Postoperative Chemotherapy With/Without Radiotherapy and Immunotherapy for Colorectal Liver Metastases With High Risk of Locally Recurrence

Study Overview
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Brief Summary
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This study is a randomized controlled phase II trial to evaluate the efficacy of the combination of stereotactic body radiation therapy (SBRT) and immunotherapy with postoperative chemotherapy in colorectal cancer liver metastasis (CRLM) patients with high risk of locally recurrence. Researchers will compare the combination therapy with the postoperative chemotherapy alone to see if postoperative chemotherapy plus SBRT and immunotherapy can further reduce the risk of recurrence and metastasis after surgery.

Detailed Description
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40-50% of colorectal cancer patients have metastases at the time of diagnosis, of which liver metastases are the most common. Surgical resection is the most likely cure for CRLM patients, however, more than 50% of patients will experience recurrence within 2 years after resection of liver metastases. SBRT can be an effective and safe treatment modality, which can not only provide better local control of metastatic lesions, but also has a sensitizing immunotherapeutic effect. SBRT can effectively synergize with anti-PD-1/PD-L1 antibodies to activate the immune microenvironment of CRLM patients and improve survival. However, in CRLM patients after surgery, whether combining SBRT, immunotherapy and adjuvant chemotherapy results in better survival than chemotherapy alone, the evidence is insufficient.

Official Title
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Postoperative Chemotherapy With/Without Radiotherapy and Immunotherapy for Colorectal Liver Metastases With High Risk of Locally Recurrence: A Randomized Controlled Phase II Trial

Conditions
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Radiotherapy, Immunotherapy, Liver Metastases, Colorectal Cancer

Intervention / Treatment
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* Radiation: SBRT
* Drug: Chemotherapy
* Drug: PD-1 antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥ 18 years old, female and male pathological and imaging confirmed colorectal colorectal liver metastases (synchronous or heterochronous) Metastatic liver lesions <= 5 Primary colorectal cancer under control Absence of evidence of extra-hepatic diseases Metastatic liver lesions received resection with insufficient margin (<0.5cm) or R1/R2 resection Karnofsky >= 70 Adequate organ function without contraindications to surgery, radiotherapy and immunotherapy Without previous antitumoral immunotherapy With good compliance Signed the inform consent Exclusion Criteria: Pregnancy or breast-feeding women History of other malignancies within 5 years (except cured skin cancer and cervical cancer in situ) History of uncontrolled epilepsy, central nervous system disease, or psychiatric disorders Clinically serious heart disease, such as symptomatic coronary artery disease, New York Heart Association (NYHA) class II or worse congestive heart failure or severe arrhythmia requiring pharmacologic intervention, or history of myocardial infarction within the last 12 months Immunodeficiency disease, autoimmune diseases or long-term using of immunosuppressive agents Severe uncontrolled recurrent infections Baseline blood and biochemical indicator do not meet the following criteria: neutrophils >=1.5×10^9/L, Hb >=90g/L, PLT >=100×10^9/L, ALT/AST<=2.5 ULN, Cr <= 1ULN Allergic to any component of the therapy

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: adjuvant radiotherapy: SBRT; immunotherapy: sintilimab chemotherapy: XELOX
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: chemotherapy with radiotherapy and immunotherapy<br>radiotherapy: SBRT of liver lesions; postoperative chemotherapy and immunotherapy: chemotherapy by investigators' choice with sintilimab for 18 weeks | Radiation: SBRT<br>* postoperative SBRT of liver lesions<br>* Other names: radiotherapy;Drug: Chemotherapy<br>* XELOX/FOLFOX/FOLFIRI<br>Drug: PD-1 antibody<br>* Sintilimab (200mg d1，q3w)<br>* Other names: Sintilimab;|
| Active Comparator: chemotherapy<br>postoperative chemotherapy: chemotherapy by investigators' choice for 18 weeks | Drug: Chemotherapy<br>* XELOX/FOLFOX/FOLFIRI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Evaluate the effect of the combination of adjuvant chemotherapy, SBRT and immunotherapy versus observation on progression free survival | From the date of randomization until the date of first documented progression or date of death from any cause, whichever come first, assessed up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local control rate | To evaluate local control rate after the combination of adjuvant chemotherapy, SBRT and immunotherapy in comparison to observation alone | From the date of randomization until the date of first documented locally tumor recurrence, assessed up to 12 months | 
| Overall survival | To evaluate overall survival after the combination of adjuvant chemotherapy, SBRT and immunotherapy in comparison to observation alone | From date of randomization until the date of death from any cause, assessed up to 36 months | 
| Grade 3-4 adverse effect rate | Rate of chemotherapy, SBRT and immunotherapy related adverse events | From date of randomization until the date of death from any cause, assessed up to 3 years |