A short, intense course of radiotherapy given before extensive surgery for rectal cancer does not significantly improve overall survival for patients with this tumour type, despite decreasing the likelihood of the cancer reemerging in the same place, according to the long-term results of a randomised controlled trial published in the Annals of Surgery.

Surgery has long been the mainstay of treatment for rectal cancer. But in the past three years or so it has become standard practice to use a particularly extensive technique, which involves removal of all the fatty tissue around the rectum in addition to the area directly affected by the tumour, because of its benefits for improving survival rates. Before this procedure, known as total mesorectal excision (TME), was widely accepted, clinicians had been experimenting with adding radiation and drug therapy to normal surgery to improve outcomes. A Swedish trial showed that a short-term intense bout of radiation therapy before surgery could improve local control when the surgery was not as extensive as is the case with TME. So, to test whether additional treatment might also boost outcomes when combined with the extensive TME sur! gery procedure, a Dutch group initiated a large trial to investigate.

Recruiting patients from all over Europe and one centre in Canada between January 1996 and December 1999, the trial involved 1805 patients with clinically resectable adenocarcinoma. Patients with previous treatment of rectal cancer were excluded as were those who had had previous radiation or drug therapy to the pelvis. The patients were randomly assigned to preoperative radiotherapy---consisting of 25 Gy in 5 fractions delivered to the primary tumour and surrounding tissue containing lymph nodes during 5 to 7 days---followed by TME or TME alone. Surgery was scheduled to take place in the week after radiotherapy. The primary aim of the trial was to assess the rate of recurrence at the original cancer site (local control), but the researchers also had secondary endpoints including recurrence at distant sites and overall and cancer specific survival.

Analysing the results of the trial first at two years, the investigators found that radiation before surgery significantly reduced the risk of local recurrence (2.4% versus 8.2%), although at this early stage there was no difference in overall survival between the groups (82.0% versus 81.8%). However, a further analysis of outcomes was done 6 years after the initiation of the trial in which the investigators also looked at whether there were particular groups of patients that fared better than others.

At this final analysis, median follow-up of surviving patients was 6.1 years. Among the 1748 patients in whom a total resection had been confirmed, local recurrence risk at 5 years was 5.6% in the group assigned to radiotherapy before surgery and 10.9% in TME alone patients, corresponding to a reduction in relative risk of almost 50% among patients assigned to preoperative radiotherapy. Distant recurrence risk at 5 years was 25.8% and 28.3% for patients assigned to radiotherapy plus surgery or surgery alone, respectively.

None of the subgroup analyses, which included dividing patients by the site of recurrent lesion and the tumour stage as assessed during surgery, produced significant findings that could delineate between the radiotherapy and surgery alone groups. Although the authors caution that the subgroups were probably too small to detect any outcome differences of statistical significance.

Finally, the researchers looked at survival. As of November 1, 2005, 748 patients had died. Of these patients, 374 (50.2%) died with recurrent disease. At 5 years, the overall survival rate in irradiated patients was 64.2%, which did not differ significantly from the survival rate in patients who underwent TME alone (63.5%).
Interpreting these mixed results, the researchers conclude that despite the lack of survival advantage, "short-term preoperative radiotherapy results in improved local control for patients with resectable rectal cancer undergoing TME", which is an important finding since local recurrence is responsible for substantial morbidity and death. However, the researchers emphasise that the reduction in risk of local recurrence at 5 years is smaller than that observed at 2 years.

A further surprising finding was that, against expectations, a lot of recurrences in the radiotherapy group occurred after 3 years of follow up. This observation suggests, according to the authors, that "in a proportion of irradiated patients, radiotherapy does not prevent but merely postpones local recurrence."

They conclude: "In our study, increased local control in irradiated patients does not lead to a detectable improved overall survival. Although local recurrences are known to be an important cause of death, an absolute difference in local recurrence rates of 5.3% is apparently too small to have a significant impact on survival."

The fact that there is no survival benefit of radiotherapy in TME-treated patients, and given the adverse effects of radiation on bowel function and recovery, should give rise to the search for other treatment modalities to improve survival, suggest the authors.

The TME trial after a median follow-up of 6 years increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma.
Peeters KCMJ, Marijnen CAM, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, Rutten H, Pahlman L, Glimelius B, Leer JW, van de Velde CJH for the Dutch Colorectal Cancer Group
Ann Surg 2007; 246: 693-701.

Cancer Research Summaries are overviews of important cancer research findings that have been reported in leading cancer publications. The Cancer Research Summaries are provided by the Cancer Media Service (CMS) in collaboration with Nature Clinical Practice Oncology.

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