Patients baseline characteristics
A total of 894 eligible patients with NECC were assembled from the SEER database and assigned to the training cohort (n=628) and the internal validation cohort (n=266) (Table 1). Based on the same inclusion criteria, another 106 patients with NECC from our dataset were treated as the external validation cohort (Table S1). Of the total SEER group, there was no statistical distinction in the demographic and clinical characteristics between the two subgroups. A large portion of patients (n= 749, 83.8%) were under 67 years old, and most patients were married status (n=401, 44.9%). Regarding to the disease features, the majority of patients were high grade (n=836, 93.5%), stage Ⅰ (n=411, 46.0%), greater than 4cm in tumor size (n=526, 58.8%), and absent of metastasis (n=643, 71.9%). Concerning to the treatment strategy, more than half patient had received chemotherapy (n=577, 64.5%), while had not undergone surgery (n=481, 53.8%) and had not undergone radiotherapy (n=547, 61.2%).
In the SEER group, the median follow-up duration was 20 months (ranges, 1-155 months). A total of 504/894 (56.4%) deaths occurred during follow-up, of which 401 deaths were attributed to NECC, and 103 died from competing events. The 1, 3, and 5-year cancer-specific mortalities were 24.6, 44.3, 46.9%, respectively. As shown in Figure 1, the CIF curves indicated that patients with characteristics of older age, higher grade, more advanced stage, larger tumor size, and no surgical treatment were all likely to die from both NECC and competing events. Patients with characteristics of black people, the absence of radiotherapy, the presence of metastasis, and receiving chemotherapy were observed with the increasing cumulative mortality from NECC, while not associated with competing causes. There is no statistical difference in cancer-specific mortality of the characteristics regarding marital status and year at diagnose. (Table 2).
For OS, the 1-, 3-, and 5-year survival rates were 69.2, 45.5, 41.9%, respectively. The survival curves of OS based on each variable were shown in Figure 2. Variables regarding with older age, diagnosed after 2010, divorced or widowed status, black race, higher grade, advanced stage, enlarged tumor, the presence of metastasis, and receiving chemotherapy all had an inferior OS, while patients who underwent surgery and radiotherapy had a better OS (Table 2).
Independent predictors of patients with NECC
Factors including age, marital status, grade, stage, tumor size, metastasis, surgery, radiotherapy, and chemotherapy were significantly related to CSS through univariate competing analysis. While age, year at diagnosis, marital status, histology grade, FIGO stage, tumor size, distant metastasis, surgery, radiotherapy, and chemotherapy were significantly associated with OS through univariate analysis. The race was unable to be a risk factor for both CSS and OS (Table 4). The variables identified from the univariate analysis were further analyzed by multivariate analysis for CSS and OS (Table 3). After adjusting the confounding factors, multivariate analysis revealed that age, FIGO stage, tumor size, metastasis, and chemotherapy were independent predictors for both CSS and OS (Table 4).
Construction and validation of nomograms
The nomograms for CSS and OS were constructed based on incorporating five prognostic variables from the training cohort. As shown in Figure 3, tumor size contributed most while chemotherapy accounted for the least contribution to CSS and OS. By summing up the specific point of each predictor then measuring the total points to the CSS and OS, the individual survival probability can be calculated easily. The nomograms were validated internally and externally and indicated an excellent predictive ability. The C-indexes of nomograms in the training cohort for CSS and OS were 0.784 (95% CI: 0.758-0.809), and 0.787 (95% CI, 0.765-0.808), respectively. Additionally, based on the internal and external cohort, the C-indexes of nomograms were also presented more powerful discrimination than those of the FIGO stage (Table 5). The calibration curves of each group revealed a prominent consistency between prediction and observation (Figure 4 and Figure 5 showed the results of training and internal validation cohort, respectively, and Figure S2 showed the results of external validation cohort).
Comparison with the FIGO staging system
Compared to the FIGO stage, established nomograms had a relatively higher discrimination ability (Figure 6). The AUC values of nomograms in the training cohort for 3- and 5-year OS rates were 0.836 and 0.845, respectively, while the AUC values of the FIGO stage for those were 0.769 and 0.711, respectively. Likewise, the AUC values of nomograms for 3- and 5-year CSS rates were higher than those of the FIGO staging system. For the internal and external validation cohort, the similar results were listed in Table 6.