Induction Chemotherapy Before or After Preoperative Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer (CAOAROAIO-12)

November 28, 2023 updated by: Prof. Dr. med. Claus Rödel

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

311

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Aachen, Germany
        • RWTH Aachen
      • Bochum, Germany
        • University Clinic
      • Chemnitz, Germany
        • Clinic for Radiotherapy
      • Coburg, Germany
        • Diacura Clinic for Radiotherapy
      • Dresden, Germany
        • Internist Practice
      • Dresden, Germany
        • University Clinic
      • Esslingen, Germany
        • University Clinic
      • Frankfurt, Germany, 60590
        • University Hospital Frankfurt Goethe University
      • Freiburg, Germany
        • University Clinic
      • Leipzig, Germany
        • HELIOS Park-Klinikum Leipzig
      • Leipzig, Germany
        • University Clinic
      • Mannheim, Germany
        • University Clinic
      • Moenchengladbach, Germany
        • Hospital Miria Hilf
      • Oldenburg, Germany
        • Pius Hospital Oldenburg
      • Oldenburg, Germany
        • University Clinic
      • Regensburg, Germany
        • Hospital Barmherziger Brueder
      • Regensburg, Germany
        • University Clinic
      • Rostock, Germany
        • University Clinic
      • Wuerzburg, Germany
        • University Clinic
    • Bavaria
      • Erlangen, Bavaria, Germany
        • University Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.
  • 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

Exclusion Criteria:

  • 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.
  • 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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm A: Chemotherapy -> Chemoradiotherapy
Induction chemotherapy followed by chemoradiotherapy before surgery
Drug: Induction Chemotherapy arm A

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

Other Names:
  • all brands of 5-fluorouracil (5-FU) are allowed
  • all brands of Oxaliplatin are allowed
  • all brands of Folinic acid (FA) are allowed
Radiation: Radiation arm A
Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 43 -80
Procedure: 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
Experimental: Arm B: Chemoradiotherapy -> Chemotherapy
Combined chemoradiotherapy followed by three cycles chemotherapy before surgery
Procedure: 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
Radiation: Radiation arm B
Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 1- 38
Drug: Chemotherapy arm B

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

Other Names:
  • all brands of 5-fluorouracil (5-FU) are allowed
  • all brands of Oxaliplatin are allowed
  • all brands of Folinic acid (FA) are allowed

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with pathological complete response (pCR), i.e. ypT0N0.
Time Frame: 123 +30 days
Efficacy (pCR) of induction chemotherapy followed by chemoradiotherapy, or the other way round, before surgery in patients with locally advanced rectal cancer.
123 +30 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Overall survival
Time Frame: 5 years
5 years
Safety of the respective combination sequences by Toxicity assessment according to NCI CTCAE V.4.0
Time Frame: 5 years
5 years
Surgical morbidity
Time Frame: 123 +30 days
123 +30 days
Surgical complications
Time Frame: 123 +30 days
123 +30 days
Pathological staging
Time Frame: 123 +14 days
123 +14 days
Tumor downstaging assessed by ypTNM (neoadjuvant pathological staging tumor nodes metastasis) findings in relation to initial cTNM (clinical stage tumor nodes metastasis)
Time Frame: 123 +14 days
123 +14 days
Tumor regression grading according to Dworak
Time Frame: 123 +14 days
123 +14 days
R0 resection rate; negative circumferential resection rate
Time Frame: 123 +14 days
123 +14 days
Rate of sphincter-sparing surgery
Time Frame: 123 +14 days
123 +14 days
Relapse-free survival (local / distant / overall)
Time Frame: 5 years
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Prof. Dr. med. Claus Rödel

Collaborators

Johann Wolfgang Goethe University Hospital
Deutsche Krebshilfe e.V., Bonn (Germany)

Investigators

  • Principal Investigator: Claus Rödel, Prof., MD, Head of Department of Radiation therapy and Oncology, Johann Wolfgang Goethe University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 25, 2015

Primary Completion (Actual)

September 1, 2018

Study Completion (Actual)

June 16, 2023

Study Registration Dates

First Submitted

February 3, 2015

First Submitted That Met QC Criteria

February 13, 2015

First Posted (Estimated)

February 16, 2015

Study Record Updates

Last Update Posted (Actual)

December 4, 2023

Last Update Submitted That Met QC Criteria

November 28, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CAOAROAIO-12

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Rectal Neoplasms

Clinical Trials on Induction Chemotherapy arm A

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Netherlands

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe