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      Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or the gastroesophageal junction: A meta-analysis based on clinical trials

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          Abstract

          Background

          The benefit of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy for treating cancer of the esophagus or the gastroesophageal junction remains controversial. In the present study, we conducted a comprehensive meta-analysis to examine the efficacy of these two management strategies.

          Methods

          The MEDLINE (PubMed), SinoMed, Embase, and Cochrane Library databases were searched for eligible studies. We searched for the most relevant studies published until the end of September 2017. Data were extracted independently and were analyzed using RevMan statistical software version 5.3 (Cochrane Collaboration, http://tech.cochrane.org/revman/download). Weighted mean differences, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated. Cochrane Collaboration’s risk of bias tool was used to assess the risk of bias. In this comprehensive meta-analysis, we examined the efficiency of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy for the treatment of cancer of the esophagus or the gastroesophageal junction as reported in qualified clinical trials.

          Results

          Six qualified articles that included a total of 866 patients were identified. The meta-analysis showed that for 3-year and 5-year survival rates in primary outcomes, the results favored neoadjuvant chemoradiotherapy strategies compared with neoadjuvant chemotherapy (RR = 0.78, 95% CI = 0.62–0.98, P = 0.03; RR = 0.69, 95% CI = 0.50–0.96, P = 0.03, respectively). In terms of secondary outcomes, neoadjuvant chemoradiotherapy significantly increased the rate of R0 resection and pathological complete response as well (RR = 0.87, 95% CI = 0.81–0.92, P < 0.0001; RR = 0.16, 95% CI = 0.09–0.28, P < 0.00001, respectively). However, there were no significant differences in postoperative mortality between the two groups (RR = 1.85, 95% CI = 0.93–3.65, P = 0.08). For the results of postoperative complications, revealed that there was a statistically significant difference between the two groups in the incidence of postoperative complications such as pulmonary, anastomotic leak and cardiovascular complications. The subgroup analysis of patients with esophageal adenocarcinoma or squamous cell carcinoma showed that both esophageal adenocarcinoma and squamous cell carcinoma patients achieved a high rate of R0 resection (RR = 0.85, 95% CI = 0.77–0.93, P = 0.0006; RR = 0.88, 95% CI = 0.81–0.96, P = 0.005, respectively) and pathological complete response benefit of neoadjuvant chemoradiotherapy (RR = 0.23, 95% CI = 0.09–0.57, P = 0.001; RR = 0.18, 95% CI = 0.03–0.96, P = 0.05, respectively).

          Conclusion

          Our findings suggested that compared with neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy should be recommended with a significant long-term survival benefit in patients with cancer of the esophagus or the gastroesophageal junction. In view of the clinical heterogeneity, whether these conclusions are broadly applicable should be further determined.

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          Most cited references25

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          Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial.

          After curative resection, the prognosis of gastroesophageal adenocarcinoma is poor. This phase III trial was designed to evaluate the benefit in overall survival (OS) of perioperative fluorouracil plus cisplatin in resectable gastroesophageal adenocarcinoma. Overall, 224 patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction (GEJ), or stomach were randomly assigned to either perioperative chemotherapy and surgery (CS group; n = 113) or surgery alone (S group; n = 111). Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m(2)) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m(2)/d) for 5 consecutive days (days 1 to 5) every 28 days and three or four postoperative cycles of the same regimen. The primary end point was OS. Compared with the S group, the CS group had a better OS (5-year rate 38% v 24%; hazard ratio [HR] for death: 0.69; 95% CI, 0.50 to 0.95; P = .02); and a better disease-free survival (5-year rate: 34% v 19%; HR, 0.65; 95% CI, 0.48 to 0.89; P = .003). In the multivariable analysis, the favorable prognostic factors for survival were perioperative chemotherapy (P = .01) and stomach tumor localization (P < .01). Perioperative chemotherapy significantly improved the curative resection rate (84% v 73%; P = .04). Grade 3 to 4 toxicity occurred in 38% of CS patients (mainly neutropenia) but postoperative morbidity was similar in the two groups. In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach, perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate, disease-free survival, and OS.
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            A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907).

            Patients with esophageal carcinoma receiving postoperative chemotherapy showed superior disease-free survival than those receiving surgery alone in a Japan Clinical Oncology Group trial (JCOG9204). The purpose of this study was to evaluate optimal perioperative timing-that is, before or after surgery-for providing chemotherapy in patients with locally advanced esophageal squamous cell carcinoma. Eligible patients with clinical stage II or III, excluding T4, squamous cell carcinoma were randomized to undergo surgery followed (group 1) or preceded (group 2) by chemotherapy consisting of two courses of cisplatin plus 5-fluorouracil. The primary end point was progression-free survival. We randomized 330 patients, with 166 assigned to group 1 and 164 to group 2, between May 2000 and May 2006. The planned interim analysis was conducted after completion of patient accrual. Progression-free survival did not reach the stopping boundary, but overall survival in group 2 was superior to that of group 1 (P = 0.01). Therefore, the Data and Safety Monitoring Committee recommended early publication. Updated analyses showed the 5-year overall survival to be 43% in group 1 and 55% in group 2 (hazard ratio 0.73, 95% confidence interval 0.54-0.99, P = 0.04), where the median follow-up of censored patients was 61.6 months. Concerning operative morbidity, renal dysfunction after surgery in group 2 was slightly higher than in group 1. Preoperative chemotherapy with cisplatin plus 5-fluorouracil can be regarded as standard treatment for patients with stage II/III squamous cell carcinoma.
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              Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study--JCOG9204.

              We performed a multicenter randomized controlled trial to determine whether postoperative adjuvant chemotherapy improves outcome in patients with esophageal squamous cell carcinoma undergoing radical surgery. Patients undergoing transthoracic esophagectomy with lymphadenectomy between July 1992 and January 1997 at 17 institutions were randomly assigned to receive surgery alone or surgery plus chemotherapy including two courses of cisplatin (80 mg/m2 of body-surface area x 1 day) and fluorouracil (800 mg/m2 x 5 days) within 2 months after surgery. Adaptive stratification factors were institution and lymph node status (pN0 versus pN1). The primary end point was disease-free survival. Of the 242 patients, 122 were assigned to surgery alone, and 120 to surgery plus chemotherapy. In the surgery plus chemotherapy group, 91 patients (75%) received both full courses of chemotherapy; grade 3 or 4 hematologic or nonhematologic toxicities were limited. The 5-year disease-free survival rate was 45% with surgery alone, and 55% with surgery plus chemotherapy (one-sided log-rank, P =.037). The 5-year overall survival rate was 52% and 61%, respectively (P =.13). Risk reduction by postoperative chemotherapy was remarkable in the subgroup with lymph node metastasis. Postoperative adjuvant chemotherapy with cisplatin and fluorouracil is better able to prevent relapse in patients with esophageal cancer than surgery alone.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Role: MethodologyRole: SoftwareRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: Methodology
                Role: Data curationRole: Supervision
                Role: Data curationRole: Formal analysisRole: Supervision
                Role: Project administrationRole: SupervisionRole: Validation
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 August 2018
                2018
                : 13
                : 8
                : e0202185
                Affiliations
                [1 ] Tianjin Medical University, Tianjin, China
                [2 ] Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School, Tianjin Medical University, Tianjin, China
                [3 ] Department of Bone and Joint, Tianjin Union Medicine Center, Tianjin, PR China
                Duke Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-6415-0321
                Article
                PONE-D-17-42758
                10.1371/journal.pone.0202185
                6107145
                30138325
                f3bcad75-d2b0-49ef-9890-cbeeccc6535c
                © 2018 Zhao et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 December 2017
                : 30 July 2018
                Page count
                Figures: 15, Tables: 1, Pages: 19
                Funding
                Funded by: Tianjin Clinical Medical Research Center of Acute Abdomen with integrated Chinese and Western medicine
                Award ID: 15ZXLCSY00030
                Award Recipient :
                Funded by: Key project of Tianjin science and technology support plan
                Award ID: 14ZCZDSY00021
                Award Recipient :
                This study was funded by Foundation of Tianjin Clinical Medical Research Center of Acute Abdomen with integrated Chinese and Western medicine, 15ZXLCSY00030, Key project of Tianjin science and technology support plan 14ZCZDSY00021.
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