Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy With 5-Fluorouracil and Oxaliplatin Versus 5-Fluorouracil Alone in Rectal Cancer
Prospective Randomised Multicenter Phase-III-study: Preoperative Radiochemotherapy and Adjuvant Chemotherapy With 5-Fluorouracil Plus Oxaliplatin Versus Preoperative Radiochemotherapy and Adjuvant Chemotherapy With 5-Fluorouracil for Locally Advanced Rectal Cancer
2 other identifiers
interventional
1,256
1 country
89
Brief Summary
Standard treatment for locally advanced cancer of the rectum is preoperative chemoradiotherapy with 5-Fluorouracil (5-FU) plus 4 cycles of postoperative chemotherapy with 5-FU. According to our previous study (CAO/ARO/AIO-94, published in the New England Journal of Medicine 2004; 351:1731-40) this treatment results in only 6% of local failures, yet, still 36% of all patients develop distant metastasis. Therefore, our new study (CAO/ARO/AIO-04) incorporates new drugs, i.e. 5-FU + oxaliplatin, in an effort to improve the control of distant metastases. It is our hypothesis that the rate of disease free survival will improve by 5 to 8% after 3 years of follow-up.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Jul 2006
Longer than P75 for phase_3
89 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
July 1, 2006
CompletedFirst Submitted
Initial submission to the registry
July 5, 2006
CompletedFirst Posted
Study publicly available on registry
July 6, 2006
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 1, 2015
CompletedStudy Completion
Last participant's last visit for all outcomes
June 1, 2016
CompletedAugust 1, 2016
July 1, 2016
9.4 years
July 5, 2006
July 29, 2016
Conditions
Outcome Measures
Primary Outcomes (1)
Disease free survival at 3 years defined as the interval from randomization to locoregional or metastatic recurrence or the appearance or a secondary colorectal cancer or death, whichever occurs first.
3 years
Secondary Outcomes (1)
Resection rate, rate of sphincter preservation, tumor regression, cumulative incidence of local and distant recurrences, overall survival, toxicity, quality of life
5-year follow up
Study Arms (2)
1
EXPERIMENTALPreoperative simultaneous radiochemotherapy: 5-Fluorouracil und Oxaliplatin: Radiotherapy starts on day 1 of chemotherapy; 28 fractions; single dose: 1,8 Gy once per day, monday through friday; Total dose: 50,4 Gy; Oxaliplatin: 50 mg/m² i.v., days 1, 8, 22 und 29; 5-Fluorouracil: 250 mg/m²/d continuous infusion, days 1-14 and 22-35 Adjuvant Chemotherapy: Oxaliplatin: 100 mg/m² i.v. on day 1; Calciumfolinate: 400 mg/m² on day 1; 5-Fluorouracil: 2400 mg/m² continuous infusion for 46 hours; repeat day 15, 8 cycles
2
ACTIVE COMPARATORPreoperative simultaneous radiochemotherapy: 5-Fluorouracil Radiotherapy starts on day 1 of chemotherapy; 28 fractions; single dose: 1,8 Gy once per day, monday through friday; Total dose: 50,4 Gy; 5-Fluorouracil: Days 1-5 and 29-33: 120h-continuous infusion 1000 mg/m²/d Adjuvant Chemotherapy: 5-Fluorouracil: 500 mg/m² on 5 consecutive days (day 1-5) i.v. bolus fot 2-5 minutes; repeat day 29, 4 cycles
Interventions
Preoperative radiochemotherapy: Oxaliplatin: 50 mg/m² i.v., days 1, 8, 22 und 29; 5-Fluorouracil: 250 mg/m²/d continuous infusion, days 1-14 and 22-35 Adjuvant Chemotherapy: Oxaliplatin: 100 mg/m² i.v. on day 1; Calciumfolinate: 400 mg/m² on day 1; 5-Fluorouracil: 2400 mg/m² continuous infusion for 46 hours repeat day 15, 8 cycles
Preoperative radiochemotherapy: 5-Fluorouracil: Days 1-5 and 29-33: 120h-continuous infusion 1000 mg/m²/d Adjuvant Chemotherapy: 5-Fluorouracil: 500 mg/m² on 5 consecutive days (day 1-5) i.v. bolus fot 2-5 minutes; repeat day 29, 4 cycles
Eligibility Criteria
You may qualify if:
- Minimum age: 18 years
- Histologically proven, advanced primary carcinoma of the rectum (tumor ? 12cm from the anal verge, with clinically staged T3/4 or any node-positive disease
- No prior therapy except a diverting stoma
- ECOG PS less than or equal 2
- Adequate bone marrow function: Leukocytes \> 3,5 x 10\^9/L Absolute neutrophil count \> 1,5 x 10\^9/L Platelet count \> 100 x 10\^9/L Hemoglobin \> 10 g/dl
- Adequate hepatic function: Total bilirubin \< 2,0 mg/dl ALAT, ASAT, alkaline phosphatase, gamma-GT \< 3 x ULN 7. Serum creatinine \< 1,5 mg/dl, creatinine-clearance \> 50 ml/min
- Written informed consent before randomization
You may not qualify if:
- Pregnant or breast feeding women
- Fertile patients without adequate contraception during therapy
- Past or ongoing drug abuse or alcoholic excess
- Prior chemotherapy
- Prior radiotherapy to the pelvis
- Prior (within 4 weeks) or concurrent treatment with any other investigational agent
- Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- History of severe somatic or psychological diseases: - instable cardiac disease not well controlled with medication, myocardial infarction within the last 6 months:\* Central nervous system disorders or psychiatric disability including dementia or epileptic disease; \* active uncontrolled intercurrent infections or sepsis
- Peripheral neuropathy \> 2 (NCI CTC AE grading)
- Chronic diarrhea (\> NCI CTC AE-Grad 1)
- Known allergy to substances containing platinum compounds
- Concurrent use of the antiviral agent sorivudine or chemically related analogues
- Known deficiency of dehydropyrimidindehydrogenase (DPD)
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (89)
Kreiskliniken Altötting-Burghausen
Altötting, 84503, Germany
Gesundheitszentrum St. Marien
Amberg, 92224, Germany
Onkologische Gemeinschaftspraxis
Ansbach, 91522, Germany
Krankenhaus Marienwörth
Bad Kreuznach, 55543, Germany
Caritas-Krankenhaus
Bad Mergentheim, 97980, Germany
Onkologische Schwerpunktpraxis
Bad Soden, 65812, Germany
Klinik Bad Trissl-Oberaudorf
Bad Trissl, 83080, Germany
Klinikum Bayreuth GmbH
Bayreuth, 95445, Germany
Aerzteforum Hennigsdorf
Berlin, 16761, Germany
Städtische Kliniken
Bielefeld, 33604, Germany
St.-Agnes-Hospital Bocholt
Bocholt, 46397, Germany
St. Josef-Hospital
Bochum, 44791, Germany
Ruhr-Universität Bochum; Knappschaftskrankenhaus
Bochum, 44892, Germany
Klinikum Bremen-Mitte
Bremen, 28205, Germany
Onkologische Praxis
Buchholz, 21244, Germany
Praxis für Hämatologie und Onkologie
Burgwedel, 30938, Germany
Klinikum Coburg gGmbH
Coburg, 96450, Germany
Praxis für Hämatologie und Onkologie
Cologne, 50677, Germany
Gemeinschaftspraxis für Hämatologie und Internistische Onkologie
Cologne, 51105, Germany
Onkologisches Versorgungszentrum Rehling-Donauwörth-Dachau
Donauwörth, 86609, Germany
Universitätsklinikum Carl Gustav Carus
Dresden, 01307, Germany
Katholisches Krankenhaus St. Nepomuk
Erfurt, 99097, Germany
Dept. of Radiation Therapy, University of Erlangen
Erlangen, 91054, Germany
Universitätsklinikum Essen
Essen, 45122, Germany
Alfried Krupp Krankenhaus
Essen, 45131, Germany
Klinikum Esslingen a.N.
Esslingen am Neckar, 73073, Germany
Universitätsklinikum
Frankfurt am Main, 60590, Germany
Universitätsklinikum Freiburg
Freiburg im Breisgau, 79110, Germany
Weisseritztal-Kliniken
Freital, 01705, Germany
Kliniken an der Paar, Krankenhaus Friedberg
Friedberg, 86316, Germany
Klinikum Fulda
Fulda, 36013, Germany
SRH-Waldklinikum
Gera, 07548, Germany
Wilhelm-Anton-Hospital
Goch, 47574, Germany
Klinik am Eichert
Göppingen, 73035, Germany
Georg-August-Universität Göttingen
Göttingen, 37075, Germany
Universitätsklinikum Greifswald
Greifswald, 17475, Germany
St. Elisabeth und St. Barbara Krankenhaus
Halle, 06110, Germany
Asklepios Klinik Hamburg-Harburg
Hamburg, 21075, Germany
Diakonie Klinikum Hamburg
Hamburg, 22527, Germany
Praxis für Hämatologie und Onkologie, Hamm
Hamm, 59071, Germany
Marienhospital
Herne, 44625, Germany
Onkologische Schwerpunktpraxis
Hildesheim, 31134, Germany
Universitätsklinikum des Saarlandes
Homburg/Saar, 66421, Germany
Klinik für Knochenmarkstransplantation und Hämatologie/Onkologie GmbH
Idar-Oberstein, 55743, Germany
Klinikum der Friedrich Schiller Universität
Jena, 07740, Germany
Innere Medizin, Hämatologie und Int. Onkologie
Kassel, 34117, Germany
Universitätsklinikum Schleswig-Holstein, Campus Kiel
Kiel, 24015, Germany
Onkologische Schwerpunktpraxis
Kronach, 96317, Germany
Gemeinschaftspraxis Onkologie
Landshut, 84028, Germany
Klinikum Landshut
Landshut, 84034, Germany
Universitätsklinikum Leipzig
Leipzig, 04103, Germany
Universitätsklinikum Schleswig-Holstein, Campus Lübeck
Lübeck, 23538, Germany
Universitätsklinikum - St. Hildegardis-Krankenhaus Mainz
Mainz, 65131, Germany
Phillips-Universität Marburg
Marburg, 35043, Germany
Kliniken Maria Hilf
Mönchengladbach, 41061, Germany
Gemeinschaftspraxis Onkologie
Muhr am See, 91735, Germany
Klinikum Schwäbisch Gmünd, Stauferklinik
Mutlangen, 73557, Germany
Universitätsklinikum Großhadern
München, 81377, Germany
Klinikum rechts der Isar, Technische Universität
München, 81675, Germany
Clemenshospital Münster
Münster, 48149, Germany
Universitätsklinikum Münster
Münster, 48149, Germany
Hämatologisch-onkologische Schwerpunktpraxis Northeim
Northeim, 37154, Germany
Klinikum Nürnberg
Nuremberg, 90419, Germany
Darmzentrum Ortenau
Offenburg, 77654, Germany
Klinikum Oldenburg; Pius Hospital Oldenburg
Oldenburg, 26133, Germany
Paracelsus-Krankenhaus Ruit
Ostfildern, 73760, Germany
St. Vincenz Krankenhaus
Paderborn, 33098, Germany
Klinikum Passau
Passau, 94032, Germany
St. Josefs Krankenhaus
Potsdam, 14471, Germany
Universitätsklinikum Regensburg
Regensburg, 93042, Germany
Schwerpunktpraxis für Hämatologie und Onkologie mit Tagesklinik
Regensburg, 93047, Germany
Krankenhaus Barmherzige Brüder
Regensburg, 93049, Germany
Klinikum Rosenheim
Rosenheim, 83022, Germany
Medizinische Fakultät der Universität Rostock
Rostock, 18059, Germany
Kreiskrankenhaus Rottweil
Rottweil, 78628, Germany
Thüringen-Kliniken Saalfeld-Rudolstadt
Saalfeld, 07318, Germany
Hämatologisch-Onkologische Schwerpunktpraxis
Singen, 78224, Germany
Onkologische Praxisgemeinschaft Stade
Stade, 21680, Germany
Klinikum Traunstein
Traunstein, 83278, Germany
Onkologische Schwerpunktpraxis Traunstein
Traunstein, 83278, Germany
Krankenhaus der Barmherzigen Brüder
Trier, 54292, Germany
Universitätsklinikum Ulm
Ulm, 89081, Germany
Marienhaus Klinikum, St. Elisabeth Klinik Saarlouis, St. Michael Krankenhaus Völklingen
Völklingen, 66333, Germany
Klinikum Wetzlar-Braunfels
Wetzlar, 35578, Germany
Asklepios Paulinen Klinik
Wiesbaden, 65197, Germany
Reinhard-Nieter-Krankenhaus
Wilhelmshaven, 26389, Germany
Juliusspital
Würzburg, 97070, Germany
Missionsärztliche Klinik
Würzburg, 97074, Germany
Universitätsklinikum Würzburg
Würzburg, 97080, Germany
Related Publications (9)
Diefenhardt M, Fleischmann M, Martin D, Hofheinz RD, Piso P, Germer CT, Hambsch P, Grutzmann R, Kirste S, Schlenska-Lange A, Ghadimi M, Rodel C, Fokas E; German Rectal Cancer Study Group. Clinical outcome after total neoadjuvant treatment (CAO/ARO/AIO-12) versus intensified neoadjuvant and adjuvant treatment (CAO/ARO/AIO-04) a comparison between two multicenter randomized phase II/III trials. Radiother Oncol. 2023 Feb;179:109455. doi: 10.1016/j.radonc.2022.109455. Epub 2022 Dec 23.
PMID: 36572280DERIVEDDiefenhardt M, Ludmir EB, Hofheinz RD, Ghadimi M, Minsky BD, Fleischmann M, Fokas E, Rodel C. Impact of body-mass index on treatment and outcome in locally advanced rectal cancer: A secondary, post-hoc analysis of the CAO/ARO/AIO-04 randomized phase III trial. Radiother Oncol. 2021 Nov;164:223-231. doi: 10.1016/j.radonc.2021.09.028. Epub 2021 Oct 4.
PMID: 34619239DERIVEDKosmala R, Fokas E, Flentje M, Sauer R, Liersch T, Graeven U, Fietkau R, Hohenberger W, Arnold D, Hofheinz RD, Ghadimi M, Strobel P, Staib L, Grabenbauer GG, Folprecht G, Kirste S, Uter W, Gall C, Rodel C, Polat B; of the German Rectal Cancer Study Group. Quality of life in rectal cancer patients with or without oxaliplatin in the randomised CAO/ARO/AIO-04 phase 3 trial. Eur J Cancer. 2021 Feb;144:281-290. doi: 10.1016/j.ejca.2020.11.029. Epub 2020 Dec 28.
PMID: 33383348DERIVEDDiefenhardt M, Ludmir EB, Hofheinz RD, Ghadimi M, Minsky BD, Rodel C, Fokas E. Association of Treatment Adherence With Oncologic Outcomes for Patients With Rectal Cancer: A Post Hoc Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Sep 1;6(9):1416-1421. doi: 10.1001/jamaoncol.2020.2394.
PMID: 32644104DERIVEDKitz J, Fokas E, Beissbarth T, Strobel P, Wittekind C, Hartmann A, Ruschoff J, Papadopoulos T, Rosler E, Ortloff-Kittredge P, Kania U, Schlitt H, Link KH, Bechstein W, Raab HR, Staib L, Germer CT, Liersch T, Sauer R, Rodel C, Ghadimi M, Hohenberger W; German Rectal Cancer Study Group. Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial. JAMA Surg. 2018 Aug 1;153(8):e181607. doi: 10.1001/jamasurg.2018.1607. Epub 2018 Aug 15.
PMID: 29874375DERIVEDHofheinz RD, Arnold D, Fokas E, Kaufmann M, Hothorn T, Folprecht G, Fietkau R, Hohenberger W, Ghadimi M, Liersch T, Grabenbauer GG, Sauer R, Rodel C, Graeven U; German Rectal Cancer Study Group. Impact of age on the efficacy of oxaliplatin in the preoperative chemoradiotherapy and adjuvant chemotherapy of rectal cancer: a post hoc analysis of the CAO/ARO/AIO-04 phase III trial. Ann Oncol. 2018 Aug 1;29(8):1793-1799. doi: 10.1093/annonc/mdy205.
PMID: 29873684DERIVEDRodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Strobel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. doi: 10.1016/S1470-2045(15)00159-X. Epub 2015 Jul 15.
PMID: 26189067DERIVEDRodel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sulberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Kohler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. doi: 10.1016/S1470-2045(12)70187-0. Epub 2012 May 23.
PMID: 22627104DERIVEDSchirmer MA, Mergler CP, Rave-Frank M, Herrmann MK, Hennies S, Gaedcke J, Conradi LC, Jo P, Beissbarth T, Hess CF, Becker H, Ghadimi M, Brockmoller J, Christiansen H, Wolff HA. Acute toxicity of radiochemotherapy in rectal cancer patients: a risk particularly for carriers of the TGFB1 Pro25 variant. Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):149-57. doi: 10.1016/j.ijrobp.2011.05.063. Epub 2011 Oct 12.
PMID: 22000747DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Rolf Sauer, M.D.
Dept. of Radiation Therapy, University of Erlangen, Germany
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
July 5, 2006
First Posted
July 6, 2006
Study Start
July 1, 2006
Primary Completion
December 1, 2015
Study Completion
June 1, 2016
Last Updated
August 1, 2016
Record last verified: 2016-07