MRI Simulation-guided Boost in Short-course Preoperative Radiotherapy for Unresectable Rectal Cancer

Study Overview
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Brief Summary
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Improvements in downstaging are required when using preoperative chemoradiation for unresectable rectal cancer. There is therefore a need to explore more effective schedules. The study arm will receive MRI simulation-guided boost in short-course preoperative radiotherapy followed by consolidation chemotherapy , which may enhance the shrinkage of tumor comparing with the concurrent chemoradiation.

Detailed Description
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The study is a prospective phase II randomized multicenter trial. The purpose of this study is to compare short-term radiotherapy with MRI simulation-guided boost followed by consolidation chemotherapy(Experimental group) with preoperative long-term chemoradiotherapy(Control group) for middle-lower unresectable locally advanced rectal cancer evaluated by MRI. The primary endpoint is the rate of R0 resection, and the secondary objectives are local recurrence-free survival, distant metastasis-free survival, disease-free survival and overall survival at 3-year and 5-year follow up. Furthermore, pathological complete response rate, the acute and late toxicity profile and quality of life (QOL) after 3 years follow-up are secondary endpoints. The exploratory end point includes the circulating tumor DNA, and other potential biomarkers from tumor tissue and blood sample for treatment response and survival predicting. For each group, a plan for collection of serum/plasma/feces at baseline and different stages during or after treatment and for obtaining fresh tumor tissue for freezing prior to treatment was defined in the protocol. The SUNRISE-trial has been designed by National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, and the hypothesis is R0 resection rate in Experimental group was superior to that in Control group. Interim analysis design: As a phase II trial, the safety of experimental intervention is a major concern. We took the toxicity data from STELLAR, a phase III randomized study led by our center, as a reference. The incidence of G3 and above side effects in the short course radiotherapy with sequential neoadjuvant chemotherapy group was 28%, and that in the standard long-course concurrent chemoradiotherapy control group was 5%. Considering that boost dose may increase toxicity, if severe toxicity in the study group significantly exceeds that in the control group by more than 35%, it is up to the principal investigator to decide whether to modify the study protocol or terminate the study. The sample size of the interim analysis was calculated by the Z-pooled test, with α=0.05 (one-sided test), 1-β=0.90, using PASS 11 software. The frequency of the toxicity of G3 and above should be compared when neoadjuvant therapy was completed in 21 patients enrolled in each group.

Official Title
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MRI Simulation-guided Boost in Short-course Preoperative Radiotherapy (SCPRT) Followed by Consolidation Chemotherapy Versus Long Course Chemoradiation for Unresectable Rectal Cancer

Conditions
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Rectal Neoplasms

Intervention / Treatment
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* Radiation: SCPRT plus neoadjuvant chemotherapy
* Radiation: long course chemoradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven rectal adenocarcinoma; Distance between tumour and anal verge≤ 10cm; Locally advanced tumour;(AJCC Cancer Staging:T3, T4 or N+) Mesorectal fascia(MRF)+ or T4b evaluated by pelvic MRI; Eastern Cooperative Oncology Group(ECOG) performance score ≤ 1; Written informed consent; Mentally and physically fit for chemotherapy; Adequate blood counts: White blood cell count ≥3.5 x 109/L Haemoglobin levels ≥100g/L Platelet count ≥100 x 109/L Creatinine levels ≤1.0× upper normal limit（UNL） Urea nitrogen levels ≤1.0× upper normal limit（UNL） Alanine aminotransferase(ALT) ≤1.5× upper normal limit（UNL） Aspartate aminotransferase(AST) ≤1.5× upper normal limit（UNL） Alkaline phosphatase(ALP) ≤1.5× upper normal limit（UNL） Total bilirubin(TBIL) ≤1.5× upper normal limit（UNL） No excision of tumor, chemotherapy or other anti-tumor treatment after the diagnosis. Exclusion Criteria: Distant metastases; Recurrent rectal cancer; Active Crohn's disease or ulcerative colitis; Concomitant malignancies;(except basocellular carcinoma or in-situ cervical carcinoma) Allergic to Fluorouracil or Platinum drugs; Contraindications to MRI for any reason; Concurrent uncontrolled medical condition; Pregnancy or breast feeding; Known malabsorption syndromes or lack of physical integrity of upper gastrointestinal tract; Symptoms or history of peripheral neuropathy

Ages Eligible for Study
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Minimum Age: 18 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: Randomized phase II trial design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>The intervention of Experimental group includes: Radiotherapy, followed by chemotherapy with capecitabine, oxaliplatin, and then surgery. The detail of procedure: 1, short-course preoperative radiotherapy(SCPRT) , which consists of SCPRT, 5 Gray(Gy) x 5, 4Gy for boost on the gross tumour volume(GTV) with MRI-simulation alone; 2,then after 7-10 days of radiotherapy completed, patients will receive consolidation chemotherapy, given in 3 week cycle of capecitabine 1000 mg/m2 twice daily, day 1-14 combined with oxaliplatin 130 mg/m2 once. In total, 4 cycles of neoadjuvant chemotherapy are prescribed preoperatively, then followed by a total mesorectal excision(TME) and postoperative adjuvant chemotherapy. | Radiation: SCPRT plus neoadjuvant chemotherapy<br>* Short-course preoperative radiotherapy(SCPRT) with neoadjuvant chemotherapy, which consists of SCPRT, 5 Gy x 5, 4Gy for boost on the GTV with MRI-simulation alone, then after 7-10 days of radiotherapy completed, patients will receive consolidation chemotherapy, given in 3 week cycle of capecitabine 1000 mg/m2 twice daily, day 1-14 combined with oxaliplatin 130 mg/m2 once. In total, 4 cycles of neoadjuvant chemotherapy are scheduled before surgery.<br>* Other names: capecitabine, oxaliplatin;|
| Active Comparator: Control group<br>The intervention of Control group includes:Radiotherapy, capecitabine, and surgery. The detail of procedure: 1, long-term chemoradiotherapy(CRT), which consists of a long-term chemoradiation (2 Gy x 25 with capecitabine) preoperatively; 2, 6-8 weeks after chemoradiation, total mesorectal excision(TME) and then postoperative adjuvant chemotherapy. The radiotherapy is given in combination with capecitabine in a dose of 825 mg/m2 twice daily on days when radiotherapy, excluding weekends. | Radiation: long course chemoradiation<br>* Long-term chemoradiotherapy(CRT), which consists of a long-term chemoradiation (2 Gy x 25 with capecitabine) preoperatively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0(microscopically margin-negative) resection rate | the rate of microscopically margin-negative resection after neoadjuvant treatment | 1-month after surgery completed | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| local recurrence-free survival | the time from surgery to local recurrence | 3-year and 5-year | 
| distant metastasis-free survival | the time from diagnosis to metastasis | 3-year and 5-year | 
| disease-free survival | the time from surgery to recurrence | 3-year and 5-year | 
| overall survival | the time from diagnosis to death | 3-year and 5-year | 
| pathological complete response rate | pathological complete response in surgery specimen | 1-month after surgery completed | 
| the acute toxicity profile | the frequency of acute adverse events during and after treatment in 1-month, including gastrointestinal (vomiting, diarrhea and incontinence), dermatitis, and hematologic toxicity evaluated weekly by the Common Terminology Criteria 4.0. | 1-month | 
| the late toxicity profile | the late toxicity after treatment completion for 1-month, the frequency of late adverse events after 1-month of treatment, including gastrointestinal function, fistula, and hematologic toxicity, evaluated regularly by LENT-SOMA scoring systems. | 3-year | 
| general quality of life (QoL) by QLQ-30 | general quality of life of patients evaluated by questionaire of EORTC QLQ-C30. The higher score in total indicates the worse quality of life in general. | 3-year | 
| QoL by QLO-CR29 | quality of life related to colorectal disease of patients evaluated by questionaire of EORTC QLQ-CR29. The higher score in total of this module indicates the worse quality of life by colorectal module. | 3-year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, short-term radiotherapy, neoadjuvant chemotherapy, total mesorectal excision, MRI-simulation, boost