Chinese Medical Journal 2013;126(16):3138-3145
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 and FAN Qing-xia

Keywords
oesophageal carcinoma; chemoradiotherapy followed by surgery; surgery alone; randomized controlled trial; meta-analysis
Abstract
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.
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.1Currently, 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.2Preoperative chemoradiotherapy followed by surgery (CRTS) were well tolerated.3Interest 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.
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.
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.
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.4The 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 postoperativedistant metastasis rate.
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, theRRwas computed for each trial. TheRRand associated variance were obtained directly from each publication. All patient data were analyzed according to intention-to-treat principles. The 95%CIof theRRwas also calculated. The overallRRwas tested for significance using a Mantel-Haenszelχ2test. The outcome variables were the treatmentRRof the survival, radical incidence rate etc of the patients accept the CRTS and SA. The statistical significance of the summaryRRwas determined with aZ-test and aP<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 withχ2test. If the study included with sufficient consistency (P>0.1), using the fixed effects model to calculate the totalRRand 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.
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.7-27The 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.
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 theRR(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 survivalrate andthe meta-analysis results were indicated in Figure2.
Postoperative events
All the number of actual surgery were analyzed. SA group has ahigher 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 theRR(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 (allPvalues <0.05). The incidence of postoperative complications, distant metastasis rate and mortality of the two groups comparison, theRR(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 (allPvalues >0.05). All the results of the statistical analysis showed in the Table 2B. The forest plots were shown in the Figure 3.
Subgroup
The subgroupanalysis 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, allP<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 theP>0.05.
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,15the 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 theRRvalue 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.
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 2005.28Currently, 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.30This 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. Themeta-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 al31has 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.32Since 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.33The 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 al34also 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.35In 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.35At 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.36So 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.
REFERENCES
  • 1.

    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69­90.

  • 2.

    Mao YS, He J, Cheng GY, Zhang RG. Current consensus and controversy of staging and treatment for esophageal cancer. Chin Oncol (Chin) 2011; 21: 511-517.

  • 3.

    Kojima T, Hashimoto J, Kato K, Ito Y, Igaki H, Daiko H, et al. Feasibility study of neoadjuvant chemoradiotherapy with cisplatin plus 5-fluorouracil and elective nodal irradiation for stage II/III esophageal squamous cell carcinoma. J Clin Oncol 30, 2012; (suppl 4; abstr 130).

  • 4.

    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of report of randomized clinical trials: is blinding necessary? Controlled Clin Trials 1996; 17: 1-12.

  • 5.

    Mariette C, Seitz JF, Maillard E, Mornexet F, Thomas PA, Raoul J, et al. Surgery alone versus chemoradiotherapy followed by surgery for localized esophageal cancer: analysis of a randomized controlled phase III trial FFCD 9901. Proc Am Soc Clin Oncol 2010; 28 (15 suppl): 4005.

  • 6.

    Gaast AV, van Hagen P, Hulshof M, Richel D, van Berge Henegouwen MI, Nieuwenhuijzen GA, et al. Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esophageal or esophagogastric junction cancer: results from a multicenter randomized phase III study. Proc Am Soc Clin Oncol 2010; 28 (15 suppl): 4004.

  • 7.

    Nygaard K, Hagen S, Hansen HS, Hatlevoll R, Hultborn R, Jakobsen A, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992; 16: 1104-1109.

  • 8.

    Apinop C, Puttisak P, Preecha N. A prospective study of combined therapy in esophageal cancer. Hepatogastroenterology 1994; 41: 391­393.

  • 9.

    Le Prise E, Etienne PL, Meunier B, Maddern G, Ben Hassel M, Gedouin D, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994; 73: 1779-1784.

  • 10.

    Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335: 462-467.

  • 11.

    Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997; 337: 161-167.

  • 12.

    Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001; 19: 305-313.

  • 13.

    An FS, Huang JQ, Xie YT, Chen SH, Rong TH. A prospective study of combined chemoradiotherapy followed by surgery in the treatment of esophageal carcinoma. Chin J Oncol (Chin) 2003; 25: 376-379.

  • 14.

    Lee JL, Park SI, Kim SB, Jung HY, Lee GH, Kim JH, et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol 2004; 15: 947-954.

  • 15.

    Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol 2005; 6: 659-­668.

  • 16.

    Natsugoe S, Okumura H, Matsumoto M, Uchikado Y, Setoyama T, Yokomakura N, et al. Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Dis Esophagus 2006; 19: 468-472.

  • 17.

    Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 2008; 26: 1086-1092.

  • 18.

    Peng L, Xie TP, Han YT, Lang JY, Li T, Fu BY, et al. Randomized controlled study on preoperative concurrent chemoradiotherapy versus surgery alone for esophageal squamous cell carcinoma. Tumor (Chin) 2008; 28: 620­-622.

  • 19.

    Jin MG, Jiang SC, Chen ZW, Wang ZQ. Clinical trial of preoperative concurrent chemoradiation followed by surgery versus surgery alone for advanced esophageal carcinoma. Chin J Cancer Prev Treat 2008; 15: 1815-1817.

  • 20.

    Cao XF, He XT, Ji L, Xiao J, Lv J. Effects of neoadjuvant radiochemotherapy on pathological staging and prognosis for locally advanced esophageal squamous cell carcinoma. Dis Esophagus 2009; 22: 477-481.

  • 21.

    Lv J, Cao XF, Zhu B, Ji L, Tao L, Wang DD. Operation combined with preoperative radiochemotherapy on esophageal squamous carcinoma. Chin J Exp Surg (Chin) 2009; 26: 1378-1380.

  • 22.

    Lv J, Cao XF, Zhu B, Ji L, Tao L, Wang DD. Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma. World J Gastroenterol 2010; 16: 1649-1654.

  • 23.

    Xie J, Cui JC, Wang GC. The treatment value of neoadjuvant chemoradiotherapy in locally advanced esophageal cancer. J Nantong Univ (Med Sci) (Chin) 2010; 30: 488, 490.

  • 24.

    Zhang WS, Pan KY, Cai ZS, Lin Y. A prospective study of preoperative concurrent chemoradiotherapy combined with surgery in the treatment of locally advanced esophageal carcinoma. Chin J Surg Oncol (Chin) 2011; 03: 266-268.

  • 25.

    Jin FL, Hu ZL, Ma HF, Du JY. Treatment effect of neoadjuvant chemoradiotherapy followed by surgery versus surgery alone in local advanced esophageal carcinoma. J Pract Oncol (Chin) 2011; 26: 523­-526.

  • 26.

    van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012; 366: 2074-2084.

  • 27.

    Yang H, Fu JH, Liu MZ, Fang WT, Wang JM, Chen YP, et al. A multi-centered randomized controlled study of neo-adjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of esophagus:an interim analysis. Natl Med J Chin (Chin) 2012; 92: 1028-1032.

  • 28.

    Rutegard M, Charonis K, Lu Y, Lagergren P, Lagergren J, Rouvelas I. Population-based esophageal cancer survival after resection without neoadjuvant therapy: an update. Surgery 2012; 152: 903-910.

  • 29.

    Kelly P, Appleyard V, Murray K, Paulin F, Lamont D, Baker L, et al. Detection of oesophageal cancer biomarkers by plasma proteomic profiling of human cell line xenograf ts in response to chemotherapy. Br J Cancer 2010; 103: 232-238.

  • 30.

    Kobayashi N, Nakayama H, Osaka Y, Tachibana S, Nogi S, Tajima Y, et al. Tumor response after low-dose preoperative radiotherapy combined with chemotherapy for squamous cell esophageal carcinoma. Anticancer Res 2013; 33: 1157-1161.

  • 31.

    Siddiqui FA, Dolan JP, Hunter JG, Douthit MA, Bloker LM, Holland JM, et al. Retrospective analysis of neoadjuvant chemoradiotherapy for esophageal cancer: the Knight Cancer Institute experience. J Clin Oncol 30, 2012; (suppl 4; abstr 126).

  • 32.

    Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011; 12: 681-692.

  • 33.

    Bagheri R, RajabiMashhadi MT, Ghazvini K, Asnaashari A, Zahediyan A, Sahebi MA. The effect of neoadjuvant chemoradiotherapy on airway colonization and postoperative respiratory complications in patients undergoing oesophagectomy for oesophageal cancer. Interact Cardiovasc Thorac Surg 2012; 14: 725-728.

  • 34.

    Njei BM, Appiah J, Ditah IC, Birk JW. Chemoradiotherapy plus surgery versus surgery alone for resectable esophageal cancer: a systematic review of randomized control trials. J Clin Oncol 30, 2012; (suppl 4; abstr 94).

  • 35.

    Zheng B, Zheng W, Zhu Y, Lin XY, Xu BH, Chen C. Role of adjuvant chemoradiotherapy in treatment of resectable esophageal carcinoma: a meta-analysis. Chin Med J 2013; 126: 1178-1182.

  • 36.

    Vallböhmer D, Schröder W, Brabender J, Hölscher AH. Oesophageal cancer: current status of multimodality therapy. Zentralbl Chir 2011; 136: 312-316.

  • 37.

    Zemanova M, Novak F, Vitek P, Pazdro A, Smejkal M, Pazdrova G, et al. Outcomes of patients with oesophageal cancer treated with preoperative chemoradiotherapy, followed by tumor resection: influence of nutritional factors. J BUON 2012; 17: 310-316.

  • 38.

    Hingorani M, Crosby T, Maraveyas A, Dixit S, Bateman A, Roy R. Neoadjuvant chemoradiotherapy for resectable oesophageal and gastro-oesophageal junction cancer—do we need another randomised trial? Clin Oncol (R Coll Radiol) 2011; 23: 696-705.

  • 39.

    Fan QX. Neoadjuvant therapy of esophageal cancer. The tumor multidisciplinary diagnosis and treatment of the concept Symposium Proceedings 2010: 54-58.

(Received December 10, 2012)
Edited by WANG Mou-yue and CUI Yi

view in a new window
Figure 1. Flow chart of the meta-analysis. Flow diagram showing inclusion and exclusion of studies. Includes 21 studies that were included in this meta-analysis and 293 studies that could not be included. The total number of patients within these 21 randomized controlled trials was 2755.
Table 1.Outline of the literature search findings and the general characteristics of the included study
First author Year Country Radiotherapy schedule Chemotherapy schedule Sequence Pathology Group Case Median survival (m) Jadad score
Nygaard7
1992
Norway
35 Gy, 1.75 Gy per fraction over 4 weeks
Two cycles: cisplatin 20 mg/m2days 1–5; bleomycin 5 mg/m2days 1–5
Sequential
SCC
CRTS 47 7
2
SA 41 7
Apinop8
1994
Thailand
40 Gy, 2 Gy per fraction over 4 weeks
Two cycles: cisplatin 100 mg/m2days 1; fluorouracil 1000 mg/m2days 1–4
Concurrent
SCC
CRTS 35 9.7
1
SA 34 7.4
Le Prise9
1994
France
40 Gy, 20 Gy in 10 fractions over 12 days
Two cycles: cisplatin 100 mg/m2days 1, 21; fluorouracil 600 mg/m2days 2–5, 22–25
Sequential
SCC
CRTS 41 10.2
2
SA 45 11
Walsh10
1996
Ireland
40 Gy in 15 fractions over 3 weeks
Two cycles: cisplatin 75 mg/m2days 1; fluorouracil 15 mg/kg days 1–5
Concurrent
AC
CRTS 58 16
2
SA 55 11
Bosset11
1997
France
37 Gy, 3.7 Gy per fraction over 2 weeks
Two cycles: cisplatin 80 mg/m2days 0–2
Sequential
SCC
CRTS 143 18.6
3
SA 139 18.6
Urba12
2001
USA
45 Gy; 1.5 Gy per fraction over 3 weeks
Two cycles: cisplatin 20 mg/m2days1–5; fluorouracil 300 mg/m2days 1–21; vinblastine 1 mg/m2days 1–4
Concurrent
SCC(25%); AC(75%)
CRTS 50 16.9
2
SA 50 17.6
An13
2003
China
36 Gy, 1.2 Gy per fraction over 17 days
First cycle: 5-fluorouracil 1 mg/m2, 5–6 hours, days 1–5; cisplatin 25 mg/m2.
Second cycle: 5-fluorouracil 0.5 g/m2, days 21–25; cisplatin 25 mg/m2, days 22–25
Sequential
SCC
CRTS 48 42
3
SA 49 28
Lee14
2004
Korea
45.6 Gy, 1.2 Gy per fraction over 28 days
Two cycles: cisplatin 60 mg/m2days 1; fluorouracil 1000 mg/m2days 3–5
Concurrent
SCC
CRTS 51 28.2
2
SA 50 27.3
Burmeister15
2005
Australia
35 Gy in 15 fractions over 3 weeks
One cycles: cisplatin 80 mg/m2days 1; fluorouracil 800 mg/m2days 1–4
Concurrent
SCC(37%); AC(62%)
CRTS 128 22.2
3
SA 128 19.3
Natsugoe16
2006
Japan
40 Gy, 2 Gy per fraction over 4 weeks
cisplatin 7 mg over 2 hours; 5-fluorouracil 350 mg over 24 hours
Concurrent
SCC
CRTS 22 *
2
SA 23 *
Tepper17
2008
USA
50.4 Gy, 1.8 Gy per fraction over 5.6 weeks
Two cycles: cisplatin 100 mg/m2days 1; fluorouracil 1000 mg/m2per day days 1–4
Concurrent
SCC(25%); AC(75%)
CRTS 30 53.76
2
SA 26 21.48
Peng18
2008
China
40 Gy, 2 Gy per fraction over 4 weeks
Two cycles: cisplatin 75 mg/m2day 1;
5-fluorouracil 500 mg/m2over 5 day
Concurrent
SCC
CRTS 40 30
3
SA 40 24
Jin19
2008
China
38–44 Gy, 2 Gy per fraction, total 19–22 fractions
Paclitaxe 135 mg/m2, day 1,22;
cisplatin 20–30 mg/m2, days l–5, 22–26
Concurrent
SCC(92%); AC(8%)
CRTS 30 *
3
SA 30 *
Cao20
2009
China
40 Gy, 2 Gy per fraction
over 4 weeks
cisplatin 20 mg/m2per day days 1–5; fluorouracil 500 mg/m2per day days 1–5; mitomycin 10 mg/m2per day day 1
Concurrent
SCC
CRTS 118 59
2
SA 118 43
Lv21
2009
China
40 Gy, 2 Gy/d, d1–5, 8–12, 15–19, 22- 26
Two cycles: Paclitaxe 125 mg/m2, day 1;
cisplatin 20 mg/m2, days 1–3
Concurrent
SCC
CRTS 119 30.5
2
SA 119 18.3
Lv22
2010
China
40 Gy, 2 Gy per fraction
over 4 weeks
Two cycles: cisplatin 20 mg/m2per day,
days 1–3, 22–25; paclitaxel 135 mg/m2starting on day 1, 22 of radiotherapy
Concurrent
SCC
CRTS 80 53
2
SA 80 36
Xie23
2010
China
45- 5l Gy, 2 Gy per faction,d1- 5/week, total 21–25 actions
5-fluorouracil 2.4 g/m2days l–3, 22–24; cisplatin 75 mg/m2, days 1, 22
Concurrent
SCC
CRTS 35 *
3
SA 35 *
Zhang24
2011
China
40 Gy, 1.8–2.0 Gy per fraction over 4 weeks
Two cycles 5-fluorouracil 500 mg/m2,
days 1- 5; cisplatin 30 mg/m2per day
Concurrent
*
CRTS 29 40
3
SA 40 29
Jin25
2011
China
50 Gy, 2 Gy per fraction over5 weeks mg/ m2per day, d1–5
Two cycles: cisplatin 75 mg/m2per day, day 1;5-fluorouracil 500 mg/m2per day, days 1–5
Concurrent
SCC(92%); AC(8%)
CRTS 30 34
2
SA 30 22
van Hagen26
2012
Netherlands
41.4 Gy, 1.8 Gy per fraction over 4.6 weeks
5 weeks chemotherapy; carboplatin area under curve =2 and paclitaxel 50 mg/m2on day 1 weekly
Concurrent
SCC(23%); AC(75%)
CRTS 178 49.4
2
SA 188 24
Yang27
2012
China
40 Gy, 2 Gy per fraction over 4 weeks
Two cycles: navelbine 25 mg/m2days 1, 8, 22, 29; cisplatin 75 mg/m2days 1, 22
Concurrent
SCC
CRTS 54 *
3
SA 69 *
SCC: Squamous cell carcinoma; AC: Adenocarcinoma; CRTS: Chemoradiotherapy followed by surgery; SA: Surgery alone; * Not reported in the literature.
Table 2.Meta-analysis of the 1, 3- and 5-year survival rate, the incidence of postoperative events and subgroup meta analysis of the CRTS group versus SA group
Indicators of survival analysis
Included
studies (N)
CRTS group
SA group
Test for heterogeneity
Statistical analysis methods
Meta-analysis of the results
n N n N I2(%) Pvalues RR(95%CI) Pvalues
A: meta-analysis of the 1, 3- and 5-year survival rate of the CRTS group versus SA group
1 year survival rate
217-27 1028 1366 975 1389 28% 0.11 RR(M-H, Fixed, 95%CI) 1.08 (1.03, 1.12) 0.001
3-year survival rate
207-26 649 1312 476 1320 6% 0.38 RR(M-H, Fixed, 95%CI) 1.38 (1.26, 1.50) <0.00001
5-year survival rate
138,11-13,15-18,20-22,24,26 396 1020 285 1034 0% 0.80 RR(M-H, Fixed, 95%CI) 1.41 (1.25, 1.60) <0.00001
B: meta-analysis of the incidence of postoperative events of the CRTS group versus SA group
Surgery rate
127-9,11-12,14-17,23,26,27 708 814 798 828 74% < 0.0001 RR(M-H, Random, 95%CI) 0.89 (0.84, 0.94) <0.0001
Radical resection rate
117,9,11-13,18-23 657 714 546 738 62% 0.003 RR(M-H, Random, 95%CI) 1.21 (1.12, 1.30) <0.00001
R0 resection rate
414-15,26-27 333 357 288 413 86% 0.0001 RR(M-H, Random, 95%CI) 1.28 (1.09, 1.50) 0.003
postoperative complications rate
187-23,25 357 1024 324 1064 42% 0.03 RR(M-H, Random, 95%CI) 1.13 (0.98, 1.30) 0.10
Postoperative mortality
177-22,26 112 1133 127 1188 55% 0.01 RR(M-H, Random, 95%CI) 1.10 (0.73, 1.65) 0.66
Postoperative metastasis rate
99,12-18,22 130 438 152 463 44% 0.07 RR(M-H, Random, 95%CI) 0.88 (0.66, 1.17) 0.37
Local recurrence rate
99,12-18,22 54 438 96 463 33% 0.16 RR(M-H, Fixed, 95%CI) 0.60 (0.44, 0.81) 0.0008
C: subgroup meta analysis of the CRTS group versus SA group
Ethnicity
Eastern
3-y 128,13-15,16,18-25 380 637 279 648 0% 0.90 RR(M-H, Fixed, 95%CI) 1.38 (1.24, 1.54) <0.00001
5-y 78,13,18,20-22,24 207 469 140 480 0% 0.81 RR(M-H, Fixed, 95%CI) 1.50 (1.27, 1.78) <0.00001
Western
3-y 87,9-12,15,17,26 269 675 197 672 52% 0.04 RR(M-H, Random,95%CI) 1.47 (1.13, 1.93) 0.005
5-y 611-12,15-17,26 189 551 145 554 0% 0.56 RR(M-H, Fixed, 95%CI) 1.32 (1.11, 1.58) 0.002
Sequence
C
3-y 168,10,12,14-26 557 1033 401 1046 16% 0.27 RR(M-H, Fixed, 95%CI) 1.41 (1.29, 1.55) <0.00001
5-y 118,12,15-18,20-22,24,26 340 829 240 846 0% 0.81 RR(M-H, Fixed, 95%CI) 1.45 (1.27, 1.65) <0.00001
S
3-y 47,9,11,13 79 279 63 274 0% 0.7 RR(M-H, Fixed, 95%CI) 1.24 (0.94, 1.64) 0.13
5-y 211,13 56 191 45 188 11% 0.29 RR(M-H, Fixed, 95%CI) 1.23 (0.88, 1.72) 0.23
Pathological type
SCC
3-y 147-9,11,13-16,18,20-23,26 440 486 331 866 0% 0.79 RR(M-H, Fixed, 95%CI) 1.34 (1.21, 1.48) <0.00001
5-y 108,11,13,15-16,18,21-22,26 256 696 187 690 16% 0.30 RR(M-H, Fixed, 95%CI) 1.37 (1.17, 1.59) <0.0001
AC
3-y 310,15,26 131 270 90 276 71% 0.03 RR(M-H, Random,95%CI) 1.62 (0.93, 2.82) 0.09
5-y 215,26 76 212 68 221 0% 0.99 RR(M-H, Fixed, 95%CI) 1.17 (0.90, 1.52) 0.24
Chemotherapy
regimen
C+F
3-y 128-10,13-18,23-25 233 547 159 555 27% 0.18 RR(M-H, Fixed, 95%CI) 1.49 (1.27, 1.75) <0.00001
5-y 78,13,15-18,24 111 332 75 340 0% 0.66 RR(M-H, Fixed, 95%CI) 1.52 (1.18, 1.95) 0.001
C+P
3-y 319,21-22 153 229 112 229 0% 0.44 RR(M-H, Fixed, 95%CI) 1.37 (1.16, 1.60) 0.0001
5-y 221-22 95 199 63 199 0% 0.34 RR(M-H, Fixed, 95%CI) 1.51 (1.17, 1.94) 0.001
Radiation dose
<40 Gy
3-y 47,11,13,15 131 366 110 357 0% 0.66 RR(M-H, Fixed, 95%CI) 1.17 (0.96, 1.44) 0.12
5-y 311,13,15 90 319 75 316 0% 0.54 RR(M-H, Fixed, 95%CI) 1.19 (0.91, 1.55) 0.20
≥40 Gy
3-y 158-10,12,14,16-18,20-26 502 916 358 933 11% 0.33 RR (M-H, Fixed, 95%CI) 1.43 (1.30, 1.57) <0.00001
5-y 108,12,16-18,20-22,24,26 306 701 210 718 0% 0.85 RR(M-H, Fixed, 95%CI) 1.49 (1.30, 1.71) <0.00001
CRTS: Chemoradiotherapy followed by surgery; SA: Surgery alone,RR:risk ratio;CI: confidence interval; Eastern: The Eastern patients; Western: The Western patients; 3-y: 3-year survival rate; 5-y: 5-year survival rate; C: Concurrent; S: Sequential; SCC: Squamous cell carcinoma; AC: Adenocarcinoma; C+F: Cisplatin + fluorouracil; C+P: Cisplatin + paclitaxel.

view in a new window
Figure 2.The forest plot of the 1, 3- and 5-year survival rate of the chemoradiotherapy followed by surgery (CRTS) versus the surgery alone (SA) using a fixed effects model. The risk ratios (RRs, rectangles) and 95% confidence interval (95% CIs, horizontal lines) for specific studies that compared the 1, 3- and 5-year survival outcomes between patients from the CRTS and SA groups. The area of the rectangles reflects the weight (inverse of the variance), whereas the diamond represents the summary RR and 95% CI.

view in a new window
Figure 3.Meta-analysis of 21 randomized controlled trials of chemoradiotherapy followed by surgery (CRTS) versus surgery alone (SA) for resectable oesophageal carcinoma. A: The risk ratio (RR) and 95% confidence interval (95% CI) for the effect of treatment on surgery rate, radical resection rate, R0 resection rate, postoperative complications rate, postoperative mortality and postoperative metastasis rate are shown in the forest plot using a random effects model. B: The forest plot of local recurrence rate of CRTS versus SA using a fixed effects model.

view in a new window
Figure 4. Funnel plot of CRTS versus SA demonstrating publication bias. The middle vertical line represents the extension cord of merger measurement. Each of the small figurerepresents one of the included randomized controlled trials (RCTs). The symmetric inclined line laid on both ends of the vertical line indicates that there is no publication bias between the RCTs included in the study. A: Funnel plot of the 1, 3-, 5-year survival rate of the 21 RCTs included in. B: Funnel plot of the surgery rate, radical resection rate, R0 resection rate, postoperative complications rate, postoperative mortality, postoperative metastasis rate of the RCTs included in.
  1. Key Research Program Foundation from Health Department of Henan Province (No. 201203011).