Systemic Neoadjuvant and Adjuvant Control by Precision Medicine in Rectal Cancer

Study Overview
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Brief Summary
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Rectal cancer represents the most complex area of multidisciplinary treatment in bowel surgery. In 2017, there were 1221 new rectal cancers in Finland. The prognosis of colorectal cancer (CRC) patients these days is almost exclusively driven by the occurrence of the metastatic form of the disease. The treatment of rectal cancer often includes a long delay between diagnosis and the initiation of systemic chemotherapy, increasing risk for systemic metastases for those at high risk. On the other hand, the waiting time during pretreatment before surgery enables comprehensive systematic characterization of the primary tumor status before the decisions on adjuvant chemotherapy, opening a window to the use of precision in decision-making. In this randomized controlled treatment trial, outcomes of novel precision methods to select right rectal cancer patients for treatment that they need will be compared to conventional treatment. The study aims to reduce over-treatment of those that most likely do not benefit from additional treatments. With the overall aim to reduce metastatic form of the disease, patients with high-risk features will be randomized to a treatment strategy with early systemic control by chemotherapy followed by circulating tumor DNA (ctDNA) and organoid-guided adjuvant therapy, or to conventional treatment strategy. Both state-of-the-art laboratory practice and routine diagnostic clinical pipelines are introduced to bring future diagnostic models of minimal residual disease and chemoresistance closer to current practice. The outcomes will reveal the clinical benefit of such strategy by recurrence-free survival at highest level of evidence, and produce important clinical outcome data on the application of ctDNA in everyday cancer treatment practice. The translational data on the use of ctDNA organoids to inform treatment decision and regimen selection will build knowledge of the use of such biomarkers as tools for clinical practice and clinical research. The results will be scalable worldwide in the practice of rectal cancer treatment.

Official Title
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Systemic Neoadjuvant and Adjuvant Control by Precision Medicine in Rectal Cancer (SYNCOPE) - Approach on High-risk Group to Reduce Metastases

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Total neoadjuvant therapy (TNT)
* Diagnostic Test: Minimal residual disease (MRD)
* Radiation: Long radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: rectal adenocarcinoma, World Health Organization (WHO) performance status 0-1, assessed by the MDT to be able to undergo capecitabine and oxaliplatin (CAPOX) treatment, 3) extramural vein invasion by magnetic resonance imaging (mrEMVI+) and 4) assessed by the multi-disciplinary team (MDT) to require either radiotherapy (RT) or long chemoradiotherapy (CRT) by the current standards. Exclusion Criteria: deficient mismatch repair (MMR) status, non-dihydropyrimidine dehydrogenase (DPYD) genotype, a contraindication to capecitabine, oxaliplatin or RT, or failing in blood tests that describe the adequate circulatory, liver and kidney function for chemotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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 |
| --- | --- |
| Experimental: TNT + precision<br> | Drug: Total neoadjuvant therapy (TNT)<br>* Short radiotherapy (5X5 Gy) and capecitabine/oxaliplatin<br>Diagnostic Test: Minimal residual disease (MRD)<br>* Postoperative MRD on circulating cell-free DNA<br>|
| Active Comparator: Conventional<br> | Radiation: Long radiation therapy<br>* Long-course 50.4 Gy radiation with capecitabine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival |  | 3 years from surgery | 
| Recurrence-free survival |  | 5 years from surgery | 
| Postoperative ctDNA | number of patients with detectable ctDNA at postoperative sample in the conventional treatment arm that are not assigned to chemotherapy | 3 weeks postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CRC-specific survival |  | 3 years | 
| CRC-specific survival |  | 5 years | 
| overall survival |  | 3 years | 
| overall survival |  | 5 years | 
| number of surgically resected patients resected patients |  | 1 year | 
| R0-resection rate |  | 1 year | 
| local recurrence rate |  | 5 years postoperatively | 
| complete pathological response response rate |  | 12 weeks after initiation of pretreatment | 
| complete clinical response rate |  | 12 weeks after initiation of pretreatment | 
| total uptake of chemotherapy |  | 1year | 
| total uptake of chemotherapy |  | 3 years | 
| total uptake of chemotherapy |  | 5 years | 
| adverse effects of surgery effects of surgery |  | 1 year | 
| adverse effects of chemotherapy |  | 1 year | 
| adverse effects of chemotherapy |  | 3 years | 
| Treatment response by patient-derived organoid (PDO) therapy response | population distribution of PDO treatment response is compared to their corresponding clinical response by response MRI and pathological response and compared to organoid in vitro response | 1 year |