Clinical trial NCT00349076: Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy With 5-Fluorouracil and Oxaliplatin Versus 5-Fluorouracil Alone in Rectal Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rectal Neoplasms
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
First posted: 2006-07-06
Enrollment: 1256
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: 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.


Eligibility criteria: 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)

Primary outcomes:
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.
timeFrame: 3 years
Secondary outcomes:
measure: Resection rate, rate of sphincter preservation, tumor regression, cumulative incidence of local and distant recurrences, overall survival, toxicity, quality of life
timeFrame: 5-year follow up
Other outcomes:
Locations:
city: Altötting
country: Germany
facility: Kreiskliniken Altötting-Burghausen
city: Amberg
country: Germany
facility: Gesundheitszentrum St. Marien
city: Ansbach
country: Germany
facility: Onkologische Gemeinschaftspraxis
city: Bad Kreuznach
country: Germany
facility: Krankenhaus Marienwörth
city: Bad Mergentheim
country: Germany
facility: Caritas-Krankenhaus
city: Bad Soden
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Bad Trissl
country: Germany
facility: Klinik Bad Trissl-Oberaudorf
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth GmbH
city: Berlin
country: Germany
facility: Aerzteforum Hennigsdorf
city: Bielefeld
country: Germany
facility: Städtische Kliniken
city: Bocholt
country: Germany
facility: St.-Agnes-Hospital Bocholt
city: Bochum
country: Germany
facility: St. Josef-Hospital
city: Bochum
country: Germany
facility: Ruhr-Universität Bochum; Knappschaftskrankenhaus
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Buchholz
country: Germany
facility: Onkologische Praxis
city: Burgwedel
country: Germany
facility: Praxis für Hämatologie und Onkologie
city: Coburg
country: Germany
facility: Klinikum Coburg gGmbH
city: Donauwörth
country: Germany
facility: Onkologisches Versorgungszentrum Rehling-Donauwörth-Dachau
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
city: Erfurt
country: Germany
facility: Katholisches Krankenhaus St. Nepomuk
city: Erlangen
country: Germany
facility: Dept. of Radiation Therapy, University of Erlangen
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Essen
country: Germany
facility: Alfried Krupp Krankenhaus
city: Esslingen
country: Germany
facility: Klinikum Esslingen a.N.
city: Frankfurt/Main
country: Germany
facility: Universitätsklinikum
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Freital
country: Germany
facility: Weisseritztal-Kliniken
city: Friedberg
country: Germany
facility: Kliniken an der Paar, Krankenhaus Friedberg
city: Fulda
country: Germany
facility: Klinikum Fulda
city: Gera
country: Germany
facility: SRH-Waldklinikum
city: Goch
country: Germany
facility: Wilhelm-Anton-Hospital
city: Greifswald
country: Germany
facility: Universitätsklinikum Greifswald
city: Göppingen
country: Germany
facility: Klinik am Eichert
city: Göttingen
country: Germany
facility: Georg-August-Universität Göttingen
city: Halle
country: Germany
facility: St. Elisabeth und St. Barbara Krankenhaus
city: Hamburg
country: Germany
facility: Asklepios Klinik Hamburg-Harburg
city: Hamburg
country: Germany
facility: Diakonie Klinikum Hamburg
city: Hamm
country: Germany
facility: Praxis für Hämatologie und Onkologie, Hamm
city: Herne
country: Germany
facility: Marienhospital
city: Hildesheim
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Homburg/Saar
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Idar-Oberstein
country: Germany
facility: Klinik für Knochenmarkstransplantation und Hämatologie/Onkologie GmbH
city: Jena
country: Germany
facility: Klinikum der Friedrich Schiller Universität
city: Kassel
country: Germany
facility: Innere Medizin, Hämatologie und Int. Onkologie
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Kiel
city: Kronach
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Köln
country: Germany
facility: Praxis für Hämatologie und Onkologie
city: Köln
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Internistische Onkologie
city: Landshut
country: Germany
facility: Gemeinschaftspraxis Onkologie
city: Landshut
country: Germany
facility: Klinikum Landshut
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Lübeck
city: Mainz
country: Germany
facility: Universitätsklinikum - St. Hildegardis-Krankenhaus Mainz
city: Marburg
country: Germany
facility: Phillips-Universität Marburg
city: Muhr am See
country: Germany
facility: Gemeinschaftspraxis Onkologie
city: Mutlangen
country: Germany
facility: Klinikum Schwäbisch Gmünd, Stauferklinik
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf
city: München
country: Germany
facility: Universitätsklinikum Großhadern
city: München
country: Germany
facility: Klinikum rechts der Isar, Technische Universität
city: Münster
country: Germany
facility: Clemenshospital Münster
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Northeim
country: Germany
facility: Hämatologisch-onkologische Schwerpunktpraxis Northeim
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg
city: Offenburg
country: Germany
facility: Darmzentrum Ortenau
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg; Pius Hospital Oldenburg
city: Ostfildern
country: Germany
facility: Paracelsus-Krankenhaus Ruit
city: Paderborn
country: Germany
facility: St. Vincenz Krankenhaus
city: Passau
country: Germany
facility: Klinikum Passau
city: Potsdam
country: Germany
facility: St. Josefs Krankenhaus
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Regensburg
country: Germany
facility: Schwerpunktpraxis für Hämatologie und Onkologie mit Tagesklinik
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder
city: Rosenheim
country: Germany
facility: Klinikum Rosenheim
city: Rostock
country: Germany
facility: Medizinische Fakultät der Universität Rostock
city: Rottweil
country: Germany
facility: Kreiskrankenhaus Rottweil
city: Saalfeld
country: Germany
facility: Thüringen-Kliniken Saalfeld-Rudolstadt
city: Singen
country: Germany
facility: Hämatologisch-Onkologische Schwerpunktpraxis
city: Stade
country: Germany
facility: Onkologische Praxisgemeinschaft Stade
city: Traunstein
country: Germany
facility: Klinikum Traunstein
city: Traunstein
country: Germany
facility: Onkologische Schwerpunktpraxis Traunstein
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Völklingen
country: Germany
facility: Marienhaus Klinikum, St. Elisabeth Klinik Saarlouis, St. Michael Krankenhaus Völklingen
city: Wetzlar
country: Germany
facility: Klinikum Wetzlar-Braunfels
city: Wiesbaden
country: Germany
facility: Asklepios Paulinen Klinik
city: Wilhelmshaven
country: Germany
facility: Reinhard-Nieter-Krankenhaus
city: Wuerzburg
country: Germany
facility: Juliusspital
city: Würzburg
country: Germany
facility: Missionsärztliche Klinik
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
Study officials:
affiliation: Dept. of Radiation Therapy, University of Erlangen, Germany
name: Rolf Sauer, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.