Influence of marital status on overall survival in adult chordoma patients: A SEER-based study

Background. As a rare primary bone tumor, no studies have reported the relationship between prognosis and marital status in patients with chordoma. Methods. We classified chordoma patients identified from the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2016 into four groups: married, divorced/separated, widowed and single groups. Kaplan-Meier curves with log-rank test and Cox regression were used to analyse the effect of marital status on overall survival (OS). Results. A total of 1,080 patients were included in the study, 700 (64.8%) were married, 88 (8.1%) were divorced/separated, 78 (7.2%) were widowed and 214 (19.8%) were single. Among the four groups, the 5-year OS (45.2%), 10-year OS (12.5%) and median OS (56.0 months) were the lowest in the widowed group. After including age, sex, primary site, marital status, disease stage, tumor size, histological type, and treatment pattern, multivariate analysis showed that marital status was still an independent risk factor for chordoma patients, widowed patients have the lowest OS (hazard ratio [HR]: 1.71; 95% confidence interval [CI]: 1.25–2.33, p<0.001) compared with married patients. Similar results were observed after stratifying the primary site and disease stage. Conclusion. Marital status was an independent prognostic indicator for adult chordoma patients, and marital status was conducive to patient survival. Compared with married patients, widowed patients have a higher risk of death.


Introduction
Chordomas was a rare bone tumor that accounts for approximately 20% of primary spinal tumors and 3% of all bone tumors (1). It was a rare and locally destructive tumor that originates from the residual tissue of the embryonic spinal cord structure and can occur anywhere along the midline bone, especially the slope of the skull base, the saddle area, and the tail of the spine (2,3). The survey of European and American population shows that the incidence rate of chordomas was about 0.08/100,000, which was slightly higher in male (4). Although chordomas grow slowly, due to its aggressive and easy metastasis, the chordoma can infiltrate the surrounding bone structure. (5). Due to its high recurrence rate, which seriously affects the survival rate and the quality of life of patients, the total 5-year survival rate was only about 67% (6).
There were many factors affect the prognosis of chordoma patients. Previous studies have shown that surgical margin and distant metastasis were independent prognostic factors in patients with chordoma (7,8). In addition, patient age, histological type and tumor size may also affect the survival of chordoma patients (7,9,10).
Marital status has always been closely related to the prognosis of cancer. Many studies have confirmed that marital status may affect the prognosis of various tumors, including osteosarcoma (11), chondrosarcoma (12), penile cancer (13) and breast cancer (14). However, retrospective or prospective studies have not been conducted to report whether marital status affects the survival of adult chordoma patients. Therefore, the purpose of this study was to investigate the effect of marital status on the survival of chordoma patients according to the Surveillance, Epidemiology, and End Results (SEER) database.

Materials & Methods Patients selection
The patients we studied were selected from the Surveillance Epidemiology and End Results (SEER) database funded by the National Cancer Institute. The SEER database covers approximately 28% of the US population and includes demographic information and cancer characteristics, such as year of diagnosis, age, origin, race, insurance, marital status, primary tumour location, income status, tumour grade, disease stage, histological type, Tumor-Node-Metastasis (TNM) stage, treatment modality and survival time (15

Demographic and clinicopathologic characteristics of chordoma patients
According to the inclusion and exclusion criteria in Fig. 1, our study included a total of 1,080 eligible chordoma patients from 1975 to 2017. The number of married group, divorced/separated group, widowed group and single group was 700 (64.8%), 88 (8.1%), 78 (7.2%) and 214 (19.8%), respectively. Table 1 shows the clinical characteristics and demographic of all adult chordoma patients. Chi-square test showed that marital status was related to diagnosis year (p = 0.014), age at diagnosis (p < 0.001), sex (p < 0.001), primary site (p = 0.019) and surgery (p < 0.001). With the increase of years, the proportion of chordoma patients also increased. In the whole cohort, the majority of patients were male (59.9%), the primary site was bones of skull and face and associated joints (40.4%), and the localized stage (40.9%). In addition, the proportion of widowed patients over 60 years old (94.9%), female (73.1%) and surgery not performed (37.2%) was higher than other three groups.  (Table 3 and Fig. 3).

Identification Of Prognostic Factors Of Chordoma Patients OS
Univariate and multivariate Cox regression were used to analyze the prognostic factors associated with OS of chordoma patients (Table 4). Univariate Cox regression analysis showed that age at diagnosis, marital status, primary site, disease stage, tumor size, histological type, surgery and chemotherapy were related factors (all p < 0.05) of OS in chordoma patients (Fig. 4). Moreover, after the all factors were included in multivariate analysis, primary site, histological type, radiotherapy and 9 chemotherapy were not independent risk factors for patients with chordoma (Fig. 5). In addition, multivariate analysis showed that widowed patients had the worst OS (HR: 1.71; 95% CI: 1.25-2.33, p < 0.001) compared with married patients. In the stratification of primary site and disease stages (Table 5), univariate analysis showed that marital status was a risk factor for OS in the primary site of "Bones of skull and face and associated joints", "Vertebral column", and "Localized", "Regional", and "Distant" disease stages. In addition, multivariate analysis showed that marital status was an independent risk factor for the primary site of "Bones of skull and face and associated joints" and "Vertebral column". Moreover, although marital status was not an independent risk factor for the prognosis of chordoma patients at the disease stages of "Localized", "Regional", and "Distant", widowed patients were at higher risk of survival compared with married, divorced/separated or single patients. Marital status was widely considered to be an independent prognostic factor for many malignancies (17)(18)(19)(20) The effect of marital status on the survival of chordoma patients has been studied before. Pan et al (8) analyzed 808 patients with primary spinal chordoma from 1973 to 2014 and found that marital status was not main factor affecting OS. Huang et al (16) also showed that marital status was not a prognostic factor for patients with primary spinal chordoma. In our study, we included chordoma in the skull base, excluded all patients younger than 18 years old, and divided patients into four groups (married group, divorce/separation group, widowed group and single group). It was found that marital status was an independent prognostic factor for adult chordoma patients, which reduced the bias in case selection.
We speculate that the reasons for the worst survival of widowed patients may be as follows: first, the widowed group patient's proportion over 60 years old was 94.9%, while the proportion of the elderly was significantly higher than other groups. Elderly patients are more likely to die due to their poor physical quality and more complications (21). Second, the proportion of women (73.1%) in widowed patients was highest, and women tend to suffer higher psychological troubles (22). In addition, the proportion of surgery not performed (37.2%) was highest in the widowed group, and inadequate treatment may also lead to deterioration of the prognosis of the widowed group (23). Moreover, widowed patients may have more complex psychological and mental stress due to the lack of a partner (24). On the contrary, married patients have better family conditions and can get more social support from their spouses and families (25).
There are limitations to be recognized in this study. First, this study was a retrospective study with obvious limitations. Second, marital status was recorded at the time of diagnosis, and this information may change during follow-up, which may affect the patient's OS. In addition, the specific contents of radiotherapy and chemotherapy were not included, which may also be a prognostic factor for chordoma patients.

Conclusions
Our study found that marital status was an independent prognostic indicator for adult chordoma patients and marital status was conducive to patient survival. Widowed patients had worst OS than other group patients, and similar results were observed in the subgroup analysis.
Declarations Figure 2 Kaplan-Meier survival curves according to marital status in chordoma patients.  Forest plot of multivariable Cox analyses of overall survival. The black squares on the transverse lines represent the hazard ratio (HR), and the transverse lines represent 95% CI.