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Rectal NeoplasmsPhase 2CAOAROAIO-12NCT02363374

Induction Chemotherapy Before or After Preoperative Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer

A Phase 2 study testing Induction Chemotherapy arm A, Radiation arm A and Radiation arm B in people with Rectal Neoplasms and Rectal Cancer Stage II, run by Prof. Dr. med. Claus Rödel at 20 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

Preoperative 5-FU-based (5-fluorouracil) chemoradiotherapy (CRT), total mesorectal excision surgery, and 4 cycles of adjuvant 5-FU - as established by CAO/ARO/AIO-94 - is at present a standard of care for patients with locally advanced rectal cancer (UICC stage II and III). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Induction Chemotherapy arm A, Radiation arm A and Radiation arm B
Could I receive a placebo?
No, everyone receives an active treatment
How many people
311 participants
Where
20 sitesGermany
Study dates
25 Mar 2015to 16 Jun 2023
Phase
Phase 2
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

  • Male and female patients with histologically confirmed diagnosis of rectal cancer 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 (clinical stage tumor-3) if the distal extent of the tumor is < 6 cm from anocutaneous line or cT3 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 resectable cT4 tumors, or any clear cN+ (clinical staging nodes) based on MRI-criteria
  • 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.
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  • WHO/ECOG (World Health Organisation/Eastern Cooperative Oncology Group) Performance Status ≤ 1
  • Adequate haematological, hepatic, renal and metabolic function parameters: Leukocytes ≥ 3.000/mm^3, absolute neutrophil count (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, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), and alkaline phosphatase (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 (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly).
  • On-treatment participation in a clinical study in the period 30 days prior to inclusion
  • Previous or current drug abuse
  • Concomitant other 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
  • Chronic diarrhea (> grade 1 according NCI CTCAE)
  • Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO (International Federation of Gynecology and Obstetrics) 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

20 sites in 1 country.

20 sites in 1 country

Germany20 sites

  • RWTH Aachen

    Aachen

  • University Clinic

    Bochum

  • Clinic for Radiotherapy

    Chemnitz

  • Diacura Clinic for Radiotherapy

    Coburg

  • Internist Practice

    Dresden

  • University Clinic

    Dresden

  • University Clinic

    Erlangen, Bavaria

  • University Clinic

    Esslingen am Neckar

  • University Hospital Frankfurt Goethe University

    Frankfurt, 60590

  • University Clinic

    Freiburg im Breisgau

  • HELIOS Park-Klinikum Leipzig

    Leipzig

  • University Clinic

    Leipzig

  • University Clinic

    Mannheim

  • Hospital Miria Hilf

    Mönchengladbach

  • Pius Hospital Oldenburg

    Oldenburg

  • University Clinic

    Oldenburg

  • Hospital Barmherziger Brueder

    Regensburg

  • University Clinic

    Regensburg

  • University Clinic

    Rostock

  • University Clinic

    Würzburg

Other trials in Germany

About this study

Official title: Induction Chemotherapy Before or After Preoperative Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer: A Randomized Phase II Trial of the German Rectal Cancer Study Group

Preoperative 5-FU-based (5-fluorouracil) chemoradiotherapy (CRT), total mesorectal excision surgery, and 4 cycles of adjuvant 5-FU - as established by CAO/ARO/AIO-94 - is at present a standard of care for patients with locally advanced rectal cancer (UICC stage II and III). The phase III German CAO/ARO/AIO-04 trial showed, that the addition of oxaliplatin increased treatment efficacy in terms of early secondary efficacy endpoints (e.g. the pCR-rate). With a median follow-up of 50 months, the primary endpoint of this trial - disease free survival - was significantly improved in the oxaliplatin-containing treatment arm (3-year disease-free survival (DFS) 71.2% versus 75.9%, hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.64-0.98, p=0.03). The hereby proposed randomized phase II trial CAO/ARO/AIO-12 aims at finding novel and innovative aspects of rectal cancer treatment, and will thus provide important information for defining the experimental arm in the upcoming large scale trial of the group. Compared to the current standard, in both study arms, the sequence of the three treatment modalities is modified, placing the chemotherapy block before surgery. The pre-operative sequence of chemotherapy -> chemoradiotherapy (arm A) has been shown to be feasible with no early tumor progression prior to definitive surgical resection in a small randomized phase II study from Spain. The sequence chemoradiotherapy -> chemotherapy (arm B) may be beneficial according to response kinetics considerations, and by maintaining a highly effective local treatment in the first place. Both approaches could avoid the problem of major compliance problems with post-operative adjuvant chemotherapy. CAO/ARO/AIO: German Rectal Cancer Study Group

Being tested
Induction Chemotherapy arm A, Radiation arm A, Radiation arm B, Chemotherapy arm B, Surgery
Keywords
Rectal cancer stage II, Rectal cancer stage III, Multimodality treatment of locally advanced rectal cancer
Medical subject headings
Rectal Neoplasms

What participants receive

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

  • Induction Chemotherapy arm ADrug

    Also called all brands of Oxaliplatin are allowed, all brands of 5-fluorouracil (5-FU) are allowed, all brands of Folinic acid (FA) are allowed

    Patients receive three induction chemotherapy cycles, starting on day 1, 15 and 29, consisting of:

    Folinic acid: 400 mg/sqm, 2h-iv; Oxaliplatin: 100 mg/sqm, 2h-iv; 5-FU: 2400 mg/sqm, 46h-iv

    After a break of two weeks, radiotherapy starts combined with:

    5-FU: 250 mg/sqm per day, iv, on day 43-57, day 64-77 Oxaliplatin: 50 mg/sqm, day 43, 50, 64, and 71

  • Radiation arm ARadiation

    Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 43 -80

  • Radiation arm BRadiation

    Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 1- 38

  • Chemotherapy arm BDrug

    Also called all brands of Oxaliplatin are allowed, all brands of 5-fluorouracil (5-FU) are allowed, all brands of Folinic acid (FA) are allowed

    chemoradiotherapy is started according to the following schedule: 5-FU: 250 mg/sqm per day, iv, on day 1-14, day 22-35; Oxaliplatin: 50 mg/sqm, day 1, 8, 22, and 29.

    After a break of two and a half weeks, patients receive three chemotherapy cycles, starting on day 57, 71 and 85, consisting of:

    Folinic acid: 400 mg/sqm, 2h-iv; Oxaliplatin: 100 mg/sqm, 2h-iv; 5-FU: 2400 mg/sqm, 46h-iv

  • SurgeryProcedure or surgery

    Surgery should be performed about 5 (arm B) or 6 (arm A) weeks after the last radiation or chemotherapy, i.e. around day 123

Study groups in NCT02363374
Study groupRoleWhat they receive
Arm A: Chemotherapy -> ChemoradiotherapyActive comparatorInduction chemotherapy followed by chemoradiotherapy before surgery
Receives: Drug: Induction Chemotherapy arm A; Radiation: Radiation arm A; Procedure: Surgery
Arm B: Chemoradiotherapy -> ChemotherapyExperimentalCombined chemoradiotherapy followed by three cycles chemotherapy before surgery
Receives: Radiation: Radiation arm B; Drug: Chemotherapy arm B; Procedure: Surgery

What is being measured

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

  1. Number of patients with pathological complete response (pCR), i.e. ypT0N0.

    Efficacy (pCR) of induction chemotherapy followed by chemoradiotherapy, or the other way round, before surgery in patients with locally advanced rectal cancer.

    Measured: 123 +30 days

Secondary outcomes (10)

  1. Safety of the respective combination sequences by Toxicity assessment according to NCI CTCAE V.4.0

    Measured: 5 years

  2. Surgical morbidity

    Measured: 123 +30 days

  3. Surgical complications

    Measured: 123 +30 days

  4. Pathological staging

    Measured: 123 +14 days

  5. Tumor downstaging assessed by ypTNM (neoadjuvant pathological staging tumor nodes metastasis) findings in relation to initial cTNM (clinical stage tumor nodes metastasis)

    Measured: 123 +14 days

  6. Tumor regression grading according to Dworak

    Measured: 123 +14 days

  7. R0 resection rate; negative circumferential resection rate

    Measured: 123 +14 days

  8. Rate of sphincter-sparing surgery

    Measured: 123 +14 days

  9. Relapse-free survival (local / distant / overall)

    Measured: 5 years

  10. Overall survival

    Measured: 5 years

Timeline

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

  1. First posted16 Feb 2015 (estimated)
  2. Study start25 Mar 2015
  3. Primary completionSep 2018
  4. Study completion16 Jun 2023

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
311 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02363374
Sponsor's protocol ID
CAOAROAIO-12
Acronym
CAOAROAIO-12
Status last verified
Nov 2023
First submitted
3 Feb 2015
Last updated
4 Dec 2023
Results posted
No
Data monitoring committee
Yes

Publications

  • Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. doi: 10.1056/NEJMoa040694.

    PubMed 15496622

  • Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012 Jun 1;30(16):1926-33. doi: 10.1200/JCO.2011.40.1836. Epub 2012 Apr 23.

    PubMed 22529255

  • 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

  • Diefenhardt M, Fokas E, Kosmala R, Polat B, Germer CT, Schlenska-Lange A, Kuhnt T, Ghadimi M, Rieken S, Wiegering A, Schwarzbach M, Fleischmann M, Grutzmann R, Ott OJ, Martus P, Konigsrainer A, Zips D, Hofheinz RD, Gani C, Rodel C. Organ Preservation and Quality of Life After Total Neoadjuvant Treatment in Rectal Cancer. JAMA Netw Open. 2026 Oct 1;9(10):e2639063. doi: 10.1001/jamanetworkopen.2026.39063.

    PubMed 42879156

  • 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

  • Fokas E, Schlenska-Lange A, Polat B, Klautke G, Grabenbauer GG, Fietkau R, Kuhnt T, Staib L, Brunner T, Grosu AL, Kirste S, Jacobasch L, Allgauer M, Flentje M, Germer CT, Grutzmann R, Hildebrandt G, Schwarzbach M, Bechstein WO, Sulberg H, Friede T, Gaedcke J, Ghadimi M, Hofheinz RD, Rodel C; German Rectal Cancer Study Group. Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. JAMA Oncol. 2022 Jan 1;8(1):e215445. doi: 10.1001/jamaoncol.2021.5445. Epub 2022 Jan 20.

    PubMed 34792531

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Induction Chemotherapy arm A, Radiation arm A and Radiation arm B in people with Rectal Neoplasms and Rectal Cancer Stage II, run by Prof. Dr. med. Claus Rödel at 20 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 9 inclusion and 17 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 4 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 20 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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?

Number of patients with pathological complete response (pCR), i.e. ypT0N0. (time frame: 123 +30 days). 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 NCT02363374, which also lists 6 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 4 Dec 2023.

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