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

Study Overview
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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

Official Title
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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

Conditions
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Rectal Neoplasms, Rectal Cancer Stage II, Rectal Cancer Stage III

Intervention / Treatment
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* Drug: Induction Chemotherapy arm A
* Radiation: Radiation arm A
* Radiation: Radiation arm B
* Drug: Chemotherapy arm B
* Procedure: Surgery


Participation Criteria
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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. 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Chemotherapy -> Chemoradiotherapy<br>Induction chemotherapy followed by chemoradiotherapy before surgery | Drug: Induction Chemotherapy arm A<br>* 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<br>* Other names: all brands of Folinic acid (FA) are allowed;Radiation: Radiation arm A<br>* Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 43 -80<br>Procedure: Surgery<br>* Surgery should be performed about 5 (arm B) or 6 (arm A) weeks after the last radiation or chemotherapy, i.e. around day 123<br>|
| Experimental: Arm B: Chemoradiotherapy -> Chemotherapy<br>Combined chemoradiotherapy followed by three cycles chemotherapy before surgery | Radiation: Radiation arm B<br>* Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 1- 38<br>Drug: Chemotherapy arm B<br>* 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<br>* Other names: all brands of Folinic acid (FA) are allowed;Procedure: Surgery<br>* Surgery should be performed about 5 (arm B) or 6 (arm A) weeks after the last radiation or chemotherapy, i.e. around day 123<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Tumor regression grading according to Dworak |  | 123 +14 days | 
| R0 resection rate; negative circumferential resection rate |  | 123 +14 days | 
| Rate of sphincter-sparing surgery |  | 123 +14 days | 
| Relapse-free survival (local / distant / overall) |  | 5 years | 
| Overall survival |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal cancer stage II, Rectal cancer stage III, Multimodality treatment of locally advanced rectal cancer