Elsevier

The Lancet Oncology

Volume 12, Issue 6, June 2011, Pages 575-582
The Lancet Oncology

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Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial

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Summary

Background

The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median follow-up of 12 years.

Methods

Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 × 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection.

Findings

10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0·0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0·032).

Interpretation

For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains.

Funding

The Dutch Cancer Society, the Dutch National Health Council, and the Swedish Cancer Society.

Introduction

For rectal cancer treatment, the use of total mesorectal excision (TME) instead of conventional blunt surgery has led to substantial improvements in morbidity and survival.1 Preoperative short-term radiotherapy in combination with conventional surgery improves local control and survival.2 To investigate the value of short-term radiotherapy in combination with TME, the Dutch Colorectal Cancer Group initiated the TME trial.3 For a reliable assessment of the value of preoperative radiotherapy, surgical, pathological, and radiotherapeutical techniques were standardised and controlled for quality. Early results showed a decreased risk of local recurrence for irradiated patients at 2 years (2% vs 8%, p<0·001) without a difference in overall survival.3 After a median follow-up of 6 years, the effect of radiotherapy on local recurrence persisted (6% vs 11%, p<0·001), as well as the absence of a survival benefit.4 Because of the serious consequences associated with local recurrence, guidelines in the Netherlands and several other countries recommend preoperative radiotherapy for all rectal cancer patients with the exception of those with T1 tumours. Unfortunately, preoperative radiotherapy can induce serious side-effects such as faecal incontinence, sexual dysfunction, and secondary malignancies.5, 6, 7, 8, 9, 10, 11 In the absence of a survival benefit, for some patient groups the adverse effects might outweigh the benefits of decreased local recurrence. We report the effect of short-term radiotherapy on local recurrence, distant recurrence, and overall survival from the TME trial after a median follow-up of 12 years.

Section snippets

Patients

Patients were recruited in 118 European centres and one Canadian centre. Patients were eligible if they had clinically resectable adenocarcinoma of the rectum without evidence of distant disease. Tumours had to be below the level of S1/S2 with an inferior tumour margin located 15 cm or less from the anal verge as measured during withdrawal of a flexible coloscope or a rigid rectoscope. No upper age limit was given. Central and local ethics committees gave approval for the study and included

Results

Figure 1 shows the trial profile. Between Jan 12, 1996, and Dec 31, 1999, 1861 patients from 84 Dutch, 24 Swedish, ten other European centres, and one Canadian centre were included. 56 patients were considered ineligible after randomisation. The reasons for ineligibility were reported previously.3, 4

Of the 1805 eligible patients, 62 patients did not receive the intended treatment and 85 patients were treated with postoperative adjuvant treatment against protocol guidelines. Minor violations

Discussion

After a median follow-up of 12 years, preoperative short-term radiotherapy for patients with resectable rectal cancer decreases local recurrence rates by more than 50% relative to surgery alone, with a decreased overall recurrence rate. Compared with the results after a follow-up of 6 years, the relative risk reduction remains stable at about 50%. In previous reports of this trial,3, 4 the possibility that in some cases radiotherapy might not prevent but merely postpone local recurrence could

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