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Bevacizumab (bevacizumab, Avastin) is a recombinant human monoclonal IgG1 antibody that works by inhibiting the biological activity of human vascular endothelial growth factor. This means that bevacizumab binds to VEGF and prevents it from binding to receptors (Flt-1 and KDR) on the surface of endothelial cells. In an in vitro model of angiogenesis, binding of VEGF to its receptors leads to endothelial cell proliferation and neovascularization. In a nude (thymus-free) mouse model of colon cancer, the use of bevacizumab reduced micro angiogenesis and inhibited the progression of metastatic lesions.
Clinical Studies
Two randomized clinical trials evaluated the efficacy and safety of bevacizumab in combination with 5-FU-based chemotherapy for the treatment of metastatic colorectal cancer. Bevacizumab was administered intravenously in combination with an IFL regimen. Patients were randomly assigned to three groups: group 1 was IFL IV push + placebo (irinotecan 125 mg/m2 IV push, 5-fluorouracil 500 mg/m2 IV push and calcium tetrahydrofolate 20 mg/m2 IV push once a week for 4 weeks, with 6 weeks as a cycle); group 2 was IFL IV push + bevacizumab (5 mg/kg once every 2 weeks); and group 3 was 5-FU/LV + bevacizumab (5 mg/kg once every 2 weeks).
The group receiving 5-FU/LV + bevacizumab 5 mg/kg was significantly better than the group not receiving bevacizumab in terms of progression-free survival. There were no significant differences between the two groups in terms of overall survival and overall response rate. The group receiving 5-FU/LV + bevacizumab 10 mg/kg did not differ significantly from the group not receiving bevacizumab in terms of efficacy.
Major adverse events with bevacizumab
In Study 1, 1 of 396 patients (0.3%) in the IFL + placebo group, 6 of 392 (2%) in the IFL + bevacizumab group and 4 of 109 (4%) in the 5-FU/LV + bevacizumab group developed gastrointestinal perforations, some of which were fatal; these complications may or may not be associated with intra-abdominal abscesses and may occur at any time during treatment. In addition, 2 of 396 patients (0.5%) in the IFL + placebo group, 4 of 392 patients (1%) in the IFL + bevacizumab group and 1 of 109 patients (1%) in the 5-FU/LV + bevacizumab group developed wound dehiscence during treatment. One patient (study 1 had a total of 501 patients treated with bevacizumab) who received bevacizumab more than 2 months post-operatively developed anastomotic dehiscence.
Two different types of bleeding occur in patients treated with bevacizumab. The most common is mild bleeding, mainly in the form of grade 1 nosebleeds; the second is severe and sometimes fatal bleeding. The serious bleeding events were first seen in patients treated for non-small cell lung cancer, suggesting that bevacizumab should not be approved for non-small cell lung cancer.
Four months after discontinuation, 18 of 26 patients treated with IFL + bevacizumab and 8 of 10 patients treated with IFL + placebo had persistent hypertension. In all clinical trials (n=1032), 17 patients developed hypertension or worsening of hypertension requiring hospitalization or discontinuation of bevacizumab therapy.
In study 1, the incidence and severity of proteinuria (urine protein of + or higher) was increased in patients treated with IFL + bevacizumab compared to IFL + placebo. Urine protein of ++ or higher was seen in 14% of patients in the IFL + placebo arm, 17% of patients in the IFL + bevacizumab arm and 28% of patients in the 5-FU/LV bevacizumab arm.
occurred in 6 of 44 (14%) patients who received concurrent bevacizumab and anthracyclines and in 13 of 299 (4%) patients who received anthracyclines or left chest wall radiotherapy. In another controlled trial, the incidence of congestive heart failure was higher in patients who received bevacizumab + chemotherapy than in those who received chemotherapy alone.
As a therapeutic protein, it is inherently potentially immunogenic because the assay is not sensitive enough to detect low-titer antibodies. 500 sera from patients treated with bevacizumab, primarily in combination with chemotherapy, did not contain high-titer anti-bevacizumab antibodies when tested by enzyme-linked immunosorbent assay. As immunogenicity data are highly dependent on the sensitivity and specificity of the assay, the rate of test positivity is also influenced by a number of factors, including sample handling, time of sample collection, concomitant therapy and underlying disease.
Conclusion
In the process of bevacizumab application, it must be used with chemotherapy, which can play a better therapeutic role, but bevacizumab should pay special attention to the adverse reactions caused in the process of application, such as general hypertension, proteinuria, thrombosis, hand-foot syndrome and other adverse reactions. Early detection and appropriate treatment of adverse reactions is necessary to improve the efficacy of bevacizumab.
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