Development of A Nomogram to Predict Survival Outcome Among Epithelial Ovarian Cancer Patients With Site-Distant Metastases: A Population-Based Study

Objective. The incidence of initial diagnosis with distant metastasis in patients with epithelial ovarian cancer is not rare, for which the available prognostic evaluation criteria is absent. This study aimed to develop a nomogram score to predict long-term prognosis. Methods. This study analyzed patients with epithelial ovarian cancer from the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2016. Multivariable logistic and Cox regression were performed to identify survival trajectories. A nomogram score was used to predict long-term survival probability. Results. A total of 131050 patients were included, 18.2%, 7.8% and 66.1% had localized, regional and distant metastases, respectively. Metastases were inversely associated with high probability of 5-year overall survival outcome, localized (OR, 4.62; 95%CI, 4.45-4.80), regional (OR, 2.47; 95%CI, 2.36-2.59) compared with distant metastases. Survival was poorer among regional (HR, 1.72; 95%CI, 1.65-1.79) and distant (HR, 3.39; 95%CI, 3.29-3.49) metastases at diagnosis. For incidence, 0.9%, 6.7%, 5.8% and 0.2% had bone, liver, lung and brain metastases in the all-cause mortality cohort respectively, 1.6%, 9.9%, 8.8% and 0.3% had bone, liver, lung and brain metastases in the cancer-specic mortality cohort respectively. The median survival among the all-cause mortality cohort was 21.0 months, cancer-specic mortality cohort was 15.0 months. Organ-specic metastases were independently associated with survival prognosis. Nomogram


Introduction
Epithelial ovarian cancer is a deadly malignant disease 1 . According to the Surveillance, Epidemiology, and End Results (SEER) cancer statistics review , with more than twenty-thousand cases and fourteen-thousand deaths annually 2 . Although with the continuous advancement of surgical techniques and the improvement of chemotherapy drugs, the overall survival rate of patients with epithelial ovarian cancer has improved in the past 50 years, but the ve-year overall survival rate is still less than 50% [3][4][5] . Numerous studies have investigated the association among potential survival trajectories as to prognosis of ovarian cancer 6 . However, the predictors of long-term survival are not well elucidated.
Sites-distant metastases seem to represent a signi cant cause of morbidity and mortality among patients with epithelial ovarian cancer [7][8][9] . Previous studies from case report and single institution experiences have yielded varying conclusions, especially robust population-based estimates relating to the incidence of sites-distant metastases at diagnosis are common. However, populations-level estimation for prognosis among patients with newly diagnosed epithelial ovarian cancer and sites-distant metastases are also lacking.
In autopsy studies, patients with epithelial ovarian cancer are inclined to liver, lung, bone and/or brain metastases, not all of which are clinically apparent prior to death [9][10][11] . Thus, in patients with both localized and/or organ speci c distant metastases, the risk of prognostic factors should be reassessment. Furthermore, patients diagnosed to have localized and/or distant metastases are suitable candidates for studies on postoperative adjuvant treatment, also which can help surgeons choose appropriate surgical measures for patients in advance.
Based on a lack of proven bene t, the purpose of this study was to use the SEER database to summarize the incidence proportion of organ speci c distant metastases. Based on a nomogram score, we also sought to predict survival time, in which depend on independent risk factors that contribute to prognosis.

Population-based study inclusion and exclusion criteria
The SEER database includes information on epithelial ovarian cancer incidence, outcome, and treatment for approximately thirty percent of the US population 12 . The SEER registries collect data on patient demographics, primary tumor site, tumor morphology, stage at diagnosis, and rst course of treatment, and they follow up with patients for vital status. Within the SEER 18 registries in the November 2016 data submission, we identi ed 148597 patients diagnosed as ovarian cancer from 1973 to 2016. Inclusion criteria: (1) Epithelial ovarian cancer con rmed by pathologic diagnosis, meeting the criteria of International Classi cation of Diseases for Oncology, 3rd ed 8 . The primary site was C56.9 ovary, (2) Patients who had intact clinical information and survival outcomes, (3) Evidence of distant metastases at newly diagnosis, based on the commonly used International Federation of Gynecology and Obstetrics (FIGO) staging system, distant metastases included FIGO III-A, III-B, III-C, III-NOS and IV. Likewise, due to that the database included distant metastases variables, which contributed to the presence of metastatic position like bone, liver, brain and lung at time of diagnosis. Exclusion criteria: (1) Patients who were diagnosed at autopsy or via death certi cate, (2) Patients with carcinoma for whom the presence or absence of distant metastases at diagnosis were unknown, (3) Patients who had unknown follow-up records.

Follow-up information and classi cation
Patients were strati ed by sites of distant metastases, as well as other variables included age, race/ethnicity, marital status, etc. The clinicopathologic variables in the study are shown in Table s1.

Incidence and survival analysis
The incidence proportions were calculated for patients with organ speci c metastases identi ed at diagnosis. The primary endpoint was overall survival, de ned as the time from newly diagnosis to death or loss of follow-up. Survival time was strati ed as time (t) less than or equal to or more than sixty months (cut-off point, 5-year). In addition to all-cause mortality, a separate analysis as to ovary cancer with distant metastases survival time including overall survival (OS) and cancer-speci c survival (CSS) were conducted among women diagnosed after 2010, used to assess the risk of distant metastases related to survival outcome.

Statistical analysis
Stepwise multivariable logistic and Cox regression were performed to identify survival trajectories associated with increased all-cause mortality and the presence of distant metastases. Survival estimation was performed using the Kaplan-Meier method and compared using the log-rank test. A nomogram was conducted based on the results of multivariate logistic regression analysis herein. Patients were randomly divided into the training and validation samples. The predictive performance of the nomogram was evaluated via concordance index and calibration curve. To accurately decrease the over t bias, 1000 bootstrap samples was performed. All analyses were performed using R software, version 3.6.2 (https://www.r-project.org/). P < 0.05 was considered statistical signi cance.

Results
A total of 131050 women with epithelial ovarian cancer were included in this analyses (Figs. 1). 18.2%, 7.8% and 66.1% had localized, regional and distant metastases, respectively. Among the cohort with metastatic disease, 18.6%, 81.4% were aged ≤ 50 and > 50 years, respectively. 30.0%, 70.0% were survived > 60 and ≤ 60 months, respectively. Compared to less than 5-year overall survival patients, most survivors with long-term (> 60 months) were more likely to be diagnosed with localized metastases, as well as younger age, lower grade and accepting surgery (Tables1).   overall survival prediction nomogram (Fig. 1). The nomogram score demonstrated robust accuracy in estimating the risk of 5-year overall survival probability, with an unadjusted C index of 0.78. In addition, calibration plot also showed ideal agreement as to metastases, as well as other risk factors, contributing to the estimation of long-term survival (≥ 5-year) prediction.

Incidence and median survival of patients with metastases
Among the patients in the all-cause mortality cohort(n = 33727) and cancer-speci c mortality cohort (n = 15742) with metastases at diagnosis were identi ed. For incidence, 0.9%, 6.7%, 5.8% and 0.2% had bone, liver, lung and brain metastases in the all-cause mortality cohort respectively, 1.6%, 9.9%, 8.8% and 0.3% had bone, liver, lung and brain metastases in the cancer-speci c mortality cohort respectively. The incidence proportion of patients with organ-speci c or solitary metastases at diagnosis provided in

Development and validation of a prognosis predicting nomogram
On multivariable cox regression for all-cause mortality and cancer-speci c mortality, organ-speci c metastases were independently associated with survival prognosis (Table 2). These independent associated risk factors were performed to form a prognosis (3-year/5-year overall survival) estimation nomogram. Among the all-cause mortality cohort, 70% of patients were used for training, 30% of patients were used for validation. So did the cancer-speci c mortality cohort. The nomogram score demonstrated good accuracy in estimating the prognosis of 3-year and 5-year overall survival. In the all-cause mortality training and validation cohort, a bootstrap-corrected C index was 0.79,0.78, respectively. The calibration plot also showed robust result of the estimation (Fig. 2). In the cancer-speci c mortality training and validation cohort, the nomogram displayed C index was 0.75, 0.74, respectively. So did the stable calibration curve (Fig. 3).

Discussion
Epithelial ovarian cancer is the most common pathological type in ovarian malignant tumors 5 . Based on the SEER cancer registry data analysis, the potential factors of long-term survival were comprehensively understood in this study. Taken the 5-year over survival as a cut-off point, we observed that site of metastases and organ-speci c metastases strongly were associated with overall survival in the all-cause mortality cohort and cancer-speci c mortality cohort, these survival trajectories potentially contributed to patients prognosis with distant metastases, especially among patients with organ-speci c metastases at diagnosis. Likewise, consistence with previous study, other survival trajectories such as race, ovarian involvement, histology, age (taken menopause age as borderline), insurance and marital status, which were commonly relevant to the long-term prognosis [13][14][15] . In addition, this study explored the risk of 5-year overall survival among patients with localized, regional and distant metastases, our data demonstrated that distant metastases were signi cantly associated with long-term survival (> 5 years). Collectively, tumor migration may contribute to the worse long-term survival in patients with site-distant metastases at initial diagnosis. To the best of our knowledge, this is the largest population-based study exploring prognosis in patients with epithelial ovarian cancer diagnosed with tumor metastases at diagnosis.
Our study reported the incidence and median survival time of different organ-speci c metastases.
Consistent with some but not all prior studies 8,11,16 , liver metastases showed the highest incidence in allcause death cohorts, followed by lung metastases, and bone metastases and brain metastases had relatively low incidence.
However, in solitary organ metastasis, the incidence of brain and lung metastases were relatively high. In the cancer-speci c death cohort, we found that the same rules followed, except that the incidence of solitary lung metastasis and liver metastasis were higher than the former cohort. Curiously, despite the high incidence of lung and liver metastases, the median survival time for these patients was relatively longer. Up to now, there is no standard treatment plan for distant metastasis. The main treatment is to control the primary disease. The choice of treatment plan needs to fully evaluate the patient's condition 17,18 . The multidisciplinary combined treatment mode can improve the patient's quality of life and survival time to varying degrees. In general, although the incidence of organ-speci c metastasis is not high in the entire cohort, which have potential impact on the prognosis of patients, so attention should be paid to the decision of the treatment plan for patients with distant metastases at the initial diagnosis.
In previous studies, the prognostic assessment of patients with epithelial ovarian cancer usually used postoperative FIGO staging, pathological tissue typing, and lymph node metastasis as evaluation criteria [19][20][21] . However, with the optimization and improvement of treatment methods, more and more patients already have site-distant metastases at the time of initial diagnosis, so it is necessary to fully evaluate the prognosis of patients by combining the risk of different site metastases. Our study found that organ metastasis had a signi cant impact on the 5-year overall survival time of patients, especially lung, liver and bone metastases, consistent with previous reports 17,22,23 .
Compared with lymph node metastasis, patients with organ metastasis have a relatively lower 5-year survival time and worse prognosis. Therefore, our study adopted the nomogram scoring standard to quantify the metastasis of different organs, and assign points based on the speci c location of the metastasis at the initial diagnosis of the patient, so as to effectively evaluate the 3-year survival time and 5-year survival time. In the process of establishing the nomogram, we used regression analysis to screen out 14 variables signi cantly related to prognosis. The model was robust through 1000 consecutive iteration tests. At the same time, the calibration curve also showed that the predicted value and the actual consistency.
The use of the nomogram score in estimating the risk of a patient harboring organ-speci c metastases to direct clinical treatment and prognosis assessment is a novel concept. Because there are many factors affecting the prognosis of patients, the risk of metastases is worth considering. Other factors such as age, race, surgery, pathological type, FIGO stage, insurance, and marital status also should be considered.
In short, we have established a visual prognostic evaluation model, as well as bene cial reference value for guiding patients' treatment and prognosis.
Our research also has the following limitations. First, we use the SEER database to assess the prognostic risk of patients. To the best of our knowledge, tumor metastases that affect the prognosis of patients should also consider many factors such as retroperitoneal lymph nodes and chemotherapy. This information cannot be obtained from the database. Second, there are some patients who may be at risk of distant metastasis during treatment. We cannot accurately obtain detailed information about these patients, so the risk of recurrence cannot be assessed. Third, laboratory indicators such as CA125 are related to the prognosis of ovarian cancer patients, but the database has only partial records, so it was not included in this study. Finally, we cannot obtain a detailed treatment plan for the patient, so we cannot assess the potential in uencing factors of the prognosis assessment.
Despite the above limitations, our study depended on the visual scale of organ metastasis scale for the rst time to quantitatively evaluate the 5-year survival risk of patients, for which accurately predict the 3year survival time and 5-year survival time of patients with different organ metastases. For patients with initial diagnosis of organ metastasis, the prognostic evaluation criteria should focus on organ-speci c metastasis at diagnosis, which is worthy of further research and con rmation.

Author contributions
Wu Ren and Shixuan Wang developed the original concept and study design. Bo Wang generated the initial draft of the manuscript. All authors contributed to the interpretation of the ndings and approved the nal manuscript version.