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Chemoradiotherapy followed by surgery could improve the efficacy of treatments in patients with resectable esophageal carcinoma

WANG, Feng; WANG, Ya-mei; HE, Wei; LI, Xiang-ke; PENG, Fang-hui; YANG, Xiao-li; FAN, Qing-xia

doi: 10.3760/cma.j.issn.0366-6999.20123438
Meta analysis
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Background The effectiveness of chemoradiotherapy followed by surgery (CRTS) in patients with resectable esophageal carcinoma remains controversial. We performed a systematic review of the literature with meta-analysis.

Methods Electronic databases were used to identify published studies between January 1992 and April 2012. Pooled relative risk (RR) with 95% confidence interval (95% CI) was utilized to estimate the strength of the association between CRTS and surgery alone (SA) survival of the resectable esophageal carcinoma patients. Heterogeneity and publication bias were also assessed in the present study.

Results The final analysis of 2755 resectable esophageal carcinoma cases from 21 randomized controlled trials (RCTs) are presented. Compared to the SA group, the 1, 3- and 5-year survival rates were significantly higher in the CRTS group (all P <0.05); the 3- and 5-year survival rates for the Eastern patients, Western patients, patients undergoing concurrent chemoradiotherapy, patients with squamous cell carcinoma, patients undergoing High-dose radiotherapy ( ≥40 Gy), and patients given either “cisplatin + Fluorouracil” or “cisplatin + paclitaxel” chemotherapy were significantly higher in the CRTS group (all P <0.05). There were no statistical significances in the 3- and 5-year survival rates for patients undergoing sequential chemoradiotherapy or patients with adenocarcinoma between the two groups (all P >0.05). Compared to the RCTS group, the surgery rate in the SA group was higher (P <0.05), while the CRTS group had significantly higher radical resection rate, R0 resection rate and lower postoperative local recurrence rate (all P <0.05). The differences in postoperative complication incidence, post-operative distant metastasis and postoperative mortality rate were not statistically significant between the two groups (all P >0.05).

Conclusion CRTS can significantly improve the survival and surgical conditions of patients with resectable esophageal carcinoma.

Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China (Wang F, Wang YM, He W, Li XK, Peng FH, Yang XL and Fan QX)

Chin Med J 2013;126 (16): 3138-3145

Correspondence to: Prof. FAN Qing-xia, Department of Oncology, First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi District, Zhengzhou, Henan 450052, China (Tel: 86-371-66295533. Email: fqx2243@163.com).

This study was supported by Key Research Program Foundation from Health Department of Henan Province (No. 201203011). Conflict of interest statement: none declared.

(Received December 10, 2012)

Edited by WANG Mou-yue and CUI Yi

Esophageal cancer presents now as a significant health problem in the world, the new cases of esophageal cancer are approximately 482 300 cases annually, and the deaths are 406 800 cases annually.1 Currently, it is well documented that compared to preoperative radiotherapy is limited for extending the role of the overall long-term survival and chemotherapy is not obvious in improving the resection rate and complete resection rate, while increase side effects in patients compared to those patients with surgery alone.2 Preoperative chemoradiotherapy followed by surgery (CRTS) were well tolerated.3 Interest in preoperative chemoradiotherapy for patients with resectable esophageal cancer is based not only on the expected survival benefit achieved with this treatment, but also on the potential advantages of delivering both agents preoperatively. These advantages include improved compliance with the chemoradiotherapy regimen if it is given before major surgery, as well as down-staging, which may enhance the rate of curative surgery and permit sphincter preservation in patients with low-lying tumors. In addition, because tumor oxygenation is better with preoperative treatment than with postoperative treatment, irradiation seems to be more effective with the former approach.

However, the results of those researches on preoperative chemoradiotherapy for resectable esophageal are inconsistent on whether it can prolong the survival, reduce postoperative complication rate, decrease postoperative mortality of patients with esophageal cancer. Therefore, we perform a meta-analysis of the prospective randomized controlled trial (RCT) about the resectable esophageal carcinoma treated with CRTS versus surgery alone (SA) to compare the advantages and disadvantages of the two treatment regimens, expecting it can provide valuable evidence on clinical decision-making.

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METHODS

Identification and eligibility of relevant studies

We searched the electronic database including PubMed, China National Knowledge Infrastructure (CNKI) and Wan Fang databases between January 1992 and April 2012. The following search terms were included: “neoadjuvant therapy”, “chemoradiotherapy followed by surgery”, “chemoradiotherapy”, “surgery or operation or esophagectomy”, “esophagus or esophageal cancer or carcinoma”. While using search engines to find relevant literature on the internet and performing manual searches of reference lists, in order to broaden the search and ensure that no studies were missed.

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Inclusion and exclusion criteria

The search results were then checked by the inclusion and exclusion criteria described as follows. Inclusion criteria: (1) The study was a prospective RCT designed to compare CRTS with SA treatment of resectable esophageal, whether blinded; (2) The study was diagnosed by the organization or cytopathology, and confirmed untreated, resectable esophageal cancer without distant metastasis, and the assessment of the liver and kidney, heart and lung and so on of the included patients have been confirmed to be tolerate for surgery; (3) The study had to clearly describe the diagnoses and the sources of the cases and controls; and the sample size, risk ratio (RR) and their 95 % confidence interval (CI), or data that would allow those findings to be inferred, was presented. (4) Clear follow-up censored survival number of cases or a clear survival curve, follow-up rate of > 95% in the original study. Exclusion criteria: (1) The study design was non-RCT; (2) Patients with esophageal cancer who had received chemotherapy alone or radiotherapy alone; (3) The publication was a duplication of an existing study; (4) The reported data were in the form of an abstract or report from a meeting; and (5) the information were too little to describe clearly. Two authors did the search and identification independently, and the selection of an article was reached by consensus. No efforts were made to obtain data on individual patients.

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Data extraction

All data were extracted by two reviewers and differences were resolved through consultations. For each study, the following data were extracted: the first author of the study, the year of publication, the author's country, the regimen and sequence (concurrent CRTS or sequential CRTS) of the CRTS, the tumor histology, the preoperative stage, the number (male/female), the median age, the median survival and the median follow-up of participants, and the literature evaluation were evaluate by Jadad quality scoring method.4 The outcomes of the meta-analysis including 1 year, 3-year and 5-year survival rate, the operation rate, radical resection rate, R0 resection rate, incidence of postoperative complications, postoperative mortality, postoperative local recurrence rate and postoperative distant metastasis rate.

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Statistical analysis

Analysis was performed using Review Manager Version 5.1 software (Cochrane Collaboration, Denmark). To combine results from individual trials, we used the proportion of events observed in the CRTS and SA groups. With these observed proportions of events, the RR was computed for each trial. The RR and associated variance were obtained directly from each publication. All patient data were analyzed according to intention-to-treat principles. The 95% CI of the RR was also calculated. The overall RR was tested for significance using a Mantel-Haenszel χ2 test. The outcome variables were the treatment RR of the survival, radical incidence rate etc of the patients accept the CRTS and SA. The statistical significance of the summary RR was determined with a Z-test and a P <0.05 was considered statistically significant. The trial quality score was assigned through three aspects: blinding, randomization and handling withdrawals and dropouts, along a scale of 1-5, according to methods previously described by Jadad.4

The heterogeneity assumption was evaluated with χ2 test. If the study included with sufficient consistency (P >0.1), using the fixed effects model to calculate the total RR and 95% CI; otherwise using a random effects model. Funnel plots, Egger's test and subgroup analysis of the main results were performed to assess whether there was any publication bias due to the literature evaluated.

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RESULTS

Characteristics of eligible studies

Initially, 314 relevant literatures were searched out, 59 studies were preliminary included after reading the title and summary of the literature. Exclude 38 literatures after reading the full text even further (11 not meet the standard of enrolled patients, 15 non-randomized controlled, 10 retrospective study, 2 unpublished full-text articles5,6). Eventually, 21 RCTs that met our inclusion criteria were identified.7-27 The flow chart of the meta-analysis was show in Figure 1. The total number of patients within these 21 RCTs was 2755, which 1366 patients were included in the CRTS group and 1389 patients were included in the SA Group. The selected study characteristics were summarized in Table 1.

Table 1

Table 1

Figure 1.

Figure 1.

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One, three-and five-year survival outcomes

Compared to the SA group, the 1, 3- and 5-year survival rates were significantly higher in the CRTS group, while the RR (95% CI) =1.08 (1.03-1.12), 1.38 (1.26-1.50), 1.41 (1.25-1.60); P=0.001, <0.00001, <0.00001, respectively (Table 2A). The forest plot of the 1, 3- and 5-year survival rate and the meta-analysis results were indicated in Figure 2.

Table 2

Table 2

Figure 2.

Figure 2.

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Postoperative events

All the number of actual surgery were analyzed. SA group has a higher rate of surgery than CRTS group, RR (95% CI)=0.89 (0.84-0.94), P <0.0001; the CRTS group has a significantly higher radical resection rate and R0 resection rate and lower local recurrence rate than the SA group, while the RR (95% CI)=1.21 (1.12-1.30), 1.28 (1.09-1.50), 0.60 (0.44-0.81); P <0.00001, =0.003, =0.0008, the differences were statistically significant (all P values <0.05). The incidence of postoperative complications, distant metastasis rate and mortality of the two groups comparison, the RR (95% CI)=1.13 (0.98-1.30), 0.88 (0.66-1.17), 1.10 (0.73-1.65); P=0.66, 0.37, 0.66, the difference was not statistically significant (all P values >0.05). All the results of the statistical analysis showed in the Table 2B. The forest plots were shown in the Figure 3.

Figure 3.

Figure 3.

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Subgroup

The subgroup analysis of 3-year and 5-year survival rate of the two treatment regimens were summarized in Table 2C, according to their ethnicity, chemoradiotherapy sequence, pathological type, chemotherapy regimen, chemoradiotherapy dose. The 3-, 5-year survival rates for the Eastern patients, Western patients, patients undergoing concurrent chemoradiotherapy, patients with squamous cell carcinoma, and patients undergoing cisplatin plus fluorouracil chemotherapy regimen, the cisplatin and paclitaxel chemotherapy regimen and high-dose radiotherapy ( ≥40 Gy) were significantly higher in the CRTS group than the SA group, the differences were all statistically significant, all P <0.05. Then, comparing the 3-, 5-year survival rates for patients undergoing sequential chemoradiotherapy, patients with adenocarcinoma and patients undergoing low-dose radiotherapy ( <40 Gy) of the two groups, there was no significant difference, each value of the P >0.05.

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Sensitivity analysis and publication bias

Excluding any one literature before and after, the differences in 3-year survival rate, 5-year survival surgery, surgical cure rate, R0 resection rate, postoperative mortality, postoperative local recurrence rate and postoperative distant metastasis rate of the two groups were not changed significantly between the two groups, the nature of the conclusions did not change. Excluding the Jadad quality score is 1 and 2 of the studies, the meta-analysis of the 1-year survival rate of the two groups did not change significantly. Eliminate the study by Burmeister et al,15 the difference in the postoperative complication rate was statistically significant between the two groups (RR =1.19, 95% CI =1.00-1.41; P=0.05), the nature of the conclusion has been changed. But it was at the edge of statistical significance, and low stability, so still need to verify this result further. Draw funnel plots of the effect size of all the observed results by using the RR value as a horizontal coordinate, SE (log(RR)) value as vertical coordinate, all funnel plots are basically symmetrical, which also showed the literature of the study included no publication bias existed, was shown in the Figure 4.

Figure 4.

Figure 4.

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DISCUSSION

It is difficult to diagnosis the esophageal cancer early. The proportion of patients surviving for 5 years increased from 19.7% in 1987-1991 to 30.7% in 1997-2000, but remained at 30.5% between 2001 and 2005.28 Currently, there are no single treatment to improve the survival rate of esophageal cancer greatly, but studies demonstrate multimodality therapy can significantly improve the therapeutic effects of esophageal cancer.29

Recently, one study showed seventy percent of patients with esophageal cancer who received radiotherapy dose of 30 Gy in 15 fractions combined with chemotherapy achieved a stage reduction with low toxicity.30 This article performed a meta-analysis on 21 RCTs, the collection of literature was relatively complete, which classified and compared the survival rate and the rate of the postoperative events in detail, and performed subgroup, sensitivity analysis and publication bias between CRTS and SA, to evaluate the advantages and disadvantages of the treatment of CRTS versus SA in the resectable esophageal carcinoma comprehensively. The meta-analysis showed that compared with the treatment of the SA for resectable esophageal carcinoma, the CRTS reduced the tumor postoperative local recurrence, improved the survival rate, tumor resection, R0 resection rate of the patients, and improved the long-term survival rate of the East, the West, the concurrent chemoradiotherapy, the squamous cell carcinoma and high dose radiotherapy (≥40 Gy) patients, and the postoperative complications rate, mortality, meanwhile, the distant metastases rate of the patients were not increased, but the stability of the postoperative complication rate was reduced. One study by Siddiqui et al31 has revealed some clinical unresectable esophageal cancer patients improve their operation resection rates after preoperative chemoradiation, 2/3 (81 patients) of the patients achieved complete remission or the descending stage, 4 cases of which were not successful operation, although initially also carry out the operation of esophageal carcinoma resection. An updated meta-analysis displayed that CRTS improved the survival of patients with resectable esophageal carcinoma than SA, which may become a standard treatment.32 Since the use of preoperative chemoradiotherapy neoadjuvant therapy is increasing for oesophageal carcinoma, because it is not related to the presentation of major negative complications and not does it result in mortality, this method can be used safely in patients.33 The meta-analysis showed that CRTS didn't improve the long term survival rate of the patients with the sequential chemoradiotherapy, adenocarcinoma and low dose radiotherapy ( <40 Gy) (P >0.05). Another study by Njei et al34 also showed that CRTS improved long-term survival in esophageal cancer patients, the results seemed to be limited only to patients with squamous cell cancer, but not adenocarcinoma, suggesting that concurrent chemoradiotherapy and squamous cell carcinoma of the esophagus is the real beneficiaries of CRTS, then the patients undergoing sequential chemoradiotherapy and patients with adenocarcinoma would got benefit from the surgery followed by chemoradiotherapy possibly. While, one study found that patients with resectable esophageal carcinoma could gain a survival benefit from surgery followed by adjuvant chemoradiotherapy.35 In contrast, another meta-analyses reveal that patients with excellent histopathological responses seem to highly benefit from neoadjuvant regimens. Patients with poor histopathological responses have no benefit but rather disadvantageous prognoses. Therefore, predictive markers to allow individualisation of multimodality treatment in locally advanced esophageal cancer are urgently needed.34

At the same time, this paper also indicated the SA has higher operation rate than the CRTS (P <0.05), this may be related to the preoperative radiochemotherapy increased a part of toxicity. Appropriate nutritional support of these patients increased the probability of attaining full dosage of CRTS and radical disease resection.35 At present, the best regimen for the CRTS and the optimum dosage are not clear, the application of new drugs are relatively little. The meta-analysis also indicated that CRTS improved the long term survival rate of the patients given either “cisplatin+Fluorouracil” or “cisplatin + paclitaxel” chemotherapy.

However, the meta-analysis has some limitations: the patients of the meta-analysis came from different ethnic, the different histological types and stages; research in chemoradiotherapy doses, schemes and operation modes are not same and the time span large. Therefore, more high quality and large clinical studies are still needed to further clarify the role of the RCTS and explore more effective, safe RCTS program.

The management of esophageal cancer with combined modality neoadjuvant strategies is complex and the available evidence is conflicting. We have discussed some of these controversies and recommend attempting 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.36 So far, there is no consensus for the treatment of esophageal carcinoma to standard treatment regimens, but most clinical studies show that CRTS combined with operation is a triple therapy model, which may improve the clinical efficiency and long term survival rate, are more feasible, has the prospects for development and worthy of further study on for locally advanced esophageal carcinoma, may become the standard treatment regimen.37

In conclusion, CRTS significantly improve the 1, 3- and 5-year survival rates, the radical resection rate, R0 resection rate and reduce postoperative local recurrence rate than SA. Concurrent CRTS is superior to sequential CRTS. Patients with squamous cell carcinoma and high-dose radiotherapy ( ≥40 Gy) may get more benefits from CRTS than those with adenocarcinoma and low-dose radiotherapy ( <40 Gy). CRTS improves the long term survival rate of the patients given either “cisplatin+Fluorouracil” or “cisplatin + paclitaxel” chemotherapy, and the patients both in the East and West. In contrast, CRTS is not related to any increase in postoperative complication incidence, post-operative distant metastasis, postoperative mortality rate compared with SA. In summary, the CRTS significantly improves the survival prognosis and operation situation, and increase the efficacy in patients with resectable esophageal cancer than the SA.

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      Keywords:

      oesophageal carcinoma; chemoradiotherapy followed by surgery; surgery alone; randomized controlled trial; meta-analysis

      © 2013 Chinese Medical Association