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

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ClinicalTrials.gov Identifier: NCT02363374
Recruitment Status : Active, not recruiting
First Posted : February 16, 2015
Last Update Posted : March 1, 2019
Sponsor:
Collaborator:
Johann Wolfgang Goethe University Hospital
Information provided by (Responsible Party):
Prof. Dr. med. Claus Rödel, Goethe University

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

Condition or disease Intervention/treatment Phase
Rectal Neoplasms Rectal Cancer Stage II Rectal Cancer Stage III Drug: Induction Chemotherapy arm A Radiation: Radiation arm A Radiation: Radiation arm B Drug: Chemotherapy arm B Procedure: Surgery Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 311 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 25, 2015
Actual Primary Completion Date : September 2018
Estimated Study Completion Date : June 2023

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

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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Safety of the respective combination sequences by Toxicity assessment according to NCI CTCAE V.4.0 [ Time Frame: 5 years ]
  2. Surgical morbidity [ Time Frame: 123 +30 days ]
  3. Surgical complications [ Time Frame: 123 +30 days ]
  4. Pathological staging [ Time Frame: 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) [ Time Frame: 123 +14 days ]
  6. Tumor regression grading according to Dworak [ Time Frame: 123 +14 days ]
  7. R0 resection rate; negative circumferential resection rate [ Time Frame: 123 +14 days ]
  8. Rate of sphincter-sparing surgery [ Time Frame: 123 +14 days ]
  9. Relapse-free survival (local / distant / overall) [ Time Frame: 5 years ]
  10. Overall survival [ Time Frame: 5 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02363374


Locations
Show Show 22 study locations
Sponsors and Collaborators
Prof. Dr. med. Claus Rödel
Johann Wolfgang Goethe University Hospital
Investigators
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Principal Investigator: Claus Rödel, Prof., MD Head of Department of Radiation therapy and Oncology, Johann Wolfgang Goethe University Hospital
Additional Information:
Publications:
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Responsible Party: Prof. Dr. med. Claus Rödel, Prof. MD, Goethe University
ClinicalTrials.gov Identifier: NCT02363374    
Other Study ID Numbers: JWGUniversity
First Posted: February 16, 2015    Key Record Dates
Last Update Posted: March 1, 2019
Last Verified: February 2019
Keywords provided by Prof. Dr. med. Claus Rödel, Goethe University:
Rectal cancer stage II
Rectal cancer stage III
Multimodality treatment of locally advanced rectal cancer
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Folic Acid
Fluorouracil
Oxaliplatin
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances