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

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.

• SBRT (Radiation), also known as radiotherapy: postoperative SBRT of liver lesions
• Chemotherapy (Drug): XELOX/FOLFOX/FOLFIRI
• PD-1 antibody (Drug), also known as Sintilimab: Sintilimab (200mg d1，q3w)

Primary outcomes

• 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]: Evaluate the effect of the combination of adjuvant chemotherapy, SBRT and immunotherapy versus observation on progression free survival

Secondary outcomes

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

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. age ≥ 18 years old, female and male
2. pathological and imaging confirmed colorectal colorectal liver metastases (synchronous or heterochronous)
3. Metastatic liver lesions <= 5
4. Primary colorectal cancer under control
5. Absence of evidence of extra-hepatic diseases
6. Metastatic liver lesions received resection with insufficient margin (<0.5cm) or R1/R2 resection
7. Karnofsky >= 70
8. Adequate organ function without contraindications to surgery, radiotherapy and immunotherapy
9. Without previous antitumoral immunotherapy
10. With good compliance
11. Signed the inform consent

Exclusion Criteria:

1. Pregnancy or breast-feeding women
2. History of other malignancies within 5 years (except cured skin cancer and cervical cancer in situ)
3. History of uncontrolled epilepsy, central nervous system disease, or psychiatric disorders
4. 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
5. Immunodeficiency disease, autoimmune diseases or long-term using of immunosuppressive agents
6. Severe uncontrolled recurrent infections
7. 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
8. Allergic to any component of the therapy

• Fan Xia, M.D,PH.D, Principal investigator, Fudan University