Neoadjuvant Chemotherapy in Patients With Intermediate Risk Upper and Mid Rectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether 4 cycles of neoadjuvant CapOx chemotherapy is more effective than the upfront surgery in patients with intermediate risk CRM- mid and upper rectal cancer.

Detailed Description
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This trial aims to investigate the efficacy of neoadjuvant chemotherapy compared to upfront surgery in intermediate risk rectal cancer patients. This is a prospective multicenter open-label randomized phase III clinical trial. Patients will be randomized using an online randomization system to receive either 4 cycles of neoadjuvant CapOx (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 per os bid days 1-14) chemotherapy and surgery or surgery alone. A stratification will be performed based on N stage, tumor location in the middle or upper rectum and clinical center. Patients with cT3-4aN1-2M0, T4aN0M0 cancer in the upper rectum and сТ2-Т3bN1M0 (based on preoperative MRI) cancer in the middle rectum are included. All patients are potential candidates for adjuvant chemotherapy, according to preoperative staging. Chemoradiotherapy (50 Gy with concomitant capecitabine 825 mg/m2 per os bid on radiation days) will be performed for patients with tumor progression after neoadjuvant chemotherapy. The decision to proceed with adjuvant chemotherapy postoperatively will be based on pTNM stage in both treatment arms, according to actual treatment guidelines. The target accrual is 280 patients in each treatment arm (including 10% potential data loss) based on potential benefit of 10% 3-yr disease-free survival (75% vs 85%), α=0,05, power 80% in the experimental arm. An interim analysis is planned after 50% of the patients will reach a 3-year followup. Pelvic Magnetic Resonance Imaging (MRI) is performed in all patients for staging before and after neoadjuvant chemotherapy and before surgery. Pelvic MRI isbject to central review. Conduction of this study and data collection are controlled by a local institutional board.

Official Title
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A Multicenter Prospective Phase III Clinical Trial of Neoadjuvant CapOx Chemotherapy in Patients With Intermediate Risk Middle and Upper Rectal Cancer

Conditions
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Rectal Neoplasms Malignant, Rectum Carcinoma, Rectal Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Oxaliplatin
* Drug: Capecitabine
* Radiation: Radiotherapy
* Procedure: Rectal cancer surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent Histologically verified colon rectal adenocarcinoma cT3-4aN1-2M0 cancer of the upper rectum or сТ2-Т3bN1M0 cancer of the middle rectum (based on pelvic MRI) Tumor more than 2 mm from mesorectal fascia (based on pelvic MRI) Eastern Cooperative Oncology Group (ECOG) status 0-2 Haemoglobin (HGB) > 90 g/L Platelet Count (PLT) > 120x10*9/L Serum creatinine < 150 µmol/L Total bilirubin < 25 µmol/L Exclusion Criteria: inability to obtain informed consent distant metastases synchronous or metachronous tumors previous chemotherapy or radiotherapy clinically significant cardiovascular disorders (myocardial infarction < 6 months before visit, stroke < < 6 months before visit, instable angina < 3 months before visit, arrhythmia, uncontrolled hypertension > 160/100 mm hg clinically significant neurological disorders previous neuropathy 2 or higher current infection or heavy systemic disease pregnancy, breastfeeding ulcerative colitis individual intolerance to treatment components proven dihydropyrimidine dehydrogenase (DPD) deficiency participation in other clinical trials psychiatric disorders, which render patient unable to follow instructions or understand his/her condition technical inability to perform pelvic MRI inability of long-term followup of the patient

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: 4xCapOx<br>Patients will receive 4 cycles of neoadjuvant CapOx chemotherapy (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 bid per os days 1-14 every 3 weeks). In case of partial response or stable disease (based on pelvic MRI) patients proceed to surgery. In case of disease progression patients receive 50 Gy pelvic chemoradiotherapy with capecitabine 825 mg/m2 bid per os on radiation days and then surgery. The decision to proceed with adjuvant chemotherapy postoperatively will be based on pTNM stage | Drug: Capecitabine<br>* 2000 mg/m2, bid, per os, days 1-14, 4 cycles<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* 130 mg/m2 iv day 1, 4 cycles<br>Drug: Capecitabine<br>* 825 mg/m2, bid, per os, only on days of radiation (Monday through Friday)<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* Pelvic radiotherapy dose: 44 Gy on regional nodes, 50 Gy on primary tumor<br>Procedure: Rectal cancer surgery<br>* Laparoscopic or open partial or total mesorectal excision (based on exact tumor location and surgeons discretion)<br>|
| Active Comparator: Surgery<br>Patients will receive standard surgery for rectal cancer with partial or total mesorectal excision (based on exact tumor location and surgeons discretion). The decision to proceed with adjuvant chemotherapy postoperatively will be based on pTNM stage | Drug: Capecitabine<br>* 2000 mg/m2, bid, per os, days 1-14, 4 cycles<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* 130 mg/m2 iv day 1, 4 cycles<br>Procedure: Rectal cancer surgery<br>* Laparoscopic or open partial or total mesorectal excision (based on exact tumor location and surgeons discretion)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year disease-free survival |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjuvant chemotherapy compliance | Proportion of patients who receive a complete course of adjuvant chemotherapy | 6 months | 
| Acute chemotherapy toxicity | Toxicity measured according to NCI-CTCAE v.5.0 | 14 weeks | 
| pathologic complete response rate (pCR) |  | 1 month | 
| local recurrence rate |  | 3 years | 
| 3-year overall survival |  | 3 years | 
| Operative morbidity | Morbidity measured according to Clavien-Dindo classification | 30 days | 
| Neoadjuvant chemotherapy disease progression rate | Proportion of patients with disease progression during neoadjuvant chemotherapy | 14 weeks | 
| Preoperative tumor-associated complications rate | The rate of tumor-associated complications (bowel obastruction, bleeding etc) during neoadjuvant chemotherapy | 14 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, neoadjuvant chemotherapy, mesorectal excision