Previous studies have demonstrated that CRTS significantly improves the long-term survival rate of esophageal cancer compared with SA alone . Consistent with this result, many RCTs and Meta studies have reached a consensus. We emphasized the investigation of neoadjuvant chemoradiotherapy in the present meta-analysis due to persistent anxiety that neoadjuvant chemoradiotherapy has a negative impact on postoperative treatment effects.
The results of our meta-analysis showed there was a statistically significant advantage for postoperative mortality, local recurrence and distant metastasis of esophageal cancer patients treated with CRTS compared with SA (p < 0.05). This finding is interestingwith respect to a recently updated meta-analysis performed by Sjoquist et al  published in Lancet Oncology. The study included 12 RCTs with 1854 cases and had strict inclusion criteria and rigorous statistical analysis. The HR for all-cause mortality for neoadjuvant chemoradiotherapy was 0.78 (95% CI 0.70-0.88; p < 0.0001). The updated meta-analysis is in accordance with our results and demonstrated the benefit of CRTS in decreasing postoperative mortality compared with SA. The survival benefits for neoadjuvant chemoradiotherapy were similar for squamous-cell carcinoma (HR 0.8, 95% CI 0.68-0.93; p = 0.004) and adenocarcinoma (HR 0.75, 0.59-0.95; p = 0.02) subgroups. The survival benefit for SCC was consistent with our subgroup analysis for SCC (RR 0.54, 95% CI 0.42–0.68; p < 0.0001). There was a smaller benefit associated with AC in our analysis, but it was not statistically significant (RR 1.26, 95% CI 0.76–2.06; p = 0.37).
In a meta-analysis conducted by K. Kumagai1 et al , neoadjuvant chemoradiotherapy patients with SCC were associated with a significantly higher risk of postoperative mortality (RR 1.95, 1.06 - 3.60; p = 0.032) compared with SA. However, there was no difference among patients with AC or in the esophageal cancer group overall. The reason for this finding may be that most of the included trials were conducted in the 1980s. After excluding trials conducted in the 1980s, the results revealed the difference was not statistically significant compared with surgery alone in the SCC subgroup.
Our meta-analysis investigated postoperative local recurrence and distant metastasis. The two indictors were rarely published in previous meta-analyses. Compared with SA, CRTS significantly decreased the local recurrence and distant metastasis rates of the tumor (p < 0.05). This finding may contribute to better survival outcomes and lower postoperative mortality. There was evidence that patients treated with SA were more likely to undergo the scheduled surgery. However, the rate of complete resection in the CRTS group was higher than in the SA group . In theory, neoadjuvant chemoradiotherapy might lead to downstaging of the primary tumor and have positive effects on mediastinal nodes. This may account for the lower local recurrence rate. In this study, no subgroup analysis of postoperative complications, local recurrence or distant metastasis based on histology was investigated because the exact number of patients with these complications was not reported separately for SCC and AC.
We screened 13 RCTs based on different databases from the period of 2000 to 2013 with a larger sample size and a wider distribution range than used in previous studies. This difference is the strength of our study compared to other previous meta-analyses that included studies mostly published in 1990s. The use of radiation has developed rapidly in the past 20 years. Thus, the role of chemoradiotherapy in multimodality therapy has become more important. A systematic analysis using the latest research data is expected to produce more accurate results.
The management of esophageal cancer with neoadjuvant strategies is complex, and the available evidence is conflicting. We have discussed some of these controversies and attempted to resolve them within the context of a well-designed randomized controlled trial. We have made initial recommendations for the trial design, but this remains open for discussion and scrutiny. The meta-analysis in this study has the following limitations: some eligible studies may be missing although our big effort; the current study did lack the accurate number of patients who suffered with postoperative complication, local recurrence and distant metastasis with SCC and AC, respectively. Publication bias existed in postoperative mortality and distant metastasis, which may attribute to less studies included. It seems to us that the conclusions should be interpreted with caution. A larger number studies will be needed to verify our results further.
There is no consensus for the treatment of esophageal carcinoma and standard treatment regimens. However, most clinical studies show that preoperative chemoradiotherapy combined with surgery is a triple therapy model that may improve the clinical efficiency and the long-term survival rate. Thus, this strategy may become the standard treatment regimen . A meta-analysis by Cavallin  revealed that patients with excellent histopathological responses benefit from neoadjuvant regimens. However, patients with poor histopathological responses have no benefit and have worse prognoses. Therefore, predictive markers to allow for individualization of multimodality treatment in locally advanced esophageal cancer are urgently needed. There was evidence that ATP-binding cassette sub-family G member 2 (ABCG2) and Vacuolar-H + -ATPase (V-ATPase) were associated with pathological grade, TNM stage and tumor metastasis in esophageal squamous cancer cells . Furthermore, HER2 overexpression was associated with gastroesophageal junction (GEJ) site, intestinal cancer subtype, and well or moderately differentiated carcinomas . All these markers are associated with clinicopathological features for esophageal carcinoma and contribute to optimize treatment regimen.