Clinical trial NCT01500993: Capecitabine in the Perioperative Treatment of Rectal Cancer
Official title: 5-Fluorouracil Versus Capecitabine as Perioperative Treatment for Locally Advanced Rectal Cancer. a Randomized Phase III Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rectal Cancer
Keywords: Rectal cancer
Chemoradiotherapy
Capecitabine
phase-III trial
Lead sponsor: Universitätsmedizin Mannheim
Sponsor class: OTHER
First posted: 2011-12-29
Enrollment: 401
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study compares capecitabine with standard 5-FU in the perioperative treatment of locally advanced rectal cancer.

Detailed description: 5-Fluorouracil (5-FU) based chemoradiotherapy (CRT) is regarded a standard perioperative treatment in locally advanced rectal cancer (LARC). We investigate the replacement of 5-FU by the oral pro-drug capecitabine (cape) within a randomized phase III trial. Patients aged ≥18 years with LARC stage II or III are recruited into this two-arm, two-cohort randomized non-inferiority phase-III trial (arm A: cape, arm B: 5-FU; cohort \[C\] I: adjuvant, C II: neoadjuvant). Regimens: Arm A: CRT: 50.4 Gy + cape 1,650 mg/m² days 1-38 plus five cycles of cape 2,500 mg/m² d 1-14, repeated d 22 (C I: 2 x cape, CRT, 3 x cape; C II: CRT, TME surgery followed by cape x 5). Arm B: CRT: 50.4 Gy + infusional 5-FU 225 mg/m² daily \[C I\] or infusional 5-FU 1,000 mg/m² d 1-5 and 29-33 \[C II\] plus 4 cycles of bolus 5-FU 500mg/m² d 1-5, repeated d 29 (C I: 2 x 5-FU, CRT, 2 x 5-FU; C II: CRT, TME surgery followed by 5-FU x 4). Primary endpoint is 5-year overall survival (OS), secondary endpoints comprise 3-year disease-free survival (DFS) and safety.

The study is designed to investigate whether 5- year overall survival rate (SR5) is non-inferior in arm A versus arm B. We hypothesize that SR5 in the standard arm B is 57.5%. Sample size calculation is performed with a power of 80% and a type I error of 5% and with a drop-out rate of 5%. Therefore, a total of at least 372 evaluable patients (i.e. 186 per arm) is required to confirm non-inferiority of the experimental arm A with a non-inferiority margin of maximal 12.5% and a median follow-up time of 48 months.

Eligibility criteria: Inclusion Criteria:

* Eligible patients are 18 years or older and have histologically confirmed adenocarcinoma of the rectum (defined as the distal border of the tumour less than 16 cm from the anal verge measured by rigid rectoscopy) with no evidence of distant metastases (identified by abdominal ultrasound or CT scan and chest radiography).
* Patients in the adjuvant cohort have undergone R0-resection by total mesorectal excision (TME) of a pT3-4 N any or T any N positive non-metastatic rectal cancer.
* Patients treated in the neoadjuvant cohort need to have a clinical T3-4 N any or T any N positive tumour staged by endoscopic ultrasound, provided the lower border of the tumour is located 0 - 16 cm from the anal verge measured by rigid rectoscopy and the primary tumour is deemed resectable by TME surgery on the basis of clinical assessment. Other eligibility criteria comprise: WHO status of zero or one; adequate liver, renal, and bone marrow function defined as follows: leucocyte count \> 3,500/µl, thrombocyte count \> 100,000/µl, hemoglobin \> 10.0 g/dl; serum bilirubin \< 2.0 mg/dl, serum creatinine \< 2.0 mg/dl.

Exclusion criteria:

* Prior treatment for rectal cancer, prior chemo- or immunotherapy, prior pelvic radiotherapy, or a history of other malignant diseases within the past five years with the exception of successfully treated basal carcinoma of the skin or carcinoma in situ of the uterine cervix.
* Participation in another trial, pregnancy, breast-feeding, unwillingness to use effective contraception, or a medical condition or concomitant illness which could potentially interfere with compliance to the protocol are regarded as exclusion criteria, as well.

Primary outcomes:
measure: Overall survival
timeFrame: 5-year
Secondary outcomes:
measure: disease-free survival (DFS)
timeFrame: 3-year DFS
measure: Local recurrence rate
timeFrame: 5 years
Other outcomes:
Locations:
city: Aschersleben
country: Germany
facility: Dr Martina Grunewald
city: Hagen
country: Germany
facility: Dr Hans Walter Lindemann
city: Kaiserslautern
country: Germany
facility: Prof Hartmut Link
city: Koblenz
country: Germany
facility: Dr Elisabeth Fritz
city: Lebach
country: Germany
facility: Dr Stephan Kremers
city: Leer
country: Germany
facility: Dr Lothar Müller
city: Lemgo
country: Germany
facility: Dr Christain Constantin
city: Magdeburg
country: Germany
facility: Dr Erika Kettner
city: Mainz
country: Germany
facility: Dr Markus Moehler
city: Mannheim
country: Germany
facility: Dr Udo Hieber
city: Mannheim
country: Germany
facility: Prof Ralf Hofheinz
city: Regensburg
country: Germany
facility: Dr Matthias Hipp
city: Saarbrücken
country: Germany
facility: Prof Axel Matzdorff
city: Tübingen
country: Germany
facility: Dr Stephan Laechelt
Study officials:
affiliation: Universitätsmedizin Mannheim Germany, University of Heidelberg
name: Ralf Hofheinz, MD
role: STUDY_CHAIR
affiliation: Universitätsmedizin Mannheim, Germany, University of Heidelberg
name: Frederik Wenz, MD
role: STUDY_CHAIR
affiliation: Universitätsmedizin Mannheim, Germany, University of Heidelberg
name: Stefan Post, MD
role: STUDY_CHAIR
affiliation: Universitätsklinikum Jena, Germany
name: Andreas Hochhaus, MD
role: STUDY_CHAIR
References:
citation: Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, Muller L, Link H, Moehler M, Kettner E, Fritz E, Hieber U, Lindemann HW, Grunewald M, Kremers S, Constantin C, Hipp M, Hartung G, Gencer D, Kienle P, Burkholder I, Hochhaus A. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012 Jun;13(6):579-88. doi: 10.1016/S1470-2045(12)70116-X. Epub 2012 Apr 13.
citation: Garcia-Albeniz X, Gallego R, Hofheinz RD, Fernandez-Esparrach G, Ayuso-Colella JR, Bombi JA, Conill C, Cuatrecasas M, Delgado S, Gines A, Miquel R, Pages M, Pineda E, Pereira V, Sosa A, Reig O, Victoria I, Feliz L, Maria de Lacy A, Castells A, Burkholder I, Hochhaus A, Maurel J. Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation. World J Gastroenterol. 2014 Nov 14;20(42):15820-9. doi: 10.3748/wjg.v20.i42.15820.