Doubling the Dose of Bevacizumab Beyond Progression in Metastatic Colorectal Cancer–the Experience of a Tertiary Cancer Center

Abstract

Background: Colorectal cancer (CRC) is the third most common cancer in Europe, with an annual increase in incidence ranging between 0.4 and 3.6% in various countries. Although the development of CRC was extensively studied, limited number of new therapies were developed in the last few years. Bevacizumab is frequently used as first- and second-line therapy for management of metastatic CRC (mCRC). The aim of this study is to present our experience with using bevacizumab beyond disease progression at different dosage levels in mCRC patients, in terms of overall survival, progression-free survival, time to treatment failure, and toxicities.Methods: We performed a consecutive retrospective analysis of patients with confirmed mCRC who were treated with bevacizumab at "Prof Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca, Romania. We included patients who had received bevacizumab as first- or second-line therapy and further stratified them according to the dose administered as a second-line (either standard dose of 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks, or double dose of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks–depending on the classical chemotherapy partner). All patients had received bevacizumab beyond progression (BYP) which is defined as continuing bevacizumab administration through second-line treatment despite disease progression. In each group, we evaluated the prognostic factors that influenced survival and treatment outcome.Results: One hundred and fifty-one (151) patients were included in the study. Themedian age of patients receiving double dose bevacizumab (DDB) and standard dose bevacizumab (SDB) was 58 years (range 41–71) and 57 years (range 19–75), respectively. The median overall survival in the DDB group was 41 months (range 27–49) compared to 25 months (range 23–29) in the SDB group (p = 0.01 log-rank test). First-line oxaliplatin-based treatment was used more frequently regardless of group, while irinotecan-based more frequently used as a second-line treatment (p = 0.014). Both oxaliplatin- and irinotecan-based regimens were found to be suitable partners for BYP. Statistical analysis revealed that dose intensity, primary tumor location, and cumulative exposure to BYP had significant influence on survival.Conclusion: Doubling the dose of bevacizumab after first progression may improve survival in mCRC patients. Increasing bevacizumab dose intensity could override the prognostic impact of primary tumor location in patients receiving double the dose of bevacizumab after first disease progression.

Bevacizumab side effects and adverse clinical complications in colorectal cancer patients: review article

“…The last cardiovascular adverse event that could happen is hypertension, which, some studies in this systematic review reported that hypertension was a significant side effect caused by bevacizumab toxicity 12 , 13 , 16 , 20 . On the other hand, a gastrointestinal adverse event caused by bevacizumab is GIT perforation 8 , 20 .…”

“…The study by Bencsikova and Vallerio reported that thromboembolic event often happen in CRC patients receiving bevacizumab. On the other hand, studies conducted by Căinap, Bennouna, and Tsai reported that the thromboembolic event was minimal 8 , 13 , 14 , 19 , 20 . Meanwhile, a study by Kapelakis showed that people with past thromboembolic event belong to a high risk group of taking bevacizumab, so it should be administered carefully 6 .…”

“…The other hematological events were anemia and thrombocytopenia, but the study did not stated those as statistically significant 12 . Other adverse events such as proteinuria was observed in the group with bevacizumab added to their therapy 9 , 12 , 13 , 16 , 20 , 21 . Proteinuria adverse event was statistically significant in one study 9 .…”

“…Proteinuria adverse event was statistically significant in one study 9 . Another study comparing double and single-dose bevacizumab administration found that grade-3 proteinuria reached statistical significance 13 . Asthenia was also a common severe adverse events, but studies did not stated it as statistically significant, considering asthenia was also common in the control group 8 , 12 .…”