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Rectal NeoplasmsPhase 3NCT00349076

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

A Phase 3 study testing 5-FU and oxaliplatin and 5-FU in people with Rectal Neoplasms, run by University of Erlangen-Nürnberg Medical School at 89 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Rectal Neoplasms
What is being tested?
5-FU and oxaliplatin and 5-FU
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,256 participants
Where
89 sitesGermany
Study dates
Jul 2006to Jun 2016
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 14Show fewer
  • 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)

Trial locations and contacts

89 sites in 1 country.

89 sites in 1 country

Germany89 sites

  • Kreiskliniken Altötting-Burghausen

    Altötting, 84503

  • Gesundheitszentrum St. Marien

    Amberg, 92224

  • Onkologische Gemeinschaftspraxis

    Ansbach, 91522

  • Krankenhaus Marienwörth

    Bad Kreuznach, 55543

  • Caritas-Krankenhaus

    Bad Mergentheim, 97980

  • Onkologische Schwerpunktpraxis

    Bad Soden, 65812

  • Klinik Bad Trissl-Oberaudorf

    Bad Trissl, 83080

  • Klinikum Bayreuth GmbH

    Bayreuth, 95445

  • Aerzteforum Hennigsdorf

    Berlin, 16761

  • Städtische Kliniken

    Bielefeld, 33604

  • St.-Agnes-Hospital Bocholt

    Bocholt, 46397

  • St. Josef-Hospital

    Bochum, 44791

  • Ruhr-Universität Bochum; Knappschaftskrankenhaus

    Bochum, 44892

  • Klinikum Bremen-Mitte

    Bremen, 28205

  • Onkologische Praxis

    Buchholz, 21244

  • Praxis für Hämatologie und Onkologie

    Burgwedel, 30938

  • Klinikum Coburg gGmbH

    Coburg, 96450

  • Praxis für Hämatologie und Onkologie

    Cologne, 50677

  • Gemeinschaftspraxis für Hämatologie und Internistische Onkologie

    Cologne, 51105

  • Onkologisches Versorgungszentrum Rehling-Donauwörth-Dachau

    Donauwörth, 86609

  • Universitätsklinikum Carl Gustav Carus

    Dresden, 01307

  • Katholisches Krankenhaus St. Nepomuk

    Erfurt, 99097

  • Dept. of Radiation Therapy, University of Erlangen

    Erlangen, 91054

  • Universitätsklinikum Essen

    Essen, 45122

  • Alfried Krupp Krankenhaus

    Essen, 45131

  • Klinikum Esslingen a.N.

    Esslingen am Neckar, 73073

  • Universitätsklinikum

    Frankfurt am Main, 60590

  • Universitätsklinikum Freiburg

    Freiburg im Breisgau, 79110

  • Weisseritztal-Kliniken

    Freital, 01705

  • Kliniken an der Paar, Krankenhaus Friedberg

    Friedberg, 86316

  • Klinikum Fulda

    Fulda, 36013

  • SRH-Waldklinikum

    Gera, 07548

  • Wilhelm-Anton-Hospital

    Goch, 47574

  • Klinik am Eichert

    Göppingen, 73035

  • Georg-August-Universität Göttingen

    Göttingen, 37075

  • Universitätsklinikum Greifswald

    Greifswald, 17475

  • St. Elisabeth und St. Barbara Krankenhaus

    Halle, 06110

  • Asklepios Klinik Hamburg-Harburg

    Hamburg, 21075

  • Diakonie Klinikum Hamburg

    Hamburg, 22527

  • Praxis für Hämatologie und Onkologie, Hamm

    Hamm, 59071

  • Marienhospital

    Herne, 44625

  • Onkologische Schwerpunktpraxis

    Hildesheim, 31134

  • Universitätsklinikum des Saarlandes

    Homburg/Saar, 66421

  • Klinik für Knochenmarkstransplantation und Hämatologie/Onkologie GmbH

    Idar-Oberstein, 55743

  • Klinikum der Friedrich Schiller Universität

    Jena, 07740

  • Innere Medizin, Hämatologie und Int. Onkologie

    Kassel, 34117

  • Universitätsklinikum Schleswig-Holstein, Campus Kiel

    Kiel, 24015

  • Onkologische Schwerpunktpraxis

    Kronach, 96317

  • Gemeinschaftspraxis Onkologie

    Landshut, 84028

  • Klinikum Landshut

    Landshut, 84034

  • Universitätsklinikum Leipzig

    Leipzig, 04103

  • Universitätsklinikum Schleswig-Holstein, Campus Lübeck

    Lübeck, 23538

  • Universitätsklinikum - St. Hildegardis-Krankenhaus Mainz

    Mainz, 65131

  • Phillips-Universität Marburg

    Marburg, 35043

  • Kliniken Maria Hilf

    Mönchengladbach, 41061

  • Gemeinschaftspraxis Onkologie

    Muhr am See, 91735

  • Universitätsklinikum Großhadern

    München, 81377

  • Klinikum rechts der Isar, Technische Universität

    München, 81675

  • Clemenshospital Münster

    Münster, 48149

  • Universitätsklinikum Münster

    Münster, 48149

  • Klinikum Schwäbisch Gmünd, Stauferklinik

    Mutlangen, 73557

  • Hämatologisch-onkologische Schwerpunktpraxis Northeim

    Northeim, 37154

  • Klinikum Nürnberg

    Nuremberg, 90419

  • Darmzentrum Ortenau

    Offenburg, 77654

  • Klinikum Oldenburg; Pius Hospital Oldenburg

    Oldenburg, 26133

  • Paracelsus-Krankenhaus Ruit

    Ostfildern, 73760

  • St. Vincenz Krankenhaus

    Paderborn, 33098

  • Klinikum Passau

    Passau, 94032

  • St. Josefs Krankenhaus

    Potsdam, 14471

  • Universitätsklinikum Regensburg

    Regensburg, 93042

  • Schwerpunktpraxis für Hämatologie und Onkologie mit Tagesklinik

    Regensburg, 93047

  • Krankenhaus Barmherzige Brüder

    Regensburg, 93049

  • Klinikum Rosenheim

    Rosenheim, 83022

  • Medizinische Fakultät der Universität Rostock

    Rostock, 18059

  • Kreiskrankenhaus Rottweil

    Rottweil, 78628

  • Thüringen-Kliniken Saalfeld-Rudolstadt

    Saalfeld, 07318

  • Hämatologisch-Onkologische Schwerpunktpraxis

    Singen, 78224

  • Onkologische Praxisgemeinschaft Stade

    Stade, 21680

  • Klinikum Traunstein

    Traunstein, 83278

  • Onkologische Schwerpunktpraxis Traunstein

    Traunstein, 83278

  • Krankenhaus der Barmherzigen Brüder

    Trier, 54292

  • Universitätsklinikum Ulm

    Ulm, 89081

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

    Völklingen, 66333

  • Klinikum Wetzlar-Braunfels

    Wetzlar, 35578

  • Asklepios Paulinen Klinik

    Wiesbaden, 65197

  • Reinhard-Nieter-Krankenhaus

    Wilhelmshaven, 26389

  • Juliusspital

    Würzburg, 97070

  • Missionsärztliche Klinik

    Würzburg, 97074

  • Universitätsklinikum Würzburg

    Würzburg, 97080

Other trials in Germany

About this study

Official title: 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

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.

Being tested
5-FU and oxaliplatin, 5-FU
Medical subject headings
Rectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 5-FU and oxaliplatinDrug

    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

  • 5-FUDrug

    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

Study groups in NCT00349076
Study groupRoleWhat they receive
1ExperimentalPreoperative 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
Receives: Drug: 5-FU and oxaliplatin
2Active 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
Receives: Drug: 5-FU

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 3 years

Secondary outcomes (1)

  1. Resection rate, rate of sphincter preservation, tumor regression, cumulative incidence of local and distant recurrences, overall survival, toxicity, quality of life

    Measured: 5-year follow up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Jul 2006 (estimated)
  2. Study startJul 2006
  3. Primary completionDec 2015
  4. Study completionJun 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
1,256 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00349076
Sponsor's protocol ID
CAO/ARO/AIO-04
Other IDs
German Cancer Aid (no. 106759)
Status last verified
Jul 2016
First submitted
5 Jul 2006
Last updated
1 Aug 2016
Results posted
No

Publications

  • 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.

    PubMed 36572280

  • 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.

    PubMed 34619239

  • 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.

    PubMed 33383348

  • 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.

    PubMed 32644104

  • 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.

    PubMed 29874375

  • 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.

    PubMed 29873684

  • 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.

    PubMed 26189067

  • 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.

    PubMed 22627104

  • 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.

    PubMed 22000747

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing 5-FU and oxaliplatin and 5-FU in people with Rectal Neoplasms, run by University of Erlangen-Nürnberg Medical School at 89 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 89 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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. (time frame: 3 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00349076, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Aug 2016.

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