A Study of Total Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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A Phase II Study of Total Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer

Detailed Description
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Recommended treatment of patients with locally advanced rectal cancer (LARC) includes preoperative chemoradiation (CRT), total mesorectal excision (TME) and postoperative adjuvant chemotherapy (ACT). However, treatments fail to show an improved therapeutic effect on high-risk patients now. Total neoadjuvant therapy (TNT) is a new try for rectal cancer treatment,and this trial aims to identify and select the more promising TNT sequence. This trail is a multicenter, randomized, phase II trial . Eligible patients age from 18 to 75 years with histologically confirmed rectal adenocarcinoma. MRI is mandatory, and patients of stage II or III rectal cancer are eligible if any of the following criteria are fulﬁlled: Categories T3,Categories N2, MRF involvement, EMVI positive, and lateral lymph node involvement. Patients are randomly assigned to 3 groups, group 1: concurrent chemoradiotherapy → TME → adjuvant chemotherapy (control group);or group 2: concurrent chemoradiotherapy → consolidation chemotherapy → TME (experimental group);Or group 3: induction chemotherapy → concurrent chemoradiotherapy →TME ( experimental group).The primary end point is the rate of tumor down-staging, which is deﬁned as stage yp0-II after surgery. Secondary end points include acute toxicity, compliance with TNT, surgical complications, 3-year overall survival (3yOS),3-year disease free survival (3yDFS),3-year distant metastatic free survival(3yDMFS),3-year locoregional recurrence-free survival(3yLRRFS) and quality of life.

Official Title
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A Prospective, Multicenter, Randomized Controlled Trial of Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Combination Product: Concurrent Chemoradiotherapy
* Drug: XELOX
* Drug: mFOLFOX
* Procedure: TME


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 18-75 years old, regardless of gender Histologically confirmed rectal adenocarcinoma; Up to 12 cm above the anal verge on the basis of rigid rectoscopy. MRI of the rectum is acceptable; Patients in stage II or III rectal cancer are eligible if any of the following criteria are fulﬁlled: Categories T4,Categories N2, MRF involvement, EMVI positive, and lateral lymph node involvement. ECOG score 0-1 or KPS score ≥80. Exclusion Criteria: History of malignant tumor in other parts; Cannot complete MRI; Allergic to 5-fu drugs; Allergic to platinum drugs; During thrombolytic and anticoagulant therapy, the patient has bleeding diathesis or coagulation dysfunction; Or aneurysm, stroke, transient ischemic attack, arteriovenous malformation in the past year; History of kidney, urine test found proteinuria or clinical renal function was significantly abnormal; History of digestive tract fistula, perforation or severe ulcer; Active infection is present; Clinically obvious heart disease; New York heart association (NYHA) of Ⅱ level or congestive heart failure; Unstable symptomatic arrhythmia or peripheral vascular disease ≥ grade II; Myocardial infarction and cerebrovascular accident occurred within 6 months before enrollment.

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 |
| --- | --- |
| Active Comparator: adjuvant chemotherapy group<br>concurrent chemoradiotherapy → TME → adjuvant chemotherapy (control group) | Combination Product: Concurrent Chemoradiotherapy<br>* Radiotherapy: 50Gy in 25 fractions to the primary tumor and to mesorectal, presacral,and internal iliac lymph nodes. Concurrent chemotherapy: Capecitabine 1650 mg/m2/d<br>Drug: XELOX<br>* Intravenous infusion of oxaliplatin (130 mg/m2 over 2 h) on day 1 and oral administration of capecitabine (1000 mg/m2 twice daily) from day 1 to day 14, is repeated every 3 weeks for 6 cycles. 6 courses，3 weeks per course<br>* Other names: CAOPX;Drug: mFOLFOX<br>* Administration of l-LV (400 mg/m2) and oxaliplatin (85 mg/ m2) by intravenous infusion over 2 h, followed by rapid intravenous infusion (iv) of 5-FU (400 mg/m2) and then slow infusion (civ) of 5-FU (2400 mg/m2 over 46 h), is repeated every 2 weeks for 9 cycles.<br>Procedure: TME<br>* Total mesorectal excision<br>|
| Experimental: consolidation chemotherapy group<br>concurrent chemoradiotherapy → consolidation chemotherapy → TME (experimental group) | Combination Product: Concurrent Chemoradiotherapy<br>* Radiotherapy: 50Gy in 25 fractions to the primary tumor and to mesorectal, presacral,and internal iliac lymph nodes. Concurrent chemotherapy: Capecitabine 1650 mg/m2/d<br>Drug: XELOX<br>* Intravenous infusion of oxaliplatin (130 mg/m2 over 2 h) on day 1 and oral administration of capecitabine (1000 mg/m2 twice daily) from day 1 to day 14, is repeated every 3 weeks for 6 cycles. 6 courses，3 weeks per course<br>* Other names: CAOPX;Drug: mFOLFOX<br>* Administration of l-LV (400 mg/m2) and oxaliplatin (85 mg/ m2) by intravenous infusion over 2 h, followed by rapid intravenous infusion (iv) of 5-FU (400 mg/m2) and then slow infusion (civ) of 5-FU (2400 mg/m2 over 46 h), is repeated every 2 weeks for 9 cycles.<br>Procedure: TME<br>* Total mesorectal excision<br>|
| Experimental: induction chemotherapy group<br>induction chemotherapy → concurrent chemoradiotherapy →TME ( experimental group). | Combination Product: Concurrent Chemoradiotherapy<br>* Radiotherapy: 50Gy in 25 fractions to the primary tumor and to mesorectal, presacral,and internal iliac lymph nodes. Concurrent chemotherapy: Capecitabine 1650 mg/m2/d<br>Drug: XELOX<br>* Intravenous infusion of oxaliplatin (130 mg/m2 over 2 h) on day 1 and oral administration of capecitabine (1000 mg/m2 twice daily) from day 1 to day 14, is repeated every 3 weeks for 6 cycles. 6 courses，3 weeks per course<br>* Other names: CAOPX;Drug: mFOLFOX<br>* Administration of l-LV (400 mg/m2) and oxaliplatin (85 mg/ m2) by intravenous infusion over 2 h, followed by rapid intravenous infusion (iv) of 5-FU (400 mg/m2) and then slow infusion (civ) of 5-FU (2400 mg/m2 over 46 h), is repeated every 2 weeks for 9 cycles.<br>Procedure: TME<br>* Total mesorectal excision<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of tumor down-staging | Tumor down-staging is considered as Stage yp0-II after surgery. | 6-8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of compliance with TNT | Rate of compliance with TNT | 6-8 months | 
| 3y OS | 3-year overall survival (3yOS) | 3years | 
| 3y DFS | 3-year disease free survival (3yDFS) | 3years | 
| 3y DMFS | 3-year distant metastatic free survival(3yDMFS) | 3 years | 
| 3y LRRFS | 3-year locoregional recurrence-free survival(3yLRRFS) | 3 years | 
| EORTC QLQ-C30 | EORTC QLQ-C30 to assess the quality of life | 3 years | 
| EORTC QLQ-CR29 | EORTC QLQ-CR29 to assess the quality of life | 3 years | 
| Wexner continence grading scale | Wexner continence grading scale | 3 years | 
| CTCAE 4.0 | Severe acute adverse reaction rate（≥III degree） | 6-8months | 
| Incidence of surgical complications | Incidence of surgical complications | 6-8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal Cancer, Radiotherapy, High Risk, Total Neoadjuvant Therapy