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.
Infantile hemangioma is one of the most common benign tumors affecting children, with ~10–15% requiring medical treatment. These tumors consist of endothelial cells and stromal components, including fibroblasts, pericytes and mast cells. Effects of propranolol treatment in combination with bevacizumab or vincristine on cell growth were compared in the current study using human umbilical vein endothelial cells (HUVECs) and BJ human normal fibroblasts (BJs) to determine potential synergic effects in vitro. Inhibition of cell growth was investigated using MTT assays and cytotoxicity of the drugs in various combinations was expressed as half inhibitory concentration (IC50). Apoptosis was investigated using flow cytometry, with Alexa Fluor 488 and propidium iodide. Propranolol inhibited BJ and HUVEC growth in a dose-dependent manner, with increased response observed in BJs (IC50, 148,32 µg/ml; standard error logIC50, 0.07). Treatment with vincristine induced the strongest growth inhibition in HUVECs (IC50, 17,89 µg/ml; standard error log IC50, 0.07) and BJs (IC50, 24,81 µg/ml; standard error log IC50, 0.08) compared with propranolol (HUVEC IC50, 81,94 µg/ml; standard error log IC50, 0.06; BJ-IC50, 148,32 µg/ml; standard error logIC50, 0.07) or bevacizumab (HUVEC IC50 96,91 µg/ml; standard error log IC50, 0.06; BJ IC50, 182,70 µg/ml; standard error log IC50, 0.09) alone. Bevacizumab was the weakest cytotoxic agent. Combination treatment of vincristine with bevacizumab induced the highest levels of apoptosis in HUVECs compared with all other treatments and triple-drug therapy induced the levels of apoptosis in BJs. Single treatment with vincristine, propranolol or bevacizumab induced apoptosis in BJs and HUVECs. In BJs, triple treatment exhibited the greatest influence on apoptosis, compared with single and dual treatments and in HUVECs, vincristine and bevacizumab combination treatment induced apoptosis to the highest level. The present study offers novel perspectives in drug repurposing studies for the three drugs, particularly in diseases where the pathogenesis is based on healthy endothelial cell proliferation, including hemangiomas.
Colorectal cancer remains one of the most frequent malignancies (third place at both genders) worldwide in the last decade, owing to significant changes in modern dietary habits. Approximately half of the patients develop metastases during the course of their disease. The available therapeutic armamentarium is constantly evolving, raising questions regarding the best approach for improving survival. Bevacizumab remains one of the most widely used therapies for treating metastatic colorectal cancer and can be used after progression. This study aimed to identify the best chemotherapy partner for bevacizumab after progression. We performed a retrospective analysis of patients with metastatic colorectal cancer who were treated with bevacizumab as first- and second-line chemotherapy. Data were collected for 151 patients, 40 of whom were treated with double-dose bevacizumab after the first progression. The two standard chemotherapy regimens combined with bevacizumab were FOLFIRI/CAPIRI and FOLFOX4/CAPEOX. The initiation of first-line treatment with irinotecan-based chemotherapy improved progression-free survival and time to treatment failure but not overall survival. After the first progression, retreatment with the same regimen as that used in the induction phase was the best approach for improving overall survival (median overall survival: 46.5 vs. 27.0 months for the same vs. switched strategy, respectively). No correlations were observed between the dose intensity of irinotecan, oxaliplatin, 5-fluorouracil, or bevacizumab and the overall survival, progression-free survival in the first-/second-line treatment, and time to treatment failure. Interaction between an irinotecan-based regimen as a second-line treatment and double-dose bevacizumab after progression was associated with an improved overall survival (p = 0.06). Initiating systemic treatment with an irinotecan-based regimen in combination with bevacizumab improved the progression-free survival in the first-line treatment and time to treatment failure. In terms of overall survival, bevacizumab treatment after the first progression is better partnered with the same regimen as that used in the induction phase.
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