A total of 4424 patients who met our inclusion criteria were included in the study (Supplementary Table 1). Mean age was 66.8 years. Males accounted for 66.5% of all patients. Most patients had regional (37.6%) or distant (31.4%) stages of disease at the time of diagnosis. Patients were divided in 4 groups according to the year of diagnosis, (Supplementary Table 2). Although SCC (85.3%) remained the most common pathological type of UEC, the proportion of AC gradually increased over the study period (from 3.6% to 11.8%, p < 0.001). Most patients had undergone RT (75.7%) and only a few (13.3%) had been treated with surgery. While patients with localized or regional stages of disease were more likely to receive surgery (p < 0.001). RT was more commonly used in patients with regional-stage disease (p < 0.001 Supplementary Table 3). The rate of surgical resection was higher for AC, compared with SCC. Patients with SCC were more likely to receive RT than were patients with AC (p<0.001 for all, Supplementary Table 4).
Patients were divided in four groups based on the type of treatment received (Supplementary Table 5). Patients with localized disease were more likely to undergo SWR, while patients with regional-stage tumors tended to choose R+S (p<0.001). Patients who chose neither surgery nor radiotherapy tended to have advanced-stage disease (p < 0.001).
In order to evaluate the effect of RT sequence on survival among patients who underwent surgery, we divided patients into 3 groups (Supplementary Table 6): SWR, neoadjuvant radiotherapy (NRT), and adjuvant radiotherapy (ART). The proportion of SCC was lower in the SWR group, compared with the ART and NRT (p < 0.001). The number of patients who elect to undergo NRT has increased over recent decades (p < 0.001). SWR was most likely to be performed for patients with localized disease (p < 0.001). While ART was most commonly used in the treatment of patients with regional-stage (p < 0.001), NRT was most commonly used in patients with distant-stage (p < 0.001).
Median OS was approximately 9.0 months (95% CI: 8.65–9.35). Overall ECSS was also approximately 9.0 months (95% CI: 8.60–9.40). OS at 1, 3, and 5 years was 37.0%, 13.2%, and 10.0% respectively; ECSS at 1, 3, and 5 years was 40.8%, 17.9%, and 14.1%, respectively.
OS values at 1, 2, 3, and 5 years, respectively, increased further for each year that elapsed between 1973 and the time of diagnosis (Figure 1A). OS and ECSS differed significantly among these four groups (p < 0.05 for all, Figure 1B and Figure 1C). These results indicate significant increases (1973-1982 vs. 2004-2013) in median OS (7 months vs. 10 months, p < 0.001) and median ECSS (7 months vs. 11 months, p < 0.001) since 1973.
The OS and ECSS were greater for AC than for SCC (p < 0.001 for all, Figure 2A and Figure 2B). OS was higher among females, compared with males (p < 0.001; Figure 2C). ECSS was also higher among females, compared with males (p < 0.001; Figure 2D). Univariate (Supplementary Table 7) and multivariate (Supplementary Table 8) Cox analyses identified the following independent factors associated with ECSS as well as OS: date of diagnosis, ethnicity, sex, age, marital status, histologic subtype, SEER historic stage, surgical treatment, and RT, were.
Median OS for the control, RWS, SWR, and R+S groups was 3 months, 9 months, 15 months, and 15 months, respectively. ECSS and OS were improved among patients who underwent RT or surgery, compared with patients who did not receive treatment (p < 0.001 for all, Figure 3A and Figure 3B). ECSS and OS were lower in the RWS group, compared with the SWR and R+S groups (p < 0.001 for all, Figure 3A and Figure 3B).
Subgroup analyses by SEER historical stage A revealed that, for patients with localized disease, ECSS and OS were greatest in the SWR group (Figure 3C and Figure 3D). For patients with regional disease, ECSS and OS were highest in the R+S group (Figure 4A and Figure 4B). Univariate (Supplementary Table 9) and multivariate (Table 1) analysis demonstrated that treatment strategy was independently associated with both ECSS and OS.
Radiation sequence with surgery
No significant difference in ECSS or OS was found among the SWR, NRT, and ART groups (p > 0.05 for all, Figure 5A and Figure 5B).
Sub-group analysis by SEER stage showed that, for patients with localized disease, OS was highest in the SWR group. Among patients with regional disease, OS was lowest in the SWR group, compared with the ART and NRT groups. However, multivariate analysis did not reveal a significant difference in OS in localized or regional sub-groups.
Next, we performed sub-group analysis by histologic subtype. For the SCC subgroup, among patients with regional disease, OS was lower with SWR (median OS: 9 months, 95% CI: 6.34–11.67), compared with NRT (median OS:17 months, 95% CI: 11.79–22.21) and ART (median OS:15 months, 95% CI: 11.42–18.59; Figure 5C). Multivariate analysis for this subgroup also demonstrated that RT sequence was an independent factor for OS (SWR as reference, HR of NRT: 0.633, 95% CI: 0.427–0.938, p = 0.023; HR of ART: 0.635, 95% CI: 0.453–0.889, p = 0.008, Supplementary Table 10). No other subgroup analysis yielded statistically significant results.