Risk factors associated with suicide among esophageal carcinoma patients from 1975 to 2016

Throughout the world, esophageal cancer patients had a greater suicidal risk compared with ordinary people. Thus, we aimed to affirm suicide rates, standardized mortality rates, and underlying suicide-related risk factors of esophageal cancer patients. Patients suffering esophageal cancer were chosen from the Surveillance, Epidemiology, and End Results repository in 1975–2016. Suicide rates as well as standardized mortality rates in the patients were measured. Univariable and multivariable Cox regression had been adopted for establishing the latent suicide risk factors among patients suffering esophageal cancer. On multivariable Cox regression, gender (male vs. female, HR: 6.37), age of diagnosis (70–105 vs. 0–55, HR: 2.69), marital status, race (white race vs. black race, HR: 6.64; American Indian/Alaska Native, Asian/Pacific Islander vs. black race, HR: 8.60), histologic Grade (Grade III vs. Grade I, HR: 2.36), no surgery performed (no/unknown vs. yes, HR: 2.01), no chemotherapy performed were independent risk factors related to suicide in patients suffering esophageal cancer. Male sex, the older age, unmarried state, non-black race, histologic Grade III, no surgery performed, no chemotherapy performed were strongly related to suicide in patients suffering esophageal cancer.

reported suicides per 100,000 person-years of follow-up. The U.S. population suicide rates at the National Center for Health Statistics were accessed from the SEER Program for a comparison with those of our cohort and ordinary people. Data were described using SMRs, which could be adjusted according to age, race, as well as sex in the U.S. population during the same period. Five-year age groupings were chosen in normalization 34 . SMRs were measured as the ratio of reported suicides in esophageal cancer patients to expected suicide counts of overall population. Expected suicide counts were calculated through multiplying overall population suicide rate by person-time of our cohort, considering the strata in age, race, and sex. Ninety-five percent of confidence interval (CI) in the SMRs was measured in the mid-P test 35 . In addition, between-group suicide rates were figured out by the chi-square test, and Bonferroni-corrected P value was used in multiple comparisons. Further, SMRs were evaluated in accordance with survival months (< 2 months, 2 months-11 months, 12 months-59 months, ≥ 6 0 months), and the initiative 2-month cutoff was chosen as the best estimation for the rational window between diagnosis and starting cancer therapy. The duration was supposed to be linked to the maximum suicide rate. To investigate interactions between different factors, we performed likelihood ratio testings to assess interactions among Sex, Age of diagnosis, SEER disease stage, Race, and Treatment performed (Surgery, Radiotherapy, and Chemotherapy). Univariable and multivariable Cox regression had been conducted to determine crude and adjusted hazard ratios (HRs) as well as 95% CI, to reveal underlying suicide-related risk factors. Merely variables satisfying P < 0.1 under univariate Cox regression model are proper for multivariate Cox regression model. In relevant analyses, patients who had 0-month follow-up were given a value of 0.5 months. Age of diagnosis was the sole continuous variable. For investigating suicide risk in patients at various age groups, X-tile software (http:// tissu earray. org/) had been employed for discovering the optimal cutoffs of age (see Supplementary Thus, approval from the institutional review board was unnecessary. Informed consent was abandoned in the anonymous study.  Difference in suicide rates and SMRs. Suicide rates. During 1975 and 2016, 161 suicide cases had been reported in 69,773 esophageal cancer patients surveyed for 128,508.08 person-years, resulting in the suicide rate of 125.28 per 100,000 person-years. Higher suicide rates in esophageal cancer patients correlated with male sex (vs. female sex, P < 0.001), white race (vs. black race, P < 0.001), as well as the middle third of the esophagus (vs. lower third of the esophagus, P < 0.01). The chi-square test of linear trend revealed growing suicide rate in esophageal cancer patients with age of diagnosis (P < 0.01) as well as survival months (P < 0.01). However, there were no significant discrepancies about suicide rates concerning year of diagnosis, marital status, histology recodebroad groupings, histologic grade, SEER disease stage, surgical procedures performed, radiotherapy performed, and chemotherapeutic options administered. Details are presented in Table 2.
SMRs. SMRs were used for a comparison on suicide fatality rate between studied population and general population. An SMR as 5. 45 Table 3 described all the details linked to suicide indexes of the whole cohort.

Discussion
By reference to associated surveys, suicide risk in cancer patients across various countries has gone up 24,25,36,37 . To be specific, the Italian data analysis performed by Ravaioli. A. et al. verified the growing suicide risk among cancer patients (pooled SMR: 1.7; 95% CI: 1.5-1.9) 24 . In addition to the finding, scholars in Norway (HR: 2.5; 95% CI: 1.7-3.8) 38 36 , as well as the U.S. (SMR: 2.06; 95% CI: 2.00-2.12) have also given alike reports over the past few decades 25 . A novel contribution of this research is that analysis on suicide-associated risk factors among esophageal cancer patients on the basis of SEER database, which has the largest sample size at present, provides an important basis for clinical prevention and intervention of esophageal cancer suicide. As indicated by the population-based research, suicide rate among esophageal cancer patients reached up to 125.28 per 100,000 person-years, while gross SMR amounted to 5.45 (95% CI: 4.66-6.35). Male sex (SMR: 12.72), diagnosed at an older age (SMR: 7.76), unmarried state, non-black race, histologic grade III (SMR: 7.66), no surgery performed (SMR: 8.56) and no chemotherapy performed (SMR: 6.54) might significantly increase suicide rate in esophageal cancer patients. Details are presented in Table 2.
The SMR results of the above risk factors suggested suicide rates among patients suffering esophageal cancer were obviously greater compared with those of the general U.S. population, especially in men, older age, patients  Tables 2, 3, the male suicide rate (154.52 per 100,000 person-years) was almost five times larger relative to the female suicide rate (P < 0.001). Besides that, males had a higher risk of committing suicide in contrast to females, with an HR of 6.34 in our results, which was corresponding to some previous findings, such as those for the general population 48 53,54 . A possible reason was young females showed a stronger propensity for desperation in physiology and psychology compared with middle-aged and elder counterparts following breast cancer diagnosis. This intensified their suicidal action and intention 53 .

Gender. In
Marital status. The 55 . Besides, this trend was also consistent with patients suffering kidney cancers 56 , head and neck cancers as well as genitourinary malignancies 57,58 , which might be attributed to the superior physical quality, higher socioeconomic rank, and greater emotional support and social attention of the married 43-45 . Race. In addition, the research continued to inspect all risk factors related to suicide of patients from the perspective of race. Research results found that the white race proved to be one risk factor, which contributed to suicide, and the suicide rate of white (vs. black race, HR: 6.64, 95% CI: 2.10-21.06, P < 0.01) was 135.25 per 100,000 person-years. The finding demonstrated that the white race was possibly a major predictor related to suicide among cancer patients. Further, white race is considered as another risk factor related to suicide in a good number of studies 54,59 . As to the low suicide rate in black race, the most plausible reason can be probably attributable to the influence of genetics 15,16 , religious beliefs, family support as well as suicide-rejection culture 60-62 .  64 . We further found that no chemotherapy performed (HR: 1.72, 95% CI: 1.18-2.49, P < 0.01) predicted higher suicide risks compared with those with chemotherapies. Fortunately, the combination chemotherapy regimen was still one of the main treatments for esophageal cancer, particularly among patients with advanced or metastatic tumors. Findings obtained in the current research basically conformed to a former survey which discovered that maximal standardized mortality ratios (SMRs) of suicide of cancer patients could be seen from those who had more serious tumour grades as well as those who had not received therapy 49 . Patients having advanced cancers were likely to experience more sufferings and showed a stronger propensity to anxiety or depression in comparison with those having early tumours 65 . A reasonable explanation for the correlation of therapy with lower suicide risk was that post-cancer diagnosis treatment provided more comfort and further reinforced their confidence in rehabilitation. This, to some extent, relieved the suffering caused by cancers 66 . For radiotherapy, we speculate that it may be because the dysphagia of patients after radiotherapy would not improve immediately. In most cases, patients would have weakness, neck and shoulder pain, and other symptoms after radiotherapy, which may increase the pressure and discomfort of patients. However, the tumor size after radiotherapy may be further reduced, increasing the resectability rate of surgery, and the prognosis may be improved, thus alleviating the pessimistic mood of patients 67 .
Therefore, the effect of radiotherapy on suicide in patients with esophageal cancer may not be significant, but the role of chemotherapy and surgery on suicide prevention can not be underestimated.

Survival months.
Survival months proved to be a main suicide risk factor in esophageal cancer patients, in particular two months following diagnosis (SMR: 216.79, 95% CI: 153.36-298.17; Table 2). In good agreement with former studies for other cancers, suicide risk among esophageal cancer patients often seemed better in the early stage following diagnosis compared with that in other stages, underscoring the necessity for social support and monitoring of esophageal cancer patients during such particular periods 26,37,46,47 . The government, clinicians, as well as family members are supposed to make regular evaluations on esophageal cancer patients about their suicide attempts or potential suicide risk actions, and meanwhile, use proper strategies to lower their suicide risk, particularly among patients diagnosed within two months 26,68 .
Additionally, examining variables not included by the SEER dataset, in particular those about perceived discrimination, as well as sentiment of estrangement from the mainstream culture seems necessary.

Limitations
There are many inevitable constraints in the current study, such as rich retrospective data in SEER. Underlying confounders, including comorbidities, cancer recurrences, socioeconomic status, health insurance, underlying psychiatric diseases, suicide attempts, as well as details about therapeutic interventions cannot be used for further analysis because of the non-availability of corresponding data sources in the SEER program. However, by far, it remains to be the most all-round investigation about the subject. Moreover, incomplete information on psychological status is a common issue among patients with physical illness (i.e., cancer). Further work should be conducted to improve the prediction ability by applying more appropriate models incorporating Table 3. Univariable and multivariable analysis for the suicide of esophageal cancer patients. SMR, standardized mortality ratio; SEER, the surveillance, epidemiology, and end results; HR, Hazard Ratio; 95% CI, 95% confidence interval; NOS, Not Otherwise Specified. a Included divorced, widowed and separated. b Included never married. # The Bonferroni-corrected P value was used for multiple comparisons. $ The chisquare 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 model. www.nature.com/scientificreports/ other potential risk factors. Due to the retrospective design of this study, it was difficult to explain some ratings. Besides, anonymization of information inhibited the verification of whether respondent descriptions had precisely figured out the events happened 69 .

Conclusions
To sum up, males, with older ages (70-105), bachelor, non-black race, histologic grade III, no surgical treatment or chemotherapy performed constituted remarkable indicators of suicide among esophageal cancer.

Data availability
Data involved in the research can be provided by the corresponding author if required.