Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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Rectal cancer still remains one of the most popular tumors, however, distance metastasis still remains as high as 30% and the long-term survival outcomes are still unsatisfying. The recent conception of total neoadjuvant therapy and immune therapy is becoming popular and the oncologic effects are encouraging, especially in terms of circulating tumor DNA (ctDNA), the prognostic value of ctDNA has been demonstrated by our prior study. This study will carry out accurate ctDNA-guided neoadjuvant therapy on the basis of previous studies of the research group, and give appropriate treatment plans and treatment intensity to patients with different disease degrees. At the same time, combined with the latest progress in clinical diagnosis and treatment, the potential beneficiaries of immunotherapy were screened scientifically, and the combined immunotherapy was implemented accordingly.

Detailed Description
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Rectal cancer still remains one of the most popular tumors, a multidisciplinary approach including neoadjuvant chemoradiotherapy, total mesorectal excision and adjuvant chemotherapy has resulted a satisfying oncologic outcome in terms of reducing local recurrence and improving local control of disease for the treatment of rectal cancer, however, distance metastasis still remains as high as 30% and the long-term survival outcomes is still unsatisfying. The recent conception of total neoadjuvant therapy and immune therapy is becoming popular and the oncologic effects are encouraging, especially in terms of circulating tumor DNA (ctDNA), the prognostic value of ctDNA has been demonstrated by our prior study. This study demonstrated that ctDNA is an effective marker of tumor burden in real time and for the first time identified baseline ctDNA mutation frequency before nCRT as an independent prognostic factor for recent LARC recurrence and metastasis. This suggests that patients with different tumor burden according to baseline ctDNA mutation frequency should be given neoadjuvant therapy with corresponding intensity, in order to improve systemic disease control in patients with high risk of recurrence and metastasis, and to avoid overtreatment in patients with low risk. In conclusion, this study will carry out accurate ctDNA-guided neoadjuvant therapy on the basis of previous studies of the research group, and give appropriate treatment plans and treatment intensity to patients with different disease degrees. At the same time, combined with the latest progress in clinical diagnosis and treatment, the potential beneficiaries of immunotherapy were screened scientifically, and the combined immunetherapy was implemented accordingly. With the development of this study, several precision medicine research results obtained by our research group will be expected to be translated into clinical practice as soon as possible, which will improve the efficacy of LARC patients, reduce the rate of adverse reactions, and ultimately promote the improvement of the treatment level of rectal cancer and the more reasonable use of public medical resources. The patients with locally advanced rectal cancer staged as cT3-4N0/cTanyN+ will be included in this study. Patients will be randomized into two groups, the treatment group will receive different strategies after next generation sequencing of tumor tissue and IMC, those with MSI-H or TMB-H or POLE/PLOD1 mutation will be advised to receive immune therapy following neoadjuvant chemoradiotherapy (NCRT), and the others will be arranged to randomly receive NCRT (VAF<0.4%) or total neoadjuvant therapy (TNT) (VAF>0.4%) according to the VAF value of ctDNA; the control group will receive NCRT only.

Official Title
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Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer --- a Multicenter Randomized Controlled Trial (CINTS-R)

Conditions
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Locally Advanced Rectal Carcinoma, Circulating Tumor DNA

Intervention / Treatment
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* Other: circulating tumor DNA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-75 years; ECOG score 0-2; Rectal adenocarcinoma confirmed by pathology; The lower margin of the tumor was less than 12cm from the anal margin; Patients with clinical stage cT3-4N0M0 or cTanyN+M0; Newly treated patients who have not received treatment including radiotherapy, chemotherapy and surgery; Liver, kidney and other organs have good function and can tolerate radiotherapy, chemotherapy and surgery; Patients and family members can understand the study protocol, voluntarily participate in the study and sign informed consent. Exclusion Criteria: ECOG score > 2; Patients with multiple primary colorectal cancers; A history of other malignant tumors (other than cured basal cell carcinoma, cervical carcinoma in situ, surgically treated localized prostate cancer, or surgically resected breast ductal carcinoma in situ) within the past 5 years; Complicated with intestinal obstruction, intestinal perforation, gastrointestinal bleeding and other patients requiring emergency surgery; pregnant or lactating women; Patients with a history of severe mental illness, immune disease, hormone medication; Patients contraindicated by MRI examination, chemoradiotherapy, immunotherapy or surgery; Participated in other clinical researchers in the past 3 months; Any other circumstances that the investigator considers inappropriate for inclusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Traditional neoadjuvant chemoradiotherapy group<br>Eligible patients randomized into arm A will receive traditional neoadjuvant chemoradiotherapy, including long-course radiotherapy with a total number of 45-50.4Gy in 25-28 fractions, and with concurrent 3 times of oral capecitabine, the strategies of capecitabine are: During radiotherapy: capecitabine 1650mg/m2/d, orally administered twice a day, d1-d14, every 3 weeks as a course; During the non-radiotherapy period: capecitabine 2000mg/m2/d, orally administered twice daily, d1-d14, every 3 weeks as a course | |
| Experimental: ctDNA-guided neoadjuvant treatment group<br>After sequencing tumor tissue, those with MSI-H/TMB-H or POLD/POLE2 mutation willed be arranged to receive immune therapy following NCRT，Terelizumab，200mg. The others are arranged to randomly receive TNT (VAF>0.4%) or NCRT (VAF<0.4%) according to VAF value by the level of ctDNA. TNT： Long course radiotherapy combined with 2 courses of single-agent capecitabine chemotherapy → 6 courses of CapeOX (Capecitabine 2000mg/m2/ day, twice orally, d1-14; Oxaliplatin 100-130mg/m2, intravenous infusion, d1; Every 3 weeks for a course of treatment.) chemotherapy was performed 2 to 3 weeks after the end of chemotherapy. | Other: circulating tumor DNA<br>* This study will further testify the prognostic value of ctDNA in the treatment term of locally advanced rectal cancer, the higher the VAF value, the higher the risk of recurrence and metastasis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-related treatment failure, DrTF | Refers to the time from the start of treatment to the first interruption of treatment Reasons for treatment interruption include tumor progression, adverse effects, patient selection, and death events | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to recurrence, TTR | The median time from randomization to the first observation of recurrence. | 2 years | 
| overall survival, 2yOS | Refers to the proportion of patients still alive at 2 years after surgery | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced rectal cancer, circulating tumor DNA, Neoadjuvant chemoradiotherapy, Total neoadjuvant therapy, Randomized Controlled Trial