Induction Chemotherapy Plus Chemoradiotherapy With or Without Aspirin in High Risk Rectal Cancer

Study Overview
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Brief Summary
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The benefit of aspirin in cancer of the colon and rectum is already known. Recently, it was described its potential activity during chemoradiotherapy, with higher rate of tumor downstaging. Furthermore, induction chemotherapy followed by chemoradiation represents an attractive approach, with more favorable compliance and toxicity profiles. The aim of this study was to evaluate the efficacy of total neoadjuvant treatment and assess the efficacy and feasibility of aspirin use during chemoradiotherapy for high-risk rectal cancer.

Detailed Description
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Methods: This is a randomized trial to evaluate induction treatment with XELOX and Capecitabine-based chemoradiotherapy with or without aspirin in a high-risk population selected by MRI. High-risk will be defined by presence of at least one of the following criteria on high-resolution thin-slice MRI (3 mm): tumors extending to within 1 mm of, or beyond the mesorectal fascia; tumor extending 5 mm or more into perirectal fat; resectable cT4 tumors; lower third; nodal involvement; extramural vascular invasion. Random assignment of treatment will be stratified by MRI tumour regression grade. All the patients enrolled in the study will receive XELOX every 21 days for four cycles, unless unacceptable toxicity or progression is detected. After this treatment, patients will be randomized to receive Capecitabine-based chemoradiotherapy with aspirin or placebo (Capecitabine 850 mg/m² 5 days per week combined with radiotherapy with total dose of 50.4 Gy in 28 days). After 8-10 weeks, they will be evaluate by MRI. Patients with incomplete clinical response will be referred to immediate surgery and patients with complete clinical response will be managed with watch and wait approach. Patients with progression disease during the treatment phase will be withdrawn from the study and will receive their treatment according to the investigator's judgment. The sample size was calculated according to Simon's optimal two-stage design. Accordingly, 11 patients must be included in each group during the first stage and 20 during the second stage. A treatment regimen will be considered effective if more than 18 patients of the total 31 show downstaging (final analysis), reaching 80% power with an alpha of 0.05 level of significance.

Official Title
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Phase II Randomized Study of Induction Chemotherapy Followed by Chemoradiotherapy With or Without Aspirin in High Risk Locally Advanced Rectal Cancer

Conditions
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Rectal Cancer, Adenocarcinoma, Locally Advanced Malignant Neoplasm, Chemoradiation

Intervention / Treatment
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* Drug: Aspirin
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of mid or low rectum Locally advanced rectal cancer with one of the high-risk factors confirmed by high-resolution thin-slice Magnetic resonance image (3 mm) tumors extending to within 1 mm of, or beyond the mesorectal fascia; tumor extending 5 mm or more into perirectal fat; resectable cT4 tumors; lower third; nodal involvement; extramural vascular invasion ECOG performance status of 0-2 An informed consent has been signed by the patient Exclusion Criteria: Upper rectal cancer Metastatic disease The patient received any previous therapy for colorectal cancer or another malignancy Other malignant tumours within the last 5 years except cervical carcinoma in situ and basal cell carcinoma of the skin Previous thromboembolic or haemorrhagic events within 6 months prior to registration Patients with malabsorption syndrome or difficulties in swallowing The patient has severe underlying diseases or poor condition to receive chemotherapy or radiotherapy Pregnant of breastfeeding women The patient who participate in another clinical trial, or receives any drug for the trial Uncontrolled peripheral neuropathy (more than grade 2) Active gastrointestinal bleeding

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
Interventional Model Description: preoperative induction chemotherapy followed by combined radiochemotherapy with capecitabine and aspirin
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aspirin<br>Induction chemotherapy followed by chemoradiotherapy with aspirin Aspirin 100mg daily during the chemoradiotherapy | Drug: Aspirin<br>* chemoradiotherapy with capecitabine and aspirin Aspirin daily during chemoradiotherapy<br>* Other names: aas;|
| Placebo Comparator: Placebo Oral Tablet<br>Induction chemotherapy followed by chemoradiotherapy without aspirin Placebo daily during the chemoradiotherapy | Drug: Placebo Oral Tablet<br>* chemoradiotherapy with capecitabine and placebo Placebo daily during chemoradiotherapy<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor downstaging after induction chemotherapy followed by chemoradiotherapy with or without aspirin | This will be assessed by MR imaging 8-10 weeks after chemoradiotherapy and it will be considered tumor downstaging if mrTRG 1 to 3 | 8-10 weeks after chemoradiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological Tumor response rate after induction chemotherapy | This will be assessed by MR imaging after induction chemotherapy | 3-4 weeks after last induction chemotherapy | 
| Pathological Tumor response rate | Amount of tumor regression after surgery according to the guideline including Mandard | 10-12 weeks after chemoradiotherapy | 
| Pathologic complete response | it will be defined as the absence of residual invasive cancer on pathological evaluation of the complete resected rectal specimen | 8-10 weeks after chemoradiotherapy | 
| Disease-free survival | defined as the time from surgery to relapse or death, whichever occurred first | 3 years | 
| Overall survival | defined as the time from surgery to death, whichever occurred first | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal Cancer, Total neoadjuvant therapy, Induction chemotherapy, Aspirin colorectal cancer