Clinical trial NCT03714490: MRI Simulation-guided Boost in Short-course Preoperative Radiotherapy for Unresectable Rectal Cancer
Official title: MRI Simulation-guided Boost in Short-course Preoperative Radiotherapy (SCPRT) Followed by Consolidation Chemotherapy Versus Long Course Chemoradiation for Unresectable Rectal Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Rectal Neoplasms
Keywords: rectal cancer
short-term radiotherapy
neoadjuvant chemotherapy
total mesorectal excision
MRI-simulation
boost
Lead sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Sponsor class: OTHER
First posted: 2018-10-22
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized phase II trial design
Primary purpose: TREATMENT

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.

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 cCR, 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.

Eligibility criteria: 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

Primary outcomes:
measure: R0(microscopically margin-negative) resection and cCR rate
timeFrame: 1-month after surgery completed
Secondary outcomes:
measure: local recurrence-free survival
timeFrame: 3-year and 5-year
measure: distant metastasis-free survival
timeFrame: 3-year and 5-year
measure: disease-free survival
timeFrame: 3-year and 5-year
measure: overall survival
timeFrame: 3-year and 5-year
measure: pathological complete response rate
timeFrame: 1-month after surgery completed
measure: clinical complete response rate
timeFrame: 3-month after neoadjuvant treatment
measure: the acute toxicity profile
timeFrame: 1-month
measure: the late toxicity profile
timeFrame: 3-year
measure: general quality of life (QoL) by QLQ-30
timeFrame: 3-year
measure: QoL by QLO-CR29
timeFrame: 3-year
measure: Sum of sustained clinical complete response rate and R0 resection rate
timeFrame: 12 months after neoadjuvant therapy
Other outcomes:
measure: circulating tumor DNA, single cells, Cytokines and other potential biomarkers such as T-cell receptor
timeFrame: 3-year
Locations:
city: Beijing
country: China
facility: Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Study officials:
affiliation: National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
name: Jing Jin, M.D.
role: STUDY_DIRECTOR
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