Preoperative Hyperfractionated Radiotherapy or Radiochemotherapy in Locally Advanced Rectal Cancer.

Study Overview
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Brief Summary
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Clinical objective of the study is to compare the rates of pathologic response, acute toxicity and sphincter preservation with two schedules of preoperative regiment in patients with locally advanced rectal cancer.

Detailed Description
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Overview of randomized trials conducted in patients with advanced colorectal cancer with the use of preoperative radiotherapy or radiochemotherapy clearly shows the superiority of combined therapy over surgery alone. In these studies documented a significant reduction in tumor mass as a result of preoperative radiotherapy or radiochemotherapy theoretically increases the chance of performing operations with sphincters preservation, even in cases originally eligible for abdomino - perineal resection. There is the question whether the combination of preoperative hyperfractionated radiotherapy and concurrent chemotherapy may cause the further improvement of treatment outcome in patients with locally advanced rectal cancer. Published in 2012 by Gerard et al. meta-analysis of randomized trials dedicated to the treatment of patients with advanced colorectal cancer, confirms a higher percentage of sphincters preservation in patients operated after more than 5-week interval between neoadjuvant therapy and surgery. Analysis of these issues will be taken in the current study. Comparison of the two treatment regimens as preoperative phase III study with stratification for time interval between the end of radiotherapy or radiochemotherapy and surgery may show differences that have not been seen in previously published data.

Official Title
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Preoperative Hyperfractionated Radiotherapy Versus Combined Radiochemotherapy for Patients With Locally Advanced Rectal Cancer: a Phase III Randomized Trial.

Conditions
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Rectal Cancer

Intervention / Treatment
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* Radiation: Hyperfractionated Radiochemotherapy
* Radiation: Hyperfractionated Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Karnofsky Index 80% or better (Zubrod 0-1) Histological proved diagnosis of rectal cancer (adeno- or mucinous carcinoma) Primary rectal cancer: 3.1. Maximum 12 cm above dentate line (upper limit) 3.2. Staged T2N+ or T3N0 or T3N+ (by endorectal ultrasound or Computed Tomography [CT]/Magnetic Resonance Imaging [MRI] scan) No evidence of metastatic disease as determined by chest X-ray and abdominal ultrasound (or CT-scan of chest and abdomen or other investigations such as Positron Emission Tomography [PET] scan or biopsy if required) Adequate bone marrow function with platelets more than 100 × 10^9/l and neutrophils more than 2.0 × 10^9/l Creatinine clearance more than 50 ml/min Serum bilirubin less than 2.0 × Upper Limit of institutional Normal range (ULN) Written informed consent is obtained prior to commencement of trial treatment (confirmed the signature on the consent form for the proposed project and the standard medical consent form for radiotherapy within the abdominal cavity). Exclusion Criteria: Rectal cancer other than adeno- or mucinous carcinoma Previous or concurrent malignancies, with the exception of adequately treated basal cell carcinoma of the skin Patients with locally advanced inoperable disease, such as T4-tumour Presence of metastatic disease or recurrent rectal tumour Any previous chemotherapy or radiotherapy, and any investigational treatment for rectal cancer Concurrent uncontrolled medical conditions Pregnancy or breast feeding Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease) or myocardial infarction within the last six months Evidence of hereditary colorectal cancer (Hereditary Non-Polyposis Colorectal Cancer [HNPCC] and Familial Adenomatous Polyposis [FAP]) Medical or psychiatric conditions that compromise the patient's ability to give informed consent No agreement for randomisation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hyperfractionated Radiochemotherapy<br>radiotherapy in rectal tumor area due to the placing of pelvic nodal groups to a total dose of 42 Gy, 1.5 Gy d fx 2 times a day; (gap between the factions min. 6-8h) - duration of treatment 2.5 weeks with simultaneous two cycles of chemotherapy according to the scheme: 5FU-325mg/m2 (bolus) on 1-3 and 16-18 (last 3 days of radiotherapy). Surgical resection has to be done within 14 days or 5-6 weeks after the completion of hyperfractionated radiochemotherapy (HRTCT). | Radiation: Hyperfractionated Radiochemotherapy<br>* 28 x 1.5Gy 2 times a day; gap between the fractions min. 6-8h - duration of treatment 2.5 weeks + simultaneous bolus 5-Fluorouracil (the each cycle consisted of 5-fluorouracil 325 mg/m2 per day) on 1-3 and 16-18 (last 3 days of radiotherapy).<br>* Other names: Hyperfractionated Radiochemotherapy (HRTCT);|
| Active Comparator: Hyperfractionated Radiotherapy<br>radiotherapy in rectal tumor area due to the placing of pelvic nodal groups to a total dose of 42 Gy, 1.5 Gy d fx 2 times a day; (gap between the factions min. 6-8h) - duration of treatment 2.5 weeks. Surgical resection has to be done within 14 days or 5-6 weeks after the completion of hyperfractionated radiotherapy (HRT). | Radiation: Hyperfractionated Radiotherapy<br>* 28 x 1.5Gy 2 times a day; gap between the factions min. 6-8h - duration of treatment 2.5 weeks<br>* Other names: Hyperfractionated Radiotherapy (HRT);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • The rate of patients with downstaging after radiotherapy or radiochemotherapy to pathological response or disease with negative margins |  | Surrogate endpoint available immediatly after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of local failures |  | 3 years | 
| Progression-free long-term survival |  | 3 years | 
| The rate of distant metastases |  | 3 years | 
| Overall long-term survival |  | 3 years | 
| The rate of late toxicity according to the RTOG/EORTC scale |  | 3 years | 
| The rate of postoperative complications |  | 3 months | 
| The rate of early toxicity of neoadjuvant treatment according to the NCI CTCAE (version 4.0) |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal neoplasm, Preoperative hyperfractionated radiotherapy, Preoperative hyperfractionated radiochemotherapy