Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR ) Combined With Anti-PD1，Chemotherapy and Target Therapy for Metastatic Colorectal Cancer

Inclusion criteria

• Patient is 18-75 years old at the time of signing the informed consent form.
• ECOG performance status 0-1.
• Histopathological confirmed MSS/pMMR adenocarcinoma of the colon or rectum.
• Distant metastasis lesions are no more than 10 and all sites of disease can be safely treated based on a pre-plan.
• At least one evaluable metastatic lesion for radiotherapy and evaluation according to RECIST 1.1.
• No prior radiotherapy within 6 month.
• Previous system therapy. Patients Group Cohort A: participants who have not previously been treated with first-line chemotherapy. Cohort B: Patients with disease progression after first-line chemotherapy or stopped first-line therapy due to unacceptable toxic effects .
• Has an investigator determined life expectancy of at least 24 weeks.
• Demonstrate adequate organ function (bone marrow, liver, kidney and clotting function) within 7 days before the first administration without using blood products or hematopoietic stimulating factors.
• Non pregnant or lactating patients. Effective contraceptive methods should be used during the study and within 6 months of the last administration.
• Fully informed and willing to provide written informed consent for the trial.

Exclusion criteria

• History of checkpoint inhibitor therapy.
• Neutrophil\< 1.5×109/L, PLT\< 100×109/L (PLT\< 80×109/L in patients with liver metastasis), or Hb\< 90 g/L.
• TBIL \> 1.5 ULN, or TBIL \> 2.5 ULN in patients with liver metastasis. AST or ALT \> 2.5 ULN, or ALT and/or AST \> 5 ULN in patients with liver metastasis.
• Cr \> 1.5 ULN, or creatinine clearance\< 50 mL/min (calculated according to Cockcroft Gault formula).
• APTT \> 1.5 ULN, PT \> 1.5 ULN (subject to the normal value of the clinical trial research center).
• Serious electrolyte abnormalities.
• Urinary protein ≥ 2+, or 24-h urine protein ≥1.0 g/24 h.
• Uncontrolled hypertension: SBP \>140 mmHg or DBP \> 90 mmHg.
• A history of arterial thrombosis or deep vein thrombosis within 6 months; a history of bleeding or evidence of bleeding tendency within 2 months.
• A history of heart disease within 6 months.
• Uncontrolled malignant pleural effusion, ascites, or pericardial effusion.
• The presence of a clinically detectable second primary malignancy, or history of other malignancies within 5 years.
• A history of liver disease including, but not limited to, HBV infection or HBV DNA positive (≥1×104/mL), HCV infection or HCV DNA positive (≥1×103/mL),and liver cirrhosis.
• Pregnant or lactating women or women who may be pregnant have a positive pregnancy test before the first medication, or the female participants themselves and their partners who were unwilling to implement strict contraception during the study period.
• The investigator considers that the subject is not suitable to participate in this clinical study due to any clinical or laboratory abnormalities or compliance problems.
• Serious mental abnormalities.
• The diameter of brain metastasis is greater than 3 cm or the total volume is greater than 30 cc.
• Clinical or radiological evidence of spinal cord compression, or tumors within 3 mm of the spinal cord on MRI.