Elsevier

The Lancet Oncology

Volume 13, Issue 6, June 2012, Pages 579-588
The Lancet Oncology

Articles
Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial

https://doi.org/10.1016/S1470-2045(12)70116-XGet rights and content

Summary

Background

Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine.

Methods

This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II–III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m2 days 1–14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m2 days 1–38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m2 days 1–5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m2 daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m2 daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m2 per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m2 days 1–5 and 29–33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m2 for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993.

Findings

Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41–72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67–82] vs 67% [58–74]; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68–81) in the capecitabine group and 67% (59–73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3–4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3–4 vs three [2%] any grade, no grade 3–4), fatigue (55 [28%] any grade, no grade 3–4 vs 29 [15%], two [1%] grade 3–4), and proctitis (31 [16%] any grade, one [<1%] grade 3–4 vs ten [5%], one [<1%] grade 3–4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3–4 vs 50 [25%] any grade, three [2%] grade 3–4).

Interpretation

Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer.

Funding

Roche Pharma AG (Grenzach-Wyhlen, Germany).

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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