title: Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.
abstract: 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/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m(2) 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/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer.
  
  
  BACKGROUND
  Roche Pharma AG (Grenzach-Wyhlen, Germany).
authors.affiliation: University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. ralf.hofheinz@umm.de
authors.forename: Ralf-Dieter
authors.initials: RD
authors.lastname: Hofheinz
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.forename: Stefan
authors.initials: S
authors.lastname: Post
authors.forename: Axel
authors.initials: A
authors.lastname: Matzdorff
authors.forename: Stephan
authors.initials: S
authors.lastname: Laechelt
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Hartmann
authors.forename: Lothar
authors.initials: L
authors.lastname: Müller
authors.forename: Hartmut
authors.initials: H
authors.lastname: Link
authors.forename: Markus
authors.initials: M
authors.lastname: Moehler
authors.forename: Erika
authors.initials: E
authors.lastname: Kettner
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Fritz
authors.forename: Udo
authors.initials: U
authors.lastname: Hieber
authors.forename: Hans Walter
authors.initials: HW
authors.lastname: Lindemann
authors.forename: Martina
authors.initials: M
authors.lastname: Grunewald
authors.forename: Stephan
authors.initials: S
authors.lastname: Kremers
authors.forename: Christian
authors.initials: C
authors.lastname: Constantin
authors.forename: Matthias
authors.initials: M
authors.lastname: Hipp
authors.forename: Gernot
authors.initials: G
authors.lastname: Hartung
authors.forename: Deniz
authors.initials: D
authors.lastname: Gencer
authors.forename: Peter
authors.initials: P
authors.lastname: Kienle
authors.forename: Iris
authors.initials: I
authors.lastname: Burkholder
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069287:Capecitabine; D059248:Chemoradiotherapy / Q000379:methods*; D018592:Cross-Over Studies; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005500:Follow-Up Studies; D005858:Germany; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018579:Patient Selection; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil