Rectal Neoplasms
Conditions
Keywords
rectal cancer, short-term radiotherapy, neoadjuvant chemotherapy, total mesorectal excision, MRI-simulation, boost
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.
Interventions
RADIATIONSCPRT
Short-course preoperative radiotherapy(SCPRT), which consists of 5 Gy x 5f and 4Gy for boost on the GTV with MRI-simulation alone.
RADIATIONCRT
Long-term chemoradiotherapy(CRT), which consists of a long-term chemoradiation (2 Gy x 25 with capecitabine) preoperatively.
DRUGCAPOX
Patients will receive consolidation chemotherapy after 7-10 days of SCPRT completed, 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.
Sponsors
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized phase II trial design
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| R0(microscopically margin-negative) resection and cCR rate | 1-month after surgery completed | The composite outcome of R0 (microscopically margin-negative) resection and cCR, that is, the combined rate of radical resection and cCR management after neoadjuvant treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| distant metastasis-free survival | 3-year and 5-year | the time from diagnosis to metastasis |
| local recurrence-free survival | 3-year and 5-year | the time from surgery to local recurrence |
| 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. |
| Sum of sustained clinical complete response rate and R0 resection rate | 12 months after neoadjuvant therapy | the rate of sustained clinical complete response plus rate of R0 resection |
| clinical complete response rate | 3-month after neoadjuvant treatment | clinical complete response evaluated by MDT |
Other
| Measure | Time frame | Description |
|---|---|---|
| circulating tumor DNA, single cells, Cytokines 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.Single cells test by cytof. Cytokines test by the Olink Proteomics panel. |
Countries
China
Contacts
Primary ContactJing Jin, M.D.
Backup ContactWen-Yang Liu, M.D.
Outcome results
None listed