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

NCT02363374 | Completed Phase 2 DMC

• 1 other identifier: CAOAROAIO-12
• Study Type: interventional
• Target: 311
• Locations: 1 country
• Sites: 20

Brief 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). 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

Conditions

Rectal Neoplasms; Rectal Cancer Stage II; Rectal Cancer Stage III

Keywords

Rectal cancer stage II; Rectal cancer stage III; Multimodality treatment of locally advanced rectal cancer

Outcome Measures

Primary Outcomes (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.

  123 +30 days

Secondary Outcomes (10)

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

  5 years

• Surgical morbidity

  123 +30 days

• Surgical complications

  123 +30 days

• Pathological staging

  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)

  123 +14 days

Study Arms (2)

Arm A: Chemotherapy -> Chemoradiotherapy

ACTIVE COMPARATOR

Induction chemotherapy followed by chemoradiotherapy before surgery

Drug: Induction Chemotherapy arm A; Radiation: Radiation arm A; Procedure: Surgery

Arm B: Chemoradiotherapy -> Chemotherapy

EXPERIMENTAL

Combined chemoradiotherapy followed by three cycles chemotherapy before surgery

Radiation: Radiation arm B; Drug: Chemotherapy arm B; Procedure: Surgery

Interventions

Induction Chemotherapy arm A DRUG

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

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

Arm A: Chemotherapy -> Chemoradiotherapy

Radiation arm A RADIATION

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

Arm A: Chemotherapy -> Chemoradiotherapy

Radiation arm B RADIATION

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

Arm B: Chemoradiotherapy -> Chemotherapy

Chemotherapy arm B DRUG

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

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

Arm B: Chemoradiotherapy -> Chemotherapy

Surgery PROCEDURE

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

Arm A: Chemotherapy -> Chemoradiotherapy; Arm B: Chemoradiotherapy -> Chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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
• 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).
• 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)

Sponsors & Collaborators

• Prof. Dr. med. Claus Rödel: lead
• Johann Wolfgang Goethe University Hospital: collaborator
• Deutsche Krebshilfe e.V., Bonn (Germany): collaborator

Study Sites (20)

University Clinic

Erlangen, Bavaria, Germany

Location

RWTH Aachen

Aachen, Germany

Location

University Clinic

Bochum, Germany

Location

Clinic for Radiotherapy

Chemnitz, Germany

Location

Diacura Clinic for Radiotherapy

Coburg, Germany

Location

Internist Practice

Dresden, Germany

Location

University Clinic

Dresden, Germany

Location

University Clinic

Esslingen am Neckar, Germany

Location

University Hospital Frankfurt Goethe University

Frankfurt, 60590, Germany

Location

University Clinic

Freiburg im Breisgau, Germany

Location

HELIOS Park-Klinikum Leipzig

Leipzig, Germany

Location

University Clinic

Leipzig, Germany

Location

University Clinic

Mannheim, Germany

Location

Hospital Miria Hilf

Mönchengladbach, Germany

Location

Pius Hospital Oldenburg

Oldenburg, Germany

Location

University Clinic

Oldenburg, Germany

Location

Hospital Barmherziger Brueder

Regensburg, Germany

Location

University Clinic

Regensburg, Germany

Location

University Clinic

Rostock, Germany

Location

University Clinic

Würzburg, Germany

Location

Related Publications (5)

• 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.

  PMID: 15496622 BACKGROUND

• 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.

  PMID: 22529255 BACKGROUND

• 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.

  PMID: 22627104 BACKGROUND

• 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.

  PMID: 36572280 DERIVED

• 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.

  PMID: 34792531 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Fluorouracil; Surgical Procedures, Operative

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Claus Rödel, Prof., MD

  Head of Department of Radiation therapy and Oncology, Johann Wolfgang Goethe University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. MD

Study Record Dates

• First Submitted: February 3, 2015
• First Posted: February 16, 2015
• Study Start: March 25, 2015
• Primary Completion: September 1, 2018
• Study Completion: June 16, 2023
• Last Updated: December 4, 2023

Record last verified: 2023-11

Locations

DE (20)