ArticlesChemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial
Introduction
The combination of optimised surgery (total mesorectal excision [TME]1) and systematic radiotherapy has substantially improved multimodal treatment of rectal cancer;2, 3 TME plus short-course radiotherapy yields a 10-year cumulative local recurrence rate of only 5%.3
Fluorouracil in conjunction with neoadjuvant long-term radiotherapy reduced local recurrences in two trials but did not prolong survival.4, 5 Fluorouracil is often given as adjuvant treatment of rectal cancer, after resection of the primary tumour and neoadjuvant irradiation.6 In the European Organisation for Research and Treatment of Cancer (EORTC) 22922 trial,5 patients were randomised to bolus fluorouracil or follow-up after resection of the primary tumour and long-term neoadjuvant radiotherapy. 5-year overall survival was 67·2% in the treatment group and 63·2% in controls (p=0·12); the hazard ratio (HR) for death in the chemotherapy group was 0·85.5 Current evidence favouring the use of fluorouracil in this setting is limited, and national treatment recommendations reflect divergent interpretations of the published data. German guidelines consider adjuvant fluorouracil the standard of care.7
Optimisation of local tumour control has meant that distant metastases now represent the most common type of treatment failure in rectal cancer. Modifications of perioperative fluorouracil treatment have been investigated in an attempt to improve overall survival and disease-free survival (DFS); however, neither biomodulation of fluorouracil by folinic acid or levamisole,8 nor combination with other cytostatic drugs,9, 10 have proved superior to bolus fluorouracil, with the exception of infusional fluorouracil given during radiotherapy.9
Capecitabine is an oral fluoropyrimidine derivative that was as effective as fluorouracil plus folinic acid for adjuvant treatment of stage III colon cancer.11 It was also non-inferior to infusional fluorouracil in combination with oxaliplatin for first-line treatment of metastatic colorectal cancer.12 Several phase 1 and 2 trials have investigated capecitabine as part of combinations for perioperative treatment of rectal cancer,13 but no randomised trial has compared capecitabine with perioperative fluorouracil in locally advanced disease. Our choice of a non-inferiority trial design was based on the expectation that non-inferiority of capecitabine, given orally on an outpatient basis, would be sufficient to tip the risk–benefit ratio in its favour. Here, we report final results of our phase 3 trial comparing capecitabine with fluorouracil as part of perioperative chemoradiotherapy regimens for locally advanced rectal cancer.
Section snippets
Study design and patients
This was a two-arm, two-cohort, multicentre, randomised, open-label, non-inferiority, phase 3 trial comparing fluorouracil with capecitabine for perioperative treatment of patients with locally advanced rectal cancer. Patients were recruited from 35 German institutions between March, 2002, and December, 2007. The protocol was approved by the institutional review boards of all participating centres. All participants provided written informed consent.
The study was initiated to compare
Results
401 patients were randomised between March 20, 2002, and Dec 10, 2007 (figure 3). Nine patients were excluded because no post-randomisation data were available for analysis. Thus, the full analysis set comprised 392 patients; 197 in the capecitabine group and 195 in the fluorouracil group (231 in the adjuvant cohort, 161 in the neoadjuvant cohort). Baseline patient and tumour characteristics were well balanced between the two groups (table 1). Men accounted for two-thirds of patients in both
Discussion
Six cycles of capecitabine were non-inferior to five cycles of fluorouracil with regard to 5-year overall survival in patients receiving neoadjuvant or adjuvant chemoradiotherapy for locally advanced rectal cancer. DFS was higher in the capecitabine group than in the fluorouracil group because fewer distant metastases occurred with capecitabine than with fluorouracil. A post-hoc exploratory test of superiority in 5-year overall survival showed a clinically meaningful survival benefit in favour
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