Concurrent neoadjuvant chemoradiotherapy could improve survival outcomes for patients with esophageal cancer: a meta-analysis based on random clinical trials

Background The long-term survival benefit of concurrent neoadjuvant chemoradiotherapy in patients with resectable esophageal cancer remains controversial. In the present study, we conducted a meta-analysis to assess these effectiveness. Methods We searched for most relevant studies published up to the end of August 2016, using Pubmed and web of knowledge. And additional articles were identified from previous meta-analysis. The hazard ratio (HR, for overall survival and progression free survival) or risk ratio (RR, for R0 resection) with its corresponding 95 % confidence interval (CI) were used to assess the pooled effect. Results Twelve articles including 1756 patients were included in the meta-analysis. Concurrent neoadjuvant chemoradiotherapy followed by surgery was associated with significantly improved overall survival (HR=0.76 , 95% CI= 0.68-0.86), progression survival (HR =0.69, 95% CI= 0.59-0.81), and R0 resection rate(RR =1.17, 95% CI= 1.03-1.33). Subgroup analysis suggested that concurrent neoadjuvant chemoradiotherapy could improve overall survival outcome for squamous cell carcinoma (HR=0.73, 95%CI=0.61-0.88) but not those for adenocarcinoma (HR=0.72, 95%CI=0.48-1.04). Conclusion Our findings suggested that concurrent neoadjuvant chemoradiotherapy was associated with a significant survival benefit in patients with esophageal cancer.


INTRODUCTION
With more than 456,000 newly diagnosed cases and 400,000 related deaths annually, esophageal cancer is the tenth most common cancer and the eighth leading cause of cancer-related deaths worldwide. [1,2] Since most esophageal cancer patients are diagnosed at the advanced stages, the 5-year survival rate is less than 20%. [3] Despite surgical care and improvements in preoperative staging, surgery alone leads to relatively few long-term survivors. [4] A great number of patients who underwent esophagectomy continue to die as a result of tumor recurrence. [5] Adjuvant therapies, with either radiotherapy or chemotherapy, have not shown survival any benefits. [5] This, along with the evident difficulties of administering radiotherapy and chemotherapy after resection for esophageal cancer, makes recent trials focus on the role of neoadjuvant treatment, especially the concurrent neoadjuvant chemoradiotherapy (NCRT). A recent metaanalysis showed that concurrent NCRT was associated with improved 1-, 3-and 5-year survival rate. [6] Review Oncotarget 20411 www.impactjournals.com/oncotarget However, the outcomes of their study are pooled risk ratio (RR), which did not consider the survival time, Moreover, analysis for R0 resection and progression-free survival were not conducted.
Several Randomized clinical trials (RCTs) have investigated the effect of concurrent NCRT on operable esophageal cancer. However, these results are controversial. A meta-analysis pooling current literatures might be helpful for confirming such effect. Therefore, the aim of the current study was to determine whether concurrent NCRT plus surgery is superior to surgery alone for operable esophageal cancer.

Literature search and study characteristics
In total, 12 RCTs including 1756 patients (877patients were treated with concurrent NCRT plus surgery and 879 patients were treated with surgery alone) were included in the meta analysis. [7][8][9][10][11][12][13][14][15][16][17][18] The detailed processes of our literature search are displayed in Figure 1. Of these 12 studies, twelve studies reported the outcome of overall survival, six studies reported the R0 resection rate, and four studies reported the progression-free survival. The main characters of these studies are presented in Table  1.

Primary outcome
The primary outcome overall survival was reported in twelve RCTs. Compared with the surgery alone group, the pooled hazard ratio (HR) for the concurrent NCRT plus surgery group was 0.76 (95% CI 0.68-0.86) ( Figure  2). As presented in Table 2, when we carried out the stratified analysis by geographical location, significant results were observed both in the west and east (HR = 0.75, 95%CI = 0.64-0.85 and HR = 0.82, 95%CI = 0.67-0.88, respectively). Furthermore, the subgroup analysis by histological type showed that concurrent NCRT plus surgery can improve squamous cell carcinoma (SCC) patients (HR = 0.73, 95%CI = 0.61-0.88), but not   Figure 3 show Forest plots for the secondary outcomes, including the R0 resection rate and progressionfree survival. Four RCTs reported the progression-free survival, indicating a statistically significant difference (HR 0.69, 95% CI 0.59-0.81, Figure 3B) for the concurrent NCRT plus surgery group compared to the surgery alone group. Six RCTs reported the R0 resection rate, indicating a statistically significant difference (RR 1.17, 95% CI 1.03-1.33, Figure 3A) for the concurrent NCRT plus surgery group compared to the surgery alone group.

Publication bias
A funnel plot of the effect size for overall survival was found to be symmetrical ( Figure. 4), indicating little publication bias. The P value based on Egger's test for overall survival was 0.990 (t = -0.01), which also showed no publication bias existed.

DISCUSSION
The results of present meta-analysis showed that concurrent NCRT was associated with improved overall survival, progression-free survival, and R0 resection rate in patients with esophageal cancer. And this is the largest meta-analysis to explore the survival benefit with concurrent NCRT plus surgery versus surgery alone.
Several potential explanations exist for the improved effects of concurrent NCRT. First, chemotherapy has a radio sensitizing effect, which can enhance the local effects of concurrent radiotherapy, reducing the possibility of tumor spreading from the primary tumor site prior to surgery. Second, concurrent chemoradiotherapy may have the ability to inhibit the proliferation of tumor cells in the primary lesion site, decreasing the length of preoperative treatment required.
Our subgroup analysis also demonstrated that concurrent NCRT plus surgery significantly improved overall survival outcome for patients in the west. Whereas in the east, concurrent NCRT plus surgery was only associated with improved overall outcome with a borderline significant. It might be ascribed the different genetic backgrounds and/or ethnicities of the participants, which should be further investigated with well-designed multicenter RCTs from different ethnics. Moreover, in order to verify the effect of concurrent NCRT, subgroup analysis based on histology was also introduced. Through this subgroup analysis, we found that concurrent NCRT plus surgery improved the overall survival outcome for SCC patients, but not for AC patients or AC+SCC patients. Several explanations may partly explain the reasons. Firstly, participants with SCC may gain more benefits from concurrent NCRT plus surgery than those with AC. Secondly, SCC patients have a greater potential to involve the superior mediastinum and cervical region than AC patients, which is more difficult for aggressive intrathoracic and cervical nodal dissection to be carried out. Besides, SCC is more sensitive to radiotherapy and chemotherapy than AC. [6] Thus, the addition of chemoradiotherapy to the treatment regime might have improved therapeutic outcome.
In order to determine the reasons that patients with resectable esophageal cancer could receive a survival advantage from concurrent NCRT, we chose the R0 resection rate as a secondary outcome. The final results revealed that the RR of R0 resection rate favored the group of concurrent NCRT, which approximated the results of previous study. [19] However, they included not only concurrent NCRT but also sequential NCRT, suggesting that the combination of concurrent and sequential NCRT rather than concurrent NCRT was the likely cause of improved R0 resection. In addition to R0 resection rate, our meta-analysis also investigated progression-free  survival which is rarely published in previous metaanalysis. Compared with surgery alone, concurrent NCRT plus surgery significantly improved the progression-free survival. This finding also demonstrated that concurrent NCRT plus surgery could improve therapeutic outcomes.
Although subgroup analysis based on postoperative complications failed to be conducted, the included studies showed that treatment-related complications in the NCRT group had no significant difference from that of the surgery alone group [13,17]. In addition, loss to followup was low (ranging from 0.4% to 4.2%), thus the result from our study is robust.
Several potential limitations of our meta-analysis should also be acknowledged. At first, since most studies included patients without clear identification of tumornode-metastasis (TNM) classification, the subgroup based on TNM classification could not be achieved. In addition, as the primary endpoint was overall survival, the difference of complications between NRCT plus surgery group and surgery alone group was not clear.
In conclusion, concurrent NCRT improves overall survival, progression-free survival and R0 resection rate in patients with esophageal cancer. This improvement is statistically significant and clinically relevant for SCC but not for AC subtypes. Concurrent NCRT followed by surgery should be viewed as a standard care for patients with resectable esophageal squamous cell carcinoma. Further well-designed multicenter RCTs are warranted to verify the beneficial effect.

Study selection
Articles included should fit all the following criteria: (1) Studies were designed as RCTs; (2) compared concurrent NCRT with surgery alone were considered; (3) the outcome of interest was defined as overall survival, progression-free survival, or R0 resection rate; and (4) the sample size, hazard ratio (HR) and their 95 % confidence interval (CI), or data that would allow those findings to be inferred, was presented. If several publications reporting on the same population data met our criteria, the one with the longest follow-up period was selected.

Data extraction and outcome measures
The primary outcome was overall survival. The secondary outcomes were progression-free survival and R0 resection rate, which was defined by a tumor-free resection margin. Two authors (Baoxing Liu and Yacong Bo) independently extracted the following data from each eligible study, and discrepancies were resolved by a third investigator: first author, year of publication, number of patients randomized, and those who received chemoradiotherapy or surgery, HR for overall survival and progression-free survival, the total number of participants for each study, and the number of patients for R0 resection.

Statistical analysis
The meta-analysis was performed using STATA software (version 12.0; StatCorp, College Station, TX, USA) and P < 0.05 was considered as statistically significant. Overall survival and progression-free survival were measured with a hazard ratio (HR), while the R0 resection rate was measured using risk ratios (RR). If permitted, HR and the 95% confidence interval (CI) were obtained directly from the article; otherwise, they were calculated using the methods of Parmar, [20] Tierney, [21] and Williamson, [22] which use number of events and Kaplan-Meier survival curves to estimate the HR and 95% CI. The chi-square test and I 2 test were used to assess heterogeneity, with P < 0.05 and/or I 2 > 50% representing significant heterogeneity, and the random-effect model was selected. Otherwise, a fixed-effect model was applied [23]. Subgroup analyses were applied to evaluate potential effect modification of variables including geographic locations, and histological type (SCC and AC). Begger's Funnel plots and Egger's tests were performed to assess the publication bias [24,25].