Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy With 5-Fluorouracil and Oxaliplatin Versus 5-Fluorouracil Alone in Rectal Cancer

NCT ID: NCT00349076

Last Updated: 2016-08-01

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

1256 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-07-31

Study Completion Date

2016-06-30

Brief Summary

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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.

Detailed Description

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Conditions

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Rectal Neoplasms

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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1

Preoperative 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

Group Type EXPERIMENTAL

5-FU and oxaliplatin

Intervention Type DRUG

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

2

Preoperative 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

Group Type ACTIVE_COMPARATOR

5-FU

Intervention Type DRUG

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

Interventions

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5-FU and oxaliplatin

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

Intervention Type DRUG

5-FU

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

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* 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

Exclusion Criteria

* 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)
* Previous or concurrent malignancies, with the exception of adequately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix. The inclusion of patients with other adequately treated tumors within the last 5 years has to be discussed with the principal investigator
* 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)
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Erlangen-Nürnberg Medical School

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Rolf Sauer, M.D.

Role: PRINCIPAL_INVESTIGATOR

Dept. of Radiation Therapy, University of Erlangen, Germany

Locations

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Kreiskliniken Altötting-Burghausen

Altötting, , Germany

Site Status

Gesundheitszentrum St. Marien

Amberg, , Germany

Site Status

Onkologische Gemeinschaftspraxis

Ansbach, , Germany

Site Status

Krankenhaus Marienwörth

Bad Kreuznach, , Germany

Site Status

Caritas-Krankenhaus

Bad Mergentheim, , Germany

Site Status

Onkologische Schwerpunktpraxis

Bad Soden, , Germany

Site Status

Klinik Bad Trissl-Oberaudorf

Bad Trissl, , Germany

Site Status

Klinikum Bayreuth GmbH

Bayreuth, , Germany

Site Status

Aerzteforum Hennigsdorf

Berlin, , Germany

Site Status

Städtische Kliniken

Bielefeld, , Germany

Site Status

St.-Agnes-Hospital Bocholt

Bocholt, , Germany

Site Status

St. Josef-Hospital

Bochum, , Germany

Site Status

Ruhr-Universität Bochum; Knappschaftskrankenhaus

Bochum, , Germany

Site Status

Klinikum Bremen-Mitte

Bremen, , Germany

Site Status

Onkologische Praxis

Buchholz, , Germany

Site Status

Praxis für Hämatologie und Onkologie

Burgwedel, , Germany

Site Status

Klinikum Coburg gGmbH

Coburg, , Germany

Site Status

Praxis für Hämatologie und Onkologie

Cologne, , Germany

Site Status

Gemeinschaftspraxis für Hämatologie und Internistische Onkologie

Cologne, , Germany

Site Status

Onkologisches Versorgungszentrum Rehling-Donauwörth-Dachau

Donauwörth, , Germany

Site Status

Universitätsklinikum Carl Gustav Carus

Dresden, , Germany

Site Status

Katholisches Krankenhaus St. Nepomuk

Erfurt, , Germany

Site Status

Dept. of Radiation Therapy, University of Erlangen

Erlangen, , Germany

Site Status

Universitätsklinikum Essen

Essen, , Germany

Site Status

Alfried Krupp Krankenhaus

Essen, , Germany

Site Status

Klinikum Esslingen a.N.

Esslingen am Neckar, , Germany

Site Status

Universitätsklinikum

Frankfurt am Main, , Germany

Site Status

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Site Status

Weisseritztal-Kliniken

Freital, , Germany

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Kliniken an der Paar, Krankenhaus Friedberg

Friedberg, , Germany

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Klinikum Fulda

Fulda, , Germany

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SRH-Waldklinikum

Gera, , Germany

Site Status

Wilhelm-Anton-Hospital

Goch, , Germany

Site Status

Klinik am Eichert

Göppingen, , Germany

Site Status

Georg-August-Universität Göttingen

Göttingen, , Germany

Site Status

Universitätsklinikum Greifswald

Greifswald, , Germany

Site Status

St. Elisabeth und St. Barbara Krankenhaus

Halle, , Germany

Site Status

Asklepios Klinik Hamburg-Harburg

Hamburg, , Germany

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Diakonie Klinikum Hamburg

Hamburg, , Germany

Site Status

Praxis für Hämatologie und Onkologie, Hamm

Hamm, , Germany

Site Status

Marienhospital

Herne, , Germany

Site Status

Onkologische Schwerpunktpraxis

Hildesheim, , Germany

Site Status

Universitätsklinikum des Saarlandes

Homburg/Saar, , Germany

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Klinik für Knochenmarkstransplantation und Hämatologie/Onkologie GmbH

Idar-Oberstein, , Germany

Site Status

Klinikum der Friedrich Schiller Universität

Jena, , Germany

Site Status

Innere Medizin, Hämatologie und Int. Onkologie

Kassel, , Germany

Site Status

Universitätsklinikum Schleswig-Holstein, Campus Kiel

Kiel, , Germany

Site Status

Onkologische Schwerpunktpraxis

Kronach, , Germany

Site Status

Gemeinschaftspraxis Onkologie

Landshut, , Germany

Site Status

Klinikum Landshut

Landshut, , Germany

Site Status

Universitätsklinikum Leipzig

Leipzig, , Germany

Site Status

Universitätsklinikum Schleswig-Holstein, Campus Lübeck

Lübeck, , Germany

Site Status

Universitätsklinikum - St. Hildegardis-Krankenhaus Mainz

Mainz, , Germany

Site Status

Phillips-Universität Marburg

Marburg, , Germany

Site Status

Kliniken Maria Hilf

Mönchengladbach, , Germany

Site Status

Gemeinschaftspraxis Onkologie

Muhr am See, , Germany

Site Status

Klinikum Schwäbisch Gmünd, Stauferklinik

Mutlangen, , Germany

Site Status

Universitätsklinikum Großhadern

München, , Germany

Site Status

Klinikum rechts der Isar, Technische Universität

München, , Germany

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Clemenshospital Münster

Münster, , Germany

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Universitätsklinikum Münster

Münster, , Germany

Site Status

Hämatologisch-onkologische Schwerpunktpraxis Northeim

Northeim, , Germany

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Klinikum Nürnberg

Nuremberg, , Germany

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Darmzentrum Ortenau

Offenburg, , Germany

Site Status

Klinikum Oldenburg; Pius Hospital Oldenburg

Oldenburg, , Germany

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Paracelsus-Krankenhaus Ruit

Ostfildern, , Germany

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St. Vincenz Krankenhaus

Paderborn, , Germany

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Klinikum Passau

Passau, , Germany

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St. Josefs Krankenhaus

Potsdam, , Germany

Site Status

Universitätsklinikum Regensburg

Regensburg, , Germany

Site Status

Schwerpunktpraxis für Hämatologie und Onkologie mit Tagesklinik

Regensburg, , Germany

Site Status

Krankenhaus Barmherzige Brüder

Regensburg, , Germany

Site Status

Klinikum Rosenheim

Rosenheim, , Germany

Site Status

Medizinische Fakultät der Universität Rostock

Rostock, , Germany

Site Status

Kreiskrankenhaus Rottweil

Rottweil, , Germany

Site Status

Thüringen-Kliniken Saalfeld-Rudolstadt

Saalfeld, , Germany

Site Status

Hämatologisch-Onkologische Schwerpunktpraxis

Singen, , Germany

Site Status

Onkologische Praxisgemeinschaft Stade

Stade, , Germany

Site Status

Klinikum Traunstein

Traunstein, , Germany

Site Status

Onkologische Schwerpunktpraxis Traunstein

Traunstein, , Germany

Site Status

Krankenhaus der Barmherzigen Brüder

Trier, , Germany

Site Status

Universitätsklinikum Ulm

Ulm, , Germany

Site Status

Marienhaus Klinikum, St. Elisabeth Klinik Saarlouis, St. Michael Krankenhaus Völklingen

Völklingen, , Germany

Site Status

Klinikum Wetzlar-Braunfels

Wetzlar, , Germany

Site Status

Asklepios Paulinen Klinik

Wiesbaden, , Germany

Site Status

Reinhard-Nieter-Krankenhaus

Wilhelmshaven, , Germany

Site Status

Juliusspital

Würzburg, , Germany

Site Status

Missionsärztliche Klinik

Würzburg, , Germany

Site Status

Universitätsklinikum Würzburg

Würzburg, , Germany

Site Status

Countries

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Germany

References

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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.

Reference Type DERIVED
PMID: 36572280 (View on PubMed)

Diefenhardt 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.

Reference Type DERIVED
PMID: 34619239 (View on PubMed)

Kosmala 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.

Reference Type DERIVED
PMID: 33383348 (View on PubMed)

Diefenhardt 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.

Reference Type DERIVED
PMID: 32644104 (View on PubMed)

Kitz 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.

Reference Type DERIVED
PMID: 29874375 (View on PubMed)

Hofheinz 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.

Reference Type DERIVED
PMID: 29873684 (View on PubMed)

Rodel 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.

Reference Type DERIVED
PMID: 26189067 (View on PubMed)

Rodel 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.

Reference Type DERIVED
PMID: 22627104 (View on PubMed)

Schirmer 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.

Reference Type DERIVED
PMID: 22000747 (View on PubMed)

Other Identifiers

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German Cancer Aid (no. 106759)

Identifier Type: -

Identifier Source: secondary_id

CAO/ARO/AIO-04

Identifier Type: -

Identifier Source: org_study_id

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