The influence of marital status on survival of gallbladder cancer patients: a population-based study

Marital status has been found to be a prognostic factor for survival in various cancers, but its role in gallbladder cancer (GBC) has not been fully studied. In this study, we used the Surveillance, Epidemiology, and End Results Program (SEER)-registered database to analyze the survival of GBC patients with different marital status. A total of 6,627 GBC patients were selected from SEER database from 2004 to 2013. The age, race, grade, histologic type, AJCC stage, SEER stage and marital status were identified as independent prognostic factors. Married GBC patients had a higher 5-year cancer-specific survival (CSS) than that of unmarried ones (20.1% v.s. 17.8%, P < 0.05). Subgroup analyses showed that widowed patients had 14.0% less of 5-year CSS compared to married ones of stage I (55.9% v.s. 41.9%, P < 0.05), 14.7% of stage II (15.6% v.s. 10.9%, P < 0.05), and 1.5% of stage III + IV (2.9% v.s. 1.4%, P < 0.05). In addition, single is an independent prognostic factor at stage III + IV (HR = 1.225, 95%CI 1.054–1.423, P = 0.008). These results indicated that widowed patients were at a high risk of cancer-specific mortality and marriage can be a protective prognostic factor in CSS.


Effect of marital status on CSS in the SEER database.
Married patients showed a higher 5-year CSS compared to unmarried patients (Fig. 1, 20.1% v.s. 17.8%, P < 0.001). Married group had higher survival rate in patients of TNM stage I, II and IV (stage I: χ2 = 12.891, P < 0.001; stage II: χ2 = 9.258, P = 0.002; stage IV: χ2 = 25.514, P < 0.001). This difference was not significant for stage III because of the small number of patients (stage III: χ2 = 1.512, P = 0.219). There were significant differences between married group and unmarried group of stage II + III patients (χ2 = 9.640, P = 0.002) and stage III + IV patients (χ2 = 26.430, P < 0.001). A shown in Fig. 2, the subgroup analysis of marital status (married, widowed, divorced/separated and single) confirmed these findings.
Married group had the highest 3-year and 5-year CSS (24.3% and 20.1%) compared to divorced/separated group (22.4% and 18.1%), single group (22.3% and 19.2%), and widowed group (19.1% and 14.9%, P < 0.05). While the CSS of the married group was higher than the single group (P < 0.05). Additionally, age, race, grade, histologic type, AJCC stage, SEER stage and marital status were identified as significant risk factors for the survival of GBC on univariate analysis ( Table 2, P < 0.05). All these seven variables were independent prognostic factors in multivariate analysis of Cox regression ( Table 2, P < 0.05).
Effect of marital status on CSS stratified by gender, age and race. We further explored the effect of marital status on CSS stratified by gender, age and race. As shown in Fig. 3a 17 . In this study, we first reported that widowed patients were at high risk of cancer-specific mortality and marriage can be a protective prognostic factor in CSS. Our finding showed that married group had higher survival rate in patients of TNM stage I, II and IV. Although this correlation between marriage and cancer was supported by previous studies [18][19][20][21][22] , the reasons were not fully understood. Unlike unmarried ones, married patients are more likely to receive standard treatments and social support. It has been reported that social support can increase 1-year survival of patients with metastatic breast cancer 23 , and mitigate the harmful physiologic effects of stress and restrain cancer progression through immunologic or neuroendocrine pathways [24][25][26] . In addition, marriage reflects better economic status, which can   28 . Also, healthy lifestyles have been shown among married population and married patients can have extra health care from spouses. Finally, married patients showed less distress, depression, and anxiety than unmarried counterparts [29][30][31] . Many neuroendocrine mediators and cytokines present in depression and stress were found to be related to cancer metastasis 32,33 . In addition, marital status also affects the diagnosis and treatment of patients. It has been reported that married patients would have better prognosis because of diagnosis and treatment at the early stage [34][35][36] . As mentioned above, marriage is known as the most important social support. Lack of economic and psychological support provided by marriage may attribute to the poor survival outcomes in unmarried patients. Therefore, we suggest that more psychological care and social support are needed for unmarried patients with GBC, especially for who are diagnosed at late stage and without treatment. We also found that old (age ≥ 60) and female patients had worse prognosis. It might because aging would impair immune response, increase oxidative stress, shorten telomeres, and cause accumulation of senescent cells 37,38 . While elder females experienced the changes of estrogen and progesterone which are closely related to the progression of cancer 39,40 .

5-year CCS
This study has several potential limitations. First, the SEER database does not include therapeutic information such as radical resection, palliative therapy, and detailed information of chemotherapy, recurrence and metastasis, which may also impact the prognosis of GBC patients 4 . Second, information of education, economic, social status and quality of marriage is not provided by this database, which would also effect on the prognosis of patients 12 . Third, marital status is not followed up after diagnosis, which may not be the real marital status of patients.
In conclusion, we found that married GBC patients had a higher 5-year cancer-specific survival (CSS) than that of unmarried ones. Widowed patients were at a high risk of cancer-specific mortality and marriage can be a protective prognostic factor in CSS.

Method
Patients. Data was obtained from the SEER database. The current SEER database consists of 18 population-based cancer registries that represent approximately 26% of the population in the United States. The SEER data contain no identifiers and are publicly available for studies of cancer-based epidemiology and health policy.
The National Cancer Institute's SEER*Stat software (Surveillance Research Program, National Cancer Institute SEER*Stat software, www.seer.cancer.gov/seerstat (Version 8.3.2) was used to identify patients who were pathologically diagnosed as GC between 2004 and 2013 with single primary GBC and a known marital status of age ≥ 18. Histological types were limited to adenomas adenocarcinomas, epithelial neoplasms, cystic, mucinous and serous neoplasms, and unspecified neoplasms and others (squamous cell carcinoma/complex epithelial neoplasms/complex mixed and stromal neoplasms/ductal and lobular neoplasms). Patients were excluded if they had multiple primary malignant neoplasm, with distant metastasis (M1), died within 30 days after surgery or unavailable information of CSS and survival months.
Statistical analysis. Clinicopathological parameters were analyzed by chi-square (χ2) test. Survival curves were generated using Kaplan-Meier estimates, and the differences were analyzed by log-rank test. Cox regression models were built for analyzing the risk factors of survival outcomes. Statistical analyses were performed using the statistical software package SPSS (version 19.0, Inc, Chicago, IL, USA). Results were considered to be statistically significant when a two-sided p values of less than 0.05.  Table 3. Univariate and multivariate analysis of marital status on CSS of GBC patients based on TNM stage. P-values refer to comparisons between two groups and were adjusted for age, race, grade and histologic type as covariates. NI: not included in the multivariate survival analysis.