This is an open-label, prospective phase II clinical trial to evaluate the therapeutic and prognostic implications of tumor immune microenvironment in the neoadjuvant immunotherapy combined with chemoradiotherapy for patients with rectal cancer. A total of 100 patients will be enrolled in this trial. The primary end point is the rate of pathological complete response (pCR). The long-term prognosis and adverse effects will also be evaluated and analyzed.
Objectives: 1. To clarify the efficacy and safety of combined therapy for locally advanced rectal cancer (LARC) patients and verify the efficacy and safety of neoadjuvant immunotherapy for dMMR/MSI-H LARC patients. 2. To clarify the effect of nCRT on TIME for rectal cancer, and the further effect of adding Immunotherapy. 3. To verify the feasibility of predicting the efficacy of combined therapy by the infiltration level of CD8+ PD1+ TILs in tumor tissue before treatment in pMMR/MSS LARC patients and explore the comprehensive prediction index of the efficacy of combined therapy for LARC patients. 4. To clarify the potential mechanism of immune response or immune escape to neoadjuvant immunotherapy for LARC patients.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
100
Tislelizumab (3 cycles): 200mg i.v. q3w on day 1 of each cycle, and starting from the second week after the start of radiotherapy
Capecitabine 1650mg/m2/d orally twice-daily, 5 days a week for a total of 5 weeks.
45-50 Gy/day, 5 days a week for a total of 5 weeks.
Pathological complete response (pCR) rates
Proportion of patients who achieve a pathological complete response following treatment
Time frame: 1-2 weeks after surgery
Major pathological response (MPR) rates
The proportion of patients experiencing a major pathological response to neoadjuvant treatment.
Time frame: 1-2 weeks after surgery
Pathological tumor regression grade (TRG)
TRG is evaluated according to the AJCC system. TRG0-1 is defined as good response, TRG2 as moderate response, and TRG3 as poor response.
Time frame: 1-2 weeks after surgery
Rate of tumor down-staging
The proportion of patients experiencing tumor down-staging will be assessed by pathology.
Time frame: 1-2 weeks after surgery
Lymphocytes infiltration changes after treatment
The categories, number and distribution of lymphocytes infiltrated in tumor and tumor stroma are measured by Multiplex immunofluorescence assay.
Time frame: 2 weeks before treatment and 1-2 weeks after surgery
The expression of immune-related pathways
The expression of immune-related pathways is measured by RNAseq.
Time frame: 2 weeks before treatment and 1-2 weeks after surgery
Rectal MRI defined tumor regression
Proportion of patients achieving rectal MRI-confirmed near or complete tumor regression.
Time frame: Baseline and 1 week before surgery
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Rectal MRI defined tumor down-staging
Proportion of patients achieving rectal MRI-confirmed down-staging.
Time frame: Baseline and 1 week before surgery
Rectal MRI defined tumor volume change
The change of patients' tumor volume will be confirmed by rectal MRI.
Time frame: Baseline and 1 week before surgery
Local recurrence(LR) rate
Presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology
Time frame: 3, 5 years
Disease free survival (DFS)
The three-year and five-year disease-free survival of patients.
Time frame: 3, 5 years
Overall survival (OS)
The three-year and five-year overall survival of patients.
Time frame: 3, 5 years
Surgical complications
Rate of surgical complications, such as intraoperative hemorrhage, anastomotic leakage, intestinal obstruction, etc, which will also be assessed according to "Clavien-Dindo Classification of surgical complications".
Time frame: The surgical complications are assessed up to 5 years from the surgery
R0 resection rate
Rate of complete tumor removal with negative microscopically resection margin.
Time frame: Within two weeks after surgery
Rate of sphincter-sparing surgery
Rate of sphincter-sparing surgery if surgery is performed.
Time frame: Within two weeks after surgery
Rate of adverse event
Rate of adverse events will be assessed according to National Cancer Institution Common Terminology Criteria of Adverse Events (NCI-CTCAE) v.4.02. Adverse events of this trial will include immune-related adverse events, chemo- and radiotherapy related adverse events, and combined treatment-related adverse events.
Time frame: From date of randomization until the date of death from any cause, assessed up to 5 years
Patient reported outcome: Quality of life according to questionnaire European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) (v 3.0)
Score values from 1 (not at all) to 4 (very much) respectively from 1 (very poor) to 7 (excellent). Score outcome depends on score type.
Time frame: Baseline and months 3, 6, 12, 24, 36, 60
Patient reported outcome: Quality of life according to questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29)
Score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.
Time frame: Baseline and months 3, 6, 12, 24, 36, 60
Patient reported outcome: Functional outcome according to Wexner score
Five score values from "never" to "1 per day or more often". The more often the worse outcome.
Time frame: Baseline and months 3, 6, 12, 24, 36, 60