Editorial
Bevicizumab and Thrombosis: Some Answers But Questions Remain Thomas G. DeLoughery, MD and Tomasz M. Beer, MD
In this issue of Cancer, a report by Patel and colleagues examines the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer.1 Using the results from Cancer and Leukemia Group B (CALGB) trial 90401, which evaluated the addition of bevacizumab to standard docetaxel chemotherapy, the authors demonstrate that bevacizumab treatment is associated with an increased risk of arterial—but not venous—thromboembolism in patients with metastatic, castrate-resistant prostate cancer. Bevacizumab is an antitumor agent whose mechanism of action is not direct cytotoxicity but interference with tumor vessel growth through the inhibition of vascular endothelial growth factor (VEGF). This unique mechanism of action may also be responsible for the complications discussed in the report by Patel et al: thrombosis. The association between bevacizumab and thrombosis is important, both because cancer patients are at high risk of developing thrombosis and because the patients who have the tumors that often are treated with bevacizumab (brain, colon, and lung tumors) suffer from high rates of thrombosis at baseline.2 It is believed that the etiology of thrombosis in patients with cancer is multifactorial. Tumors themselves are thrombogenic, perhaps because of increased expression of prothrombotic proteins, such as tissue factor. Cancer treatments add to this risk. The same surgery performed in patients who have cancer increases the risk of thrombosis 3-fold compared with patients who do not have cancer.3 Cytotoxic chemotherapy also increases the risk of thrombosis. The development of noncytotoxic cancer therapies has revealed that certain agents are associated with a substantial risk of thrombosis. For example, thalidomide in association with chemotherapy produces venous thrombosis in up to 25% of patients treated,4 and the VEGF tyrosine kinase inhibitor ponatinib (Iclusig; ARIAD Pharmaceuticals, Cambridge, Mass) leads to arterial thrombosis in greater than 20% of patients who receive it (prescribing information for ponatinib is available at: http:// www.iclusig.com/pi/; accessed October 19, 2014). Past studies have demonstrated an increased rate of arterial thrombosis with the receipt of bevacizumab. Single studies and meta-analyses have indicated an increase in the relative risk ranging from 1.5-fold to 2-fold among patients who receive bevacizumab compared with controls.5 The risk of venous thrombosis has been less clear, with some studies demonstrating an increased risk but a large meta-analysis demonstrating no increase in risk.6 Given the use of bevacizumab for common tumors, such as lung cancer, even a small increase in vascular complications would put many patients at risk. Thus, the vascular risks associated with this agent are an important subject. The CALGB 90401 study helps provide important information about bevacizumab and the risk of thrombosis for patients with prostate cancer who are receiving chemotherapy. In that study, 1008 patients with prostate cancer received prednisone and docetaxel with or without bevacizumab. The median age of the patients was 69 years. Patients who had previous arterial or venous events were included, with the exception of those who had arterial thrombotic events in the previous 12 months. The overall study indicated that the addition of bevacizumab improved progression-free survival but not overall survival and increased the risk of treatment-related death. The relatively homogenous population of the study allowed for a detailed analysis of the vascular risks associated with bevacizumab. The study confirmed the elevated risk of arterial thrombosis from the receipt of bevacizumab, with a 2.70-fold increase (range, 1.14-fold to 6.43-fold increase) in risk observed. Prior arterial thrombosis and increasing age were
Corresponding authors: Thomas G. DeLoughery, MD, Division of Hematology and Medical Oncology, OHSU Knight Cancer Institute, 3181 SW Sam Jackson Park Road, L586, Portland, OR 97239; Fax: (503) 494-4285; [email protected]; Tomasz M. Beer, MD, Division of Hematology and Medical Oncology, OHSU Knight Cancer Institute, 3303 SW Bond Avenue, CH14R, Portland, OR 97239; Fax: (503) 494-4393; [email protected] Division of Hematology and Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon See referenced original article on pages 1025-31, this issue. DOI: 10.1002/cncr.29168, Received: November 3, 2014; Accepted: November 6, 2014, Published online November 21, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
April 1, 2015
975
Editorial
identified as risk factors for arterial events. For venous thrombosis, a trend toward decreased rates was observed (0.60-fold increase; range, 0.35-fold to 1.02-fold increase), and increasing age was identified as a risk factor. The finding of increased arterial thrombosis is consistent with previous studies.5 The mechanism that mediates a bevacizumab-related increase in the risk of thrombosis is not known but is believed to be caused by several factors. Bevacizumab can be associated with increased blood pressure, and hypertensions is a known risk factor for arterial thrombosis.7 VEGF is an important growth factor for endothelial cells and plays a role in maintaining their normal function. Decreased levels of VEGF may lead to a more prothrombotic endothelial cell phenotype.8 The finding that VEGF tyrosine kinase inhibitors, such as sorafenib and sunitinib, also increase arterial thrombosis 2.2-fold9 provides more evidence for this concept. Finally, VEGF increases the production of nitric oxide and prostacyclins—chemicals that are both vasodilators and inhibitors of platelet function. The study also verified the unanticipated finding from previous studies that the use of aspirin appeared to fail to protect against arterial thrombosis.5 Because the study did not control for the use of aspirin, a definitive statement cannot be made regarding its effect on the risk of arterial thrombosis. Patient selection biases complicate such analyses. For example, it is possible that the patients who were taking aspirin were those at higher risk of thrombosis. If that had happened, then a protective effect would have been hard if not impossible to detect. However, given the consistency of this finding across studies, it is possible that aspirin is not effective at preventing arterial thrombosis in this population or at preventing arterial thrombosis that is mediated by these mechanisms. It also may be reasonable to speculate that the protective effects of aspirin could be dose-dependent and that the low doses prescribed were insufficient to be effective. Like the results from a large meta-analysis,6 in this study, bevacizumab did not increase the rate of venous thrombosis but actually appeared to decrease the risk. The authors speculate that this may be caused by improved tumor control, leading to a less prothrombotic state. It is impossible to determine whether this speculation is true; however, the differences in antitumor activity between the chemotherapy only (control) arm and the chemotherapy plus bevacizumab arm of the study were modest. A potential confounder may have been the choices patients and physicians made. Because it is believed that bevacizumab is prothrombotic, the patients who received bevacizumab 976
may have been more likely to receive prophylaxis against venous thrombosis than patients in the control arm. A unique objective of this study was the validation of a previously developed venous thrombosis risk factor scoring tool, the Khorana score, which uses the complete blood count variables of white cell and platelet counts plus hemoglobin, body mass index, and tumor location to derive a risk score. In this study, the majority of patients were in the low-risk category (68%), a minority of patients were in the high-risk category, (0.5%), and the rest were in the intermediate-risk category. The low number of high-risk patients reflects the finding that, in this scoring system, patients with prostate cancer are identified as having a low risk for thrombosis. Thus, it is exceedingly difficult for patients with prostate cancer to accumulate enough risk points to be deemed high risk. The intermediate-risk and higher risk patients had an increased risk of thrombosis, confirming the utility of this scoring system. The ability to identify cancer patients at higher risk of thrombosis will allow improved targeting of patients for future clinical trials of thrombosis prevention and is an important contribution. Now that the arterial risk of bevacizumab is well established, attention needs to be directed to the amelioration of this risk. To our knowledge, there are no prospective data that provides guidance; therefore, the recommendations that can be considered are pragmatic rather than evidence-based. Control of known risk factors for arterial thrombosis, such as smoking and hypercholesterolemia, through smoking cessation and the use of statins seem reasonable. Given the propensity of bevacizumab to cause hypertension, aggressive control of blood pressure also is probably important. The role of antiplatelet agents remains uncertain. Perhaps higher doses or novel dosing schemes, such as twice-daily dosing with aspirin, would decrease arterial thrombosis, but these may also raise the risk of bleeding; thus, any novel approach needs to be carefully, prospectively tested. Another important area for future research is to define the mechanisms that drive the development of arterial thrombosis with agents like bevacizumab and ponatininib. Although we have speculated on several potential mechanisms, there is a clear need and opportunity for rigorous research to definitively clarify how VEGF inhibition promotes arterial thrombosis. The identification of any unique pathways not only may help develop safer anticancer agents but also may provide novel insights into the mechanism of arterial thrombosis Cancer
April 1, 2015
Editorial/DeLoughery and Beer
and the potential development of novel antithrombotic agents. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Patel NJ, Jiang C, Hertz DL, et al. Bevacizumab and the risk of arterial and venous thromboembolism in metastatic castration-resistant prostate cancer patients treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance). Cancer. 2015;121:1025-1031. 2. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122:17121723.
Cancer
April 1, 2015
3. Orfanakis A, Deloughery T. Patients with disorders of thrombosis and hemostasis. Med Clin North Am. 2013;97:1161-1180. 4. Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood. 2001;98:1614-1615. 5. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232-1239. 6. Hurwitz HI, Saltz LB, Van Cutsem E, et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol. 2011;29:1757-1764. 7. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49:186-193. 8. Ferroni P, Formica V, Roselli M, Guadagni F. Thromboembolic events in patients treated with anti-angiogenic drugs. Curr Vasc Pharmacol. 2010;8:102-113. 9. Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28: 2280-2285.
977
Copyright of Cancer (0008543X) is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Bevicizumab and Thrombosis: Some Answers But Questions Remain Thomas G. DeLoughery, MD and Tomasz M. Beer, MD
In this issue of Cancer, a report by Patel and colleagues examines the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer.1 Using the results from Cancer and Leukemia Group B (CALGB) trial 90401, which evaluated the addition of bevacizumab to standard docetaxel chemotherapy, the authors demonstrate that bevacizumab treatment is associated with an increased risk of arterial—but not venous—thromboembolism in patients with metastatic, castrate-resistant prostate cancer. Bevacizumab is an antitumor agent whose mechanism of action is not direct cytotoxicity but interference with tumor vessel growth through the inhibition of vascular endothelial growth factor (VEGF). This unique mechanism of action may also be responsible for the complications discussed in the report by Patel et al: thrombosis. The association between bevacizumab and thrombosis is important, both because cancer patients are at high risk of developing thrombosis and because the patients who have the tumors that often are treated with bevacizumab (brain, colon, and lung tumors) suffer from high rates of thrombosis at baseline.2 It is believed that the etiology of thrombosis in patients with cancer is multifactorial. Tumors themselves are thrombogenic, perhaps because of increased expression of prothrombotic proteins, such as tissue factor. Cancer treatments add to this risk. The same surgery performed in patients who have cancer increases the risk of thrombosis 3-fold compared with patients who do not have cancer.3 Cytotoxic chemotherapy also increases the risk of thrombosis. The development of noncytotoxic cancer therapies has revealed that certain agents are associated with a substantial risk of thrombosis. For example, thalidomide in association with chemotherapy produces venous thrombosis in up to 25% of patients treated,4 and the VEGF tyrosine kinase inhibitor ponatinib (Iclusig; ARIAD Pharmaceuticals, Cambridge, Mass) leads to arterial thrombosis in greater than 20% of patients who receive it (prescribing information for ponatinib is available at: http:// www.iclusig.com/pi/; accessed October 19, 2014). Past studies have demonstrated an increased rate of arterial thrombosis with the receipt of bevacizumab. Single studies and meta-analyses have indicated an increase in the relative risk ranging from 1.5-fold to 2-fold among patients who receive bevacizumab compared with controls.5 The risk of venous thrombosis has been less clear, with some studies demonstrating an increased risk but a large meta-analysis demonstrating no increase in risk.6 Given the use of bevacizumab for common tumors, such as lung cancer, even a small increase in vascular complications would put many patients at risk. Thus, the vascular risks associated with this agent are an important subject. The CALGB 90401 study helps provide important information about bevacizumab and the risk of thrombosis for patients with prostate cancer who are receiving chemotherapy. In that study, 1008 patients with prostate cancer received prednisone and docetaxel with or without bevacizumab. The median age of the patients was 69 years. Patients who had previous arterial or venous events were included, with the exception of those who had arterial thrombotic events in the previous 12 months. The overall study indicated that the addition of bevacizumab improved progression-free survival but not overall survival and increased the risk of treatment-related death. The relatively homogenous population of the study allowed for a detailed analysis of the vascular risks associated with bevacizumab. The study confirmed the elevated risk of arterial thrombosis from the receipt of bevacizumab, with a 2.70-fold increase (range, 1.14-fold to 6.43-fold increase) in risk observed. Prior arterial thrombosis and increasing age were
Corresponding authors: Thomas G. DeLoughery, MD, Division of Hematology and Medical Oncology, OHSU Knight Cancer Institute, 3181 SW Sam Jackson Park Road, L586, Portland, OR 97239; Fax: (503) 494-4285; [email protected]; Tomasz M. Beer, MD, Division of Hematology and Medical Oncology, OHSU Knight Cancer Institute, 3303 SW Bond Avenue, CH14R, Portland, OR 97239; Fax: (503) 494-4393; [email protected] Division of Hematology and Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon See referenced original article on pages 1025-31, this issue. DOI: 10.1002/cncr.29168, Received: November 3, 2014; Accepted: November 6, 2014, Published online November 21, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
April 1, 2015
975
Editorial
identified as risk factors for arterial events. For venous thrombosis, a trend toward decreased rates was observed (0.60-fold increase; range, 0.35-fold to 1.02-fold increase), and increasing age was identified as a risk factor. The finding of increased arterial thrombosis is consistent with previous studies.5 The mechanism that mediates a bevacizumab-related increase in the risk of thrombosis is not known but is believed to be caused by several factors. Bevacizumab can be associated with increased blood pressure, and hypertensions is a known risk factor for arterial thrombosis.7 VEGF is an important growth factor for endothelial cells and plays a role in maintaining their normal function. Decreased levels of VEGF may lead to a more prothrombotic endothelial cell phenotype.8 The finding that VEGF tyrosine kinase inhibitors, such as sorafenib and sunitinib, also increase arterial thrombosis 2.2-fold9 provides more evidence for this concept. Finally, VEGF increases the production of nitric oxide and prostacyclins—chemicals that are both vasodilators and inhibitors of platelet function. The study also verified the unanticipated finding from previous studies that the use of aspirin appeared to fail to protect against arterial thrombosis.5 Because the study did not control for the use of aspirin, a definitive statement cannot be made regarding its effect on the risk of arterial thrombosis. Patient selection biases complicate such analyses. For example, it is possible that the patients who were taking aspirin were those at higher risk of thrombosis. If that had happened, then a protective effect would have been hard if not impossible to detect. However, given the consistency of this finding across studies, it is possible that aspirin is not effective at preventing arterial thrombosis in this population or at preventing arterial thrombosis that is mediated by these mechanisms. It also may be reasonable to speculate that the protective effects of aspirin could be dose-dependent and that the low doses prescribed were insufficient to be effective. Like the results from a large meta-analysis,6 in this study, bevacizumab did not increase the rate of venous thrombosis but actually appeared to decrease the risk. The authors speculate that this may be caused by improved tumor control, leading to a less prothrombotic state. It is impossible to determine whether this speculation is true; however, the differences in antitumor activity between the chemotherapy only (control) arm and the chemotherapy plus bevacizumab arm of the study were modest. A potential confounder may have been the choices patients and physicians made. Because it is believed that bevacizumab is prothrombotic, the patients who received bevacizumab 976
may have been more likely to receive prophylaxis against venous thrombosis than patients in the control arm. A unique objective of this study was the validation of a previously developed venous thrombosis risk factor scoring tool, the Khorana score, which uses the complete blood count variables of white cell and platelet counts plus hemoglobin, body mass index, and tumor location to derive a risk score. In this study, the majority of patients were in the low-risk category (68%), a minority of patients were in the high-risk category, (0.5%), and the rest were in the intermediate-risk category. The low number of high-risk patients reflects the finding that, in this scoring system, patients with prostate cancer are identified as having a low risk for thrombosis. Thus, it is exceedingly difficult for patients with prostate cancer to accumulate enough risk points to be deemed high risk. The intermediate-risk and higher risk patients had an increased risk of thrombosis, confirming the utility of this scoring system. The ability to identify cancer patients at higher risk of thrombosis will allow improved targeting of patients for future clinical trials of thrombosis prevention and is an important contribution. Now that the arterial risk of bevacizumab is well established, attention needs to be directed to the amelioration of this risk. To our knowledge, there are no prospective data that provides guidance; therefore, the recommendations that can be considered are pragmatic rather than evidence-based. Control of known risk factors for arterial thrombosis, such as smoking and hypercholesterolemia, through smoking cessation and the use of statins seem reasonable. Given the propensity of bevacizumab to cause hypertension, aggressive control of blood pressure also is probably important. The role of antiplatelet agents remains uncertain. Perhaps higher doses or novel dosing schemes, such as twice-daily dosing with aspirin, would decrease arterial thrombosis, but these may also raise the risk of bleeding; thus, any novel approach needs to be carefully, prospectively tested. Another important area for future research is to define the mechanisms that drive the development of arterial thrombosis with agents like bevacizumab and ponatininib. Although we have speculated on several potential mechanisms, there is a clear need and opportunity for rigorous research to definitively clarify how VEGF inhibition promotes arterial thrombosis. The identification of any unique pathways not only may help develop safer anticancer agents but also may provide novel insights into the mechanism of arterial thrombosis Cancer
April 1, 2015
Editorial/DeLoughery and Beer
and the potential development of novel antithrombotic agents. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Patel NJ, Jiang C, Hertz DL, et al. Bevacizumab and the risk of arterial and venous thromboembolism in metastatic castration-resistant prostate cancer patients treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance). Cancer. 2015;121:1025-1031. 2. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122:17121723.
Cancer
April 1, 2015
3. Orfanakis A, Deloughery T. Patients with disorders of thrombosis and hemostasis. Med Clin North Am. 2013;97:1161-1180. 4. Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood. 2001;98:1614-1615. 5. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232-1239. 6. Hurwitz HI, Saltz LB, Van Cutsem E, et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol. 2011;29:1757-1764. 7. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49:186-193. 8. Ferroni P, Formica V, Roselli M, Guadagni F. Thromboembolic events in patients treated with anti-angiogenic drugs. Curr Vasc Pharmacol. 2010;8:102-113. 9. Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28: 2280-2285.
977
Copyright of Cancer (0008543X) is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
