Neoadjuvant Treatment for Advanced Rectal Carcinoma

Study Overview
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Brief Summary
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The purpose of the study is to compare pre-operative radio-chemotherapy (RT + capecitabine) to a short course RT associated with a delayed surgery, with two primary objectives: the efficacy evaluation (rate of R0 resection) and the preservation of autonomy (score IADL).

Detailed Description
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Colorectal cancer is one of the most frequent cancers diagnosed in France. The average age of diagnosis in 2012 was 70 years old for men and 73 years for women, confirming that colorectal cancer is a disease of the elderly population. The literature concerning combined treatments of colorectal cancer in the elderly is extremely limited. The application of combined treatments in the geriatric population is associated with an increase in the therapeutic complications. These post-operative complications together with the comorbidities and age are unfavorable prognostic factors for survival in patients with cancer of the rectum; this explains why the improved results obtained during the last decades are perceptible in younger patients and not in the elderly. In the general population, pre-operative radio-chemotherapy has imposed itself as a standard treatment for the cancer of the rectum locally advanced. The utilization of fluoropyrimidines associated with radiotherapy (RT) delivered in fractions [long course RT (50 Gy in 5 weeks), surgery planned 6 to 8 weeks later] increases the complete histological response rate and decreases significantly the rate of local relapse. The short-course RT [short course RT using the Swedish model (5x5 Gy in 5 days), with the surgery programmed the following week] is the standard neoadjuvant protocol in an important number of countries and/or academic groups. The studies that have compared the fractioned RT scheme to the short-course RT protocols have not shown any evidence of a change in efficacy of the short course RT concerning the following criteria: rate of R0 resection, rate of sphincter conservation, rate of relapse at 3 years, the disease free survival or the overall survival. Similarly, there appears to be no difference in severe toxicities in the long term. It should however be noted that short-course RT followed by immediate surgery may be less efficient than combined treatment in patients with a distal T3 cancer, even though these conclusions published by Ngan have been criticized by certain. On the other hand, the fractioned combined treatments results in more tumor and stage reduction and thus more sterilization. Nevertheless a retrospective analysis, performed in the Stockholm region, in patients irradiated with short-course protocol but operated with a delay of at least 4 weeks resulted in a sterilization rate of 8%. This result is even more interesting since in this cohort, 46% of the patients had a tumor classified T4 and that 38% of the patients had a primitive tumor considered inoperable. In the elderly population, the neoadjuvant treatment has rarely been studied. An exploratory analysis of the PRODIGE 2 study, based on age as the criteria, has shown that pre-operative radio-chemotherapy is significantly more toxic in the elderly population, from 70 years of age. Globally the lower tolerance for the pre-operative radio-chemotherapy results in more frequent early termination of RT and a statistically significant decrease in the number of patients operated. Furthermore, if the type of surgery was not significantly different between patients <70 years and those ≥70 years, we observe a non-significant increase in the rate of prolonged stoma (patients amputated without closure of the stoma). These differences in the surgical procedures is also observed in other publications, placing the emphasis on the fact that in the absence of any difference in the clinical presentation or the characteristic of the tumor, the risk of real or supposed decompensation modifies the surgical care. These data, as well as those in the literature, provides evidence that the pre-operative radio-chemotherapy strategy followed by surgery, the standard strategy in younger patients, is associated with more side effects in the elderly, resulting in the benefit-risk balance, in this population, to be more questionable. It is therefore necessary to conduct a specific studies in the elderly population, with cancer of the rectum with the objective to maintain the carcinological results obtained with classical radio-chemotherapy with at the same time better controlling the secondary effects of the treatment and the risk of decompensation of the patients: the short course radiotherapy associated with a delayed surgery may be a therapeutic scheme well adapted to this population. The investigators therefore propose a study comparing pre-operative radio-chemotherapy (RT + capecitabine) to a short course RT associated with a delayed surgery, with two primary objectives: the efficacy evaluation (rate of R0 resection) and the preservation of autonomy (score IADL).

Official Title
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A Phase III Study Evaluating Two Neoadjuvant Treatments Radiochemotherapy (5 Weeks - 50Gy+Capecitabine) and Radiotherapy (1week - 25Gy) in Patient Over 75 With Locally Advanced Rectal Carcinoma

Conditions
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Rectal Carcinoma

Intervention / Treatment
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* Radiation: 50 Gy
* Drug: Capecitabine
* Radiation: 25 Gy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient ≥75 years Eastern Cooperative Oncology Group (ECOG) ≤2 Adenocarcinoma of the rectum histologically proven Tumor ≤12 cm from the anal margin, the measurement done by rigid rectoscopy or by sub peritoneal MRI Require a pre-operative treatment (tumor classified T3 or T4 resectable by MRI and tomodensitometry or T2 of the very low rectum) Patient operable No radiologically detectable metastases Absolute Neutrophile count (ANC) ≥1500/mm³; Platelets ≥100 000/mm³ and Hemoglobin ≥10 g/dL Bilirubin ≤1.5 x upper limit of normal (ULN), aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤1.5 x upper limit of normal (ULN), Alkaline Phosphatase ≤1.5 x upper limit of normal (ULN) Creatinine clearance ≥30 ml/min (Cockcroft and Gault) Uracilemia < 16ng/mL Public or private Health Insurance coverage Patient has been informed and signed the informed consent document Exclusion Criteria: Non-resectable tumor History of chronic diarrhea or an inflammatory disease of the colon or rectum, or intestinal obstruction or sub-obstruction History of pelvic radiotherapy Any active febrile infection or any other serious underlying pathology that may prevent the patient from receiving the treatment Significant Cardiovascular diseases such as, but not limited to: cardiovascular or myocardial infarction ≤6 months before inclusion, congestive heart failure class II or higher (NYHA), unstable angina, arrhythmia requiring medication or uncontrolled hypertension; Significative cardiovascular conditions such as, but not limited to : Cardiac angioplasty or stenting, Myocardial infarction, Unstable angina, Coronary artery bypass graft surgery Symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA), clinically significant irregular heartbeat requiring medication Severe and unexpected reactions to fluoropyrimidine therapy Any contra-indication to capecitabine and its excipients; patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not included. Uracilemia ≥ 16ng/mL Any other concomitant cancer or history of cancer in the last 3 years, with the exception of the in situ cancer of the uterus, treated, or squamous-cell or basal-cell carcinoma. Patients already included in another therapeutic trail with an experimental molecule Person deprived of liberty Patient that for geographical, social and/or physical reasons will not be able to follow the procedure as required by the protocol

Ages Eligible for Study
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Minimum 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 |
| --- | --- |
| Active Comparator: Radiochemotherapy<br>Patients who will be treated with radiotherapy 50 Gy in 25 fractions of 2 Gy, five times per week, over a period of 5 weeks associated with oral capecitabine 800 mg/m2 twice daily from the first day of radiotherapy and given 5 days per week during radiotherapy. The surgery will be planned 7 weeks (±1 week) after the end of preoperative treatment | Radiation: 50 Gy<br>* radiotherapy 50 Gy in 25 fractions of 2 Gy, five times per week, over a period of 5 weeks<br>Drug: Capecitabine<br>* oral capecitabine 800 mg/m2 twice daily from the first day of radiotherapy and given 5 days per week during radiotherapy.<br>* Other names: Xeloda;|
| Experimental: Radiotherapy<br>Patients who will be treated with radiotherapy 25 Gy in 5 fractions of 5 Gy delivered in one week (short-course arm) without chemotherapy. The surgery will be planned 7 weeks (±1 week) after the end of preoperative treatment | Radiation: 25 Gy<br>* radiotherapy 25 Gy in 5 fractions of 5 Gy delivered in one week (short-course arm)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0 resection rate | Compare the efficacy between the arm A and the arm B (with an objective of non-inferiority) | 3 months | 
| IADL (Instrumental Activities of Daily Living) Score | Compare the maintenance of autonomy between the arm A and arm B (with an objective of superiority) | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.03 | Description of the Adverse Events during the pre-operative period. | 3 months | 
| Post-operative complications | according to Dindo-Clavien classification | 3 months | 
| Death rate | Death rate is defined as the percentage of patients who died since the date of randomisation at 6 and 12 months post-surgery (M6 and M12) from any cause | at 6 and 12 months | 
| Overall survival (OS) | The OS is defined as the interval between the date of randomization and the date of deaths from any cause | 10 years | 
| Specific survival | The specific survival is defined as the interval between the date of randomization and the date of deaths due to cancer. | 10 years | 
| Disease free survival | The disease free survival is defined as the interval between the date of randomization and the date of cancer relapse (local regional or distant), second cancer or death from any cause. | 10 years | 
| Loco-regional disease free survival | The disease free survival is defined as the interval between the date of randomization and the date of cancer relapse (local or regional). | 10 years | 
| Rate of stoma | percentage of patients with definitive or transitional stoma after surgery. | at 6 and 12 months | 
| Instrumental Activities of Daily Living (IADL) | Autonomy Assessment | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 
| Activities of Daily Living (ADL) | Autonomy Assessment | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 
| Questionnaire G8 | Geriatric Screening | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 
| Mini-Mental Score Examination (MMSE) | Cognitive functioning | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 
| Walking gate |  | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 
| Geriatric Depression Scale (GDS15) | Depression Assessment | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 
| Charlson score | Comorbidities evaluation | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 
| Mini Nutritional Assessment (MNA) | Nutritional Evaluation | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 
| EORTC QLQ-C30 + EDL14 | Quality of Life (QLQ) | Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elderly patient, Radiotherapy, Radio chemotherapy, Neoadjuvant treatment