Capecitabine in the Perioperative Treatment of Rectal Cancer (Rektum-III)

5-Fluorouracil Versus Capecitabine as Perioperative Treatment for Locally Advanced Rectal Cancer. a Randomized Phase III Trial

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

Study Overview

• Status: Completed
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: 5-FU; Drug: Capecitabine

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.

• Study Type: Interventional
• Enrollment (Actual): 401
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Aschersleben, Germany
    • Dr Martina Grunewald
  • Hagen, Germany
    • Dr Hans Walter Lindemann
  • Kaiserslautern, Germany
    • Prof Hartmut Link
  • Koblenz, Germany
    • Dr Elisabeth Fritz
  • Lebach, Germany
    • Dr Stephan Kremers
  • Leer, Germany
    • Dr Lothar Müller
  • Lemgo, Germany
    • Dr Christain Constantin
  • Magdeburg, Germany
    • Dr Erika Kettner
  • Mainz, Germany
    • Dr Markus Moehler
  • Mannheim, Germany
    • Dr Udo Hieber
  • Mannheim, Germany
    • Prof Ralf Hofheinz
  • Regensburg, Germany
    • Dr Matthias Hipp
  • Saarbrücken, Germany
    • Prof Axel Matzdorff
  • Tübingen, Germany
    • Dr Stephan Laechelt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 5-Fluorouracil (5-FU); Drug - 5FU based chemoradiotherapy and chemotherapy	Drug: 5-FU; 4 cycles of bolus 5-FU (500 mg/sqm) and 1 cycle of 5-FU based chemoradiotherapy (either 1,000 mg/sqm/day infusional 5-Fu days 1-5 and 29-33 or 225 mg/sqm/day infusional 5-Fu throughout the time of chemoradiotherapy); Other Names: 5-Fluorouracil
Experimental: Capecitabine; Drug - Capecitabine-based radiochemotherapy and chemotherapy	Drug: Capecitabine; Capecitabine standard therapy (i.e. 2,500 mg/sqm) x 5 cycles plus 1 cycle of capecitabine based chemoradiotherapy (1.650 mg/sqm); Other Names: Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	5-year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
disease-free survival (DFS)		3-year DFS
Local recurrence rate	Percentage of patient with local recurrence	5 years

Collaborators and Investigators

• Sponsor: Universitätsmedizin Mannheim
• Investigators: Study Chair: Ralf Hofheinz, MD, Universitätsmedizin Mannheim Germany, University of Heidelberg; Study Chair: Frederik Wenz, MD, Universitätsmedizin Mannheim, Germany, University of Heidelberg; Study Chair: Stefan Post, MD, Universitätsmedizin Mannheim, Germany, University of Heidelberg; Study Chair: Andreas Hochhaus, MD, Universitätsklinikum Jena, Germany

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2002
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: December 21, 2011
• First Submitted That Met QC Criteria: December 26, 2011
• First Posted (Estimate): December 29, 2011

Study Record Updates

• Last Update Posted (Actual): November 27, 2020
• Last Update Submitted That Met QC Criteria: November 24, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Capecitabine; Rectal cancer; Chemoradiotherapy; phase-III trial
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil; Capecitabine
• Other Study ID Numbers: Rektum III