Effect of Concurrent Capecitabine-based Long-term Radiotherapy Followed by XELOX Plus TME in Patients With High Risk Rectal Cancer: a Multi-centers, Randomized Controlled, Open-Label Trial

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the effect of concurrent capecitabine-based long-term radiotherapy followed by 4 cycles XELOX pre- a delayed TME compared with 6 cycles XELOX post- a Regular Timing TME in patients with high-risk rectal cancer defined by MRI.

Detailed Description
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This is the randomized controlled, multi-centers, and open-labeled study. Delivering systemic chemotherapy between concurrent capecitabine-based long-term radiotherapy and total mesorectal excision (TME) surgery would be more effectively improved local control rates and improved metastases-free survival rates. The investigators attempted to investigate the effect on pathological response of delivering 4 cycles XELOX between concurrent capecitabine-based long-term radiotherapy and TME with lengthening the interval from radiation to surgery. In this study, the participants with high risk of deeper infiltration, or extramural vessel invasion, or circumferential resection margin involvement, or surrounding organs and structures invaded et al. were recruited. The participants will be randomized (1:1 ratio) to a control and intervention arm. The participants in the control arm will receive best current practice of concurrent capecitabine-based long-term radiotherapy followed by TME and then a 6 cycles of XELOX as standard adjuvant chemotherapy. The participants in the intervention arm will receive concurrent capecitabine-based long-term radiotherapy followed by 4 cycles XELOX as neoadjuvant chemotherapy pre- a delayed TME.

Official Title
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Effect of Concurrent Capecitabine-based Long-term Radiotherapy Followed by 4 Cycles XELOX Pre- a Delayed TME Compared With 6 Cycles XELOX post-a Regular Timing TME in Patients With High Risk Rectal Cancer: a Multi-centers, Randomized, Open-Label Trial

Conditions
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Rectal Cancer, Pathological Complete Response, Disease Free Survival

Intervention / Treatment
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* Drug: concurrent capecitabine-based long-term radiotherapy followed by 4 cycles XELOX and a delayed TME
* Drug: concurrent capecitabine-based long-term radiotherapy followed by a Regular TME and 6 Cycles XELOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18-75 years; Histologically confirmed adenocarcinoma; The rectal adenocarcinoma 0-12cm from the anal margin on Magnetic resonance imaging (MRI) and/or rigid sigmoidoscopy; High risk of rectal cancer defined by high-resolution MRI: tumor invasion 5mm beyond the muscularis propria, or extramural vascular invasion, or circumferential resection margin unsafe, or the lower rectal cancer invades intersphincteric space, or rectal cancer invades the adjacent structures. Eastern Collaborative Oncology Group performance status score of 0 or 2 Able and willing to give informed consent to participate. Exclusion Criteria: Received preoperative chemoradiotherapy for rectal cancer before the recruitment of this study; Have metastatic disease (including non-regional lymph nodes metastases or resectable liver metastases); Other malignancies, non-adenocarcinoma rectal malignancies or rectal malignancies on the basis of inflammatory bowel disease; Emergency surgery due to bowel obstruction, perforation, bleeding, etc.; Abnormality of capecitabine absorption due to gastrointestinal disease e.g. short bowel syndrome, inflammation bowel disease, et al.; Unresectable concurrent intestinal lesions; Concurrent severe infection； Cardiac Disease：uncontrolled or symptomatic cardiac angina，or uncontrolled arrhythmias and hypertension, or severe congestive heart failure grade II or more based on New York Heart Association (NYHA); myocardial infarction within the past 12 months Peripheral neuropathy more than grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 3·0) Bone marrow, liver and kidney function are abnormal e.g., white blood cell ≤ 1.5 × 109 / L; platelet ≤ 100 × 109 / L; Haemoglobin ≤ 80 g/L; Bilirubin > 1.5 times the upper limit; aspartate aminotransferase and alanine aminotransferase > 2.5 times the upper limit; creatinine > 1.5 times the upper limit; Pregnant or lactating women; Life prediction less than 3 months, other severe diseases; Contraindication to MRI; e.g. non-MRI compatible hip prosthesis, cardiac pacemaker; Contraindication to standard chemotherapy including drug interactions and glomerular filtration rate <50 mL/min at baseline; Participators who had been recruited by other clinical trial within three months.

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: 4 Cycles XELOX pre- TME<br>experimental group (arm B): concurrent capecitabine-based long-term radiotherapy, 4 cycles of XELOX as neoadjuvant chemotherapy and TME surgery | Drug: concurrent capecitabine-based long-term radiotherapy followed by 4 cycles XELOX and a delayed TME<br>* concurrent capecitabine-based long-term radiotherapy: capecitabine 825mg/m2,bid,d1-5, q week with Radiation treatment. Radiation treatment was given at 1·8 Gy per day, 5 days per week for 5-6 weeks, after a 45 Gy radiation dose in 25 fractions to the pelvis, a boost dose of 5·4 Gy in 3 fractions to the tumor bed or concurrent boosted. XELOX: Oxaliplatin: 130mg/m2,IV,d1; Capecitabine: 1000mg/m2,bid,d1-14; repeated every 3 weeks Surgery Procedure: Total Mesorectal Excision<br>|
| Active Comparator: 6 Cycles XELOX post- TME<br>control group (arm A): concurrent capecitabine-based long-term radiotherapy, TME surgery and 6 cycles of XELOX as adjuvant chemotherapy. | Drug: concurrent capecitabine-based long-term radiotherapy followed by a Regular TME and 6 Cycles XELOX<br>* concurrent capecitabine-based long-term radiotherapy: capecitabine 825mg/m2,bid,d1-5, q week with Radiation treatment. Radiation treatment was given at 1·8 Gy per day, 5 days per week for 5-6 weeks, after a 45 Gy radiation dose in 25 fractions to the pelvis, a boost dose of 5·4 Gy in 3 fractions to the tumor bed or concurrent boosted. XELOX: Oxaliplatin: 130mg/m2,IV,d1; Capecitabine: 1000mg/m2,bid,d1-14; repeated every 3 weeks Surgery Procedure: Total Mesorectal Excision<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rate | Pathological complete response (pCR) rate between control and intervention arm | up to 30days after total mesorectal excision | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | Disease Free Survival was defined as the time from the date of surgery to the date of the local recurrence, and/or distant disease, or tumor-related death. | 3-year | 
| R0 of total mesorectal excision rate | Overall R0 of total mesorectal excision rate between the control and intervention arm | up to 30days after total mesorectal excision | 
| Surgery morbidity | Surgical morbidity reported according to Clavien-Dindo classification | 30 days and 12-months | 
| quality of surgery | Quality of surgery determined using the mesorectal grading system | Time of surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High Risk Rectal Cancer, Total neoadjuvant chemoradiotherapy, Lengthening interval between radiotherapy and surgery