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

Sponsor

Chinese Academy of Medical Sciences (Other)

Overall Status

Recruiting

CT.gov ID

NCT03714490

Collaborator

(none)

200

Enrollment

Location

Arms

71.3

Anticipated Duration (Months)

2.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Rectal Neoplasms	Radiation: SCPRT plus neoadjuvant chemotherapy Radiation: long course chemoradiation	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomized phase II trial designRandomized phase II trial design

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 23, 2018

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental group 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 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. Other Names: capecitabine, oxaliplatin
Active Comparator: Control group 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 Long-term chemoradiotherapy(CRT), which consists of a long-term chemoradiation (2 Gy x 25 with capecitabine) preoperatively.

Arm

Intervention/Treatment

Experimental: Experimental group

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

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.

Other Names:

capecitabine, oxaliplatin

Active Comparator: Control group

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

Long-term chemoradiotherapy(CRT), which consists of a long-term chemoradiation (2 Gy x 25 with capecitabine) preoperatively.

Outcome Measures

Primary Outcome Measures

R0(microscopically margin-negative) resection rate [1-month after surgery completed]
the rate of microscopically margin-negative resection after neoadjuvant treatment

Secondary Outcome Measures

local recurrence-free survival [3-year and 5-year]
the time from surgery to local recurrence
distant metastasis-free survival [3-year and 5-year]
the time from diagnosis to metastasis
disease-free survival [3-year and 5-year]
the time from surgery to recurrence
overall survival [3-year and 5-year]
the time from diagnosis to death
pathological complete response rate [1-month after surgery completed]
pathological complete response in surgery specimen
the acute toxicity profile [1-month]
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.
the late toxicity profile [3-year]
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.
general quality of life (QoL) by QLQ-30 [3-year]
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.
QoL by QLO-CR29 [3-year]
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.

Other Outcome Measures

circulating tumor DNA, and other potential biomarkers such as T-cell receptor [3-year]
The exploratory end point for predicting of treatment response and survival. The circulating tumor DNA test by sequencing will includes KRAS, NRAS, BRAF,PI3K,TP53,PTEN, EGFR, NEGF etc (509-gene panel). And Measuring change in T cell receptor sub-types during treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College	Beijing		China	100021

Sponsors and Collaborators

Chinese Academy of Medical Sciences

Investigators

Study Director: Jing Jin, M.D., National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College