Raltitrexed is an inhibitor of thymidylate synthase.As a folate antimetabolite drug, raltitrexed has been used in treatment of colorectal cancer(CRC) since 1998, and also used in malignant mesothelioma.Several phase III studies performed in patients with advanced CRC showed that it is as effective as 5-fluorouracil(5-FU) /leucovorin(LV) with regard to response rates and survival. The combination of raltitrexed with oxaliplatin shows response rates of 41%-54% and median survivals of 14.6-14.8 months, which are comparable to those achieved with 5-FU/LV combination with oxaliplatin. This study discussed the efficacy and safety of raltitrexed-oxaliplatin(RALOX) combined with bevacizumab or capecitabine-oxaliplatin(CAPOX) combined with bevacizumab in first-line treatment of patients with advanced colorectal cancer who could not undergo radical surgery. The main endpoint will be progression free survival (PFS). The secondary endpoints will be overall survival, objective response rate and disease control rate (OS,ORR and DCR).It is expected that raltitrexed may be one of options for the treatment of advanced CRC in the first-line setting.

According to the inclusion and exclusion criteria, the patients will be randomly divided into two groups: the experimental group (group A) will be administered with raltitrexed 3mg/m2 intravenously combined with oxaliplatin and bevacizumab, repeated every 21 days. The control group (group B) will be administered with orally capecitabine (1000mg/m2, d 1-14) combined with oxaliplatin and bevacizumab, repeated every 21 days. After 8 cycles of treatments, if evaluated as complete response(CR),partial response(PR) or stable disease(SD), CRC patients will go into maintenance therapy wtih raltitrexed combined with bevacizumab in group A or capecitabine combined with bevacizumab in group B respectively, ended in disease progression(PD) , symptoms deterioration, unacceptable toxicity, death or withdrawal of consent (whichever occurs first). The radiological efficacy will be evaluated every 6 weeks (2 treatment cycles) and non-PD (PD criteria referring to RECIST 1.1 criteria) patients will continue to be treated until the cancer progression or the patient's intolerable toxicity or death. Toxic side effects and quality of life will be assessed at the same time.

Follow up participants and analyse primary endpoint (PFS) and secondary endpoints (OS,ORR and DCR).The causes of confirmed missing data in the trial should be recorded in detail to determine the mechanism of missing data and choose the suitable missing data handling methods.

Inclusion Criteria:

• Age 18~75 years;
• Patients are diagnosed by histopathological and/or cytological examination as local advanced or metastatic colorectal cancer who are unable to undergo radical surgery with no symptom of the primary lesions；
• There are one or more measurable lesions, the longest diameter of which is at least 10 mm by spiral CT scanning (RECIST standard, version 1.1)
• ECOG performance status (ECOG PS) 0~1;
• Life expectancy not less than 3 month
• Blood routine, liver and kidney function reached the following criteria within 14 days before screening:

Absolute neutrophil count (> 1.5x109/L); hemoglobin (> 9.0 g/dl); platelet count (> 100 x109/L); total bilirubin (< 1.5 times the normal upper limit (ULN); alanine aminotransferase and glutamic oxaloacetate aminotransferase (< 2.5 x ULN) in patients with liver metastasis (< 5 x ULN); alkaline phosphatase （< 3 x ULN（ in patients with liver metastasis < 5 x ULN)）; serum creatinine （< 1.5 x ULN）;

• Adequate blood coagulation function [International Normalized Ratio (INR) ≤1.5 and Partial Thromboplastin Time (PTT) or activated PTT (aPTT) ≤1.5 x upper limit of normal (ULN)). Participants on full-dose anticoagulation must be in a stable phase of anticoagulant therapy and if taking oral anticoagulation, participants must have an INR ≤3 without clinically significant active bleeding or a high risk of bleeding.
• Agree to provide histological specimens from previous operations for biomarker assessment and specimens remain。
• Signed informed consent to be provided

Exclusion Criteria:

• Previous treatment with Raltitrexed；
• With a large amount of pleural effusions or ascites requiring puncture drainage；
• Active clinical severe infections include hepatitis；
• One of the following complications: 1) Gastrointestinal obstruction (including paralytic ileus) or gastrointestinal bleeding 2) Symptomatic cardiac disease (including unstable angina, myocardial infarction, and heart failure) 3) Pulmonary fibrosis or interstitial pneumonia 4) Uncontrolled diabetes mellitus 5) Uncontrolled diarrhea (that affects daily activities although adequate therapy )
• Symptomatic brain or meningeal metastasis (unless the patient has been treated for > 6 months, the imaging results are negative in the 4 weeks before entering the study, and the clinical symptoms associated with the tumor are stable at the time of entering the study);
• Undergoing kidney dialysis；
• History of other malignant tumors within 5 years, except for cured cervical carcinoma in situ or basal cell carcinoma of the skin;
• Drug abuse and medical, psychological or social conditions may interfere with patients' participation in the study or have an impact on the evaluation of the study results；
• Pregnant or lactating females, and males and females reluctant to use contraception
• History of concurrent gastrointestinal perforation or gastrointestinal perforation within 1 year prior to enrollment
• Pulmonary hemorrhage/hemoptysis ≥ Grade 2 (identified as bright red blood of not less 2.5mL) within 1 month before enrollment.
• History of thoracotomy,laparotomy, or intestinal resection within 28 days prior to enrollment;
• Unhealed wound (other than suture wounds due to implantation of a central venous port), traumatic fracture, or gastrointestinal ulcer
• Current cerebrovascular disease or thromboembolism or either within 1 year before enrollment
• Current anticoagulation therapy or requiring anticoagulation agents (> 325 mg/day of aspirin)
• Bleeding diathesis, coagulopathy, or coagulation factor abnormality (INR ≥1.5 within 14 days before enrollment)
• Uncontrolled hypertension
• Urine dipstick for proteinuria >+2
• Researchers think those should be excluded](streamdown:incomplete-link)