A60 year-old man with a history of

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1 CLINICIAN UPDATE Effects of Novel Angiogenesis Inhibitors for the Treatment of Cancer on the Cardiovascular System Focus on Hypertension Babak Nazer, MD; Benjamin D. Humphreys, MD, PhD; Javid Moslehi, MD A60 year-old man with a history of prostate cancer who underwent radical prostatectomy is currently being treated with androgen-deprivation therapy and is on a clinical trial with bevacizumab (Avastin, an antiangiogenic and anti vascular endothelia growth factor [VEGF] chemotherapy) for an elevated prostate-specific antigen. At clinic visits after starting bevacizumab, he was noted to have new hypertension, with blood pressure as high as 178/98 mm Hg. After his second cycle of bevacizumab, he had sudden onset of palpitations, with workup revealing atrial fibrillation. He spontaneously cardioverted back to sinus rhythm but was referred to our institution s cardiology clinic for oncology patients (Cardio-Oncology Clinic) for management of hypertension and atrial fibrillation in the setting of bevacizumab therapy. Angiogenesis, the formation of new blood vessels from preexisting ones, is required for the growth and metastases of solid tumors. 1 Angiogenesis is mediated by the stabilization of the master transcription factor (hypoxiainducible factor- ), leading to transcription of a number of protumorigenic factors, including VEGF. Inhibiting this pathway has served as a target for antineoplastic treatment, and over the last 5 years, VEGF signaling pathway (VSP) inhibitors have been approved for the treatment of a broad spectrum of malignancies (the Figure). With increased clinical use, these agents have been shown to have cardiovascular side effects, most commonly hypertension, but also arterial or venous thrombotic events and heart failure. This review outlines the presentation, pathophysiology, and our approach to the diagnosis and treatment of VSP inhibitor induced hypertension, and briefly highlights other cardiac complications that may occur in patients receiving these agents. Pharmacology of Angiogenesis Inhibitors The VEGF family of growth factors includes 4 distinct proteins, VEGF A through VEGF D, with VEGF-A (referred to here as VEGF) being the most clinically relevant, promoting angiogenesis in tumor cells through several distinct effects. 1 The 3 VEGF receptors, VEGFR-1, -2, and -3, are members of the receptor tyrosine kinase family. Of these, VEGFR-2 is most robustly expressed on endothelial cell membranes and mediates the above angiogenic effects. 1 Decreasing VEGF activity by targeting the growth factor itself or its receptor is a primary strategy underlying a new wave of targeted oncological therapies (the Figure). The first clinically available VSP inhibitor, bevacizumab, a monoclonal antibody targeted against soluble VEGF protein, was approved by the Food and Drug Administration in 2004 for the treatment of metastatic colon cancer. 2 Since then, small receptor tyrosine kinase inhibitors, with potent VEGFR-2 inhibition, have been approved for an array of malignancies (Table 1), with many more in various stages of development (Table 2). Receptor tyrosine kinase inhibitors are not entirely specific for VEGFR-2, and From the Divisions of Cardiovascular Medicine (B.N., J.M.) and Renal Medicine (B.D.H.), Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA. Correspondence to Javid Moslehi, MD, Division of Cardiovascular Medicine, Brigham and Women s Hospital, 75 Francis St, Boston, MA, jmoslehi@partners.org (Circulation. 2011;124: ) 2011 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 1688 Circulation October 11, 2011 Figure. Schematic of vascular endothelial growth factor (VEGF) pathway and sites of action of VEGF signaling pathway inhibitors (modified from templates provided by VEGFR indicates VEGF receptor; HIF, hypoxia-inducible factor; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; and TKI, tyrosine kinase inhibitor. target other tyrosine kinase receptors. For example, sunitinib and sorafenib, the first receptor tyrosine kinase inhibitors with potent anti-vegfr inhibition, also target platelet-derived growth factor receptor, as well as c-kit (receptor for stem cell factor). The multiple receptor tyrosine kinase targets of these drugs have implications both for their therapeutic potency and for their cardiotoxicities. Hypertension Initial clinical trials with bevacizumab first identified hypertension in 28% of the patients3; subsequent trials with sorafenib, sunitinib, and pazopanib identified hypertension with similar frequency in all VSP inhibitors. Metaanalyses have shown the incidence of hypertension to be 19% to 24% in all VSP inhibitors.4,5 However, these data may underestimate the true incidence of hypertension in clinical practice today. Only recently has the classification system used by the National Cancer Institute to assess toxicities associated with novel chemotherapies been up- Table 1. Food and Drug Administration Approved Vascular Endothelial Growth Factor Signaling Pathway Inhibitors dated to more closely reflect the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) guidelines for Table 2. Vascular Endothelial Growth Factor Signaling Pathway Inhibitors Under Investigation Antibodies Ramucirumab (anti VEGFR-2) VEGF trap Aflibercept RTKs with anti-vegf properties: Axitinib Cediranib Regorafenib Generic Name Trade Name FDA-Approved Uses Semaxanib Bevacizumab Avastin Colorectal, non small-cell lung, glioblastoma multiforme Torceranib Sorafenib Nexavar Renal cell carcinoma, hepatocellular carcinoma Vandetanib Sunitinib Sutent Renal cell carcinoma, gastrointestinal stromal tumors Pazopanib Votrient Renal cell carcinoma FDA indicates Food and Drug Administration. Brivanib VEGFR-2 indicates vascular endothelial growth factor receptor-2; RTK, receptor tyrosine kinase.

3 Nazer et al Angiogenesis Inhibitors and Hypertension 1689 hypertension (Table 3). Furthermore, patients in the general population may have more comorbidities, such as diabetes mellitus or preexisting hypertension, compared with highly selected trial patients. Therefore, nontrial patients may be at increased risk of developing VSP inhibitor induced hypertension. Finally, some newer VSP inhibitors currently in clinical trials (such as axitinib) are highly potent, and may have a higher incidence of hypertension. 4 In this regard, the incidence of hypertension is dependent on drug variables (type of drug, dose, and schedule used) and patients (age and previous history of hypertension or other cardiovascular disease). Nevertheless, an absolute blood pressure increase occurs in the majority of patients, with rapid onset after the first administration of the drug. Maitland and colleagues, 6 for example, report a mean blood pressure increase of 8.2 mm Hg systolic and 6.5 mm Hg diastolic in the first 24 hours after the first treatment with sorafenib, although the authors also noted substantial variation in blood pressure increase, with some patients having no increase in blood pressure and others experiencing a doubling in systolic blood pressure. We have reported a similar rapid rise in blood pressure in most patients starting treatment with cediranib, another highpotency VSP inhibitor. 7 Interestingly, the rise in blood pressure associated with VEGF inhibitors appears to reverse as rapidly as its onset, with a return of blood pressure to nearly baseline levels by the end of the off-treatment phase, 8 an observation that has implications for patient management. Table 3. Comparison of National Cancer Institute and Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Classifications of Hypertension National Cancer Institute hypertension grading CTCAE, version 3.0, 2006 Grade 1: asymptomatic, transient ( 24 h) increase by 20 mm Hg (diastolic) or to 150/100 if previously WNL; intervention not indicated Grade 2: recurrent or persistent ( 24 h) or symptomatic increase by 20 mm Hg (diastolic) or to 150/100 mm Hg if previously WNL; monotherapy may be indicated Grade 3: requiring 1 drug or more intensive therapy than previously Grade 4: life-threatening consequences (eg, hypertensive crisis) CTCAE, version 4.03, 2010 Grade 1: prehypertension (systolic BP mm Hg or diastolic BP mm Hg) Grade 2: stage 1 hypertension (systolic BP mm Hg or diastolic BP mm Hg) or recurrent or persistent ( 24 h); symptomatic increase by 20 mm Hg (diastolic) or to 140/90 mm Hg if previously normal Grade 3: stage 2 hypertension (systolic BP 160 mm Hg or diastolic BP 100 mm Hg); 1 drug or more intensive therapy than previously used indicated Grade 4: life-threatening consequences NHLBI (JNC7, 2003) Normal: systolic BP 120 and diastolic BP 80 mm Hg Prehypertension: systolic BP 120/139 mm Hg or diastolic BP mm Hg Stage 1 hypertension: systolic BP 140/159 mm Hg or diastolic BP mm Hg Stage 2 hypertension - systolic BP 160 mm Hg or diastolic BP 100 mm Hg CTCAE indicates Common Terminology Criteria for Adverse Events; WNL, within normal limits; BP, blood pressure; NHLBI, National Heart, Lung, and Blood Institute; and JNC7, Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Pathophysiology A number of mechanisms have been proposed for VSP inhibitor associated hypertension. Activation of VEGFR-2 by VEGF induces expression of nitric oxide (NO) synthase in endothelial cells, which promotes vascular permeability and vasodilation. 9 In fact, when VEGF agonists were used in an attempt to promote angiogenesis in models of ischemic cardiomyopathy, hypotension was one of the major side effects. 10 Treatment with VSP inhibitors both in vitro and in rodent models has been shown to decrease NO synthesis and to lead to hypertension. Moreover, a recent study in patients with metastatic renal cell carcinoma receiving VSP inhibitors shows suppression of the NO pathway. 11 These data suggest an important causal role for impaired NO production in the pathogenesis of VSP inhibitor mediated hypertension. Other mechanisms are likely playing roles. Loss of parallel capillary circulation in normal, nontumor tissue a process called rarefaction has also been associated with hypertension in patients being treated with VSP inhibitors. This pathology reverses with VSP inhibitor discontinuation. 12,13 Other proposed mechanisms for VSP inhibitor induced hypertension include endothelial dysfunction, leading to an increase in endothelin-1 and an increase in aortic stiffness. There are intriguing similarities between the clinical features of VSPassociated hypertension and preeclampsia, a syndrome of hypertension and proteinuria affecting up to 5% of pregnant women. Preeclampsia has been associated with decreased VEGF signaling through increased circulating levels of a soluble VEGFR. 14 In this regard, proteinuria has been described across all VSP inhibitors. 15 Moreover, systemic endothelial dysfunction, a central feature in patients with preeclampsia, may play a pathological role in VSP-associated vascular thromboses (see below). Management There is a paucity of data to guide management of VSP inhibitor associated hypertension. A recent assembly of the Cardiovascular Toxicities Panel of the National Cancer Institute set a goal of 140/90 mm Hg (and 130/ 80 mm Hg in patients with chronic kidney disease or diabetes mellitus) for

4 1690 Circulation October 11, 2011 all hypertensive patients on VSP inhibitors. 16 These recommendations are consistent with JNC7 guidelines, although the committee noted the lack of evidence-based data in this area. Despite the lack of data, several important points concerning treatment should be emphasized. Aggressive hypertension management before the initiation of VSP inhibitor therapy is critical. Blood pressure monitoring should be performed frequently, at least weekly for the first 6 weeks of treatment. We often suggest that high-risk patients (those with preexisting hypertension or other cardiac risk factors) use an automated home blood pressure cuff to measure blood pressure daily for the first 6 weeks. Lifestyle modification should be encouraged, including moderating alcohol intake and reducing dietary salt. Because VSP inhibitors have been associated with the development of proteinuria, regular urinalysis should be performed as a screening test. If new proteinuria is detected, proteinuria should be quantified and selected patients should be referred to a nephrologist for further evaluation and treatment. We and others suggest angiotensin-converting enzyme inhibitors as a first-line therapy in these patients in the absence of any contraindications because these agents are effective at reducing blood pressure and proteinuria. 17 Sunitinib and sorafenib are metabolized by the CYP3A4 system, so nondihydropyridine calcium channel blockers (verapamil and diltiazem), which are CYP3A4 inhibitors, should be avoided in patients on these agents, but may be considered in patients on bevacizumab. Given the relationship between VEGF and NO, replacing the NO depletion induced by anti-vegf agents with a long-acting nitrate or a phosphodiesterase inhibitor is an elegant, mechanistic treatment. Ultimately, VSP dose reduction or interruption may need to be considered in the case of severe, refractory hypertension or in the case of hypertensive crisis. Of note, after drug holiday, reinitiation of a different VSP inhibitor may be better tolerated. In our practice, we recommend angiotensin-converting enzyme inhibitors or calcium channel blockers (specifically amlodipine or felodipine) as first-line agents in the treatment of VSP inhibitor associated hypertension. We recommend rapid titration of antihypertensive therapy in the first week after VSP inhibitor initiation. We also recommend patient home blood pressure monitoring to facilitate titration remotely. If patients have systolic blood pressure 165 mm Hg or diastolic blood pressure 100 mm Hg, VSP inhibitor therapy should be held until antihypertensive therapy titration is consistent with NCI recommendations. 16 To avoid hypotension, we additionally recommend close blood pressure monitoring with a reduction of antihypertensive medications when VSP inhibitor therapy is stopped. Other Cardiovascular Toxicities Original clinical trials of VSP inhibitors were not designed with standardized cardiac end points other than hypertension. For this reason, most reports of cardiotoxicity other than hypertension come from observational studies. Since the approval of these agents, observational studies of sunitinib and sorafenib have demonstrated rates of symptomatic heart failure ranging from 3% to 8% and rates of decreased left ventricular ejection fraction of at least 15%, ranging from 8% to 28%. On discontinuation of the agents, left ventricular function returned to baseline in most, but not all, patients. 18,19 Less clear is the incidence of cardiomyopathy in the setting of bevacizumab. This may be due to the relatively broad selectivity of receptor tyrosine kinase inhibitors compared with bevacizumab (which exclusively antagonizes VEGF), suggesting a mechanism other than VEGF inhibition leading to cardiomyopathy. There is growing awareness of the increased risk of venous and arterial thrombotic events in patients treated with VSP inhibitors. A recent metaanalysis of patients on bevacizumab has shown a 12% rate (relative risk, 1.33; P 0.01 versus placebo patients) of venous thromboembolism. 20 Similarly, arterial thrombotic events (including strokes and myocardial infarctions) have been shown to be more common in bevacizumab-treated patients, with an incidence of 5.5 events per 100 person-years compared with 3.1 events per 100 person-years among the placebo groups (P 0.05). 21 This toxicity was also seen with sunitinib and sorafenib, which carried a relative risk for arterial thrombotic events of 3.03 (P 0.05) compared with placebo. 22 In our experience, there is increased incidence of atrial fibrillation in patients treated with VSP inhibitors, although it is unclear whether this is due to hypertension. These observational studies raise questions for the cardiac management of patients on VSP inhibitors. For example, what is the contribution of hypertension to the various cardiac toxicities? What is the true incidence of cardiac toxicities in the nonclinical trial cancer patient, who may have more cardiac risk factors or previous cardiac history than a patient selected for a cancer clinical trial? Until further studies are done, we recommend a high index of suspicion for underlying cardiac disease, including cardiac ischemia or heart failure, for patients with symptoms on VSP inhibitors and aggressive management of their cardiac risk factors, including hypertension and hyperlipidemia. Follow-Up of Our Patient Our patient had already been started on a -blocker (extended-release metoprolol 25 mg once daily) before being sent to our cardio-oncology clinic. However, metoprolol was not sufficient to control his blood pressure as recommended by JNC7 guidelines. In the cardio-oncology clinic, he was noted to be hypertensive, with a blood pressure of 168/98 mm Hg. Lisinopril was added to the extendedrelease metoprolol. Subsequently, amlo-

5 Nazer et al Angiogenesis Inhibitors and Hypertension 1691 dipine had to be added, resulting in triple antihypertensive medication therapy. The patient has been monitoring his blood pressure at home, where his blood pressure has remained 140/90 mm Hg. He has remained in normal sinus rhythm with no report of palpitations. None. Disclosures References 1. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358: Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-vegf antibody for treating cancer. Nat Rev Drug Discov. 2004; 3: Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21: Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol. 2008;9: Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol. 2009; 48: Maitland ML, Kasza KE, Karrison T, Moshier K, Sit L, Black HR, Undevia SD, Stadler WM, Elliott WJ, Ratain MJ. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Cancer Res. 2009;15: Robinson ES, Matulonis UA, Ivy P, Berlin ST, Tyburski K, Penson RT, Humphreys BD. Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor. Clin J Am Soc Nephrol. 2010;5: Azizi M, Chedid A, Oudard S. Home bloodpressure monitoring in patients receiving sunitinib. N Engl J Med. 2008;358: Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signaling: in control of vascular function. Nat Rev Mol Cell Biol. 2006;7: Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, Shah PK, Willerson JT, Benza RL, Berman DS, Gibson CM, Bajamonde A, Rundle AC, Fine J, McCluskey ER. The VIVA trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis. Circulation. 2003; 107: Robinson ES, Khankin EV, Choueiri TK, Dhawan MS, Rogers MJ, Karumanchi SA, Humphreys BD. Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors. Hypertension. 2010;56: Mourad JJ, des Guetz G, Debbabi H, Levy BI. Blood pressure rise following angiogenesis inhibition by bevacizumab: a crucial role for microcirculation. Ann Oncol. 2008; 19: Steeghs N, Gelderblom H, Roodt JO, Christensen O, Rajagopalan P, Hovens M, Putter H, Rabelink TJ, de Koning E. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res. 2008;14: Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med. 2008;59: Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC. VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management. Eur J Cancer. 2010;46: Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott WJ, Ivy SP, Leier CV, Lindenfeld J, Liu G, Remick SC, Steingart R, Tang WH. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102: Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen A, Khayat D, Spano JP. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol. 2009;20: Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, George S, Morgan JA, Harris DM, Ismail NS, Chen JH, Schoen FJ, Van den Abbeele AD, Demetri GD, Force T, Chen MH. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370: Khakoo AY, Kassiotis CM, Tannir N, Plana JC, Halushka M, Bickford C, Trent J 2nd, Champion JC, Durand JB, Lenihan DJ. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer. 2008;112: Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300: Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, Bergsland E, Ngai J, Holmgren E, Wang J, Hurwitz H. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99: 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: KEY WORDS: bevacizumab hypertension medical oncology receptors, vascular endothelial growth factor