Marital Status, An Independent Predictor for Survival of Gastric Neuroendocrine Neoplasm Patients: A Population-based, Propensity Score-matched Study

Background Marital status proves to be an independent prognostic factor in a variety of cancers. However, its prognostic impact on gastric neuroendocrine neoplasms (G-NEN) has not been investigated.Material and Methods We identied 3947 G-NEN patients from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, propensity scores for marital status were used to match 506 unmarried patients with 506 married patients. We used Kaplan–Meier method and multivariate Cox regression to analyse the association between marital status and the overall survival (OS) and G-NEN cause-specic survival (CSS) before matching and after matching.Results Married patients enjoyed better OS and CSS, compared with divorced/separated, single, and widowed patients. Multivariate Cox regression analysis indicated that unmarried status was associated with higher mortality hazards for both OS and CSS among G-NEN patients. Additionally, widowed individuals had the highest risks of overall and cancer-specic mortality compared to other unmarried groups in both males and females. Furthermore, marital status remained an independent prognostic and protective factor for both OS and CSS in 1:1 propensity score-matched analysis.Conclusion Marital status was an independent prognostic factor for G-NEN. Meanwhile, widowed patients with G-NEN had the highest risk of death compared with single, married, and divorced/separated patients.


Background
Gastric neuroendocrine neoplasms (G-NENs) comprise a heterogeneous collective of tumours arising from the enterochroma n-like cell, and account for approximately 7% of all neuroendocrine neoplasms [1]. In the past few decades, statisticians have witnessed a tenfold rise in the incidence of G-NEN, possibly due to progressed endoscopic screening skills and increased pathologic experience [2,3]. G-NEN can be subdivided into three subtypes: type associated with autoimmune atrophic gastritis, type associated with Zolinger-Ellison syndrome/gastrinoma, and type occurring sporadic without hypergastrinemia [4].
Nowadays, many clinicians and nurses mainly focused on clinicopathological characteristics, without taking the impact of psychological and social factors into consideration. In reality, these sociopsychological factors do have an in uence on patient outcomes [5]. Marriage is one of the most important source of social support, which affects physical health through integrative physiological mechanisms [6]. Previous studies have pointed out that married patients tend to have better survival outcome in several cancer types [7][8][9][10][11][12][13][14][15]. However, whether marriage has a "protective" effect for G-NEN patients has not yet been established. In the present study, we mined the data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry database to assess the effects of marital status on outcomes of patients with G-NEN.

Data sources and study population
The analysis was performed based on data obtained from the SEER registry. Using the National Cancer Institute's SEER * Stat software (Version 8.3.5), we identi ed G-NEN patients diagnosed from 1973 to 2015 with a known marital status. Primary site codes C16.0 to C16.9 and histological type codes were 8153/3: Gastrinoma, malignant, 8240/3: Carcinoid tumour, NOS, 8241/3: Enterochroma n cell carcinoid, 8242/3: Enterochroma n-like cell tumour, malignant, 8246/3: Neuroendocrine carcinoma, NOS, and 8249/3: Atypical carcinoid tumour, according to International Classi cation of Diseases for Oncology, Third Edition (ICD-O-3). The diagnosis of G-NENs was based on CS Schema v0204+ which classi cation as NETstomach. Patients with nonprimary G-NET were excluded. The cause of death and survival of all patients were clearly known.
We have got permission to access the research data in SEER database and the reference number was 14827-Nov2017. Since this was a retrospective cohort study, no ethical approval was required for analyses of these non-identi able data.

Statistical analysis
The clinical characteristics of the patients with G-NEN were presented with descriptive statistics. The categorical variable was presented with number (%). Chi-square tests were used to examine the association between marital status and other variables. Overall survival (OS), and cause-speci c survival (CSS) rates were examined using the Kaplan-Meier method with log-rank tests.
Propensity scores (PSs) were estimated via a multivariable logistic regression model to balance 2 groups (married/unmarried) with respect to age at diagnosis, sex, year of diagnosis, ethnicity, tumour grade, and tumour stage. We then matched married and unmarried patients who had very similar PSs. 1:1 PS-matching was conducted using the nearest-neighbour algorithm with a caliper width of 0.01. Upon obtaining satisfactory subjects' characteristics between married/unmarried groups, the hazard ratios (HRs) and 95% con dence intervals (CIs) of marital status over OS and CSS was estimated via a Cox proportional hazards regression model in all subjects and PS-matched cohort. The Kaplan-Meier survival curves were also plotted.
All statistical tests were 2-sided, and a value of P less than 0.05 was considered statistically signi cant.
The effects of marital status on overall and cause-speci c survival We applied Kaplan-Meier curves to evaluate the OS rates of G-NEN patients. As shown in Figure 1A, unmarried status was associated with worse prognosis compared to married status according to the Cox regression model (HR 1.47, 95% CI 1.33-1.64, P < 0.001). After adjusting baseline parameters, including age, sex, year at diagnosis, race, tumour grade, tumour size, and surgery performed, unmarried patients still had poorer prognosis than married counterparts (HR 1.49, 95% CI 1.33-1.67, P < 0.001). The CSS rates of G-NEN patients were also displayed by plotting Kaplan-Meier curves. As shown in Figure 1B, unmarried status contributed to unfavourable prognosis (HR 1.29, 95% CI 1.10-1.51, P = 0.002) according to the Cox model and even after adjusting confounding factors (HR 1.29, 95% CI 1.09-1.54, P = 0.003).
To explore whether different unmarried status led to worse prognosis than married status, we divided unmarried subjects into three subgroups: the divorced/separated, single and widowed. On univariable analysis, windowed patients had a statistically signi cant higher risk of all-cause mortality (HR 3.35, 95% CI 2.05-2.68, P < 0.001). As shown in Figure 1C, compared with married patients, windows had signi cantly lower OS rate. On multivariable analysis, unmarried status (including single marital status) remained an independent prognostic factor for increased risk of all-cause mortality, while single status did not indicate higher risk of cancer-speci c death compared to married G-NEN patients.
In addition, age, sex, tumour grade, tumour stage, and surgery performed were validated as independent prognosis factors for OS and CSS in the multivariate Cox analyses. The detailed description of each prognostic factor is displayed in Table 2.

Subgroup analysis of the effect of marital status strati ed by gender
Since widowed patients had the poorest OS, we analysed whether unmarried status, especially widowed status contributed to the poor survival rates in the subgroups of G-NEN patients strati ed by gender. As shown in Table  3, marital status was found to be an independent prognostic factor of OS in both male and female G-NEN patients according to the log-rank tests and Cox regression analysis ( Figure 1D, 1E). Particularly, widowhood affected the prognosis more in women than in men.
Clinical outcomes after propensity score matching To further con rm the ndings that married G-NEN patients survived longer and to minimize bias in the previous analysis, we conducted a PS-matching analysis. Using a 1:1 PS-matching method, we matched 506 unmarried patients with 506 married patients. As shown in Table 4, all the baseline variables were clearly well matched (all P > 0.05).
Although the HR was not higher after matching the data than before, unmarried patients still shown poorer OS (HR 1.51, 95% CI 1.19-1.90, P = 0.001) and CSS (HR 1.50, 95% CI 1.10-2.05, P = 0.01) in univariate Cox model. In multivariate analysis (Figure 2), unmarried status was still linked with signi cantly worse OS (HR 1.39, 95% CI 1.09-1.78, P = 0.008). As shown in Figure 3A and 3B, survival curves for OS and CSS indicated that married patients showed signi cantly better survival than their unmarried counterparts. Compared with married patients, widowed patients had a signi cant reduction in both OS and CSS rate ( Figure 3C, 3D).

Discussion
In this study, we assessed the impact of marital status at diagnosis on survival outcomes in a SEER cohort of G-NEN patients. Based on relatively large sample size and PS-matched dataset, our study provided results with high validity and reliability. Being married was indicated to exert a protective effect on survival compared to any unmarried status.
The diagnosis of cancer exposes an individual to chronic psychosocial stress, which triggers ght-or-ight responses by activating the hypothalamic-pituitary-adrenal axis. From a physiology perspective, psychological stress increases epinephrine, prostaglandins, and glucocorticoid levels, and reduces NK cells and cytotoxic T cells activity [16][17][18]. Then stress induces immune suppression, contributing to tumour proliferation, progression, and metastasis [19,20]. A cell line study of ovarian cancer demonstrated that stress hormones can also enhance the capacity of tumour cells to invade the extracellular matrix, contributing to tumour metastasis [21]. The detailed mechanism for protective role of marriage on neuroendocrine tumours might be explored in further experimental studies. Typically, oncological patients deny, feel angry, bargain, experience depression, and then gradually accept the reality. Social support, or supportive social network, is greatly needed throughout this process. With emotional support of their spouse, married patients experience less stress and despair [22]. Additionally, patients with less psychosocial stress have better compliance to medical recommendations [23]. Spousal encouragement may increase G-NEN patients' willingness to survive, and they are more likely to receive treatments like surgery and/or chemotherapy.
Our results show that all unmarried groups showed poorer survival outcome compared with the married group, but windowed G-NEN patients have the poorest prognosis, which is also demonstrated in studies regarding gastrointestinal stromal tumour, gastric cancer, nasopharyngeal carcinoma, and rectal cancer [24][25][26][27]. Single and separated G-NEN patients tend to be more prepared to build social support networks other than marriage compared to widowed patients. As such, clinicians, nurses, and health care workers need to pay more attention to widowed patients' emotional need, communicate more with the widowed, and provide them with necessary social support in clinical practice.
Despite of the strengths of this study including large sample size, subgroup analysis, and PS-matching method, there were some potential limitations. First, we ignored effect of the quality of marital life among G-NEN patients in the analysis. This may cause bias since unsatisfactory marriage can result in immune dysregulation [28]. Also, previous study revealed that marital relationship may change after cancer diagnosis [29]. The SEER database did not provide information on change of marital status after G-NEN diagnosis. Besides, we failed to adjust some recognized prognostic parameters such as chemotherapy and radiation in the regression model due to lack of detailed information in the database. In addition to marital status, many other social-economic factors (e.g. household income and medical insurance status) may also play a role in G-NEN patients' outcomes, which warrant further investigation.

Conclusions
In summary, our study found that marital status was an independent prognostic factor among G-NEN patients, and married individuals enjoyed signi cant survival bene ts than those un-married. Particularly, widowed G-NEN patients suffer the highest mortality risk. It is neces-sary to provide timely psychological intervention and social support for unmarried, especially widowed G-NEN patients in clinical practice.

Declarations
Ethics approval and consent to participate: Since this was a retrospective study, no ethics approval was required for analyses of these non-identi able data.

Consent for publication: Not applicable.
Availability of data and materials: The data used to support the ndings of this study are available from the SEER database (seer.cancer.gov).
Con icts of interest: No con icts to declare. Authors' contributions: YZ identi ed the G-NENs from SEER database, designed the study and wrote the manuscript; YZ, XFL, QW, JC, QZ, and KZ analysed and interpreted the data; XFL is responsible for the statistical analyses; XBL and FY contributed to conception, design and funding. All authors have been involved in revising and proofreading of the manuscript. All authors listed have approved the manuscript.    Forest plot presenting the contribution of unmarried status compared with that of married status to the overall survival rates of patients in the PS-matched cohort. HR > 1 with P < 0.05 meant that unmarried status contributed signi cantly to poorer survival than married status. Kaplan-Meier survival curves of G-NEN patients according to marital status after propensity score matching.
(A). overall survival between married and unmarried patients; (B) G-NEN cause speci c survival between married and unmarried patients; (C). overall survival among single, married, widowed, and divorced/seperated patients; (D) G-NEN cause speci c survival among single, married, widowed, and divorced/seperated patients.