Overview of the literature search
The details of our literature search are shown in Figure 1. Computer-based database searches and complementary manual search retrieved a total of 1032 relevant articles. After removing 564 duplicates, we read the titles and abstracts of the 468 studies left, 145 studies were excluded because they either did not English studies (n=22), or did not human studies (n=40), or were letters, reviews, meta-analyses, case reports, and meeting abstracts (n=83). After meticulously reading, 301 studies were excluded: 231 studies were not RCT, 42 studies were not related to CCRT, and 28 studies were not related to LA-NSCLC. In total, 22 eligible studies [20-41] with 3178 patients were enrolled in this network meta-analysis.
Characteristics of the included studies
Twenty-two articles published between 1992 and 2017, consisting of a total number of 3,178 participants with LA-NSCLC were included in this NMA. There were 21 two-arm studies and 1 three-arm study with 20 comparisons. Briefly, study sample sizes ranged from 22 to 555. From the 22 studies, 10 studies were conducted in Caucasians, and the other 12 studies were Asians. Among all individuals, 507 were treated with CCRT (cisplatin+etoposide) regimen, 227 with CCRT (carboplatin+paclitaxel) regimen, 348 with CCRT (pemetrexed+cisplatin) regimen, 254 with CCRT (mitomycin+vindesine+cisplatin) regimen, 229 with CCRT (cisplatin) regimen, 584 with RT, and remaining 1029 were treated with other CCRT regimens. The detailed characteristics of the included trials are shown in Table 1.
Quality assessment
Two researchers were assigned to evaluate all of the included studies. The results of the quality assessment involving 22 RCTs are presented in Table 2. Their mean NOS score was 8.4 (range from 7 to 9), which suggested a good quality level.
Pairwise meta-analysis of efficacy with different CCRT regimens
A random-effects model was used to perform direct pairwise matching, and the results of efficacy were shown in Table 3A. The results suggested that RT had a worse efficacy in ORR compared with CCRT (5-FU) and CCRT (nedaplatin) (OR=0.45, 95% CI=0.23-0.90; OR=0.38, 95% CI=0.17-0.85; respectively). For the 1-year OS rate, CCRT (docetaxel+cisplatin) had a worse efficacy compared with CCRT (mitomycin+vindesine+cisplatin) (OR=0.45, 95% CI=0.23-0.87), CCRT (cisplatin) had a better efficacy compared with the RT (OR=4.08, 95% CI=2.16-7.72), and RT had a worse efficacy compared with CCRT (nedaplatin) (OR=0.39, 95% CI=0.17-0.90). As for 2-year OS rate, CCRT (S-1+cisplatin) had a better efficacy compared with CCRT (cisplatin) (OR=3.15, 95% CI=1.43-6.96), CCRT (etoposide+cisplatin) had a better efficacy compared with CCRT (docetaxel+cisplatin) (OR=3.32, 95% CI=1.47-7.51), CCRT (paclitaxel+carboplatin) had a better efficacy compared with CCRT (irinotecan+carboplatin) (OR=1.32, 95% CI=0.84-2.09), CCRT (cisplatin) had a better efficacy compared with the RT (OR=5.78, 95% CI=1.88-17.80), and RT had a worse efficacy compared with CCRT (carboplatin+etoposide) (OR=0.46, 95% CI=0.22-0.96). In terms of 3-year OS rate, CCRT (S-1+cisplatin) had a better efficacy compared with CCRT (cisplatin) (OR=3.08, 95% CI=1.37-6.94), RT had a worse efficacy compared with CCRT (carboplatin) (OR=0.42, 95% CI=0.21-0.83), CCRT (etoposide+cisplatin) had a better efficacy compared with CCRT (docetaxel+cisplatin) and CCRT (paclitaxel+cisplatin) (OR=3.09, 95% CI=1.38-6.88; OR=1.98, 95% CI=1.07-3.65; respectively), CCRT (paclitaxel+carboplatin) had a better efficacy compared with CCRT (irinotecan+carboplatin) (OR=1.70, 95% CI=1.03-2.79), and CCRT (cisplatin) had a better efficacy compared with RT (OR=4.90, 95% CI=1.03-23.37).
Pairwise meta-analysis of hematological toxicity with different CCRT regimens
We conducted a direct-paired comparison of the incidence of hematological toxicity, and the results were shown in Table 3B. Compared with CCRT (carboplatin), the incidence of leukopenia with RT was relatively lower (OR=0.01, 95%CI=0.00-0.05). Compared with CCRT (mitomycin+vindesine+cisplatin), the incidences of anemia, neutropenia, thrombocytopenia, and febrile neutropenia with CCRT (carboplatin+paclitaxel) were relatively lower (OR=0.34, 95% CI=0.15-0.76; OR=0.02, 95% CI=0.01-0.04; OR=0.20, 95% CI=0.09-0.44; OR=0.08, 95% CI=0.03-0.20; respectively). Compared with CCRT (carboplatin+paclitaxel), the incidence of neutropenia with CCRT (etoposide+cisplatin) was relatively higher (OR=3.16, 95% CI=1.57-6.34). Compared with CCRT (pemetrexed+cisplatin), the incidences of neutropenia and febrile neutropenia with CCRT (etoposide+cisplatin) were relatively higher (OR=1.79, 95% CI=1.20-2.66; OR=2.42, 95% CI=1.08-5.40; respectively). Compared with CCRT (irinotecan+carboplatin), the incidences of neutropenia and thrombocytopenia with CCRT (carboplatin+paclitaxel) were relatively lower (OR=0.26, 95% CI=0.16-0.42; OR=0.42, 95% CI=0.18-0.99; respectively). Compared with CCRT (mitomycin+vindesine+cisplatin), the incidences of neutropenia, thrombocytopenia, and febrile neutropenia with CCRT (docetaxel+cisplatin) were relatively lower (OR=0.10, 95% CI=0.04-0.26; OR=0.06, 95% CI=0.01-0.27; OR=0.45, 95% CI=0.24-0.84; respectively). Compared with CCRT (pemetrexed+cisplatin) and CCRT (S-1+cisplatin), the incidences of leukopenia with CCRT (vinorelbine+cisplatin) were relatively lower (OR=0.38, 95% CI=0.16-0.90; OR=0.19, 95% CI=0.06-0.55; respectively). Compared with CCRT (irinotecan+carboplatin), the incidences of neutropenia and thrombocytopenia with CCRT (mitomycin+vindesine+cisplatin) were relatively higher (OR=13.66, 95% CI=6.48-28.77; OR=2.13, 95% CI=1.14-3.96; respectively). Compared with CCRT (pemetrexed+cisplatin), the incidences of febrile neutropenia with CCRT (mitomycin+vindesine+cisplatin) were relatively higher (OR=7.05, 95% CI=3.31-15.01).
Pairwise meta-analysis of non-hematological toxicity with different CCRT regimens
Pairwise comparisons were accomplished for the different CCRT regimens, and the results were shown in Table 3C. Compared with CCRT (mitomycin+vindesine+cisplatin), the incidences of nausea/vomiting and pneumonitis with CCRT (carboplatin+paclitaxel) were relatively lower (OR=0.09, 95% CI=0.03-0.23; OR=0.40, 95% CI=0.21-0.76; respectively). Compared with CCRT (irinotecan+carboplatin) regimen, the incidences of nausea/vomiting and pneumonitis with CCRT (mitomycin+vindesine+cisplatin) were relatively higher (OR=8.10, 95% CI=3.51-18.69; OR=2.08, 95% CI=1.13-3.83; respectively). Compared with CCRT (paclitaxel+cisplatin), the incidence of esophagitis with CCRT (etoposide+cisplatin) was relatively higher (OR=3.75, 95% CI=1.43-9.87). Compared with CCRT (irinotecan+carboplatin), the incidence of esophagitis with CCRT (carboplatin+paclitaxel) was relatively higher (OR=3.90, 95% CI=1.07-14.28). Compared with CCRT (5-FU), the incidence of esophagitis with RT was relatively lower (OR=0.24, 95% CI=0.07-0.91). Compared with CCRT (paclitaxel+cisplatin), the incidence of pneumonitis with CCRT (etoposide+cisplatin) was relatively lower (OR=0.47, 95% CI=0.24-0.91).
Inconsistency tests of efficacy and toxicity with different CCRT regimens
Inconsistency tests showed that the results of the direct and indirect evidence of different CCRT regimens were consistency, thus the consistency model was adopted (P > 0.05) (Table 4A, 4B, 4C).
Network meta-analysis of efficacy with different CCRT regimens
The network meta-analyses results and the networkplots were showed in Table 5A and Figure 2A. The results suggested that in terms of the efficacy, CCRT (cisplatin+etoposide) had better efficacy in 1-year OS rate, 2-year OS rate, and 3-year OS rate than CCRT (5-FU) (OR=9.49, 95%CI=1.26-71.34; OR=14.68, 95% CI=1.94-110.81; OR=21.37, 95% CI=2.31-197.35; respectively). CCRT (cisplatin+pemtrexed) had better efficacy in 1-year OS rate, 2-year OS rate, and 3-year OS rate than RT (OR=9.04, 95% CI=1.25-65.44; OR=14.74, 95% CI=2.07-105.14; OR=24.05, 95% CI=2.67-216.31; respectively). CCRT (S-1+cisplatin) had better efficacy in 1-year OS rate, 2-year OS rate, and 3-year OS rate than RT (OR=6.51, 95% CI=1.81-23.34; OR=18.37, 95% CI=4.35-77.48; OR=15.11, 95% CI=2.60-87.95; respectively). CCRT (cisplatin+vinorelbine) had better efficacy in 1-year OS rate, 2-year OS rate, and 3-year OS rate than RT (OR=5.54, 95% CI=1.01-30.39; OR=16.25, 95% CI=2.78-95.14; OR=13.79, 95% CI=1.80-105.85; respectively). CCRT (cisplatin) had better efficacy in 1-year OS rate, 2-year OS rate, and 3-year OS rate than RT (OR=4.08, 95% CI=2.16-7.72; OR=5.78, 95% CI=1.78-18.71; OR=4.89, 95% CI=1.03-23.34; respectively). CCRT (carboplatin+paclitaxel) had better efficacy in 1-year OS rate and 2-year OS rate than RT (OR=10.83, 95% CI=1.28-91.52; OR=11.38, 95% CI=1.29-100.34; respectively). CCRT (S-1+cisplatin) had better efficacy in 1-year OS rate and 2-year OS rate than CCRT (5-FU) (OR=6.33, 95% CI=1.52-26.34; OR=7.57, 95% CI=1.12-51.28; respectively). CCRT (S-1+cisplatin) had better efficacy in 1-year OS rate and 2-year OS rate than CCRT (carboplatin+etoposide) (OR=4.94, 95% CI=1.12-21.81; OR=8.42, 95% CI=1.61-44.00; respectively). CCRT (S-1+cisplatin) had better efficacy in 1-year OS rate and 2-year OS rate than CCRT (carboplatin) (OR=5.35, 95% CI=1.38-20.68; OR=12.62, 95% CI=2.69-59.26; respectively). CCRT (cisplatin) had better efficacy in 1-year OS rate and 2-year OS rate than CCRT (carboplatin) (OR=3.36, 95% CI=1.54-7.29; OR=3.97, 95% CI=1.08-14.58; respectively). CCRT (carboplatin+paclitaxel) had better efficacy in 2-year OS rate and 3-year OS rate than CCRT (docetaxel+cisplatin) (OR=3.32, 95% CI=1.37-8.04; OR=3.09, 95% CI=1.38-6.88; respectively). CCRT (pemetrexed+cisplatin) had better efficacy in 2-year OS rate and 3-year OS rate than CCRT (docetaxel+cisplatin) (OR=3.34, 95% CI=1.22-9.11; OR=3.47, 95% CI=1.45-8.30; respectively). CCRT (pemetrexed+cisplatin) had better efficacy in 2-year OS rate and 3-year OS rate than CCRT (carboplatin) (OR=10.13, 95% CI=1.31-78.23; OR=10.10, 95% CI=1.01-101.01; respectively). CCRT (S-1+cisplatin) had better efficacy in 2-year OS rate and 3-year OS rate than CCRT (cisplatin) (OR=3.18, 95% CI=1.38-7.31; OR=3.09, 95% CI=1.37-6.97; respectively). CCRT (paclitaxel+cisplatin) had better efficacy in 2-year OS rate and 3-year OS rate than RT (OR=11.65, 95% CI=1.39-97.88; OR=10.80, 95% CI=1.08-108.39; respectively). CCRT (etoposide+cisplatin) had a better efficacy in 1-year OS rate than CCRT (paclitaxel+cisplatin) (OR=9.24, 95% CI=1.12-76.48). CCRT (carboplatin+paclitaxel) had better efficacy in 1-year OS rate than CCRT (5-FU) and CCRT (carboplatin) (OR=10.54, 95% CI=1.14-97.62; OR=8.91, 95% CI=1.01-78.75; respectively). CCRT (pemetrexed+cisplatin) and CCRT (cisplatin) had better efficacy in 1-year OS rate than CCRT (5-FU) (OR=8.80, 95% CI=1.10-70.28; OR=3.97, 95% CI=1.62-9.75; respectively). CCRT (cisplatin) and CCRT (paclitaxel+cisplatin) had better efficacy in 1-year OS rate than CCRT (carboplatin+etoposide) (OR=3.10, 95% CI=1.15-8.34; OR=9.87, 95% CI=1.03-94.58; respectively). CCRT (paclitaxel+cisplatin) had a better efficacy in 1-year OS rate than CCRT (carboplatin) (OR=10.69, 95% CI=1.21-94.11). CCRT (S-1+cisplatin) had a better efficacy in 2-year OS rate than CCRT (nedaplatin) (OR=8.06, 95% CI=1.32-49.10). CCRT (mitomycin+vindesine+cisplatin) had a better efficacy in 2-year OS rate than RT (OR=11.70, 95% CI=1.23-110.88). CCRT (cisplatin+vinorelbine) had better efficacy in 2-year OS rate than CCRT (carboplatin+etoposide) and CCRT (carboplatin) (OR=7.45, 95% CI=1.06-52.13; OR=11.17, 95% CI=1.75-71.40; respectively). CCRT (cisplatin+etoposide) had a better efficacy in 3-year OS rate than CCRT (irinotecan+carboplatin) (OR=1.98, 95% CI=1.07-3.65). CCRT (pemetrexed+cisplatin) had a better efficacy in 3-year OS rate than CCRT (carboplatin+paclitaxel) (OR=3.94, 95% CI=1.05-14.72). CCRT (carboplatin+paclitaxel) had better efficacy in 3-year OS rate than CCRT (cisplatin), CCRT (paclitaxel+cisplatin), CCRT (irinotecan+carboplatin), and CCRT (nedaplatin) (OR=4.91, 95% CI=1.05-23.03; OR=2.23, 95% CI=1.10-4.49; OR=4.41, 95% CI=1.07-18.18; OR=12.68, 95% CI=1.01-158.37; respectively). CCRT (carboplatin) had a better efficacy in 3-year OS rate than RT (OR=2.38, 95% CI=1.19-4.75). However, the ORR of all CCRT regimens had no differences.
Network meta-analysis of hematological toxicity with different CCRT regimens
The network meta-analysis results and the networkplots were shown in Table 5B and Figure 2B. The results suggested that in terms of the hematological toxicity, the incidences of anemia, neutropenia, and thrombocytopenia with CCRT (mitomycin+vindesine+cisplatin) were higher than CCRT (carboplatin+paclitaxel) (OR=2.94, 95% CI=1.32-6.55; OR=53.03, 95% CI=24.50-114.78; OR=5.11, 95% CI=2.28-11.45; respectively). The incidences of neutropenia and febrile neutropenia with CCRT (cisplatin+etoposide) were higher than CCRT (pemetrexed+cisplatin) (OR=1.79, 95% CI=1.20-2.66; OR=2.42, 95% CI=1.08-5.40; respectively). The incidences of neutropenia and thrombocytopenia with CCRT (irinotecan+carboplatin) were higher than CCRT (carboplatin+paclitaxel) (OR=3.88, 95% CI=2.37-6.37; OR=2.40, 95% CI=1.01-5.71; respectively). The incidence of leukopenia with CCRT (cisplatin+vinorelbine) was higher than CCRT (S-1+cisplatin) and CCRT (cisplatin) (OR=5.34, 95% CI=1.23-23.14; OR=7.41, 95% CI=1.14-48.39; respectively). The incidence of leukopenia with CCRT (carboplatin) was higher than CCRT (S-1+cisplatin), CCRT (cisplatin), and RT (OR=25.48, 95% CI=2.70-240.60; OR=35.35, 95% CI=5.23-239.20, OR=38.74, 95% CI=8.50-176.58; respectively). The incidence of leukopenia with CCRT (nedaplatin) was higher than CCRT (cisplatin) and RT (OR=22.60, 95% CI=1.74-293.03; OR=24.76, 95% CI=2.53-242.76; respectively). The incidence of neutropenia with CCRT (etoposide+cisplatin) was higher than CCRT (paclitaxel+carboplatin) (OR=3.28, 95% CI=1.52-7.09). The incidence of neutropenia with CCRT (irinotecan+carboplatin) was higher than CCRT (etoposide+cisplatin) (OR=16.15, 95% CI=5.43-48.06). The incidence of neutropenia with CCRT (mitomycin+vindesine+cisplatin) was higher than CCRT (pemetrexed+cisplatin), CCRT (docetaxel+cisplatin), and CCRT (irinotecan+carboplatin) (OR=28.85, 95% CI=9.03-92.14; OR=173.39, 95% CI=7.49-4015.10; OR=13.66, 95% CI=5.46-34.17; respectively). The incidence of febrile neutropenia with CCRT (cisplatin+vinorelbine) was higher than CCRT (cisplatin+etoposide) (OR=6.91, 95% CI=1.39-34.42).
Network meta-analysis of non-hematological toxicity with different CCRT regimens
The network meta-analysis results and the networkplots were shown in Table 5B and Figure 2B. The results suggested that in terms of the non-hematological toxicity, the incidences of pneumonia with CCRT (cisplatin+vinorelbine) and CCRT (irinotecan+carboplatin) were higher than CCRT (cisplatin+etoposide) (OR=5.65, 95% CI=1.82-17.56; OR=2.14, 95% CI=1.10-4.16; respectively). The incidences of pneumonia with CCRT (carboplatin+paclitaxel), CCRT (docetaxel+cisplatin), CCRT (mitomycin+vindesine+cisplatin), CCRT (paclitaxel+cisplatin), and CCRT (irinotecan+carboplatin) were higher than CCRT (etoposide+cisplatin+amifostine) (OR=17.61, 95% CI=1.62-191.58; OR=46.79, 95% CI=2.16-1013.71; OR=44.08, 95% CI=3.72-521.75; OR=16.68, 95% CI=1.68-165.50; OR=21.23, 95% CI=1.76-255.84; respectively). The incidence of pneumonia with CCRT (mitomycin+vindesine+cisplatin) was higher than CCRT (pemetrexed+cisplatin) (OR=6.89, 95% CI=1.42-33.51). The incidences of esophagitis with CCRT (cisplatin+etoposide) and CCRT (carboplatin+paclitaxel) were higher than CCRT (irinotecan+carboplatin) (OR=3.75, 95% CI=1.43-9.87; OR=3.90, 95% CI=1.07-14.28; respectively). The incidences of esophagitis with CCRT (carboplatin+paclitaxel) and CCRT (pemetrexed+cisplatin) were higher than CCRT (paclitaxel+cisplatin) (OR=3.96, 95% CI=1.20-13.03; OR=3.78, 95% CI=1.20-11.94; respectively). The incidence of esophagitis with CCRT (5-FU) was higher than RT (OR=4.08, 95% CI=1.10-15.11). The incidence of nausea/vomiting with CCRT (mitomycin+vindesine+cisplatin) was higher than CCRT (carboplatin+paclitaxel) and CCRT (irinotecan+carboplatin) (OR=11.41, 95% CI=4.38-29.77; OR=8.10, 95% CI=1.78-36.76; respectively). The incidence of the nausea/vomiting with CCRT (nedaplatin) was higher than CCRT (cisplatin), RT, and CCRT (carboplatin) (OR=7.88, 95% CI=1.51-41.20; OR=10.43, 95% CI=2.29-47.54; OR=15.76, 95% CI=1.45-170.99; respectively).
Cumulative probability of the efficacy and toxicity of different CCRT regimens
As shown in Table 6 and Figure 3, the SUCRA values of the efficacy and toxicity of different CCRT regimens demonstrated that in terms of efficacy, the ORR of CCRT (nedaplatin) ranked the highest (75.9%), followed by CCRT (paclitaxel) (73.2%). The 1-year OS rate of CCRT (paclitaxel+cisplatin) ranked the highest (85.9%), followed by CCRT (paclitaxel+carboplatin) (78.4%), CCRT (mitomycin+vindesine+cisplatin) (76.5%), CCRT (etoposide+cisplatin) (72.5%), and CCRT (pemetrexed+cisplatin) (70.4%). The 2-year OS rate of CCRT (S-1+cisplatin) ranked the highest (83.8%), followed by CCRT (etoposide+cisplatin) (79.7%), CCRT (pemetrexed+cisplatin) (79.7%), and CCRT (carboplatin+paclitaxel) (68.6%). The 3-year OS rate of CCRT (pemetrexed+cisplatin) ranked the highest (95.1%), followed by CCRT (etoposide+cisplatin) (89.4%). As for toxicity, the incidences of anemia and febrile neutropenia with CCRT (pemetrexed+cisplatin) ranked the lowest (26.7%; 12.0%; respectively), followed by CCRT (paclitaxel+carboplatin) (39.3%; 16.7%; respectively). The incidences of neutropenia and thrombocytopenia with CCRT (docetaxel+cisplatin) ranked the lowest (10.3%; 27.4%; respectively), followed by CCRT (paclitaxel+carboplatin) (21.6%; 32.9%; respectively). The incidences of leukopenia with CCRT (cisplatin) and RT ranked the lowest (17.9%; 17.9%; respectively). The incidence of nausea/vomiting with CCRT (carboplatin) ranked the lowest (23.2%), followed by CCRT (cisplatin+vinorelbine) (26.1%). The incidence of esophagitis with CCRT (paclitaxel+cisplatin) ranked the lowest (16.9%), and the incidence of pneumonitis with CCRT (etoposide+cisplatin+amifostine) ranked the lowest (17.7%).
Cluster analysis regarding efficacy and toxicity in the included studies
The cluster analysis based on SUCRA values indicated that the regimens with CCRT (cisplatin+etoposide), CCRT (carboplatin+paclitaxel), CCRT (pemetrexed+cisplatin), CCRT (S-1+cisplatin), and CCRT (cisplatin+vinorelbine) had relatively better efficacy compared with other regimens (Figure 4A). As for toxicity of different CCRT regimens, the hematological toxicity of CCRT (carboplatin+paclitaxel), CCRT (pemetrexed+cisplatin), and CCRT (docetaxel+cisplatin) were relatively lower (Figure 4B). However, the significance of non-hematological toxicity with different CCRT regimens were not significant (Figure 4B).
Publication bias regarding efficacy and toxicity in the included studies
The comparison-adjusted funnel plot of the efficacy and toxicity of CCRT regimens showed that there was no publication bias among the included studies (Figure 5A and Figure 5B).