Table 1.

Characteristics of inclusion studies

No	References	Country	Study design	Sample size	Mean Age/ Range	Exposure	Outcome
1	Kapelakis6	Greece	Cohort study	35	64.81	Bevacoxaliplatin (130 mg/m²) + capecitabine (2000 mg/m² ) with or without bevacizumab (15 mg/kg).	Cardiovascular adverse event (coronary artery disease, myocardial infarction, thromboembolic event).
2	Ina19	Japan	Case–control	130	41–85	Bevacizumab + oxaliplatin, 5-fluorouracil + leucovorin (modified FOLFOX-6) + capecitabine + oxaliplatin + irinotecan + 5-fluorouracil + leucovorin (FOLFIRI) + S1 plus irinotecan (IRIS), or a bolus injection of 5-fluorouracil (400 mg/m²) on day 1 and continuous infusion of 5-fluorouracil (2400 mg/m²) over 46 hours plus l-leucovorin (200 mg/m²).	Cardiovascular adverse event (thrombosis), hematology adverse event (hemorrhage), other adverse event (interstitial penumonitis, tuberculosis).
3	Bennouna11	Germany	Clinical trial	810	63 (27–84)	Infusional or bolus fluorouracil or oral capecitabine at the investigator’s discretion + irinotecan or oxaliplatin with or without bevacizumab at 2.5 mg/kg per week equivalent (5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks).	Cardiovascular adverse event (venous thromboembolism), gastrointestinal adverse event (gastrointestinal perforation), hematology adverse event (bleeding, neutropenia), other adverse event (asthenia).
4	Avallone18	Italy	Clinical trial	230	18–75	12 biweekly cycles of a modified FOLFOX-6 regimen (intravenous oxaliplatin, 85 mg/m2 , on day 1, followed by intravenous levo–folinic acid, 200 mg/m2 + bolus fluorouracil, 400 mg/m2 + 46 h intravenous administration of fluorouracil, 2400 mg/m2 ) or a modified CAPOX regimen (intravenous oxaliplatin, 85 mg/m2 , on day 1 + oral capecitabine, 1000 mg/m2 , twice daily on days 1 to 10) every 2 weeks for 12 cycles. Bevacizumab (5 mg/kg) was administered on the same day as chemotherapy (standard arm) or 4 days before (experimental arm).	Gastrointestinal adverse event (diarrhea, nausea, abdominal pain), other adverse event (proteinuria), quality of life.
5	Baek16	Korea	Case–control	488	59 (36–68)	Bevacizumab (5 mg/kg) + FOLFIRI (130-180 mg/m2) + 5-Fluoroacil (400 mg/m2) + Leucovorin (20 mg/m2).	Gastrointestinal adverse event (gastrointestinal perforation).
6	Cao20	China	Case–control	71	54 (25–75)	5-fluorouracil/leucovorin-based chemotherapy +bevacizumab. Bevacizumab 5 mg/kg was administered every 2 weeks according to 5-FU-based chemotherapy regimens (FOLFIRI or FOLFOX) or 7.5 mg/kg every 3 weeks according to a capecitabine-based regimen (XELOX).	Hematology adverse event (bleeding).
7	Reglat	France	Cohort study	1550	65.1 (21.9–84.3)	FOLFIRI regimen associated with bevacizumab. Mean (SD) starting bevacizumab dose was 5.1 (0.5) mg/kg.	Cardiovascular adverse event (hypertension, thrombotic events), gastrointestinal adverse event (gastrointestinal perforation, nausea, vomiting, diarrhea), hematology adverse event (bleeding, epistaxis, neutropenia, anemia, thrombocytopenia), other adverse event (proteinuria, asthenia).
8	Căinap	Roma	Case–control	151	57 (19–75)	Single-dose bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks) or double dose bevacizumab (10 mg/kg/every 2 weeks or 15 mg/kg every 3 weeks).	Cardiovascular adverse event (hypertension, thromboembolic event), other adverse event (proteinuria).
9	Tsai7	United states	Cohort study	6083	≥65	Regimen cycle BEV, 5-FU, capecitabine, oxaliplatin, irinotecan, and epidermal growth factor receptor inhibition.	Cardiovascular adverse event (arterial thromboembolic event, cardiac death, cardiomyopathy, congestive heart failure).
10	Gruenberger17	United kingdom	Clinical trial	80	32–77	Bevacizumab (5 mg/kg) + mFOLFOX- 6 [oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46 h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, folinic acid 200 mg/m2, 5-fluorouracil 3200 mg/m2 (46 h infusion)] every 2 weeks.	Gastrointestinal adverse event (diarrhea), hematology adverse event (neutropenia, febrile neutropenia).
11	Koca13	Turkey	Case–control	172	18–81	Oxiplatine based regime and mFOLFIRI-B regime (folinic acid 400 mg/m2 + 5-FU 400 mg/m2 bolus + 5-FU 2.400 mg/m2 46 h infusion + irinotecan 180 mg/m2 + bevacizumab 5 mg/kg every 14 days).	Cardiovascular adverse event (hypertension), hematology adverse event (neutropenia), other adverse event (proteinuria).
12	Yamazaki21	Japan	Clinical trial	395	26–75	Bevacizumab (5 mg/kg) followed by FOLFIRI (irinotecan 150 mg/m2; l-leucovorin 200 mg/m2; intravenous bolus of fluorouracil 400 mg/m2, continuous infusion of fluorouracil 2400 mg/m2), or bevacizumab followed by mFOLFOX6 (oxaliplatin 85 mg/m2 instead of irinotecan).	Quality of life
13	Kabbinavar14	United States	Cohort study	1953	–	Bevacizumab	Gastrointestinal adverse event (gastrointestinal perforation).
14	Vallerio8	Italy	Cohort study	7747	–	Bevacizumab	Cardiovascular adverse event (thrombotic events, pulmonary embolism, heart failure, rhythm disorder).
15	Bencsikova9	Czech Republic	Case–control	1622	22–85	The chemotherapy regimens were as follows: FOLFOX4 (oxaliplatin 85 mg/m2 IV day 1; leucovorin 200 mg/m2 IV days 1 and 2; 5-FU bolus 400 mg/m2 IV days 1 and 2; 5-FU 600 mg/m2 IV 22 h continuous infusion days 1 and 2 every 2 weeks), FOLFIRI (irinotecan 180 mg/m2 IV day 1; leucovorin 200 mg/m2 IV day 1 and 2; 5-FU 600 mg/m2 IV 22 h continuous infusion days 1 and 2 every 2 weeks), XELOX (oxaliplatin 130 mg/m2 IV day 1; capecitabine 1000 mg/m2 twice daily PO for 14 days every 3 weeks), or XELIRI (irinotecan 250 mg/m2 IV day 1; capecitabine 1000 mg/m2 twice daily PO for 14 days every 3 weeks). Bevacizumab was administered at a dosage of 5 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks depending on the chemotherapy regimen. Dosage of bevacizumab was not reduced.	Cardiovascular adverse event (thromboembolic complication, hypertension), gastrointestinal adverse event (gastrointestinal perforation), hematology adverse event (bleeding), other adverse event (proteinuria).
16	Bang15	Korea	Case–control	157	–	Bevacizumab 7.5 mg/kg on day 1 and capecitabine 1250 mg/m2 orally (PO) twice daily on day 1 to 14, was repeated every 3 weeks.	Gastrointestinal adverse event (gastrointestinal perforation), hematology adverse event (bleeding), other adverse event (hand-foot syndrome, proteinuria).