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. 2019 Oct 16;14:176. doi: 10.1186/s13014-019-1388-8

Elective nodal irradiation versus involved-field irradiation in patients with esophageal cancer receiving neoadjuvant chemoradiotherapy: a network meta-analysis

Tingting Liu 1,2,#, Silu Ding 1,#, Jun Dang 1,✉, Hui Wang 3, Jun Chen 4, Guang Li 1
PMCID: PMC6794743  PMID: 31619265

Abstract

Background

To assess the comparative efficacy and safety of elective nodal irradiation (ENI) and involved-field irradiation (IFI) in patients with esophageal cancer (EC) receiving neoadjuvant chemoradiotherapy plus surgery (nCRTS).

Material and methods

PubMed, Embase, Cochrane Library, Web of Science and major meetings were searched for randomized controlled trials (RCTs) that compared at least two of the following treatment regimens: nCRTS, neoadjuvant chemotherapy plus surgery (nCTS), and surgery (S) alone. Overall survival (OS) was the primary outcomes of interest, reported as hazard ratio (HR) and 95% confidence intervals (CIs). A Bayesian network meta-analysis was performed to compare all regimens simultaneously.

Results

Twenty-nine RCTs with a total of 5212 patients were included in the meta-analysis. Both nCRTS adopting ENI (nCRTS-ENI) (HR = 0.63, 95% CI: 0.48–0.83) and nCRTS adopting IFI (nCRTS-IFI) (HR = 0.75, 95% CI: 0.66–0.86) significantly improved OS compared to S alone. No significant differences in OS, locoregional recurrence, distant metastases, R0 resection and postoperative mortality were observed between nCRTS-ENI and nCRTS-IFI. In subgroup analyses, nCRTS-IFI showed a significant OS advantage over nCTS (HR = 0.78, 95% CI: 0.63–0.96) and S alone (HR = 0.50, 95% CI: 0.38–0.68) for esophagus squamous cell carcinoma (ESCC), but nCRTS-ENI did not; nCRTS-ENI using three-dimensional radiotherapy (3D-RT) resulted in an improved OS compared to that with 2D-RT (HR = 0.58, 95% CI: 0.34–0.99). Based on treatment ranking in term of OS, nCRTS-IFI (0.90) and nCRTS-ENI (0.96) was ranked the most effective treatment for ESCC and esophagus adenocarcinoma (EAC), respectively.

Conclusion

Either adopting ENI or IFI, nCRTS is likely to be the optimal treatment for resectable EC, and nCRTS-IFI and nCRTS-ENI seem to be more effective for patients with ESCC and EAC, respectively. Future head to head comparison trials are needed to confirm these findings.

Keywords: Esophagus cancer, Neoadjuvant chemoradiotherapy, Elective nodal irradiation, Involved-field irradiation, Network meta-analysis

Introduction

Esophagus cancer (EC) is the eighth most common cancer worldwide and the sixth most common cause of cancer-related deaths [1, 2]. Surgery is still considered as a major component of treatment for all resectable cases. However, surgery alone (S alone) showed poor long-term outcomes, and the 5-year survival rate was rarely > 30% even after curative resection [3, 4]. Some recent randomized control trials (RCTs) have demonstrated the survival benefit of neoadjuvant chemoradiotherapy followed by surgery (nCRTS) compared with S alone [5–8]. While, there are also trials reporting negative results [9–22].

It should be noted that radiation fields used for patients receiving nCRTS are inconsistent in trials, which might affect the outcomes. Some trials adopted elective nodal irradiation (ENI, nodal target volume covering both metastatic lymph nodes and regional nodes) [17–22], and others adopted involved-field irradiation (IFI, nodal target volume including only the metastatic nodes) [5–16]. Efficacy of ENI and IFI has been compared in patients with locally advanced EC undergoing radical CRT in some retrospective studies [23–26], but with different results. At present, no trials have compared the two radiation fields directly in patients undergoing nCRTS, and therefore, there are still questions around which is more superior, and what is the suitable patient population for adopting ENI or IFI.

In light of these issues, we performed a network meta-analysis to assess the comparative effectiveness and safety of ENI and IFI, attempting to identify the best radiation field in patients receiving nCRT.

Materials and methods

Literature search strategy

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria [27] (Additional file 1: Tables S1). PubMed, Embase, Cochrane Library, Web of Science were searched for the available studies published before April 1, 2019, using the strategy as shown in Additional file 1: Tables S2. The reference lists of retrieved studies were manually scanned for relevant additional studies missed by the electronic search.

Inclusion and exclusion criteria

Studies were included if they met the following criteria: (1) types of studies: RCTs; (2) types of participants: resectable EC; (3) types of interventions: compared at least two of the following treatments: nCRTS, neoadjuvant chemotherapy plus surgery (nCTS), and S alone; and (4) outcomes: overall survival (OS), locoregional recurrence (LR), distant metastases (DM), R0 resection, and postoperative mortality (POM) data. Studies which failed to meet the above criteria were excluded from the network meta-analysis.

Data extraction

The data were extracted by two investigators independently. The following data were extracted from each study: first author or name of individual RCT, years of publication, duration of the study, country of origin, treatments, numbers of patients, pathologic type, and data of OS, LR, DM, R0 resection, and POM.

Quality assessment

The methodological quality of RCTs was assessed by Cochrane risk of bias tool [28], which consists of the following five domains: sequence generation, allocation concealment, blinding, incomplete data, and selective reporting. A RCT was finally rated as “low risk of bias” (all key domains indicated as low risk), “high risk of bias” (one or more key domains indicated as high risk), and “unclear risk of bias”.

Statistical analysis

The primary outcome was OS, and the secondary outcomes were LR, DM, R0 resection, and POM. Hazard ratios (HRs) or odds ratios (ORs) and their 95% confidence intervals (CIs) were used as summary statistics. For direct comparisons, standard pairwise meta-analysis was performed. A statistical test for heterogeneity was performed using the chi-square (χ2) and I-square (I2) tests with the significance set at I2 > 50% or P < 0.10. If significant heterogeneity existed, a random-effects analysis model was used; otherwise, a fixed-effects model was used.

The Bayesian network-meta analysis (NMA) was performed in a random-effect model using Markov chain Monte Carlo methods [29, 30] in JAGS and the GeMTC package in R (https://drugis.org/software/r-packages/gemtc). For each outcome measure, four independent Markov chains were simultaneously run for 20,000 burn-ins and 100,000 inference iterations per chain to obtain the posterior distribution. The traces plot and Brooks-Gelman-Rubin method were used to assess the convergence of model [31]. Treatment effects were estimated by HR/OR and corresponding 95% CI. Network consistency was assessed with node-split models by statistically testing between direct and indirect estimates within treatment loop [32]. To rank probabilities of all available treatments, the surfaces under the cumulative ranking curve (SUCRAs) were calculated [33]. SUCRA equals one if the treatment is certain to be the best and zero if it’s certain to be the worst [33]. In addition, we conducted subgroup analyses according to histologic type, RT dose, and RT technique. Lastly, comparison-adjusted funnel plot was used to detect the presence of small-study effects or publication bias [34].

Results

Literature search results and characteristics of included studies

The literature search results and study selection process are shown in Fig. 1. The initial search retrieved 2740 studies. After removing the duplicates, 1555 citations were identified, and 1497 of them were excluded through an abstract review. The remaining 58 studies were screened through a full-text review for further eligibility. Finally, 29 RCTs [5–22, 35–50] with 5212 patients were included in the meta-analysis. Among them, 5 compared nCRTS using ENI (nCRTS-ENI) with S alone [17–21], 9 compared nCRTS using IFI (nCRTS-IFI) with S alone [5–15], 11 compared nCTS with S alone [38–50], 1 compared nCRTS-ENI and nCTS with S alone [22], 1 compared nCRTS-IFI and nCTS with S alone [16], 1 compared nCRTS-ENI with nCTS [35, 36], and 1 compared nCRTS-IFI with nCTS [37]. The study characteristics are shown in Table 1. Details of radiation fields are shown in Additional file 1: Tables S3.

Fig. 1.

Fig. 1

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Literature search and selection. RCTs, randomized control trials; nCRTS, neoadjuvant chemoradiotherapy plus surgery; nCTS, neoadjuvant chemotherapy plus surgery; nRTS, neoadjuvant radiotherapy plus surgery; S, surgery; RT, radiotherapy; ENI, elective nodal irradiation; IFI, involved-field irradiation

Table 1.

Characteristics of included trials

Trial Time
Range		 Region Treatment Sample
size		 Median
follow-up		 Median
Age		 pStage Histology CT RT RT
regimen dose (Gy) technique
NEOCRTEC5010/2018 [5] 2007–2014 China nCRTS-IFI 224 41 m 56 I-IV SCC NP 40 3D
S alone 227 58
CROSS/2011 [6, 7] 2004–2008 Netherlands nCRTS-IFI 178 84 m 60 I-III SCC/AC PC 41.4 3D
S alone 188 60
Lv/2010 [8] 1997–2004 China nCRTS-IFI 80 45 m NR I-III SCC PC 40 2D
S alone 80
FFCD9901/2014 [9] 2000–2009 France nCRTS-IFI 98 94 m 58.1 I-III SCC/AC FP 45 3D
S alone 97 57.6
IG9401/2005 [10] 1994–2000 Australia nCRTS-IFI 128 65 m 61 NR SCC/AC FP 35 2D
S alone 128 62
Urba/2001 [11] 1985–1987 America nCRTS-IFI 50 98 m 62 NR SCC/AC FP + Vin 45 3D
S alone 50 64
Bosset/1997 [12] 1989–1995 France nCRTS-IFI 143 55 m 56.6 I-III SCC Cis 37 3D
S alone 139 56.7
Walsh/1996 [13, 14] 1990–1995 Ireland nCRTS-IFI 58 10 m 65 I-IV AC FP 40 2D
S alone 55 65
Apinop/1994 [15] 1986–1992 Thailand nCRTS-IFI 35 NR 59.6 NR SCC FP 40 2D
S alone 34 59.8
Cao/2009 [16] 1991–2000 China nCRTS-IFI 118 NR NR II-IV SCC FP 40 2D
nCTS 119
S alone 118
Yanagi/2018 [17] 1997–2001 Japan nCRTS-ENI 20 90 m 61.5 I-IV SCC FP 40 NR
S alone 21 60
CALGB9781/2008 [18] 1997–2000 America nCRTS-ENI 30 72 m 59.9 NR SCC/AC FP 50.4 3D
S alone 26 62.2
Natsugoe/2006 [19] 1997–2001 Japan nCRTS-ENI 22 24 m NR II-IV SCC FP 40 NR
S alone 23
Lee/2004 [20] 1999–2002 Korea nCRTS-ENI 51 25 m 63 I-IV SCC FP 45.6 2D
S alone 50 63
Le Prise/1994 [21] 1988–1991 France nCRTS-ENI 41 16 m 56 NR SCC FP 20 2D
S alone 45 59
Nygaard/1992 [22] 1983–1988 Norway nCRTS-ENI 53 NR 60.1 NR SCC Cis + Ble 35 2D
nCTS 56 62.9
S alone 50 61.4
Stahl/2009 [35, 36] 2000–2005 Germany nCRTS-ENI 60 126 m 60.6 I-IV AC PLF 30 3D
nCTS 59 56
Burmeister/2011 [37] 2000–2006 Australia nCRTS-IFI 39 94 m 60 I-III AC FP 35 3D
nCTS 36 63
Boonstra/2011 [38] 1989–1996 Netherlands nCTS 85 15 m 60 I-IV SCC EP
S alone 84 14 m 60
Ychou/2011 [39] 1995–2003 Multicenter nCTS 84 NR NR NR AC FP
S alone 85
OEO2/2002 [40, 41] 1992–1998 UK nCTS 400 73 m 63 NR SCC/AC FP
S alone 402 63
MAGIC/2006 [42] 1994–2002 Multicenter nCTS 65 NR NR NR AC ECF
S alone 66
RTOG8911/2007 [43, 44] 1990–1995 Multicenter nCTS 233 NR 61 NR SCC/AC FP
S alone 234 62
Ancona/2001 [45] 1992–1997 Italy nCTS 47 NR 58 NR NR FP
S alone 47 58
Baba/2000 [46] 1993–1995 Japan nCTS 21 NR 63.6 I-IV SCC PLF
S alone 21 60.1
Law/1997 [47] 1989–1995 China nCTS 74 17 m 64 I-III SCC FP
S alone 73 63
Schlag/1992 [48] NR Germany nCTS 35 8 m NR NR SCC FP
S alone 42
Maipang/1994 [49] 1988–1990 Thailand nCTS 24 NR 64.2 NR SCC Cis + Ble
S alone 22 64.8
Roth/1988 [50] 1982–1986 America nCTS 19 30 m NR NR NR NP + Ble
S alone 20
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Abbreviations: m Months, UK United Kingdom, nCRTS Neoadjuvant chemoradiotherapy plus surgery, nCTS Neoadjuvant chemotherapy plus surgery, S Surgery, CT Chemotherapy, RT Radiotherapy, ENI Elective nodal irradiation, IFI Involved-field irradiation, Cis Cisplatin, Vin Vinblastine, FP Fluorouracil/cis, PC Paclitaxel/cis, NP Vinorelbine/cis, PLF Fluorouracil/leucovorin/cis, Ble Bleomycin, ECF Epirubicin/cisplatin/fluorouracil, SCC Squamous cell carcinoma, AC Adenocarcinoma, 2D Two-dimensional RT, 3D Three-dimensional RT, NR Not reported

Assessment of included trial

The risk of bias in included RCTs was summarized in Additional file 1: Figure S1. Seven trials [13–16, 21, 22, 48, 49] were judged to be unclear risk of bias, as they had more than three domains indicating as unclear risk. The remaining trials were rated with a low risk of bias. Funnel plot analysis in term of OS did not indicate any evident risk of publication bias (Additional file 1: Figure S2).

Conventional pairwise meta-analysis

Results of direct comparison meta-analysis are shown in Table 2. nCRTS-ENI (HR = 0.70, 95% CI: 0.54–0.92, I2 = 8%), nCRTS-IFI (HR = 0.74, 95% CI: 0.66–0.83, I2 = 10%), and nCTS (HR = 0.86, 95% CI: 0.76–0.98, I2 = 40%) showed significant OS advantage over S alone. Compared to S alone, nCRTS-IFI and nCTS showed a significant decrease in LR (OR = 0.43, 95% CI: 0.33–0.57, I2 = 0% and OR = 0.79, 95% CI: 0.62–0.99, I2 = 26%), and a trend of decrease in DM (OR = 0.79, 95% CI: 0.62–1.00, I2 = 0% and OR = 0.83, 95% CI: 0.68–1.01, I2 = 37%). nCRTS-ENI (OR = 5.75, 95% CI: 2.19–15.13, I2 = 0%), nCRTS-IFI (OR = 5.17, 95% CI: 1.95–13.67, I2 = 68%), and nCTS (OR = 1.71, 95% CI: 1.39–2.10, I2 = 0%) significantly increased R0 resection compared to S alone. nCRTS-ENI also increased R0 resection than nCTS (OR = 4.71, 95% CI: 1.98–11.24, I2 = 0%). nCRTS-IFI resulted in a significantly higher POM than S alone (OR = 1.79, 95% CI: 1.14–2.82, I2 = 27%).

Table 2.

Results of direct comparsions

Outcome Treatment No. of
studies		 No. of
patients		 HR/OR(95%CI) Heterogeneity
I2(%) P
OS nCRTS-ENI vs S alone 6 432 HR 0.70(0.54–0.92) 8 0.37
nCRTS-IFI vs S alone 10 2228 HR 0.74(0.66–0.83) 10 0.35
nCTS vs S alone 13 2526 HR 0.86(0.76–0.98) 40 0.06
LR nCRTS-ENI vs S alone 4 288 OR 0.69(0.35–1.35) 46 0.13
nCRTS-IFI vs S alone 6 1221 OR 0.43(0.33–0.57) 0 0.50
nCTS vs S alone 7 2176 OR 0.79(0.62–0.99) 26 0.23
DM nCRTS-ENI vs S alone 4 288 OR 0.87(0.35–2.21) 57 0.07
nCRTS-IFI vs S alone 6 1221 OR 0.79(0.62–1.00) 0 0.43
nCTS vs S alone 7 2176 OR 0.83(0.68–1.01) 37 0.15
R0 resection nCRTS-ENI vs S alone 2 155 OR 5.75(2.19–15.13) 0 0.61
nCRTS-IFI vs S alone 4 1119 OR 5.17(1.95–13.67) 68 0.02
nCTS vs S alone 7 1705 OR 1.71(1.39–2.10) 0 0.75
nCRTS-ENI vs nCT 2 166 OR 4.71(1.98–11.24) 0 0.85
POM nCRTS-ENI vs S alone 5 324 OR 1.52(0.66–3.52) 0 0.85
nCRTS-IFI vs S alone 8 1704 OR 1.79(1.14–2.82) 27 0.21
nCTS vs S alone 11 2453 OR 1.02(0.75–1.38) 0 0.87
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Abbreviations: No. Number, HR Hazard ratio, CI Confidence interval, OR Odds ratio, OS Overall survival, LR Locoregional recurrence, DM Distant metastases, POM Post-operative mortality, nCRTS Neoadjuvant chemoradiotherapy plus surgery, nCTS Neoadjuvant chemotherapy plus surgery, S Surgery, ENI Elective nodal irradiation, IFI Involved-field irradiation

Significant results are in bold

Network meta-analysis

Figure 2 shows the network plot established for NMA for OS. Results of the NMA are presented in Table 3a. nCRTS-ENI (HR = 0.63, 95% CI: 0.48–0.83, P = 0.001), nCRTS-IFI (HR = 0.75, 95% CI: 0.66–0.86, P < 0.001), and nCTS (HR = 0.87, 95% CI: 0.77–0.97, P = 0.012) significantly improved OS compared to S alone; nCRTS-ENI also showed a significant OS advantage over nCTS (HR = 0.73, 95% CI: 0.55–0.97, P = 0.03). nCRTS-IFI significantly decreased LR compared to nCTS (OR = 0.59, 95% CI: 0.37–0.94, P = 0.03) and S alone (OR = 0.43, 95% CI: 0.30–0.60, P < 0.001). S alone and nCTS showed a lower R0 resection than nCRTS-ENI (OR = 0.16, 95% CI: 0.07–0.34, P < 0.001 and OR = 0.29, 95% CI: 0.13–0.59, P < 0.001) and nCRTS-IFI (OR = 0.16, 95% CI: 0.09–0.28, P < 0.001 and OR = 0.28, 95% CI: 0.14–0.53, P < 0.001). S alone had a lower POM than nCRTS-IFI (OR = 0.56, 95% CI: 0.33–0.92, P = 0.02). No significant difference in OS, LR, DM, R0 resection, and POM were observed between nCRTS-ENI and nCRTS-IFI.

Fig. 2.

Fig. 2

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Network of eligible comparisons for the Bayesian network meta-analysis. The size of the nodes is proportional to the number of patients (in parentheses) randomized to receive the treatment. The width of the lines is proportional to the number of trials (beside the line) comparing the connected treatments. nCRTS, neoadjuvant chemoradiotherapy plus surgery; nCTS, neoadjuvant chemotherapy plus surgery; S, surgery; ENI, elective nodal irradiation; IFI, involved-field irradiation

Table 3.

Network meta-analysis results

a. Network meta-analysis results for five outcomes
OS
nCRTS-ENI
0.84(0.62–1.1) nCRTS-IFI
0.73(0.55–0.97) 0.87(0.73–1.0) nCTS
0.63(0.48–0.83) 0.75(0.66–0.86) 0.87(0.77–0.97) S-alone
LR
nCRTS-IFI
0.74(0.37–1.5) nCRTS-ENI
0.59(0.37–0.94) 0.61(0.30–1.3) nCTS
0.43(0.30–0.60) 0.58(0.31–1.1) 0.79(0.59–1.1) S-alone
DM
nCRTS-IFI
1.0(0.54–1.9) nCRTS-ENI
0.92(0.60–1.4) 0.90(0.50–1.6) nCTS
0.79(0.57–1.1) 0.76(0.44–1.3) 0.85(0.64–1.2) S-alone
POM
S-alone
0.99(0.68–1.4) nCTS
0.56(0.33–0.92) 0.56(0.30–1.0) nCRTS-IFI
0.56(0.27–1.1) 0.56(0.27–1.2) 1.0(0.41–2.4) nCRTS-ENI
R0 resection
S-alone
0.57(0.40–0.80) nCTS
0.16(0.09–0.28) 0.28(0.14–0.53) nCRTS-IFI
0.16(0.07–0.34) 0.29(0.13–0.59) 1.0(0.39–2.6) nCRTS-ENI
b. Network meta-analysis results of OS for four subgroups
ESCC
nCRTS-IFI
0.83(0.47–1.5) nCRTS-ENI
0.78(0.63–0.96) 0.80(0.43–1.5) nCTS
0.50(0.38–0.68) 0.61(0.35–1.0) 0.76(0.57–1.0) S-alone
EAC
nCRTS-ENI
0.70(0.37–1.3) nCRTS-IFI
0.65(0.38–1.1) 0.93(0.71–1.3) nCTS
0.50(0.28–0.87) 0.72(0.58–0.91) 0.78(0.62–0.93) S-alone
RT with dose of ≥40Gy/<40Gy
nCRTS-ENI ≥ 40Gy
0.90(0.59–1.4) nCRTS-IFI ≥ 40Gy
0.89(0.54–1.5) 0.99(0.70–1.4) nCRTS-ENI < 40Gy
0.71(0.48–1.1) 0.79(0.65–0.96) 0.80(0.58–1.1) nCTS
0.68(0.43–1.1) 0.76(0.56–1.0) 0.76(0.51–1.1) 0.96(0.72–1.3) nCRTS-IFI < 40Gy
0.62(0.43–0.92) 0.70(0.59–0.82) 0.70(0.51–0.96) 0.88(0.78–0.99) 0.92(0.71–1.2) S-alone
RT with technique of 3DRT/2DRT
nCRTS-ENI-3DRT
0.74(0.46–1.2) nCRTS-IFI-2DRT
0.68(0.42–1.1) 0.92(0.68–1.2) nCRTS-IFI-3DRT
0.58(0.34–0.99) 0.87(0.57–1.3) 0.94(0.63–1.4) nCRTS-ENI-2DRT
0.61(0.39–0.94) 0.83(0.64–1.1) 0.90(0.72–1.1) 0.96(0.66–1.4) nCTS
0.53(0.34–0.80) 0.72(0.57–0.88) 0.78(0.64–0.94) 0.82(0.58–1.2) 0.86(0.76–0.98) S-alone
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Abbreviations: OS Overall survival, LR Locoregional recurrence, DM Distant metastases, POM Post-operative mortality, nCRTS Neoadjuvant chemoradiotherapy plus surgery, nCTS Neoadjuvant chemotherapy plus surgery, S Surgery, RT Radiotherapy, ENI Elective nodal irradiation, IFI Involved-field irradiation, ESCC Esophagus squamous cell carcinoma, EAC Esophagus adenocarcinoma, 2D Two-dimensional, 3D Three-dimensional

Significant results are in bold

Inconsistency assessment and treatment ranking

There were two independent closed loops in the network for OS, LR, DM, and R0 resection: nCRTS-ENI/nCTS/S alone and nCRTS-IFI/nCTS/S alone; one independent closed loop for POM: nCRTS-ENI/nCTS/S alone. Analysis of inconsistency showed that the NMA results were similar to the PWMA results for the five outcomes, which suggested the consistency between the direct and indirect evidence (Additional file 1: Figure S3).

Results of the treatment rankings based on SUCRA are shown in Table 4a. In term of OS, nCRTS-ENI (0.93) was ranked the most effective treatment in term of OS, followed by nCRTS-IFI (0.71). nCRTS-IFI (0.95) was ranked the most effective treatment in term of LR, followed by nCRTS-ENI (0.62). With regard to DM, POM, and R0 resection, SUCRA values were similar between nCRTS-ENI and nCRTS-IFI.

Table 4.

SUCRA values

a. SUCRA values for five outcomes
OS LR DM POM R0 resection
Treatment SUCRA Treatment SUCRA Treatment SUCRA Treatment SUCRA Treatment SUCRA
nCRTS-ENI 0.93 nCRTS-IFI 0.95 nCRTS-IFI 0.69 S alone 0.83 S alone 1.00
nCRTS-IFI 0.71 nCRTS-ENI 0.62 nCRTS-ENI 0.67 nCTS 0.79 nCTS 0.67
nCTS 0.36 nCTS 0.39 nCTS 0.53 nCRTS-IFI 0.20 nCRTS-IFI 0.19
S alone 0.00 S alone 0.04 S alone 0.11 nCRTS-ENI 0.19 nCRTS-ENI 0.15
b. SUCRA values of OS for four subgroups
ESCC EAC RT dose RT-technique
Treatment SUCRA Treatment SUCRA Treatment SUCRA Treatment SUCRA
nCRTS-IFI 0.90 nCRTS-ENI 0.96 nCRTS-ENI- ≥ 40Gy 0.86 nCRTS-ENI-3DRT 0.98
nCRTS-ENI 0.68 nCRTS-IFI 0.63 nCRTS-IFI- ≥ 40Gy 0.75 nCRTS-IFI-3DRT 0.69
nCTS 0.34 nCTS 0.41 nCRTS-ENI- < 40Gy 0.73 nCRTS-IFI-2DRT 0.54
S alone 0.08 S alone 0.00 nCTS 0.35 nCRTS-ENI-2DRT 0.42
nCRTS-IFI- < 40Gy 0.25 nCTS 0.34
S alone 0.05 S alone 0.03
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Abbreviations: SUCRA Surface under the cumulative ranking curve, OS Overall survival, LR Locoregional recurrence, DM Distant metastases, POM Post-operative mortality, nCRTS Neoadjuvant chemoradiotherapy plus surgery, nCTS Neoadjuvant chemotherapy plus surgery, S Surgery, RT Radiotherapy, ENI Elective nodal irradiation, IFI Involved-field irradiation, ESCC Esophagus squamous cell carcinoma, EAC Esophagus adenocarcinoma, 2D Two-dimensional, 3D Three-dimensional

Subgroup analyses

NMA results of subgroup analyses are shown in Table 3b (SUCRA values are shown in Table 4b). Subgroup analyses for esophagus squamous cell carcinoma (ESCC) and esophagus adenocarcinoma (EAC) were conducted in 23 trials with 3164 patients and 11 trials with 1997 patients, respectively. With regard to ESCC, nCRTS-IFI showed significant OS advantage over S alone and a trend OS advantage over nCTS, and was ranked the most effective treatment (0.90); nCRTS-ENI had a trend OS benefit over S alone. As for EAC, both nCRTS-ENI and nCRTS-IFI significantly improved OS compared to S alone, and nCRTS-ENI was ranked the best treatment (0.96).

In subgroup analysis according to RT dose (18 trials with 2860 patients), nCRTS-IFI with dose of ≥40Gy significantly improved OS compared to S alone, while nCRTS-IFI with dose of <40Gy did not; both nCRTS-ENI with dose of ≥40Gy and < 40Gy showed a significant OS advantage over S alone; and nCRTS-ENI with dose of ≥40Gy was ranked the most effective regimen (0.86).

In subgroup analysis according to RT technique (16 trials with 2774 patients), nCRTS-ENI adopting three-dimensional radiotherapy (3D-RT) significantly improved OS compared to nCRTS-ENI adopting 2D-RT, nCTS, and S alone, and was ranked the most effective regimen (0.99); nCRTS-IFI was more effective than S alone regardless RT technique adopted.

Discussion

Currently, nCRTS has been the most common treatment approach for patients with resectable EC, but the optimal radiation field remains unidentified. EC is characterized as an aggressive disease, and lymph node metastasis, particularly regional lymph node involvement, usually occurs early. Taking into consideration microscopic spread, some trials adopted ENI instead of IFI for patients receiving nCRTS. In CALGB 9781 trials [18], nCRTS adopting ENI followed by surgery showed a long-term survival advantage over S alone for patients with EC. Nevertheless, there are also trials of a series of cases treated with IFI. Recently, two large phase III trials [5–7] also showed that nCRTS improved survival over surgery alone among patients with esophageal or junctional cancer, while IFI was adopted in RT. To date, there are still no trials that have compared efficacy of the two radiation fields directly in EC patients receiving nCRTS, and which is more effective remains unclear.

To our knowledge, this is the first network meta-analysis assessing the comparative efficacy and safety of nCRTS-ENI and nCRTS-IFI for patients with EC. It showed that both nCRTS-ENI and nCRTS-IFI significantly improved OS compared to S alone. nCRTS-ENI also showed significant OS advantage over nCTS. No significant difference in OS, LR, DM, and POM was observed between nCRTS-ENI and nCRTS-IFI. Based on treatment ranking in term of OS, nCRTS-ENI had the highest probability of being the most effective treatment (93%), followed by nCRTS-IFI (71%) and nCTS (36%).

However, in subgroup analysis according to pathologic type, nCRTS-IFI (90%) was ranked the most effective treatment for ESCC, followed by nCRTS-ENI (68%). nCRTS-IFI showed significant and a trend OS advantage over S alone and nCTS, respectively. While nCRTS-ENI only had a trend OS benefit compared to S alone. In the CROSS trial [6, 7], nCRTS-IFI resulted in improved OS for both ESCC and EAC, but the magnitude of this benefit was greater for ESCC patients (HR for ESCC vs. EAC were 0.48 vs. 0.73 respectively). These results suggested that nCRTS-IFI seemed to be more effective than nCRTS-ENI for patients with ESCC. Future head to head comparison trials are needed to confirm this finding and explore the mechanism.

RT dose and technique used in individual trials were various, which might also affect the outcomes. In our NMA, although nCRTS-ENI and nCRTS-IFI with dose of ≥40Gy seemed to be superior to those with dose of <40Gy based on treatment ranking, there were no significant difference in OS between the two dose group. Moreover, common dose in subgroup of ≥40Gy was only 40–41.4Gy. With developments in RT technique, whether a rather higher dose might be more reasonable needs further investigation.

In subgroup analysis of RT technique, we found that nCRTS-ENI adopting 3D-RT had a significant OS benefit compared to nCRTS-ENI adopting 2D-RT. Compared with 2D-RT, 3D-RT delivered a high dose to the tumor target volume while potentially minimizing the dose to the organ at risk. The results suggested that 3D-RT was more important for EC patients receiving nCRTS-ENI.

Treatment-related toxicities between ENI and IFI have been compared for EC patients receiving radical CRT in several retrospective studies. Results of two small meta-analysis [51, 52] showed that the incidences of esophageal and lung toxicities were significantly higher in ENI group. However, most of trials comparing nCRTS with S alone did not reported CRT-related toxicities in detail, and therefore, indirect comparison of CRT-related toxicities between nCRTS-ENI and nCRTS-IFI could not be performed. In our NMA, nCRTS seemed to had a higher POM than S alone, but no significant difference was observed between nCRTS-ENI and nCRTS-IFI.

There are several limitations in our meta-analysis. Firstly, in common with other meta-analyses, data were collected and analyzed in aggregate on the basis of results reported from trials, instead of individual patient data. Secondly, different operative techniques and CT regimens were adopted in individual trials, which might lead to heterogeneity. Thirdly, most of the studies included patients with mixed stage and tumor location and could not be extracted separately, subgroup analyses according to stage and tumor location could not be performed. Finally, majority of trials comparing nCRTS with surgery alone did not reported RT related toxicities. Thus, the comparison of RT related toxicities between nCRTS-ENI and nCRTS-IFI could not be performed.

Conclusions

Either adopting ENI or IFI, nCRTS is likely to be the optimal treatment for resectable EC, and nCRTS-IFI and nCRTS-ENI seem to be more effective for patients with ESCC and EAC, respectively. 3D-RT seems to be more important for patients receiving nCRTS-ENI. nCRTS with RT dose of ≥40Gy seems to be superior to that with radiation dose of <40Gy, while the optimal dose remains unclear. Future head to head comparison trials are needed to confirm these findings.

Supplementary information

13014_2019_1388_MOESM1_ESM.zip (3.6MB, zip)

Additional file 1: Figure S1. Assessment of risk of bias. A: Methodological quality graph: authors’ judgment about each methodological quality item presented as percentages across all included studies; B: Methodological quality summary: authors’ judgment about each methodological quality item for each included study, “+” low risk of bias; “?” unclear risk of bias; “-” high risk of bias. Figure S2. Comparison-adjusted funnel plots of publication bias test for overall survival. nCRTS, neoadjuvant chemoradiotherapy plus surgery; nCTS, neoadjuvant chemotherapy plus surgery; S, surgery; ENI, elective nodal irradiation; IFI, involved-field irradiation. Figure S3. Inconsistency evaluation by node-splitting analyses. (a) overall survival; (b) locoregional recurrence; (c) distant metastases; (d) R0 resection; (e) post-operative mortality. nCRTS, neoadjuvant chemoradiotherapy plus surgery; nCTS, neoadjuvant chemotherapy plus surgery; S, surgery; ENI, elective nodal irradiation; IFI, involved-field irradiation. Table S1. PRISMA NMA Checklist. Table S2. Search strategy. Table S3. Details of radiation fields.

Acknowledgements

None.

Abbreviations

3D-RT

Three-dimensional radiotherapy

Cis

Confidence intervals

DM

Distant metastases

EAC

Esophagus adenocarcinoma

EC

Esophagus cancer

ENI

Elective nodal irradiation

ESCC

Esophagus squamous cell carcinoma

HRs

Hazard ratios

IFI

Involved-field irradiation

LR

locoregional recurrence

nCRTS

Neoadjuvant chemoradiotherapy followed by surgery

nCRTS-ENI

nCRTs using ENI

nCRTS-IFI

nCRTS using IFI

nCTS

Neoadjuvant chemotherapy plus surgery

NMA

Network-meta analysis

ORs

Odds ratios

OS

Overall survival

POM

Postoperative mortality

PWMA

Pairwise meta-analysis

RCTs

Randomized control trials

S alone

Surgery alone

SUCRA

Surfaces under the cumulative ranking curve

Authors’ contributions

JD had full access to all the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: JD, TL, SD. Acquisition of data: TL, SD, HW, JC. Analysis and interpretation of data: TL, SD, HW, JC. Drafting of the manuscript: TL, SD, GL. Critical revision of the manuscript for important intellectual content: JD. Statistical analysis: TL, SD. All authors read and approved the final manuscript.

Funding

Present study did not receive any funding.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

There was no ethics approval necessary because in this meta-analysis we were pulling numbers from the published manuscripts and pooling results.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Tingting Liu and Silu Ding contributed equally to this work.

Contributor Information

Tingting Liu, Email: tingting504@163.com.

Silu Ding, Email: dsllnsy@163.com.

Jun Dang, Email: dangjunsy@163.com.

Hui Wang, Email: cindydyt@163.com.

Jun Chen, Email: cjsyxkyy@163.com.

Guang Li, Email: gl1963516@yahoo.com.

Supplementary information

Supplementary information accompanies this paper at 10.1186/s13014-019-1388-8.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

13014_2019_1388_MOESM1_ESM.zip (3.6MB, zip)

Additional file 1: Figure S1. Assessment of risk of bias. A: Methodological quality graph: authors’ judgment about each methodological quality item presented as percentages across all included studies; B: Methodological quality summary: authors’ judgment about each methodological quality item for each included study, “+” low risk of bias; “?” unclear risk of bias; “-” high risk of bias. Figure S2. Comparison-adjusted funnel plots of publication bias test for overall survival. nCRTS, neoadjuvant chemoradiotherapy plus surgery; nCTS, neoadjuvant chemotherapy plus surgery; S, surgery; ENI, elective nodal irradiation; IFI, involved-field irradiation. Figure S3. Inconsistency evaluation by node-splitting analyses. (a) overall survival; (b) locoregional recurrence; (c) distant metastases; (d) R0 resection; (e) post-operative mortality. nCRTS, neoadjuvant chemoradiotherapy plus surgery; nCTS, neoadjuvant chemotherapy plus surgery; S, surgery; ENI, elective nodal irradiation; IFI, involved-field irradiation. Table S1. PRISMA NMA Checklist. Table S2. Search strategy. Table S3. Details of radiation fields.

Data Availability Statement

Not applicable.

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