were used 1 to generate crude and adjusted hazard ratios (HRs) and 95% CI for revealing potential risk factors 2 of suicide. Only variables with P < 0.1 in the univariate Cox regression models can be included in 3 multivariate Cox regression models. For these analyses, patients with 0 completed months of 4 follow-up were assigned a value of 0.5 months. 35 Age at diagnosis was the unique continuous 5 variable. To investigate the risk of suicide among patients of different ages, X-tile software was 6 applied to discover the optimal cutoffs for stratifying age (Figure 2 ). 37 All statistical tests were 7 two-sided, with P < 0.05 considered to be indicative of statistical significance. Statistical analyses 8 were performed using SPSS (version 25.0, SPSS, Chicago, IL, USA) and Microsoft Excel 9 16.0.12730.20188 (Microsoft, Redmond, WA) . The X-tile program was implemented using X-tile 10 software (http://tissuearray.org/). 11 2.6 Ethical considerations 12

This study did not involve the use of human participants or access to personal identifying 13 information. Therefore, approval by an institutional review board was not required. Informed 14 consent was also waived for this anonymous survey. was only 12.14 per 100 000 person-years between 2001 and 2016, 38 which was significantly lower 38 than that of the HCC patients in our cohort (Table 2) . 39

(1) The results showed that higher suicide rates in patients with HCC were associated with male 40 sex (vs. female sex, P < 0.0001) and no surgery performed (P=0.014); 41

(2) The result of the chi-square test for linear trend showed that suicide rates among HCC 42 patients increased with SEER histologic stage (P < 0.01) and survival months (P < 0.01); 43

(3) No statistical differences in suicide rates were found concerning the year of diagnosis, age at 44 diagnosis, marital status, race, PRCDA region, histologic type, radiotherapy performed, 1 chemotherapy performed. 2

SMRs were used to compare suicide mortality in the study population with that in the general 4 population ( (2) A general decline of suicide rates from 1975-2016 (1975-1988 years , male sex, diagnosed at an older age (63-105 years old), and white race were 5 significant predictors of suicide in the result of multivariable Cox regression. Noteworthily, 6 through the chi-square test for linear trend variables, we found that suicide rates among HCC 7 patients also significantly increased with SEER histologic stage (P < 0.01) and survival months (P 8 < 0.01) ( Table 2) . Therefore, the increasing suicide rate of patients with HCC may be influenced 9 by various demographic characteristics, histopathologic features, and follow-up features. patients with bladder cancer in the early years (1973) (1974) (1975) (1976) (1977) (1978) (1979) (1980) (1981) (1982) (1983) was also significantly higher than in 15 recent years (2004) (2005) (2006) (2007) (2008) (2009) (2010) . 43 However, another research conducted by Damien Urban in 2013 16

reported that the rate of suicide in the patients diagnosed with lung cancer did not change 17 considerably over time, with 8.83 compared with 7.17 suicides per 10,000 person-years in 18 1973-1979 and 2000-2009, respectively. 44 19 4.2 Gender 20

In the present study, the suicide rate of males (56.81 per 100 000 person-years) was nearly eight 21 times higher than that of females (P＜0.0001) ( J o u r n a l P r e -p r o o f Moreover, we further analyzed the risk factors for suicide among patients in terms of race. The 1 results of the current work inferred that the white race was another factor associated with suicide. 2

Our study showed that the suicide rates of the white race (vs. American Indian/Alaska Native, 3

Asian/Pacific Islander, HR: 3.02, 95% CI: 1.35-6.76) were 53.09 per 100,000 person years. As 4 was released by the Centers for Disease Control and Prevention, the white race had a higher 5 suicide rate than the black race in the US. 56 In a retrospective study, the predominant patients who 6 committed suicide were whites (12,258, 92.1%), with HR of suicide for black race vs. white race 7 among cancer patients is 0.31 (95% CI: 0.29-0.35, P < 0.0001), which suggested that white race 8 may be significant predictors of suicide in the cancer population. Furthermore, the white race also 9 has been corroborated to be a risk factor of suicide in many previous investigations. 55,57 Regarding 10 the low suicide rate of the non-white ethnicity, the most reasonable explanation of that may be 11 attributed to being impacted by religious beliefs, family support and a culture of refusing 12 suicide. 58-60 13 4.5 SEER disease stage 14

As shown in misclassifications of the cause of death (specifically, suicide) might cause an underrepresentation 5 of that outcome in our analysis. 73 However, rather high sensitivity and specificity have been 6 proved for the coding of suicide on death certificates with a physician review panel engaged in 7

providing the gold standard for the cause of death determination. 74 Furthermore, potential 8 confounders such as psychiatric conditions, comorbidities, cancer recurrences, substance abuse, 9

and details of therapeutic interventions could not be analyzed because that data was not available 10 in the SEER program. Finally, limited by its retrospective design, some ratings are difficult to 11 explain while the anonymization of information makes it impossible to verify whether respondents' 12

descriptions accurately signified what had actually occurred. 13 6. CONCLUSIONS 14

In summary, we found an elevated risk of suicide in patients with HCC, which is mainly 15 distributed among people with the following characteristics: diagnosed in early years The P values in the bold are statistically significant. **P < 0.01, ****P < 0.0001.

J o u r n a l P r e -p r o o f HR=Hazard Ratio; 95% CI=95% confidence interval. a Included divorced, widowed and separated; b Included never married. # The Bonferroni corrected P value was used for multiple comparisons; $ The chi square test for linear trend was used for ordinal multi-categorical variables. The P and HR values in the bold were statistically significant or considered to be analyzed in multivariate regression models. **P < 0.01, ***P < 0.001.

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High suicide rate among cancer patients fuels prevention discussions

7%) 42 (60%) 47,242 (57.2%) 11,885 (59.8%) East

6%) 252 (45.1%) 45 (64.3%) 31,798 (38.5%) 14,409 (72.5%) Regional

.1%) 5 (7.1%)

3%) 67 (95.7%) 77,542 (93.9%) 18,152 (91.3%) Chemotherapy performed Yes 34,083 (33.2%) 28 (40%)

Abbreviations: SEER=the surveillance, epidemiology, and end results program

The authors indicated no potential conflicts of interest.