ArticlesOptimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial
Introduction
Preoperative radiotherapy reduces the risk of local recurrence after surgery for rectal cancer by more than 50%, even with optimised total mesorectal excision surgery.1, 2, 3, 4, 5, 6 Conventionally fractionated long-course radiotherapy (ie, five fractions of 1·8–2 Gy per week during 5–6 weeks), most often in combination with chemotherapy, has been the predominant treatment in most countries. Short-course radiotherapy (ie, five fractions of 5 Gy in 1 week [5 × 5 Gy]), and surgery within the following week has been commonly used in Sweden and in some other countries in northern and western Europe. However, the optimal fractionation and timing of surgery in relation to radiotherapy is still controversial.7 Short-course radiotherapy with surgery delayed for 4–8 weeks (short-course radiotherapy with delay) is an alternative treatment option that might lead to fewer postoperative complications and enhance tumour regression, which could facilitate surgery. These three regimens, without concomitant chemotherapy, have never been compared in a prospective randomised trial and the effects on tumour response, local recurrence, radiation toxicity, and postoperative complications are still contentious.
The Stockholm III trial aimed to compare these three different schedules of radiotherapy (short-course radiotherapy, short-course radiotherapy with delay, and long-course radiotherapy with delay) in patients with primary adenocarcinoma of the rectum. Two preplanned interim analyses have shown that patients in the short-course radiotherapy with delay group had a lower pathological tumour stage, a higher proportion of patients achieving a complete pathological response, and a greater degree of tumour regression than did patients in the short-course radiotherapy group.8, 9 Here, we present the results of the primary outcome, time to local recurrence, after a minimum follow-up of 2 years.
Section snippets
Study design and participants
The details of the Stockholm III trial, a multicentre, randomised, non-blinded, phase 3, non-inferiority trial have been described previously.8 In summary, patients scheduled for an open abdominal procedure with a biopsy-proven primary adenocarcinoma of the rectum, defined as an adenocarcinoma within 15 cm of the anal verge, without signs of non-resectability or distant metastases, and without previous radiotherapy to the abdominal or pelvic regions, signs of severe ischaemic disease, or
Results
Between Oct 5, 1998, and Jan 31, 2013, 840 eligible patients were recruited from 18 hospitals in Sweden (appendix p 9). 385 patients were randomly assigned between short-course radiotherapy, short-course radiotherapy with delay, and long-course radiotherapy with delay in the three-arm randomisation and 455 patients between short-course radiotherapy and short-course radiotherapy with delay in the two-arm randomisation (figure 1). Hospitals that chose to participate in only the two-arm
Discussion
In this multicentre, randomised, non-inferiority trial, no significant differences between three different preoperative radiotherapy regimens for rectal cancer were observed regarding time to local or distant recurrence, recurrence-free survival, or overall survival. By delaying surgery for 4–8 weeks after the end of short-course radiotherapy, a significantly lower frequency of postoperative complications was reported; however, radiation toxicity required admission to hospital in about 7% of
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