Background: The role of the widely-used angiogenesis inhibitor bevacizumab in the development of serious hemorrhage is not well defined in cancer patients. This study was conducted to determine the overall risk of hemorrhage with bevacizumab by a systematic review and meta-analysis of randomized controlled trials (RCT). Methods: Databases from PubMed and the Web of Science from January 1966 to May 2009 and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences from January 2000 to May 2009 were searched to identify relevant studies. Eligible studies included prospective RCTs in which bevacizumab was compared to controls concurrently with antineoplastic therapy. Summary incidence rates, relative risks (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models. Results: A total of 12,617 patients with a variety of solid tumors from 20 RCTs were included for analysis. The incidence of all-grade hemorrhage was 30.4% (95% CI 21.5–40.9), with 3.5% (95% CI 2.2–5.7%) being high grade (grade 3–5). Overall, bevacizumab significantly increased the risk of bleeding with an RR of 2.48 (95% CI 1.93–3.18) when compared to the controls, with RRs of 3.02 (95% CI 2.42–3.78) and 2.01 (95% CI 1.43–2.83) at 5 and 2.5 mg/kg/week, respectively. Significantly increased risks for epistaxis or pulmonary hemorrhage were observed. In addition, bevacizumab significantly increased the risk of high-grade bleeding with an RR of 1.91 (95% CI 1.36–2.68). The risk of fatal bleeding was low (0.8%; 95% CI 0.4–1.7), and significantly elevated only in lung cancer (RR 5.02; 95% CI 1.52–16.66). Conclusion: Bevacizumab may significantly increase the risk of serious hemorrhage in cancer patients.
Bevacizumab may significantly reduce the risk of anemia with chemotherapy in cancer patients.
Background: The purpose of this study was to determine which factors predicted survival and to derive a risk prediction model for patients with locally advanced non-small cell lung cancer (NSCLC) receiving concurrent chemo-radiotherapy (cCRT). Methods: This investigation included 149 patients with locally advanced NSCLC who were treated with cCRT at Stony Brook University Hospital between 2007 and 2015. A finite set of demographic, clinical, and treatment variables were evaluated as independent prognostic factors. Kaplan-Meier survival curves were generated, and log rank tests were used to evaluate difference in survival between groups. To derive a risk score for mortality, a machine learning approach was utilized. To maximize statistical power while examining replicability, the sample was split into discovery (n=99) and replication (n=50) subsamples. Elastic-net regression was used to identify a linear prediction model. Youden's index was used to identify appropriate cutoffs. Cox proportional hazards regression was used to examine mortality risk; model concordance and hazards ratios were reported. Results: One-quarter of the patients survived for three years after initiation of cCRT. Prognostic factors for survival in the discovery group included age, sex, smoking status, albumin, histology, largest tumor size, number of nodal stations, stage, induction therapy, and radiation dose. The derived model had good risk predictive accuracy (C=0.70). Median survival time was shorter in the high-risk group (0.93 years) vs the low-risk group (2.40 years). Similar findings were noted in the replication sample with strong model accuracy (C=0.69) and median survival time of 0.93 years and 2.03 years for the high-and low-risk groups, respectively. Conclusion: This novel risk prediction model for overall survival in patients with stage III NSCLC highlights the importance of integrating patient, clinical, and treatment variables for accurately predicting outcomes. Clinicians can use this tool to make personalized treatment decisions for patients with locally advanced NSCLC treated with concurrent chemo-radiation.
2639 Background: Pembrolizumab, a PD-1 immune checkpoint inhibitor (ICI), has demonstrated significant clinical activity in various cancers. Despite a favorable toxicity profile, discontinuation due to adverse events including immune related adverse events (irAE) has been reported. We conducted a meta-analysis of published clinical trials to evaluate the tolerability of pembrolizumab in cancer patients. Methods: A systematic review was conducted of relevant studies from the databases of PubMed and abstracts presented at American Society of Clinical Oncology (ASCO) from June 2015 until September 2020. Eligible studies included prospective clinical trials that reported a discontinuation rate due to adverse effects. Incidence, relative risk and 95% confidence intervals (CI) were calculated by employing fixed or random effects models. Results: A total of 6,380 patients with a variety of hematologic and solid malignancies from 20 studies of pembrolizumab were included for analysis. The overall rate of pembrolizumab discontinuation due to adverse events was 8.2% (95% CI: 6.4-10.4%). The discontinuation rate of pembrolizumab was not significantly lower than the chemotherapy controls, with RR of 0.84 (95% CI: 0.58-1.12, p = 0.33). However, the discontinuation rate of pembrolizumab was significantly higher compared to placebo control with RR of 2.20 (95% CI: 1.36-3.54, p < 0.001), and significantly lower compared to ipilimumab with RR of 0.58 (95% CI: 0.34-0.99, p = 0.04) respectively. The discontinuation rate varied widely among different tumor types with the lowest rate of 0.8% (95% CI: 0.2-3%) in gastric cancer, and the highest of 13.5% (95% CI: 10.8-16.8%) in head and neck squamous cell carcinoma. Interestingly, the discontinuation rate varied with pembrolizumab dosing, with the fixed dosing of 200mg being 9.2% (95% CI: 6.9-12%) and the weight-based dosing being 6.5% (95% CI: 4.8-8.8%). The weight-based dosing was associated with a significantly lower discontinuation rate compared to controls with RR of 0.62 (95% CI: 0.47-0.81, p < 0.0001), while the fixed dosing had similar discontinuation rate with RR of 1.03 (95% CI: 0.89-1.20, p = 0.67). Conclusions: The tolerability of pembrolizumab may be comparable to chemotherapy in cancer patients and may vary with its dosing. Future studies are warranted to evaluate the impact of different dosing.
9584 Background: Bleeding is a serious adverse event associated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) used extensively in the treatment of cancer. Currently the overall risk of bleeding remains unclear. This study was conducted to determine the overall risk of bleeding associated with bevacizumab in cancer patients by a meta-analysis of randomized controlled trials (RCT). Methods: Databases from PUBMED and the Web Science from January 1966 until July 2008 and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences from January 2000 to through July 2008 were searched to identify relevant studies. Eligible studies included prospective RCTs in which standard anti-neoplastic therapy was administered with and without the use of bevacizumab with available data of bleeding. Summary incidence rate, relative risk (RR), and 95% confidence interval (CI) were calculated employing fixed- or random-effect models based upon the heterogeneity of the included studies. Results: A total of 13048 patients with a variety of solid tumors from 20 RCTs were included for analysis. Among patients receiving bevacizumab, the incidence of all-grade bleeding was 36.3% (95% CI: 28.0 - 45.5), and the RR was 3.1 (95% CI: 2.4 - 4.1) as compared to controls. The incidence of high grade (grade 3 or above) bleeding with bevacizumab was 2.7% (95% CI: 2.0 - 3.6%), and the RR was 1.8 (95% CI: 1.2 - 2.7). The risk of bleeding varied with the dose of bevacizumab, with RR of 3.0 (95% CI: 2.4 - 3.6) at 5mg/kg/week and 1.6 (95% CI: 1.3 - 2.0) at 2.5mg/kg/week. The risk of bleeding with bevacizumab may vary with tumor type, with higher risk seen in patients with colorectal cancer (RR=6.6, 95% CI: 3.6–12.2) and renal cell cancer (RR=3.7, 95% CI: 2.6–5.5). Bevacizumab is associated with different patterns of bleeding, with epistaxis being the most common. The incidence of all grade epistaxis with bevacizumab was 33.8% (95% CI 24.5–44.6) with a RR of 3.1 (95% CI 2.4 - 4.0). Conclusions: There is a significant increase in the risk of bleeding in cancer patients receiving bevacizumab. The risk may vary with the dose of bevacizumab and tumor type. No significant financial relationships to disclose.
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