Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis

Abstract

BackgroundColorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of neoplasm-related death in the United States. Several studies analyzed the efficacy of bevacizumab combined with different chemotherapy regimens consisting on drugs such as 5-FU, capecitabine, irinotecan and oxaliplatin. This systematic review aims to evaluate the effectiveness and safety of chemotherapy plus bevacizumab versus chemotherapy alone in patients with previously untreated advanced or metastatic colorectal cancer (mCRC). MethodsSeveral databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were overall survival and progression-free survival. Data extracted from the studies were combined by using hazard ratio (HR) or risk ratio (RR) with their corresponding 95 % confidence intervals (95 % CI).ResultsThe final analysis included 9 trials comprising 3,914 patients. Patients who received the combined treatment (chemotherapy + bevacizumab) had higher response rates (RR = 0.89; 95 % CI: 0.82 to 0.96; p = 0.003) with heterogeneity, higher progression-free survival (HR = 0.69; 95 % CI: 0.63 to 0.75; p < 0.00001) and also higher overall survival rates (HR = 0.87; 95 % CI: 0.80 to 0.95; p = 0.002) with moderate heterogeneity. Regarding adverse events and severe toxicities (grade ≥ 3), the group receiving the combined therapy had higher rates of hypertension (RR = 3.56 95 % CI: 2.58 to 4.92; p < 0.00001), proteinuria (RR = 1.89; 95 % CI: 1.26 to 2.84; p = 0.002), gastrointestinal perforation (RR = 3.63; 95 % CI: 1.31 to 10.09; p = 0.01), any thromboembolic events (RR = 1.44; 95 % CI: 1.20 to 1.73; p = 0.0001), and bleeding (RR = 1.81; 95 % CI: 1.22 to 2.67; p = 0.003).ConclusionThe combination of chemotherapy with bevacizumab increased the response rate, progression-free survival and overall survival of patients with mCRC without prior chemotherapy. The results of progression-free survival (PFS) and overall survival (OS) were comparatively higher in those subgroups of patients receiving bolus 5-FU or capecitabine-based chemotherapy plus bevacizumab, when compared to patients treated with infusional %-FU plus bevacizumab (no difference in PFS and OS). Regarding the type of cytotoxic scheme, regimens containing irinotecan and fluoropyrimidine monotherapy showed superior efficacy results when combined to bevacizumab.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2734-y) contains supplementary material, which is available to authorized users.

Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta‐Analysis of More Than 20 000 Patients

“…[60][61][62][63] Naturally, the majority of the current RCTs and metaanalyses in the scope of VEGF inhibition have focused on either overall survival rates or event-free survival, particularly in patients with colorectal cancer, without describing the complete range of adverse events in all types of malignancies for which bevacizumab is prescribed. [64][65][66] A higher incidence of arterial adverse events in patients treated with bevacizumab has been previously described, concordant with our findings. 6,24,67,68 In contrast to prior analyses, here we have included several novel and important studies, assessed the differential impact of different cancer diagnoses on various types of arterial events, and approached the potential impact of dosage on risk.…”

“…Naturally, the majority of the current RCTs and meta‐analyses in the scope of VEGF inhibition have focused on either overall survival rates or event‐free survival, particularly in patients with colorectal cancer, without describing the complete range of adverse events in all types of malignancies for which bevacizumab is prescribed …”

WITHDRAWN: Efficacy and toxicities of combination maintenance therapy in the treatment of advanced colorectal cancer: a meta-analysis of randomized controlled trials

“…Due to the addition of novel biological agents to first-line chemotherapy in advanced colorectal cancer patients, the prognosis of advanced CRC patients has been significantly improved [18][19][20]. However, the optimal duration of first-line treatment remains a controversial issue [21].…”

Contribution of Angiogenesis to Inflammation and Cancer

“…The first drug approved by the FDA for the antiangiogenic treatment of solid tumors was Bevacizumab, which is a humanized anti-VEGF monoclonal antibody. Bevacizumab, in combination with chemotherapy, has been shown to increase progression-free survival (PFS) and overall survival (OS) (91)(92)(93)(94)(95). Aflibercept is a recombinant protein known as a "VEGF trap" that can bind all VEGF isoforms, along with PLGF, and inhibit their activities.…”