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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

311 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-03-25

Study Completion Date

2023-06-16

Brief Summary

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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

Detailed Description

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Conditions

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Rectal Neoplasms Rectal Cancer Stage II Rectal Cancer Stage III

Keywords

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm A: Chemotherapy -> Chemoradiotherapy

Induction chemotherapy followed by chemoradiotherapy before surgery

Group Type ACTIVE_COMPARATOR

Induction Chemotherapy arm A

Intervention Type 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

Radiation arm A

Intervention Type RADIATION

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

Surgery

Intervention Type 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 B: Chemoradiotherapy -> Chemotherapy

Combined chemoradiotherapy followed by three cycles chemotherapy before surgery

Group Type EXPERIMENTAL

Radiation arm B

Intervention Type RADIATION

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

Chemotherapy arm B

Intervention Type 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

Surgery

Intervention Type 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

Interventions

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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

Intervention Type DRUG

Radiation arm A

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

Intervention Type RADIATION

Radiation arm B

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

Intervention Type RADIATION

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

Intervention Type DRUG

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

Intervention Type PROCEDURE

Other Intervention Names

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

Eligibility Criteria

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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.
* 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)

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Prof. Dr. med. Claus Rödel

Prof. MD

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Claus Rödel, Prof., MD

Role: PRINCIPAL_INVESTIGATOR

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

CAOAROAIO-12

Identifier Type: -

Identifier Source: org_study_id

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

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Keywords

Study Design

Study Groups

Arm A: Chemotherapy -> Chemoradiotherapy

Induction Chemotherapy arm A

Radiation arm A

Surgery

Arm B: Chemoradiotherapy -> Chemotherapy

Radiation arm B

Chemotherapy arm B

Surgery

Interventions

Induction Chemotherapy arm A

Radiation arm A

Radiation arm B

Chemotherapy arm B

Surgery

Other Intervention Names

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Sponsors

Johann Wolfgang Goethe University Hospital

Deutsche Krebshilfe e.V., Bonn (Germany)

Prof. Dr. med. Claus Rödel

Responsible Party

Prof. Dr. med. Claus Rödel

Principal Investigators

Claus Rödel, Prof., MD

Locations

University Clinic

RWTH Aachen

University Clinic

Clinic for Radiotherapy

Diacura Clinic for Radiotherapy

Internist Practice

University Clinic

University Clinic

University Hospital Frankfurt Goethe University

University Clinic

HELIOS Park-Klinikum Leipzig

University Clinic

University Clinic

Hospital Miria Hilf

Pius Hospital Oldenburg

University Clinic

Hospital Barmherziger Brueder

University Clinic

University Clinic

University Clinic

Countries

References

Related Links

Other Identifiers

CAOAROAIO-12