Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial

Summary

Background

Resection remains the best treatment for carcinoma of the oesophagus in terms of local control, but local recurrence and distant metastasis remain an issue after surgery. We aimed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer.

Methods

128 patients were randomly assigned to surgery alone and 128 patients to surgery after 80 mg/m² cisplatin on day 1, 800 mg/m² fluorouracil on days 1–4, with concurrent radiotherapy of 35 Gy given in 15 fractions. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, tumour response, toxic effects, patterns of failure, and quality of life. Analysis was done by intention to treat.

Findings

Neither progression-free survival nor overall survival differed between groups (hazard ratio [HR] 0·82 [95% CI 0·61–1·10] and 0·89 [0·67–1·19], respectively). The chemoradiotherapy-and-surgery group had more complete resections with clear margins than did the surgery-alone group (103 of 128 [80%] vs 76 of 128 [59%], p=0·0002), and had fewer positive lymph nodes (44 of 103 [43%] vs 69 of 103 [67%], p=0·003). Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours (HR 0·47 [0·25–0·86] vs 1·02 [0·72–1·44]). However, the trial was underpowered to determine the real magnitude of benefit in this subgroup.

Interpretation

Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone. However, further assessment is warranted of the role of chemoradiotherapy in patients with squamous-cell tumours.

Introduction

Patients with cancer of the oesophagus have a poor outlook. Resection is the best management in terms of local control, although local recurrence and distant metastases remain an issue after surgery. Postoperative radiotherapy does not improve outcomes,1, 2 and preoperative radiotherapy, chemotherapy, or both, have become the focus of adjuvant strategies. However, toxic effects and compliance with protocols have hindered the development of suitable treatments. In 1989, as part of the multicentre Trans-Tasman Radiation Oncology Group (TROG), several Australian and New Zealand centres began to collaborate in the development of a well-tolerated preoperative chemoradiotherapy regimen that would not only downstage the tumours of most patients having curative resections, but also be suitable for widespread use. Before 1989, a variant of the original Wayne State University regimen³ had been used, consisting of two cycles of chemotherapy with cisplatin and fluorouracil and radiotherapy for 3 weeks. This regimen achieved satisfactory downstaging, but concerns remained about toxic effects.⁴ Ultimately, TROG developed a well-tolerated and effective regimen of one cycle of chemotherapy with cisplatin and fluorouracil and 35 Gy radiotherapy, which was as effective as the two-cycle regimen with regard to downstaging and postsurgical outcomes, but was associated with fewer toxic effects.⁵ Moreover, this regimen compared favourably in terms of effectiveness and toxic effects with other contemporary chemoradiotherapy regimens that had been assessed.⁶

In 1994, we started a randomised controlled trial in which patients with resectable cancer of the oesophagus were randomly assigned to surgery alone or to this preoperative chemoradiotherapy regimen followed by surgery 3–6 weeks later. The trial aimed to assess whether downstaging of the tumour as a result of chemoradiotherapy improved progression-free survival and overall survival after surgery. Here, we report mature data.