Elsevier

The Lancet Oncology

Volume 12, Issue 7, July 2011, Pages 681-692
The Lancet Oncology

Articles
Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis

https://doi.org/10.1016/S1470-2045(11)70142-5Get rights and content

Summary

Background

In a previous meta-analysis, we identified a survival benefit from neoadjuvant chemotherapy or chemoradiotherapy before surgery in patients with resectable oesophageal carcinoma. We updated this meta-analysis with results from new or updated randomised trials presented in the past 3 years. We also compared the benefits of preoperative neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy.

Methods

To identify additional studies and published abstracts from major scientific meetings, we searched Medline, Embase, and Central (Cochrane clinical trials database) for studies published since January, 2006, and also manually searched for abstracts from major conferences from the same period. Only randomised studies analysed by intention to treat were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios (HRs) if available or estimates from other survival data. We also investigated treatment effects by tumour histology and relations between risk (survival after surgery alone) and effect size.

Findings

We included all 17 trials from the previous meta-analysis and seven further studies. 12 were randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1854), nine were randomised comparisons of neoadjuvant chemotherapy versus surgery alone (n=1981), and two compared neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy (n=194) in patients with resectable oesophageal carcinoma; one factorial trial included two comparisons and was included in analyses of both neoadjuvant chemoradiotherapy (n=78) and neoadjuvant chemotherapy (n=81). The updated analysis contained 4188 patients whereas the previous publication included 2933 patients. This updated meta-analysis contains about 3500 events compared with about 2230 in the previous meta-analysis (estimated 57% increase). The HR for all-cause mortality for neoadjuvant chemoradiotherapy was 0·78 (95% CI 0·70–0·88; p<0·0001); the HR for squamous-cell carcinoma only was 0·80 (0·68–0·93; p=0·004) and for adenocarcinoma only was 0·75 (0·59–0·95; p=0·02). The HR for all-cause mortality for neoadjuvant chemotherapy was 0·87 (0·79–0·96; p=0·005); the HR for squamous-cell carcinoma only was 0·92 (0·81–1·04; p=0·18) and for adenocarcinoma only was 0·83 (0·71–0·95; p=0·01). The HR for the overall indirect comparison of all-cause mortality for neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy was 0·88 (0·76–1·01; p=0·07).

Interpretation

This updated meta-analysis provides strong evidence for a survival benefit of neoadjuvant chemoradiotherapy or chemotherapy over surgery alone in patients with oesophageal carcinoma. A clear advantage of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy has not been established. These results should help inform decisions about patient management and design of future trials.

Funding

Cancer Australia and the NSW Cancer Institute.

Introduction

Overall survival of patients with resectable oesophageal cancer remains poor, with a 5-year survival of 15–34%,1 despite changes in management over the past 20 years. Most patients who undergo radical resection for oesophageal cancer will eventually relapse and die as a result of their disease.2 Because of difficulties in administering chemotherapy or radiotherapy soon after a surgical procedure, high perioperative morbidity, and the disappointing results of trials of adjuvant chemotherapy,3 radiotherapy,4, 5 or combination chemoradiotherapy,2 the focus of recent trials has been on neoadjuvant treatment. In our previous meta-analysis,6 we reported a significant survival benefit for neoadjuvant chemoradiotherapy and, to a lesser extent, neoadjuvant chemotherapy in patients with squamous-cell carcinoma or adenocarcinoma of the oesophagus. At present, there is no evidence supporting the use of neoadjuvant radiotherapy alone.4

Most trials of chemotherapy or combined chemoradiotherapy have used a doublet of cytotoxics, usually a platinum compound, most often cisplatin, and fluorouracil,1, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 with varying doses and sequencing. Some small trials of neoadjuvant chemotherapy have used triplet chemotherapy, which resulted in increased toxicity without significant survival benefits.23, 24 Recent treatment modifications have included the use of more modern cytotoxic drugs, changes in chemotherapy sequencing, or changes in the dose and fractionation of radiotherapy.2

We aimed to assess whether the results of recently published or updated trials have changed the outcomes of our previous meta-analysis.6 We also sought to compare the benefits of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy before surgery for resectable oesophageal carcinoma, and to assess whether any increase in survival benefits was offset by an increase in perioperative mortality.

Section snippets

Methods

For the first section of the meta-analysis, we sought to assess the survival benefits of neoadjuvant treatment with either neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy of any regimen. All randomised controlled trials that compared survival after neoadjuvant chemoradiotherapy or neoadjuvant chemotherapy followed by surgery with surgery alone in the initial management of resectable oesophageal or oesophagogastric junction carcinoma (squamous-cell carcinoma, adenocarcinoma, or mixed

Results

We included 24 studies in total (figure 1),1, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 37, 39, 40, 41, 42, 43 which consisted of all 17 trials from the previous meta-analysis8, 9, 10, 12, 13, 14, 16, 17, 19, 20, 21, 22, 23, 24, 38, 39, 40 and seven further studies.7, 11, 15, 18, 37, 41, 42 12 were randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1854),10, 11, 12, 13, 14, 17, 22, 39, 40, 41, 42, 43 nine were randomised comparisons of

Discussion

Survival benefits of neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy were shown in the previous meta-analysis by our group.6 This updated analysis included updated data on previously published studies and additional studies, with 43% more patients and about 57% more events compared with the previous meta-analysis. The additional information has strengthened the evidence of a survival advantage of neoadjuvant therapy compared with surgery alone. In the present meta-analysis, there is

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