Shenhong Wu

Risk of Venous Thromboembolism With the Angiogenesis Inhibitor Bevacizumab in Cancer Patients: A Meta-analysis

CONTEXT Venous thromboembolism is one of the leading causes of morbidity and mortality in patients with cancer. Concerns have arisen regarding the risk of venous thromboembolism with the novel antiangiogenic agent bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in venous thromboembolism is controversial. OBJECTIVE To assess the overall risk of venous thromboembolism associated with the use of bevacizumab, a systematic review and meta-analysis of published randomized controlled trials was performed. DATA SOURCES The databases of PubMed and Web of Science were searched for articles published in the English language from January 1966 until January 2008 and abstracts presented at American Society of Clinical Oncology conferences held between January 2000 and January 2008 were searched to identify relevant clinical trials. STUDY SELECTION AND DATA EXTRACTION Eligible studies included prospective randomized controlled trials in which standard antineoplastic therapy was used with and without bevacizumab and data on venous thromboembolism were available. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. DATA SYNTHESIS A total of 7956 patients with a variety of advanced solid tumors from 15 randomized controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidences of all-grade and high-grade venous thromboembolism were 11.9% (95% CI, 6.8%-19.9%) and 6.3% (95% CI, 4.8%-8.3%), respectively. Patients treated with bevacizumab had a significantly increased risk of venous thromboembolism with an RR of 1.33 (95% CI, 1.13-1.56; P < .001) compared with controls. The risk was significantly increased for both all-grade and high-grade venous thromboembolism. In addition, the risk was similarly increased for bevacizumab at 2.5 mg/kg per week (low dose; RR, 1.31 [95% CI, 1.08-1.60]; P = .007) and 5 mg/kg per week (high dose; RR, 1.31 [95% CI, 1.02-1.68]; P = .04). CONCLUSION The use of bevacizumab was significantly associated with an increased risk of developing venous thromboembolism in cancer patients receiving this drug.

Treatment-Related Mortality With Bevacizumab in Cancer Patients: A Meta-analysis

CONTEXT Fatal adverse events (FAEs) have been reported in cancer patients treated with the widely used angiogenesis inhibitor bevacizumab in combination with chemotherapy. Currently, the role of bevacizumab in treatment-related mortality is not clear. OBJECTIVE To perform a systematic review and meta-analysis of published randomized controlled trials (RCTs) to determine the overall risk of FAEs associated with bevacizumab. DATA SOURCES PubMed, EMBASE, and Web of Science databases as well as abstracts presented at American Society of Clinical Oncology conferences from January 1966 to October 2010 were searched to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION Eligible studies included prospective RCTs in which bevacizumab in combination with chemotherapy or biological therapy was compared with chemotherapy or biological therapy alone. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models. DATA SYNTHESIS A total of 10,217 patients with a variety of advanced solid tumors from 16 RCTs were included in the analysis. The overall incidence of FAEs with bevacizumab was 2.5% (95% CI, 1.7%-3.9%). Compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of FAEs, with an RR of 1.46 (95% CI, 1.09-1.94; P = .01; incidence, 2.5% vs 1.7%). This association varied significantly with chemotherapeutic agents (P = .045) but not with tumor types (P = .13) or bevacizumab doses (P = .16). Bevacizumab was associated with an increased risk of FAEs in patients receiving taxanes or platinum agents (RR, 3.49; 95% CI, 1.82-6.66; incidence, 3.3% vs 1.0%) but was not associated with increased risk of FAEs when used in conjunction with other agents (RR, 0.85; 95% CI, 0.25-2.88; incidence, 0.8% vs 0.9%). The most common causes of FAEs were hemorrhage (23.5%), neutropenia (12.2%), and gastrointestinal tract perforation (7.1%). CONCLUSION In a meta-analysis of RCTs, bevacizumab in combination with chemotherapy or biological therapy, compared with chemotherapy alone, was associated with increased treatment-related mortality.

Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis

BACKGROUND Gastrointestinal perforation is a serious adverse event associated with bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF) widely used in current cancer treatment. The association is highlighted by a black-box warning issued by the US Food and Drug Administration, recommending that bevacizumab be permanently discontinued in patients with gastrointestinal perforation. However, no significant association has yet been established between bevacizumab and gastrointestinal perforation in randomised controlled trials. We did a systematic review and meta-analysis of published randomised controlled trials to assess the overall risk of gastrointestinal perforation associated with bevacizumab treatment. METHODS We searched PubMed and Web of Science for articles published between January, 1966, and July, 2008. Additionally, abstracts presented at American Society of Clinical Oncology conferences held between January, 2000, and July, 2008, were searched to identify relevant clinical trials. Eligible studies included prospective randomised controlled trials in which bevacizumab was compared with controls in combination with standard anti-neoplastic therapy. Summary incidence rates, relative risks, and 95% CIs were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. FINDINGS 12,294 patients with a variety of solid tumours from 17 randomised controlled trials were included in our analysis. The incidence of gastrointestinal perforation was 0.9% (95% CI 0.7-1.2) among patients receiving bevacizumab, with a mortality of 21.7% (11.5-37.0). Patients treated with bevacizumab had a significantly increased risk of gastrointestinal perforation compared with patients treated with control medication, with a relative risk of 2.14 (95% CI 1.19-3.85; p=0.011). Risk varied with bevacizumab dose and tumour type. Relative risks for patients receiving bevacizumab at 5 and 2.5 mg/kg per week were 2.67 (95% CI 1.14-6.26) and 1.61 (0.76-3.38), respectively. Higher risks were observed in patients with colorectal carcinoma (relative risk 3.10, 95% CI 1.26-7.63) and renal cell cancer (relative risk 5.67, 0.66-48.42). INTERPRETATION The addition of bevacizumab to cancer therapy significantly increased the risk of gastrointestinal perforation compared with controls. The risk may vary with bevacizumab dose and tumour type. Further studies are recommended to investigate the use of bevacizumab in selected patients who have recovered from gastrointestinal perforation. FUNDING Stony Brook University Research Foundation.

Evolving Strategies for the Management of Hand–Foot Skin Reaction Associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib

The multitargeted kinase inhibitors (MKIs) sorafenib and sunitinib have shown benefit in patients with renal cell carcinoma, hepatocellular carcinoma (sorafenib), and gastrointestinal stromal tumor (sunitinib). Their efficacy in other malignancies is currently being investigated because of their broad range of activity. The effectiveness of these drugs is somewhat diminished by the development of a variety of toxicities, most notably hand-foot skin reaction (HFSR). Although HFSR does not appear to directly affect survival, it can impact quality of life and lead to MKI dose modification or interruption, potentially limiting the antitumor effect. Currently, no standard guidelines exist for the prevention and management of MKI-associated HFSR. To address this issue, an international, interdisciplinary panel of experts gathered in January 2008 to discuss and evaluate the best-practice management of these reactions. Based on these proceedings, recommendations for the management of HFSR have been provided to offer patients the best possible quality of life while taking these drugs and to optimize the patient benefit associated with MKI therapy.

Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: Systematic review and meta-analysis

Background. Sunitinib is a multitargeted tyrosine kinase inhibitor used in the treatment of metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST), and undergoing evaluation for other malignancy. Hypertension is one of its major side effects with a substantial variation in the reported incidences among clinical studies. We here performed a systematic review and meta-analysis of published clinical trials to determine its overall risk. Methods. Relevant studies were searched and identified in MEDLINE (OVID 1966 to July, 2007), Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2007. Eligible studies were prospective clinical trials that had described events of hypertension for patients who received single agent sunitinib. The incidence of hypertension and relative risk (RR) were calculated using the random-effects or the fixed-effects model. Results. A total of 4, 999 patients with RCC and other malignancies from 13 clinical trials were included for analysis. Among patients receiving sunitinib, the incidence of all-grade and high-grade hypertensions were 21.6% (95% CI: 18.7–24.8%) and 6.8% (95% CI: 5.3–8.8%) respectively. The risk may vary with tumor type and the dosing schedule of sunitinib. Sunitinib was associated with a significantly increased risk of high-grade hypertension (RR=22.72, 95% CI: 4.48 to 115.29, p<0.001) and renal dysfunction (RR: 1.36, 95% CI: 1.20 to 1.54, p<0.001) in comparison with controls. Conclusions. There is a significant risk of developing hypertension and renal dysfunction among patients receiving sunitinib. Adequate monitoring and treatment of hypertension is recommended.

Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: A meta-analysis of randomized controlled trials

Abstract Background. The risk of cardiovascular toxicities is a serious concern with the increased application of angiogenesis inhibitors in current cancer therapy. Arterial thromboembolic events (ATE) were associated with bevacizumab, an antibody against vascular endothelial growth factor. To determine the risk of ATE including cardiac ischemia and stroke, a systematic review and meta-analysis of published randomized controlled trials (RCTs) was performed. Methods. We searched the databases of PubMed, Web of Science, and American Society of Clinical Oncology conferences to identify relevant clinical trials up to May, 2009. Eligible studies included prospective RCTs in which bevacizumab was compared to a control concurrently in combination with standard anti-neoplastic therapy. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models. Results. A total of 12 617 patients with a variety of advanced solid tumors from 20 RCTs were included for analysis. The incidences of all-grade and high-grade ATE in patients receiving bevacizumab were 3.3% (95% CI, 2.0–5.6%) and 2.0% (95% CI, 1.7–2.5) respectively. Patients treated with bevacizumab had a significantly increased risk of ATE with an RR of 1.44 (95% CI, 1.08–1.91; p=0.013) compared with controls. The risk similarly increased for bevacizumab at 2.5 and 5 mg/kg/week; in addition, significantly increased risks were observed in patients with renal cell cancer (RR, 3.72, 95% CI, 1.15–12.04; p=0.029) and colorectal cancer (RR, 1.89, 95% CI, 1.28–2.80, p=0.001). Notably, the risk of high-grade cardiac ischemia with bevacizumab was significantly higher than controls with an RR of 2.14 (95% CI, 1.12–4.08, p=0.021); however, the risk of ischemic stroke with bevacizumab was not significantly different from controls (RR, 1.37, 95% CI, 0.67–2.79, p=0.39). Discussion. Treatment with bevacizumab may significantly increase the risk of cardiac ischemic events in cancer patients.

Risk of hand-foot skin reaction with sorafenib: A systematic review and meta-analysis

Background. Hand-foot skin reaction (HFSR) is a dose-limiting toxicity associated with sorafenib, an oral multi-kinase inhibitor with clinical activity against solid tumors. This study was conducted to determine the risk of developing HFSR among patients receiving sorafenib. Patients and Methods. Databases from Pubmed, Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through July, 2007 were searched to identify relevant studies. Eligible studies were prospective clinical trials using single agent sorafenib. The summary incidence rate and the relative risk (RR) were calculated using random-effects model. Results. A total of 4 883 patients in 11 trials with metastatic tumors were included for analysis. Among patients receiving sorafenib, the summary incidence of all-grade HFSR was 33.8% (95% CI: 24.5–44.7%) with significant difference between patients with RCC and non-RCC malignancy (RR 1.52, 95% CI: 1.32–1.75%, p<0.001). The incidence of high-grade HFSR was 8.9% (95% CI: 7.3–10.7%). In addition, sorafenib was associated with a significant increased risk of HFSR with RR of 6.6 (95% CI: 3.7 to 11.7, p<0.001) in comparison with controls. Conclusion. There is a significant risk of HFSR associated with sorafenib. Proper management and further study are recommended to reduce the risk.

Increased Risk of High-Grade Hypertension With Bevacizumab in Cancer Patients: A Meta-Analysis

BACKGROUND Hypertension is associated with the use of bevacizumab, an angiogenesis inhibitor widely used in cancer therapy. Currently, the risk of severe hypertension associated with bevacizumab is unclear. We performed a systematic review and meta-analysis of published randomized-controlled clinical trials (RCTs) to assess the risk of high-grade hypertension in cancer patients treated with bevacizumab. METHODS Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2009 were searched to identify relevant studies. Eligible studies included prospective RCTs in which bevacizumab was directly compared with controls in cancer patients receiving concurrent antineoplastic therapy. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies. RESULTS A total of 12,656 patients with a variety of tumors from 20 studies were included for the analysis. The incidence of all-grade hypertension in patients receiving bevacizumab was 23.6% (95% CI: 20.5-27.1) with 7.9% (95% CI: 6.1-10.2) being high-grade (grade 3 or 4). Patients treated with bevacizumab had a significantly increased risk of developing high-grade hypertension with an RR of 5.28 (95% CI: 4.15-6.71, P < 0.001) in comparison with controls. Even though not statistically significant, there was a trend suggesting that bevacizumab may increase the risk of hypertensive crisis (grade 4) with an RR of 3.16 (95% CI: 0.91-10.90). The increased risk of high-grade hypertension was observed in patients receiving bevacizumab at 2.5 mg/kg/week (RR = 4.78, 95% CI: 3.59-6.36) as well as 5 mg/kg/week (RR = 5.39, 95% CI: 3.68-7.90). The risk of high-grade hypertension may vary with tumor types, with RRs ranging from 2.49 (95% CI: 0.94-6.59) in patients with mesothelioma to 14.80 (95% CI: 0.92-238.51) in patients with breast cancer. CONCLUSION Bevacizumab may significantly increase the risk of high-grade hypertension in cancer patients. Close monitoring and adequate management are highly recommended to decrease cardiovascular complications.

Increased Risk of Serious Hemorrhage with Bevacizumab in Cancer Patients: A Meta-Analysis

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.

Risk of Hand-Foot Skin Reaction with the Multitargeted Kinase Inhibitor Sunitinib in Patients with Renal Cell and Non-Renal Cell Carcinoma: A Meta-analysis

Hand-foot skin reaction (HFSR) is an emerging issue in cancer treatment with multitargeted tyrosine kinase inhibitors (TKIs), leading to morbidity, suboptimal dosing, and poor compliance. The overall risk of HFSR is not clear for sunitinib, a TKI effective for metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor. We therefore conducted a systematic review and a meta-analysis to determine the risk of developing HFSR with sunitinib. Databases from PubMed and Web of Science for articles from July 1966 until July 2007 and abstracts presented at the American Society of Clinical Oncology conferences were searched to identify relevant studies. Eligible studies were prospective clinical trials that had described events of HFSR for patients who received singleagent sunitinib. Incidence and relative risk (RR) were calculated using a random-effects or fixed-effects model. A total of 5005 patients with RCC and other cancers from 10 clinical trials were included for analysis. Among patients receiving sunitinib, the summary incidences of all-grade and high-grade HFSR were 18.9% (95% CI, 14.1%-24.8%) and 5.5% (95% CI, 3.9%-7.9%), respectively. Interestingly, patients with RCC have significantly decreased risk of HFSR compared with patients with non-RCC malignancy (RR, 0.56; 95% CI, 0.50-0.64; P < .001). In addition, sunitinib was associated with a significantly increased risk of all-grade HFSR (RR, 9.86; 95% CI, 3.1-31.31; P < .001) in comparison with controls. There is a significant risk of developing HFSR in patients with cancer receiving sunitinib. Adequate monitoring and intervention are recommended for reducing the toxicity.