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

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• 作者：Prof Ralf-Dieter Hofheinz ; MD^a ; ^{ralf.hofheinz@umm.de} ; Prof Frederik Wenz ; MD^b ; Prof Stefan Post ; MD^c ; Prof Axel Matzdorff ; MD^d ; Stephan Laechelt ; MD^e ; Prof Jö ; rg T Hartmann ; MD^f ; Lothar Mü ; ller ; MD^g ; Prof Hartmut Link ; MD^h ; Prof Markus Moehler ; MDⁱ ; Erika Kettner ; MD^j ; Elisabeth Fritz ; MD^k ; Udo Hieber ; MD^l ; Hans Walter Lindemann ; MD^m ; Martina Grunewald ; MDⁿ ; Stephan Kremers ; MD^o ; Christian Constantin ; MD^p ; Matthias Hipp ; MD^q ; Prof Gernot Hartung ; MD^r ; Deniz Gencer ; MD^a ; Prof Peter Kienle ; MD^c ; Iris Burkholder ; PhD^s ; Prof Andreas Hochhaus ; MD^t
• 刊名：Lancet Oncology
• 出版年：2012
• 期刊代码：184_14702045
• 类别：med
• 出版时间：June, 2012
• 卷：13
• 期：6
• 页码：579-588
• 文件大小：352 K

摘要

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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路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路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路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路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路5%margin. This trial is registered with , number .

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路0004; post-hoc test for superiority p=0路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路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路67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0路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).