Characteristics of RCTs included in the meta-analysis
In this systematic literature search, 2,432 articles were identified. After excluding 50 duplicates, 2,382 studies were further screened. The full texts of 28 articles were finally evaluated after excluding 2,354 studies. Of 28 studies, 3 duplicate publications, 6 repeat publications, 10 non-RCT studies, and 2 non-chemotherapeutic studies were excluded. The remaining 7 RCTs were considered eligible for the meta-analysis (Figure 1). The characteristics of the eligible RCTs are summarized in Additional files 1 and 2: Table S1 and Table S2 [7–13].
In the 7 eligible RCTs, 3,612 patients were randomly assigned to 17 treatment arms. All treatment arms comprised combination regimens with 3–5 cytotoxic drugs. One treatment arm included lung irradiation as the protocol treatment. No studies included molecular-targeted therapy or immune therapy. Study phases and post-protocol treatments were not clearly described in any study, and ITT analyses were conducted only in 2. The primary endpoint was defined in 5 of 7 RCTs as EFS, including 3-year EFS, whereas 2 older studies described both survival time and time to relapse as major endpoints [7,8]. Whereas most RCTs focused on localized ES, two had subgroup arms for high-risk and metastatic disease including 277 patients. The mean of the studies’ median follow-up time was 6.79 (5.1–8.5) years. Because the median EFS and OS were not reached in 7 and 5 treatment arms, respectively, analyses pertaining to median survival were not conducted in our study.
Meta-analyses
A significant difference in the HRs of EFS was observed between the control and experimental arms (HR 0.80, 95% CI 0.68–0.96, P = 0.01). A marginal difference in the 5-year EFS was also observed between the two arms (HR 0.73, 95% CI 0.53–1.00, P = 0.05), whereas no significant differences were observed in the 1-year EFS (HR 0.80, 95% CI 0.55–1.16, P = 0.24) or the 3-year EFS (HR 0.75, 95% CI 0.55–1.02, P = 0.06) (Table 1, Additional Files 3–6: Figures S1-S4).
Meta-analyses of the OS HRs revealed significantly better survival in the experimental arm than in the standard arm (HR 0.79, 95% CI 0.63–0.98, P = 0.03), and a significant difference in the 3-year OS between the two arms was also observed (HR 0.66, 95% CI 0.46–0.96, P = 0.03). However, no significant differences in the 1-year OS (HR 0.80, 95% CI 0.58–1.12, P = 0.19) or the 5-year OS (HR 0.74, 95% CI 0.53–1.02, P = 0.07) were observed (Table 1, Additional Files 7–10: Figures S5-S8).
The radiological response to chemotherapy was not described in any of the studies, and histological response was assessed only in 2. Therefore, the meta-analysis of tumor response could not be evaluated in our study.
Regarding AEs, the difference in the occurrence of severe (grade 3 or higher) nausea/vomiting between the standard and experimental treatment arms was not significant (HR 0.93, 95% CI 0.38–2.29, P = 0.87). However, severe AEs (HR 1.75, 95% CI 1.09–2.81, P = 0.02) and leukopenia (HR 2.12, 95% CI 1.27–3.52, P = 0.004) occurred significantly more frequently in the experimental arm than in the standard arm (Table 1, Additional Files 11–13: Figures S9-S11).
Correlations between EFS and OS
The trial-level correlation between the EFS HR and the OS HR was good (R2 = 0.747, 95% CI 0.531–0.981) (Table 2, Figure 2a). The Spearman’s rank correlation coefficient (ρ) was 0.683 (95% CI 0.035–0.927, P = 0.042). However, the R2 for the association between the OS HR and the 1-year EFS was moderate (R2 = 0.348, 95% CI 0.00–0.759; ρ = 0.450, 95% CI –0.305–0.858, P = 0.22) (Table 2, Figure 2b). The correlations between the OS HR and the 3-year EFS (R2 = 0.765, 95% CI 0.545–0.985; ρ = 0.717, 95% CI 0.10–0.936, P = 0.030) and the 5-year EFS (R2 = 0.695, 95% CI 0.423–0.967; ρ = 0.767, 95% CI 0.209–0.948, P = 0.016) were assessed as very good and good, respectively (Table 2, Figures 2c-d).
Similarly to what we observed for the 1-year EFS, the correlation between the 1-year OS and the OS HR was poor (R2 = 0.089, 95% CI 0.00–0.408; ρ = 0.214, 95% CI –0.642–0.833, P = 0.64). Meanwhile, the 3-year OS (R2 = 0.831, 95% CI 0.650–1.00; ρ = 0.929, 95% CI 0.584–0.990, P = 0.0025) and the 5-year OS (R2 = 0.809, 95% CI 0.625–0.993; ρ = 0.767, 95% CI 0.209–0.948, P = 0.016) showed very good correlations with OS HR (Table 2, Figures 3a-c).
Further sensitivity analyses were conducted for surrogacy evaluation by removing the treatment arms of the metastatic and high-risk populations. Localized ES analyses revealed an improved correlation between the surrogate endpoints and OS. The correlation between the EFS HR and the OS HR was very good (R2 = 0.818, 95% CI 0.625–1.00; ρ = 0.929, 95% CI 0.584–0.990, P = 0.0025) (Table 3, Figure 4a). The R2 for the associations between the OS HR and the 1-year EFS remained moderate (R2 = 0.436, 95% CI 0.00–0.873; ρ = 0.750, 95% CI –0.007–0.961, P = 0.052) (Table 3, Figure 4b). The correlations between the OS HR and the 3-year EFS (R2 = 0.807, 95% CI 0.604–1.00; ρ = 0.857, 95% CI 0.294–0.979, P = 0.014) and the 5-year EFS (R2 = 0.772, 95% CI 0.537–1.00; ρ = 0.929, 95% CI 0.584–0.990, P = 0.0025) were very good (Table 3, Figures 4c-d). The correlation between the 1-year OS and the OS HR remained poor (R2 = 0.136, 95% CI 0.00–0.535; ρ = 0.257, 95% CI –0.701–0.884, P = 0.62); however, the 3-year OS (R2 = 0.858, 95% CI 0.693–1.00; ρ = 0.943, 95% CI 0.559–0.994, P = 0.0048) and the 5-year OS (R2 = 0.895, 95% CI 0.778–1.00; ρ = 0.929, 95% CI 0.584–0.990, P = 0.0025) showed nearly excellent correlations with OS HR (Table 3, Figures 5a-c).