Rectal Cancer Stage IIIPhase 3NCT04246684
Short RT Versus RCT,Followed by Chemo and Organ Preservation for Interm and High-risk Rectal Cancer Patients
A Phase 3 study testing Oxaliplatin, 85 mg/m2, 5FU; 2400 mg/m2 and 5FU, 250 mg/m2 in people with Rectal Cancer Stage III, run by Prof. Dr. med. Claus Rödel at 75 sites in Germany.
Trial summary
The hereby proposed ACO/ARO/AIO-18.1 randomized trial aims to directly compare the newly established TNT concepts applying either short-course RT according to RAPIDO, or CRT according to CAO/ARO/AIO-04/-12, both followed by consolidation chemotherapy, and surgery or a watch\&wait (W\&W) approach for patients with… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rectal Cancer Stage III
- What is being tested?
- Oxaliplatin, 85 mg/m2, 5FU; 2400 mg/m2 and 5FU, 250 mg/m2
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 702 participants
- Where
- 75 sitesGermany
- Study dates
- 5 Nov 2020to 15 Sep 2028
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
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
- diagnosis of rectal adenocarcinoma localised 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum)
- Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
- MRI-defined inclusion criteria: presence of at least one of the following high-risk conditions:
- any cT3 if the distal extent of the tumor is < 6 cm from the anocutaneous line, or
- cT3c/d in the middle third of the rectum (≥ 6-12 cm) with MRI evidence of extramural tumor spread into the mesorectal fat of more than 5 mm (>cT3b), or
- cT3 with clear cN+ based on strict MRI-criteria
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- cT4 tumors, or
- Tany middle/low third of rectum with clear MRI criteria for N+
- mrCRM+ (< 1mm), or
- Extramural venous invasion (EMVI+)
- Trans-rectal endoscopic ultrasound (EUS) is additionally used when MRI is not definitive to exclude early cT1/T2 disease in the lower third of the rectum or early cT3a/b tumors in the middle third of the rectum.
- Spiral-CT of the abdomen and chest to exclude distant metastases.
- Aged at least 18 years. No upper age limit.
- WHO/ECOG Performance Status 0-1
- Adequate haematological, hepatic, renal and metabolic function parameters:
- Leukocytes ≥ 3.000/mm^3, ANC ≥ 1.500/mm^3, platelets ≥ 100.000/mm^3, Hb > 9 g/dl
- Serum creatinine ≤ 1.5 x upper limit of normal
- Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal • Informed consent of the patient
Who cannot join
- Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy
- Distant metastases (to be excluded by CT scan of the thorax and abdomen)
- Prior antineoplastic therapy for rectal cancer
- Prior radiotherapy of the pelvic region
- Major surgery within the last 4 weeks prior to inclusion
- Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
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- Subject (male or female) is not willing to use highly effective methods of Contraception during treatment and for 6 months after the end of treatment.
- On-treatment participation in a clinical study in the period 30 days prior to inclusion
- Previous or current drug abuse
- Other concomitant antineoplastic therapy
- Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder
- Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) < 6 months before enrolment
- Prior or concurrent malignancy < 3 years prior to enrolment in study (Exception: non-melanoma Skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free
- Known allergic reactions on study medication
- Known dihydropyrimidine dehydrogenase deficiency
- Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial).
Trial locations and contacts
75 sites in 1 country.
75 sites in 1 country
Germany75 sites
Clincal Center "St. Marien" Amberg
Amberg, Bavaria, 92224
Clincal Center Helios Bad Saarrow
Bad Saarow, Brandenburg, 15526
Clinic Bayreuth GmbH
Bayreuth, Bavaria, 95445
Vivantes Clincial Center in Friedrichshain
Berlin, State of Berlin, 10249
Clincal Center Helios Berlin Buch
Berlin, State of Berlin, 13125
Ev. Waldkrankenhaus, Spandau,
Berlin, State of Berlin, 13589
Helios Klinikum Berlin Emil von Behring
Berlin, State of Berlin, 14650
Klinikum Bielefeld
Bielefeld, 33604
St. Josef Hospital of the catholic clinic Bochum
Bochum, North Rhine-Westphalia, 44791
Hospital Bochum
Bochum, North Rhine-Westphalia, 44892
Clincal Center Chemnitz
Chemnitz, Saxony, 09113
Clinical Center Coburg
Coburg, Bavaria, 96450
Clincal Center Darmstadt
Darmstadt, Hesse, 64283
Onkologische Schwerpunktpraxis
Darmstadt, 64287
Clinic Lippe GmbH (Lemgo/Detmold)
Detmold, North Rhine-Westphalia, 32756
Radiotherapy Practice Dr. A. Schreiber, Dresden
Dresden, Saxony, 01067
Oncology Practice Dresden
Dresden, Saxony, 01307
University Clinic Erlangen
Erlangen, Bavaria, 91054
University Clinic Essen
Essen, North Rhine-Westphalia, 45122
Clinical Center "Essen Mitte"
Essen, North Rhine-Westphalia, 45136
Clincal Center Esslingen
Esslingen am Neckar, Baden-Wurttemberg, 73730
Department of Radiooncology
Frankfurt, Frankfurt, 60590
Clinic North West gGmbH Frankfurt
Frankfurt am Main, Hesse, 60488
University Clinic Freiburg
Freiburg im Breisgau, Baden-Wurttemberg, 79106
Clinic Fulda
Fulda, Hesse, 36043
Praxis für Hämatologie und Onkologie
Giessen, 35392
MVZ Oncological Cooperation Harz
Goslar, Lower Saxony, 38642
University Clinic Göttingen
Göttingen, Lower Saxony, 37075
Universitätsklinikum Halle
Halle, 06120
Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln
Hamelin, Lower Saxony, 31785
Medical Project Hannover
Hanover, Lower Saxony, 30171
"St. Bernward" Clincal Center Hildesheim
Hildesheim, Lower Saxony, 31134
Oncology in Medicinum Hildesheim
Hildesheim, Lower Saxony, 31135
DRK Clincal Centers North Hessen Kassel
Kassel, Hesse, 34121
Klinikverbund Allgäu
Kempten (Allgäu), Bavaria, 87439
University Clinic Kiel
Kiel, Schleswig-Holstein, 24105
Alexianer Krefeld GmbH / Maria Hilf Krankenhaus
Krefeld, 47805
Oncology UnterEms, Leer
Leer, Lower Saxony, 26789
University Clinic Leipzig
Leipzig, Saxony, 04103
Clinic Sankt Georg gGmbH, Leipzig
Leipzig, Saxony, 04129
Uniklinik Schleswig Holstein
Lübeck, 23538
University Clinic Magdeburg
Magdeburg, Saxony-Anhalt, 39120
University Clinic Mainz
Mainz, Rhineland-Palantine, 55116
University Clinic Mannheim
Mannheim, Baden-Wurttemberg, 68167
University Clinic Marburg
Marburg, Hesse, 35043
Clinic Maria Hilf GmbH
Mönchengladbach, North Rhine-Westphalia, 41063
Technical University Clinic Munich
München, Bavaria, 81675
Technical University Munich
München, Bavaria, 81675
Clincal Center "Bogenhausen" Munich
München, Bavaria, 81925
Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen
Mutlangen, Baden-Wurttemberg, 73557
Dietrich Bonhoeffer Klinik
Neubrandenburg, 17036
Sana Clinical Center Offenbach
Offenbach, Hesse, 63069
Pi.Tri-Studien GmbH, Offenburg
Offenburg, Baden-Wurttemberg, 77654
Pius Hospital, Oldenburg
Oldenburg, Lower Saxony, 25121
University Clinic Oldenburg
Oldenburg, Lower Saxony, 26133
Medius Clincal Center Ostfildern-Ruit
Ostfildern, Baden-Wurttemberg, 73760
Brother clinic St. Josef, Paderborn
Paderborn, North Rhine-Westphalia, 33098
St. Vincenz Hospital Paderborn
Paderborn, North Rhine-Westphalia, 33098
Prosper Hospital Recklinghausen
Recklinghausen, North Rhine-Westphalia, 45659
Hospital "Barmherzige Brüder" Regensburg
Regensburg, Bavaria, 93046
University Clinic Regensburg
Regensburg, Bavaria, 93053
Mathias-Spital, Rheine
Rheine, North Rhine-Westphalia, 48431
University Clinic Rostock
Rostock, Mecklenburg-Vorpommern, 18059
Med. Statistik Saarbrücken GgR
Saarbrücken, Saarbruecken, 66113
CaritasClinic Saarbrücken
Saarbrücken, Saarland, 66113
Clinic Stuttgart
Stuttgart, Baden-Wurttemberg, 70174
Clinical Center "Mutterhaus" Trier
Trier, Rhineland-Palatinate, 54290
University Clinic for Radioncology Tübingen
Tübingen, Baden-Wurttemberg, 72076
University Clinic Ulm
Ulm, Baden-Wurttemberg, 89081
Schwarzwald-Baar-Kliniken
Villingen-Schwenningen, Villingen-Schwenningen, 78052
Clinic Nordoberpfalz AG, Clinic Weiden
Weiden, Bavaria, 92637
Evangelical Clinic Wesel
Wesel, North Rhine-Westphalia, 46485
Lahn-Dill Clinics Wetzlar
Wetzlar, Hesse, 35578
Clinic Wolfsburg
Wolfsburg, Lower Saxony, 38440
University Clinic Würzburg
Würzburg, Bavaria, 97080
About this study
Official title: Short-course Radiotherapy Versus Chemoradiotherapy, Followed by Consolidation Chemotherapy, and Selective Organ Preservation for MRI-defined Intermediate and High-risk Rectal Cancer Patients
The hereby proposed ACO/ARO/AIO-18.1 randomized trial aims to directly compare the newly established TNT concepts applying either short-course RT according to RAPIDO, or CRT according to CAO/ARO/AIO-04/-12, both followed by consolidation chemotherapy, and surgery or a watch\&wait (W\&W) approach for patients with clinical complete response (cCR).
The ACO/ARO/AIO-18.1 study incorporates several novel and innovative aspects to further optimize multimodal rectal cancer treatment, partly established by our preceding CAO/ARO/AIO-04 and CAO/ARO/AIO-12 randomized trials: (1) patient selection is based on strict, quality controlled MRI features of intermediate and high-risk characteristics (and, thus, complementary to our ACO/ARO/AIO-18.2 trial in "low-risk" rectal cancer), (2) the CRT regimens incorporates 5-FU/oxaliplatin with doses and intensities shown to be effective and well-tolerated without compromising treatment compliance in CAO/ARO/AIO-04, (3) the sequence of CRT, CT, and surgery/W\&W adopts the TNT approach as established by our CAO/ARO/AIO-12 and OPRA trial, (4) surgical stratification allows for W\&W management for strictly selected patients with clinical complete response (cCR). Thus, we hypothesize that TNT with 5-FU/oxaliplatin-CRT followed by consolidation chemotherapy may increase organ preservation while maintaining DFS as compared to RAPIDO-like short-course RT followed by consolidation chemotherapy.
Read the detailed description
The primary endpoint of this trial, organ preservation, is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the primary endpoint, organ preservation, will not be reached if any of the following occurs: (1) death, (2) any major surgery other than local excision (R0) performed after randomization, during TNT, at re-staging scheduled 22-24 weeks after start of TNT due to clinical non-cCR, or for any locoregional regrowth after initial cCR requiring salvage-TME, (3) any locoregional regrowth not amenable to salvage surgery, or (4) any stoma (non-re-converted protective stoma within 6 months after completion of TNT, or any stoma needed for toxicity or poor function), whichever occurs first. We hypothesized that the 3-year organ preservation rate will improve from 30% in the control arm to 40% in the investigational arm (hazard ratio of 0.76). With a power of 90% and a two-sided type I error of 5%, the sample size required to obtain a statistically significant difference is 702 patients (564 events) in total.
- Conditions
- Rectal Cancer Stage III
- Being tested
- Oxaliplatin, 85 mg/m2, 5FU; 2400 mg/m2, 5FU, 250 mg/m2, 5FU, 2400 mg/m2, Oxaliplatin 50 mg/m2
- Medical subject headings
- Rectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oxaliplatin, 85 mg/m2Drug
Also called Control arm
85 mg/m2,2h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapy
5FU; 2400 mg/m2Drug
Also called 5-FU, control arm
2400 mg/m2, 46h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, 134 of therapy for Control arm
5FU, 250 mg/m2Drug
Also called Experimental arm: 5-FU
250 mg/m2 per day, civ, on day 1-14, day 22-35 of radiotherapy;
5FU, 2400 mg/m2Drug
Also called experimental arm
2400 mg/m2,46h-civ, d64, d78, d92, d106, d120, d134 of therapy
Oxaliplatin 50 mg/m2Drug
Also called Experimental arm
50 mg/m2, 2h-civ, d1, d8, d21, d29 of radiotherapy and
Folinic Acid, 400 mg/m2Drug
Also called Folinic Acid
2h-civ day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapyfor Control arm; 400 mg/m2, 2h-civ d 64, d78, d92, d106, d120, d134 of therapy for experimental arm
Radiotherapy control, 5x5 Gy: 25 GyRadiation
Control arm: 5x5 Gy (total: 25 Gy) 5 fractions
Capecitabine, 1000 mg/m2Drug
Also called Capecitabine
1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional
Oxaliplatin 85 mg/m2Drug
Also called experimental arm
85 mg/m2, 2h-civ, d64, d78, d92, d106, d120, d134 of therapy
radiotherapy experimental, 30 x 1,8 Gy: 54 GyRadiation
30 x 1.8 Gy (total: 54 Gy), 5 fractions per week
Capecitabine, 825 mg/m2Drug
Also called Capecitabine
825 mg/m2 bid, per os, on day 1-14, 22-35 of RT instead of 5FU optional
Oxaliplatin, 130 mg/m2Drug
Also called Oxaliplatin
day1every three weeks (optional)
| Study group | Role | What they receive |
|---|---|---|
| Control arm | Active comparator | In the control arm patients receive 5x5 Gy followed by 9 cycles of consolidation chemotherapy mFOLFOX6 or alternatively 6 cycles of CAPOX, followed by re-staging at week 22-24 as established as new preferred neoadjuvant regimen by the RAPIDO trial. Receives: Drug: Oxaliplatin, 85 mg/m2; Drug: 5FU; 2400 mg/m2; Drug: Folinic Acid, 400 mg/m2; Radiation: Radiotherapy control, 5x5 Gy: 25 Gy; Drug: Capecitabine, 1000 mg/m2; Drug: Oxaliplatin, 130 mg/m2 |
| Experimental arm | Experimental | The experimental arm starts with Fluoropyrimidin/Oxaliplatin-based CRT (1.8 Gy to 45 Gy to the primary tumor and pelvic lymph nodes; followed by sequential boost of 9 Gy to the gross tumor volume) followed by consolidation chemotherapy with 6 cycles mFOLFOX6 or alternatively 4 cycles CAPOX, followed by re-staging at week 22-24. In both arms, for patients achieving a clinical complete response (cCR), as strictly assessed by clinical investigation, endoscopy and MRI, a W\&W option with close follow-up is scheduled. In case of non-complete response, immediate TME surgery is performed. Receives: Drug: 5FU, 250 mg/m2; Drug: 5FU, 2400 mg/m2; Drug: Oxaliplatin 50 mg/m2; Drug: Folinic Acid, 400 mg/m2; Drug: Capecitabine, 1000 mg/m2; Drug: Oxaliplatin 85 mg/m2; Radiation: radiotherapy experimental, 30 x 1,8 Gy: 54 Gy; Drug: Capecitabine, 825 mg/m2; Drug: Oxaliplatin, 130 mg/m2 |
What is being measured
The primary outcome is the main question the study is designed to answer.
organ preservation
it is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the primary endpoint, organ preservation, will not be reached if any of the following occurs: (1) death, (2) any major surgery other than local excision (R0) performed after randomization, during TNT, at re-staging scheduled 22-24 weeks after start of TNT due to clinical non-cCR, or for any locoregional regrowth after initial cCR requiring salvage-TME, (3) any locoregional regrowth not amenable to salvage surgery, or (4) any stoma (non-re-converted protective stoma within 6 months after completion of TNT, or any stoma needed for toxicity or poor function), whichever occurs first.
Measured: 3 years
Secondary outcomes (21)
Disease-free survival
Disease-free survival
Measured: 3 years
Rate of clinical complete response after TNT:
TNT total neoadjuvant therapy
Measured: 3 years
Rate of immediate TME after TNT
TNT total neoadjuvant therapy TME total mesorectal excision
Measured: 3 years
Cumulative incidence of locoregional regrowth after cCR
cCR clinical complete response
Measured: 3 years
Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth
LE local Exision; TME: Transanale endoscopic Mikrochirurgie; APR Abdomino perineal Rectum exstirpation
Measured: 3 years
Cumulative incidence of local recurrence after (salvage) surgery surgery
Cumulative incidence of local recurrence after (salvage) surgery
Measured: 3 years
Postoperative complications of (salvage) surgery
Postoperative complications of (salvage) surgery
Measured: 3 years
Rate of sphincter-sparing (salvage) surgery
Rate of sphincter-sparing (salvage) surgery
Measured: 3 years
Pathological TNM-staging
Pathological tumor evaluations;TNM tumor staging
Measured: 3 years
R0 resection rate; negative circumferential resection rate
R0 Removal of the tumor in healthy tissue
Measured: 3 years
Tumor regression grading according to Dworak
pathological response from scale 1-4 poor to very good ascending
Measured: 3 years
Neoadjuvant rectal score
Neoadjuvant rectal score from low to high values means good to poor
Measured: 3 years
Quality of TME according to MERCURY
Tumor response using MRI scale 1-5 from good to poor descending
Measured: 3 years
Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0)
CTCAE V.5.0
Measured: 3 Yeears
Quality of life C30 based on treatment arm and surgical procedures/organ preservation
Quality of life based on EORTC-QLQs-C30
Measured: 3 years
functional outcome based on treatment arm and surgical procedures/organ preservation
functional outcome based on Wexner score
Measured: 3 years
Quality of life CR29 based on treatment arm and surgical procedures/organ preservation
Quality of life based on EORTC-QLQs-CR29
Measured: 3 years
Quality of life CPIN 20 based on treatment arm and surgical procedures/organ preservation
Quality of life based on EORTC-QLQs-CPIN20 Quality of life based on EORTC-QLQs-CPIN20
Measured: 3 years
Cumulative incidence of distant metastases
Cumulative incidence of distant metastases
Measured: 3 Years
Overall survival
Overall survival
Measured: 3 years
Translational / biomarker studies
The translational research program will include proteomics, genomics and immune profile assessment in primary tumor samples as well as peripheral bloods samples (liquid biopsy).
Tumor tissue samples and blood will be collected, processed and stored using protocols.
Primary tumor tissue with either fresh tissue or formalin-fixed, paraffin-embedded (FFPE) tissue will be collected at two different time points: i) preoperative biopsy; ii) before/during surgical resection. Peripheral blood samples will be stored at three different time points: i) immediately before initiation of preoperative treatment (day 1); ii) during therapy assessment at week 22-24 and iii) at the time point of the first follow up.
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2020
- Study start5 Nov 2020
- Primary completion15 Sep 2026 (estimated)
- Study completion15 Sep 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Rectal Cancer Stage IIIStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Model description
- Investigator-driven
- Masking
- Single blind
- Who is masked
- Investigator
- Enrolment
- 702 participants (actual)
Sponsor and investigators
- Lead sponsor
- Prof. Dr. med. Claus Rödel
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Prof. Dr. med. Claus Rödel, Goethe University
- Investigators
- Claus Roedel, Prof. Dr., Study director, clinic for radiotherapy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04246684
- Sponsor's protocol ID
- ACO/ARO/AIO-18.1
- Status last verified
- Aug 2026
- First submitted
- 23 Jan 2020
- Last updated
- 17 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Szeglin B, Consul MS, Breckheimer MC, Whitbread JJ Jr, Stem M, Gabre-Kidan AA, Bafford AC, Migaly J. Short- Versus Long-Course Radiation in Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Propensity-Matched National Cancer Database Analysis. Dis Colon Rectum. 2026 Nov 1;69(11):2639-2648. doi: 10.1097/DCR.0000000000004374. Epub 2026 Aug 14.
PubMed 42598830
Study at a glance
From the registry record, last updated by the sponsor on 17 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Short-course Radiotherapy Versus Chemoradiotherapy, Followed by Consolidation Chemotherapy, and Selective Organ Preservation for MRI-defined Intermediate and High-risk Rectal Cancer Patients
- ClinicalTrials.gov ID
- NCT04246684
- Acronym / sponsor ID
- ACO/ARO/AIO-18.1
- Conditions
- Rectal Cancer Stage III
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 702 participants (actual)
- Lead sponsor
- Prof. Dr. med. Claus RödelUniversity, hospital or other
- Study start
- 5 Nov 2020 (actual)
- Primary completion
- 15 Sep 2026 (estimated)
- Study completion
- 15 Sep 2028 (estimated)
- First posted
- 29 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The hereby proposed ACO/ARO/AIO-18.1 randomized trial aims to directly compare the newly established TNT concepts applying either short-course RT according to RAPIDO, or CRT according to CAO/ARO/AIO-04/-12, both followed by consolidation chemotherapy, and surgery or a watch\&wait (W\&W) approach for patients with clinical complete response (cCR).
The ACO/ARO/AIO-18.1 study incorporates several novel and innovative aspects to further optimize multimodal rectal cancer treatment, partly established by our preceding CAO/ARO/AIO-04 and CAO/ARO/AIO-12 randomized trials: (1) patient selection is based on strict, quality controlled MRI features of intermediate and high-risk characteristics (and, thus, complementary to our ACO/ARO/AIO-18.2 trial in "low-risk" rectal cancer), (2) the CRT regimens incorporates 5-FU/oxaliplatin with doses and intensities shown to be effective and well-tolerated without compromising treatment compliance in CAO/ARO/AIO-04, (3) the sequence of CRT, CT, and surgery/W\&W adopts the TNT approach as established by our CAO/ARO/AIO-12 and OPRA trial, (4) surgical stratification allows for W\&W management for strictly selected patients with clinical complete response (cCR). Thus, we hypothesize that TNT with 5-FU/oxaliplatin-CRT followed by consolidation chemotherapy may increase organ preservation while maintaining DFS as compared to RAPIDO-like short-course RT followed by consolidation chemotherapy.
Detailed description
The primary endpoint of this trial, organ preservation, is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the primary endpoint, organ preservation, will not be reached if any of the following occurs: (1) death, (2) any major surgery other than local excision (R0) performed after randomization, during TNT, at re-staging scheduled 22-24 weeks after start of TNT due to clinical non-cCR, or for any locoregional regrowth after initial cCR requiring salvage-TME, (3) any locoregional regrowth not amenable to salvage surgery, or (4) any stoma (non-re-converted protective stoma within 6 months after completion of TNT, or any stoma needed for toxicity or poor function), whichever occurs first. We hypothesized that the 3-year organ preservation rate will improve from 30% in the control arm to 40% in the investigational arm (hazard ratio of 0.76). With a power of 90% and a two-sided type I error of 5%, the sample size required to obtain a statistically significant difference is 702 patients (564 events) in total.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (investigator)
- Number of arms
- 2
- Model description
- Investigator-driven
| Arm | Type | Receives |
|---|---|---|
| Control arm | Active comparator | Drug: Oxaliplatin, 85 mg/m2, Drug: 5FU; 2400 mg/m2, Drug: Folinic Acid, 400 mg/m2, Radiation: Radiotherapy control, 5x5 Gy: 25 Gy, Drug: Capecitabine, 1000 mg/m2, Drug: Oxaliplatin, 130 mg/m2In the control arm patients receive 5x5 Gy followed by 9 cycles of consolidation chemotherapy mFOLFOX6 or alternatively 6 cycles of CAPOX, followed by re-staging at week 22-24 as established as new preferred neoadjuvant regimen by the RAPIDO trial. |
| Experimental arm | Experimental | Drug: 5FU, 250 mg/m2, Drug: 5FU, 2400 mg/m2, Drug: Oxaliplatin 50 mg/m2, Drug: Folinic Acid, 400 mg/m2, Drug: Capecitabine, 1000 mg/m2, Drug: Oxaliplatin 85 mg/m2, Radiation: radiotherapy experimental, 30 x 1,8 Gy: 54 Gy, Drug: Capecitabine, 825 mg/m2, Drug: Oxaliplatin, 130 mg/m2The experimental arm starts with Fluoropyrimidin/Oxaliplatin-based CRT (1.8 Gy to 45 Gy to the primary tumor and pelvic lymph nodes; followed by sequential boost of 9 Gy to the gross tumor volume) followed by consolidation chemotherapy with 6 cycles mFOLFOX6 or alternatively 4 cycles CAPOX, followed by re-staging at week 22-24. In both arms, for patients achieving a clinical complete response (cCR), as strictly assessed by clinical investigation, endoscopy and MRI, a W\&W option with close follow-up is scheduled. In case of non-complete response, immediate TME surgery is performed. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- diagnosis of rectal adenocarcinoma localised 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum)
- Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
- MRI-defined inclusion criteria: presence of at least one of the following high-risk conditions:
- any cT3 if the distal extent of the tumor is < 6 cm from the anocutaneous line, or
- cT3c/d in the middle third of the rectum (≥ 6-12 cm) with MRI evidence of extramural tumor spread into the mesorectal fat of more than 5 mm (>cT3b), or
Key exclusion criteria (16 listed)
- Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy
- Distant metastases (to be excluded by CT scan of the thorax and abdomen)
- Prior antineoplastic therapy for rectal cancer
- Prior radiotherapy of the pelvic region
- Major surgery within the last 4 weeks prior to inclusion
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oxaliplatin, 85 mg/m2Also: Control arm85 mg/m2,2h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapy | Drug | Control arm |
| 5FU; 2400 mg/m2Also: 5-FU, control arm2400 mg/m2, 46h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, 134 of therapy for Control arm | Drug | Control arm |
| 5FU, 250 mg/m2Also: Experimental arm: 5-FU250 mg/m2 per day, civ, on day 1-14, day 22-35 of radiotherapy; | Drug | Experimental arm |
| 5FU, 2400 mg/m2Also: experimental arm2400 mg/m2,46h-civ, d64, d78, d92, d106, d120, d134 of therapy | Drug | Experimental arm |
| Oxaliplatin 50 mg/m2Also: Experimental arm50 mg/m2, 2h-civ, d1, d8, d21, d29 of radiotherapy and | Drug | Experimental arm |
| Folinic Acid, 400 mg/m2Also: Folinic Acid2h-civ day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapyfor Control arm; 400 mg/m2, 2h-civ d 64, d78, d92, d106, d120, d134 of therapy for experimental arm | Drug | Control arm, Experimental arm |
| Radiotherapy control, 5x5 Gy: 25 GyControl arm: 5x5 Gy (total: 25 Gy) 5 fractions | Radiation | Control arm |
| Capecitabine, 1000 mg/m2Also: Capecitabine1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional | Drug | Control arm, Experimental arm |
| Oxaliplatin 85 mg/m2Also: experimental arm85 mg/m2, 2h-civ, d64, d78, d92, d106, d120, d134 of therapy | Drug | Experimental arm |
| radiotherapy experimental, 30 x 1,8 Gy: 54 Gy30 x 1.8 Gy (total: 54 Gy), 5 fractions per week | Radiation | Experimental arm |
| Capecitabine, 825 mg/m2Also: Capecitabine825 mg/m2 bid, per os, on day 1-14, 22-35 of RT instead of 5FU optional | Drug | Experimental arm |
| Oxaliplatin, 130 mg/m2Also: Oxaliplatinday1every three weeks (optional) | Drug | Control arm, Experimental arm |
Primary outcome
organ preservation
Time frame: 3 years
it is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the primary endpoint, organ preservation, will not be reached if any of the following occurs: (1) death, (2) any major surgery other than local excision (R0) performed after randomization, during TNT, at re-staging scheduled 22-24 weeks after start of TNT due to clinical non-cCR, or for any locoregional regrowth after initial cCR requiring salvage-TME, (3) any locoregional regrowth not amenable to salvage surgery, or (4) any stoma (non-re-converted protective stoma within 6 months after completion of TNT, or any stoma needed for toxicity or poor function), whichever occurs first.
21 secondary outcomes
Disease-free survival
Time frame: 3 years
Rate of clinical complete response after TNT:
Time frame: 3 years
Rate of immediate TME after TNT
Time frame: 3 years
Cumulative incidence of locoregional regrowth after cCR
Time frame: 3 years
Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth
Time frame: 3 years
Cumulative incidence of local recurrence after (salvage) surgery surgery
Time frame: 3 years
Postoperative complications of (salvage) surgery
Time frame: 3 years
Rate of sphincter-sparing (salvage) surgery
Time frame: 3 years
Pathological TNM-staging
Time frame: 3 years
R0 resection rate; negative circumferential resection rate
Time frame: 3 years
Tumor regression grading according to Dworak
Time frame: 3 years
Neoadjuvant rectal score
Time frame: 3 years
Quality of TME according to MERCURY
Time frame: 3 years
Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0)
Time frame: 3 Yeears
Quality of life C30 based on treatment arm and surgical procedures/organ preservation
Time frame: 3 years
functional outcome based on treatment arm and surgical procedures/organ preservation
Time frame: 3 years
Quality of life CR29 based on treatment arm and surgical procedures/organ preservation
Time frame: 3 years
Quality of life CPIN 20 based on treatment arm and surgical procedures/organ preservation
Time frame: 3 years
Cumulative incidence of distant metastases
Time frame: 3 Years
Overall survival
Time frame: 3 years
Translational / biomarker studies
Time frame: 3 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Aug 2026.
- Derived from this study: PubMed 42598830Szeglin B, Consul MS, Breckheimer MC, Whitbread JJ Jr, Stem M, Gabre-Kidan AA, Bafford AC, Migaly J. Short- Versus Long-Course Radiation in Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Propensity-Matched National Cancer Database Analysis. Dis Colon Rectum. 2026 Nov 1;69(11):2639-2648. doi: 10.1097/DCR.0000000000004374. Epub 2026 Aug 14.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Claus Roedel, Prof. Dr. study director
clinic for radiotherapy
75 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Oxaliplatin, 85 mg/m2, 5FU; 2400 mg/m2 and 5FU, 250 mg/m2 in people with Rectal Cancer Stage III, run by Prof. Dr. med. Claus Rödel at 75 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 18 inclusion and 16 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: under way, not looking for participants, as of the sponsor's last update on 17 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 75 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?
This study is still under way. Results are not available in the source record yet.
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?
organ preservation (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 NCT04246684, which also lists 1 linked publication.
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 17 Aug 2026.