Elsevier

European Journal of Cancer

Volume 49, Issue 15, October 2013, Pages 3149-3158
European Journal of Cancer

Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: Systematic review with meta-analysis combining individual patient and aggregate data

https://doi.org/10.1016/j.ejca.2013.05.029Get rights and content

Abstract

Background

The prognosis of patients with gastroesophageal adenocarcinoma is poor. There is conflicting evidence regarding effects of preoperative chemotherapy on survival and other outcomes.

Methods

We conducted a meta-analysis with aggregate and individual patient data (IPD) to assess the effect of preoperative chemotherapy for gastroesophageal adenocarcinoma on survival and other outcomes. Two independent reviewers identified eligible randomised controlled trials (RCTs) comparing chemotherapy+/–radiotherapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. IPD was solicited from all trials. Meta-analyses were performed using the two stage method.

Results

We identified 14 RCTs (2422 patients). For eight RCTs (1049 patients; 43.3%) we obtained IPD. Preoperative chemotherapy was associated with longer overall survival (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73–0.89; p < 0.0001). There were larger treatment effects in tumours of the gastroesophageal junction and for chemoradiotherapy compared to chemotherapy, but the tests for subgroup differences were not statistically significant. Preoperative chemotherapy was associated with longer disease-free survival, higher likelihood of R0 resection and more favourable post-treatment tumour stage, but not perioperative complications.

Conclusion

Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should be offered to all eligible patients. There appear to be larger survival advantages in tumours of the gastroesophageal junction and for chemoradiotherapy, but these findings require prospective confirmation.

Introduction

Adenocarcinoma of the stomach, gastroesophageal junction and oesophagus (‘gastroesophageal adenocarcinoma’) ranks among the most common cancers.1, 2, 3, 4 Radical surgery is the most effective curative treatment modality. Despite improved surgical techniques and perioperative management,1, 4 five-year survival after resection is only 20–30% in patients with locoregionally advanced disease.5, 6 These poor survival rates provide a strong rationale for the design of new treatment modalities. Preoperative chemotherapy, defined as chemotherapy before and, optionally, after surgery, has been tested in randomised controlled trials (RCTs).7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Results have been conflicting and inconclusive.

Systematic reviews and meta-analyses to date, that have summarised the evidence have either combined oesophageal squamous cell carcinoma and adenocarcinoma or failed to include all three tumour sites of GE adenocarcinoma.21, 22, 23, 24 Moreover, the analyses have been based on aggregate data, limiting their ability to sufficiently assess which patient and tumour characteristics might alter the treatment effect of preoperative chemotherapy. Therefore, we performed a new systematic comparison, based largely on individual patient data, of preoperative chemotherapy versus surgery alone for patients with locoregional resectable adenocarcinoma of the stomach, gastroesophageal junction and oesophagus.

Section snippets

Methods

The study was carried out according to Cochrane methodology and the previously published protocol.25 The full publication in the Cochrane Library provides a more detailed description of the methods.26

Identification of studies

Search results are displayed in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram (Fig. 1). Out of 7099 screened records, fourteen RCTs (total patients n = 3041) met our inclusion criteria (web extra table).7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Five RCTs (n = 1657) included both patients with oesophageal adenocarcinoma and squamous cell carcinoma,7, 8, 12, 15, 16 and comprised n = 1045 patients with adenocarcinoma. The total number of patients with

Discussion

This meta-analysis uses IPD to assess benefits of preoperative chemotherapy for gastroesophageal adenocarcinoma. Unlike earlier meta-analyses,21, 22, 23, 24 we included all tumour locations: oesophagus, gastroesophageal junction and stomach. Our access to IPDallowed us to selectively include patients with oesophageal adenocarcinoma from trials with mixed histology. Conversely, we were able to exclude patients with squamous cell carcinoma, which has a different biological behaviour.37 Our most

Conflict of interest statement

None declared.

Acknowledgements

This work was supported by the German Federal Ministry of Education and Research (Grant number 01KG 0807). The funding source had no role in the study design; collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. We thank the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group for assistance with the literature search and project management. We thank Jean-Pierre Pignon (Meta-Analysis Unit, Institut

References (46)

  • J. Ferlay et al.

    Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008

    Int J Cancer

    (2010)
  • A. Gallo et al.

    Updates on esophageal and gastric cancers

    World J Gastroenterol

    (2006)
  • J.A. Hagen et al.

    Curative resection for esophageal adenocarcinoma: analysis of 100 en bloc esophagectomies

    Ann Surg

    (2001)
  • J.R. Siewert et al.

    Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study

    Ann Surg

    (1998)
  • W.H. Allum et al.

    Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer

    J Clin Oncol

    (2009)
  • D. Cunningham et al.

    Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer

    N Engl J Med

    (2006)
  • L.-M. Feng et al.

    Treatment out come of neoadjuvant chemotherapy for Bormann’s type IV gastric cancer

    Chin J Cancer Prev Treat

    (2008)
  • D.P. Kelsen et al.

    Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer

    J Clin Oncol

    (2007)
  • T. Kobayashi

    Long-term outcome of preoperative chemotherapy with 5′-deoxy-5-fluorouridine (5′-DFUR) for gastric cancer

    Gan To Kagaku Ryoho

    (2000)
  • C. Schuhmacher et al.

    Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954

    J Clin Oncol

    (2010)
  • J. Tepper 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)
  • S.G. Urba et al.

    Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma

    J Clin Oncol

    (2001)
  • T.N. Walsh et al.

    A comparison of multimodal therapy and surgery for esophageal adenocarcinoma

    N Engl J Med

    (1996)
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    This work was supported by the German Federal Ministry of Education and Research (Grant number 01KG 0807).

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