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.
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.
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.
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.
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.
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.