3.1 Baseline characteristics of OC patients
As shown in Table 1, a total of 27,123 eligible OC patients were recruited and their mean age and median survival time were 60.39±14.90 years and 22 months (interquartile range 9-43 months), respectively. Among them, 5.61% (N=1,521) developed LM with the mean age and median survival time were 65.37±13.74 years and 11 months (interquartile range 3-25 months), respectively. Other demographic and medical traits of recruited OC patients were presented as well. The remarkable differences included the age, race, marital status, histology, grade, tumor size, the number of regional nodes examined, radiotherapy, chemotherapy, surgery scope, T stage, N stage, CA-125, bone metastasis, brain metastasis and liver metastasis.
3.2 Independent risk factors for the morbidity of LM in OC patients and nomogram establishment
Unadjusted and adjusted logistic regression analyses were applied to assess independent risk factors for the morbidity of LM in newly diagnosed OC patients. It was shown that the histology, grade, the number of examined regional nodes number, treatment strategies like chemotherapy and surgery, T and N stage, CA-125, and the incidence of other distant metastases were correlated with the morbidity of LM in OC patients (Table 2). The morbidity of LM in OC patients with the histological subtype of serous was significantly lower than those with non-serous adenocarcinoma (OR=0.80, 95%CI=0.70-0.92, P<0.01) was lower than those with non-serous adenocarcinoma. Concerning tumor grade, poorly differentiated (OR=2.71, 95%CI=1.53-5.34, P<0.01), and undifferentiated OC patients (OR=2.84, 95%CI=1.60-5.61, P<0.01) had a significantly higher risk of LM development than well differentiated ones. In addition, OC patients with more than 10 examined lymph nodes had a significantly lower risk for the morbidity of LM than those without lymph nodes detection (OR=0.41, 95%CI=0.33-0.51, P<0.01). Advanced T and N stage, especially T3 stage (OR=2.74, 95%CI=2.09-3.66, P<0.01) and N1 stage (OR=1.86, 95%CI=1.62-2.14, P<0.01) were risk factors for LM development in OC patients. Patients with surgical treatment of bilateral ovaries or more areas had a higher risk of LM development than those receiving unilateral ovary surgery (OR=1.30, 95%CI=1.07-1.59, P<0.01), which might be attributed to disease development itself. Besides, radiotherapy (OR=1.19, 95%CI=0.79-1.74, P<0.01), chemotherapy (OR=1.39, 95%CI=1.20-1.62, P<0.01), bone metastasis (OR=3.78, 95%CI=2.79-5.11, P<0.01), brain metastasis (OR=4.67, 95%CI=2.50-8.63, P<0.01) and liver metastasis (OR=3.60, 95%CI=3.14-4.12, P<0.01) were all risk factors for the morbidity of LM in OC patients.
Subsequently, we established a nomogram to intuitively display score assignments and predictive probability of the risk factors (Figure 2A). Simultaneously, the calibration curve with the C-index of 0.807 suggested an extremely consistency between actual observations and the probability of prediction (Figure 2B). DCAs and CICs illustrated that threshold probabilities at 0-0.3 were the most favorable predictor of LM in accordance with our nomogram model (Figure 2C-D).
3.3 Survival analyses of OC patients with LM
Kaplan-Meier method was adopted to detect the influence of LM on the outcome of OC patients. As shown in Figure 3A, OS curves revealed that LM development was significantly correlated to the prognosis of OC (HR=1.36, 95%CI=1.27-1.45, P<0.01). The OS was significantly worse in OC patients with over 80 years of age (Figure 3B, P<0.01), poorly differentiated and undifferentiated neoplasm (Figure 3C, P<0.01), bone metastasis (Figure 3D, P<0.01), brain metastasis (Figure 3E, P<0.01) and liver metastasis (Figure 3F, P<0.01) than those of controls. Meanwhile, we found that LM was significant correlated with the major cause of death in OC patients rather than other diseases via gray method [sub-distribution hazard ratio (SHR)=3.08, 95%CI=2.89-3.28, P<0.01] (Figure 3G).
3.4 Prognostic factors for OC and nomogram establishment
Prognostic factors for OC patients were analyzed using the cox regression model (Table 3). OC patients aging 50-69 years (HR=1.41, 95%CI=1.32-1.50, P<0.01), aged 70-79 (HR=1.79, 95%CI=1.67-1.93, P<0.01), and over 80 years (HR=2.52, 95%CI=2.33-2.72, P<0.01) were detected to have a higher risk of death. Concerning treatment strategies, a lower risk of death was detected in OC patients treated with chemotherapy (HR=0.62, 95%CI=0.59-0.65, P<0.01). T stage was a significant risk factor for the prognosis of OC, especially T3 stage (HR=3.66, 95%CI=3.36-3.99, P<0.01). Likewise, regional lymph nodes metastases (HR=1.40, 95%CI=1.33-1.47, P<0.01), positive CA-125 (HR=1.63, 95%CI=1.47-1.82, P<0.01), bone metastasis (HR=1.58, 95%CI=1.35-1.85, P<0.01), brain metastasis (HR=1.64, 95%CI=1.21-2.21, P<0.01) and liver metastasis (HR=1.38, 95%CI=1.30-1.47, P<0.01) were all independent risk factors for the prognosis of OC.
According to the results of cox regression analysis, significant risk factors for the prognosis of OC were subjected to the establishment of a nomogram for determining the 3-year and 5-year survival rate (Figure 4A). Stratified by the medium scores from the nomogram, the clinic effect curve revealed that the high survival feasibility of low-risk subgroup was significantly superior to that of high-risk subgroup (Figure 5, HR=1.06, 95%CI=1.03-1.10, P<0.01). Furthermore, the calculated 3-year and 5-year AUC (0.812 and 0.818, respectively, Figure 4B) and the solid lines closed to the diagonal lines (Figure 4C) both displayed the excellent accuracy of the prediction.