Thrombosis associated with angiogenesis inhibitors

Best Practice & Research Clinical Haematology 22 (2009) 115–128

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Thrombosis associated with angiogenesis inhibitors Francesca Elice, MD a, Francesco Rodeghiero, MD, Professor a, Anna Falanga, MD, Director b, Frederick R. Rickles, MD, FACP, Professor c, * a

Department of Cell Therapy and Haematology, San Bortolo Hospital, Via Rodolfi 37, 36100 Vicenza, Italy Haemostasis and Thrombosis Centre, Department of Haematology, Ospedali Riuniti, Largo Barozzi 1, Bergamo 24100, Italy Division of Hematology-Oncology, Department of Medicine, The George Washington University, Medical Faculty Associates, 2150 Pennsylvania Ave NW, Washington, DC 20037, USA

b c

Keywords: angiogenesis anti-angiogenic agents cancer thrombosis thalidomide lenalidomide bavacizumab sunitinib sorafenib semaxibin

Recent advances in the understanding of the pathogenesis of cancer have led to the introduction of a variety of biological agents with novel mechanisms of action into clinical trials and even into clinical practice. In particular, tumour-associated neoangiogenesis has become a major target for this new class of antineoplastic agents. Five anti-angiogenic agents (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use, and many others have entered clinical trials. Many new biological agents with antiangiogenic properties appear to be associated with an increased risk for thrombosis and, paradoxically, bleeding. Although the mechanisms underlying the increased thromboembolic risk remain ill defined, the main hypothesis is that perturbation of tumour-associated endothelial cells can switch the endothelium from a naturally anticoagulant surface to a prothrombotic surface, thus mediating the activation of systemic coagulation in cancer patients, who are already more susceptible to thromboembolism due to their underlying disease. The toxicity profile differs between the anti-angiogenic agents. Thalidomide, lenalidomide, semaxibin (SU5416) and prinomastat have produced more venous thromboembolic complications, whereas bevacizumab, sunitinib, sorafenib and ZD6126 have been associated with a higher risk of arterial thromboembolism and, in particular, myocardial ischaemia. The observation of these vascular toxicities suggests the need to establish, in randomized clinical

* Corresponding author. Tel.: þ1 202 741 2478; Fax: þ1 202 741 2487. E-mail address: [email protected] (F.R. Rickles). 1521-6926/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beha.2009.01.001

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trials, the usefulness of thrombosis prophylaxis when anti-angiogenic agents are used in cancer patients, especially when associated with chemotherapy. In addition, careful reporting of haemostatic complications during treatment with new anti-angiogenic drugs is warranted. Ó 2009 Elsevier Ltd. All rights reserved.

Introduction A variety of chemotherapy drugs have been linked with both venous and arterial thrombosis in cancer patients. Indeed, virtually all intravenous chemotherapeutic agents are capable of stimulating the generation of intravascular thrombin [1]. The mechanisms behind the perturbation of coagulation by standard chemotherapy agents remain poorly understood, but direct endothelial injury, as well as direct effects on procoagulant and anticoagulant proteins, have been described [2]. However, since similar abnormalities of blood coagulation also characterize the basal, underlying hypercoagulable state of malignancy, these findings do not readily distinguish the effects of chemotherapy from the effects of cancer. Recently, advances in the targeting of unique tumour metabolic pathways have led to the introduction of a variety of biological agents with novel mechanisms of action into clinical trials and even into clinical practice. However, it is the resurgent use of a very old drug, thalidomide, that has garnered the most attention, not only because of its efficacy as an anti-angiogenic agent in multiple myeloma and other neoplasms, but also for its apparent association with the development of thromboembolism (TE). Although the mechanisms underlying the increased thromboembolic risk remain ill defined, many new biological agents with anti-angiogenic properties appear to share this association with an increased risk for thrombosis and, paradoxically, bleeding. The general concern, based on early reports of both arterial thromboembolism (ATE) and venous thromboembolism (VTE) complicating the use of several of these biological agents [3], is that perturbation of tumour-associated endothelial cells may be mediating the activation of systemic coagulation in patients and rendering them even more susceptible to thromboembolism. This chapter will explore these issues and their clinical implications. Endothelial regulation of thrombosis and haemorrhage The endothelium of blood vessels plays a pivotal role in the control of thrombosis and haemostasis by expressing or modulating multiple factors. Under normal conditions, endothelial cells rarely undergo apoptosis and maintain an intravascular anticoagulant state, resulting from a finely tuned balance of pro- and anticoagulant proteins, platelet activating or inhibiting molecules, and pro- and antifibrinolytic products. However, local or systemic inflammatory stimuli, such as those produced by cancer cells (directly or by their noxious products) or derived from host cells activated in response to the neoplastic process, can switch the endothelium to a prothrombotic surface. This prothrombotic switch is mediated by the release of cytokines and growth factors, by weakening of the cell-to-cell junctions or by endothelial cell apoptosis. These effects reduce the endothelial barrier function and possibly compromise the integrity of blood vessels with subsequent exposure of the subendothelial basement membrane, which contains many procoagulant proteins [4,5]. The endothelial damage leads to activation of the entire haemostatic system by exposure of subendothelial von Willebrand factor (VWF) and tissue factor (TF). VWF induces platelet and tumour cell adhesion to the subendothelium, followed by platelet activation and aggregation (primary haemostatic response). TF, which is one of the principal initiators of the clotting cascade (secondary haemostatic response), is exposed after endothelial damage and is aberrantly expressed in cancer patients on the surface of cytokine-activated endothelial cells, monocytes and tumour cells themselves [6]. As a result, newly formed vessels within human tumours appear to be particularly susceptible to clot formation, and have been shown to express both TF and cross-linked fibrin on their endothelium [7]. In addition, the high levels of TF expressed in some tumour cells upregulate the expression of vascular endothelial growth factor

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(VEGF), a major regulatory molecule involved in neoangiogenesis, by a mechanism independent from the activation of the clotting cascade [8,9]. Thrombotic risk in cancer patients Patients with malignancies have an increased risk of both thrombosis and haemorrhage. The rates of VTE in cancer patients have a wide variability in different trials. In women with breast cancer, the VTE rate ranges from 0.1% in untreated Stage I patients to 17% in chemotherapy-treated women for advanced stages [10–12]. The MEGA study accrued 3220 unselected patients with VTE and 2131 controls, and reported that the presence of a malignancy increased the thrombotic risk 4.3 fold [13]. The relationship between cancer and VTE is further emphasized by the high rate of cancer development in patients with unprovoked venous thrombosis. Multiple studies have consistently shown four to five times greater risk in idiopathic patients compared with subjects with secondary thrombosis [14]. Haemorrhage is also a potentially life-threatening complication of malignancy due to a variety of mechanisms, including the thrombocytopenia so common in treated patients, direct physical erosion of vessel by the tumour mass, or disseminated intravascular coagulation. The mechanisms of tumourassociated thrombosis and haemorrhage are not fully understood and depend on local and systemic perturbation of the haemostatic system. As discussed previously, tumour cells express or secrete growth factors (e.g. VEGF), procoagulants (e.g. TF and cancer procoagulant) and inflammatory cytokines which activate monocytes, T cells and endothelial cells. Tumour cells, activated monocytes, platelets and endothelial cells shed prothrombotic microparticles and platelet-activating factors, enhancing both platelet aggregation (primary haemostasis) and coagulation cascade activation [15]. In addition, cancer cells are able to enhance expression of the adhesion molecule P-selectin on monocytes, endothelial cells and platelets, favouring local adhesion of cancer cells to the endothelium. In fact, in a recent study, Ay et al [16] demonstrated a higher rate of VTE in cancer patients with high plasma levels of soluble P-selectin. As a result, both systemic and local (stasis, loss of endothelial integrity) factors contribute to the development of thrombosis in cancer patients. Thrombosis with angiogenesis inhibitors Thalidomide and its derivatives (immunomodulatory drugs, IMiDs) Thalidomide was the first of the anti-angiogenic agents to be associated with clinically relevant thrombotic complications, particularly when used in combination with other agents (e.g. dexamethasone or chemotherapy). The incidence of VTE using thalidomide in association with different regimens is reviewed in Table 1. The largest studies that address the thrombotic risk of patients treated with thalidomide come from the group at the University of Arkansas. Although thalidomide used as a single agent in relapsed patients was not thrombogenic (VTE rate 1%) [17], this drug increased the rate of VTE significantly (28% vs 4% [29]) when administered with chemotherapy, especially in association with doxorubicin-containing regimens [25]. In all studies, the thrombotic risk was highest in the first 2 Table 1 Incidence of venous thromboembolism (VTE) in patients treated with thalidomide alone or associated with chemotherapy. Regimen

Incidence of VTE (%)

Patients

Reference

Thalidomide 100–800 mg Thalidomide 200–800 mg Thalidomide 100–400 mg þ dexamethasone Thalidomide 100–400 mg þ dexamethasone Thalidomide þ doxorubicin-containing chemotherapy Thalidomide þ doxorubicin-containing chemotherapy Thalidomide þ melphalan and prednisone (no prophylaxis) Thalidomide þ melphalan and prednisone (no prophylaxis)

<2–3 4 2–7 18–26 16 26–34 11

Relapsed or refractory Newly diagnosed Relapsed or refractory Newly diagnosed Relapsed Newly diagnosed Advanced disease

[17–19] [20] [21,22] [23,24] [25] [26] [27]

23–58

Newly diagnosed

[27,28]

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months of therapy [24,29], and in newly diagnosed patients compared with relapsed/refractory patients [30]. Immunomodulatory derivatives of thalidomide were designed to increase the antimyeloma efficacy of the drug, while possibly reducing side effects such as neuropathy and thrombosis. However, the use of the thalidomide derivative CC-5013 (lenalidomide) has been complicated by an increased rate of thromboembolic complications, albeit only when utilized with high-dose dexamethasone or chemotherapy. Indeed, a low rate of vascular events (1%) has been observed in a large group of patients treated with single-agent lenalidomide for myelodysplastic disease [31]. The incidence of VTE in myeloma patients treated with lenalidomide plus high-dose dexamethasone is highly variable in reports from different centres (5–75% [32,33]), as shown in Table 2. Most recent trials of lenalidomide have included thromboprophylaxis with aspirin, which appeared to be effective in reducing the thrombotic rate, as will be discussed below. An increased rate of VTE was also observed in trials with the thalidomide derivative CC-4047 (Actimid or pomalidomide). In a study of 24 patients with relapsed or refractory myeloma, four (16%) developed deep vein thrombosis (DVT), although in one patient other concomitant factors may have contributed to the thrombotic event (lymphoadenopathy due to concomitant melanoma) [40]. In a more recent Phase I study using single-agent pomalidomide with a different dosage schedule (escalating dose 1–10 mg on alternate days, maximum tolerated dose 5 mg) without thromboprophylaxis, no thromboembolic events were observed [41]. The authors hypothesize that a transient imbalance of plasma procoagulant/anticoagulant may develop after administration of pomalidomide. Given the short half-life of the drug (7 h), the alternate dose schedule may allow time for this imbalance to reverse, with coagulation factors and natural anticoagulants returning to normal levels. However, further studies are required to confirm this hypothesis and to better understand the thrombophilic potential of this drug. Overall, the mechanisms of thalidomide/IMiD-related VTE have not been fully clarified, although many studies have investigated thrombophilic factors, endothelial activation markers or growth factors variations. Many abnormalities of the haemostatic system have been observed in myeloma patients, especially at the time of diagnosis, including acquired resistance to activated protein C and increased plasma levels of factor VIII procoagulant activity, VWF antigen, fibrin, D-dimer, homocysteine and soluble thrombomodulin [42–46]. Sequential analyses of changes induced by thalidomide or other IMiDs in subgroups of patients are summarized in Table 3. As several abnormalities in the coagulation system have been observed in myeloma patients at baseline, it is sometimes difficult to differentiate the modifications related to the drug from those related to the primary disease status (which is modified by the drug itself due to its efficacy in reducing the tumour burden). Other agents have an important additive effect in increasing the risk for VTE. These include doxorubicin (an agent known to induce endothelial apoptosis), dexamethasone, docetaxel, gemcitabine and other cytotoxic drugs. Indeed, Desai et al reported a 43% VTE rate in 21 patients with metastatic renal cell cancer treated with thalidomide, gemcitabine and 5-fluorouracil as part of a Phase Table 2 Incidence of venous thromboembolism (VTE) in patients treated with different lenalidomide-containing regimens with or without thromboprophylaxis with aspirin (ASA) or low-molecular-weight heparin (LMWH). Disease status

Prophylaxis

Lenalidomide alone (þ dexamethasone if no response) Progression None Lenalidomide þ dexamethasone Diagnosis None None ASA 325 mg/day ASA 80–325 mg/day LMWH Progression Lenalidomide þ melphalan and prednisone Diagnosis ASA 100 mg/day Progression ASA 100 mg/day Lenalidomide þ chemotherapy with doxorubicin Progression ASA 81 mg/day

% VTE

Reference

3%

Richardson, 2006 [34]

75% (n ¼ 12) 14% (n ¼ 22) 19% (n ¼ 32) 3% (n ¼ 34) 2% (n ¼ 45) 11% (n ¼ 176)

Zonder, 2006 [33] Niesvizky, 2005 [35] Zonder, 2006 [33] Rajkumar, 2005 [36] Klein, 2008 [39] Dimopoulos, 2007 [32]

4.8–10% (n ¼ 54; len 5–10 mg/die) 2% (n ¼ 38)

Palumbo, 2007 [37] Palumbo, 2006 [28]

9% (n ¼ 62)

Baz, 2006 [38]

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Table 3 Modifications of markers of coagulation or endothelial activation or natural anticoagulant mechanisms in myeloma patients before and after treatment with thalidomide or the immunomodulatory drug CC-4047 (pomalidomide).

D-dimer Prothrombin 1 þ 2 fragments sTF FVIII and VWF FXIIa Homocysteine Antithrombin III Activated Protein C resistance Thrombomodulin P-selectin

Baseline

Post-thalidomide or CC-4047(*)

Reference

[

¼* ¼ ¼* ¼*

Streetly, 2008 [41] Corso, 2004 [46] Streetly, 2008 [41] Streetly, 2008 [41] Minnema, 2003 [43] Streetly, 2008 [41] Weber, 2002 [45] Weber, 2002 [45] Corso, 2004 [46] Elice, 2006 [30] Corso, 2004 [46] Corso, 2004 [46] Streetly, 2008 [41]

[ Normal [ (with active myeloma) Normal [ (56%) Y (42%) Y (24%) Normal Normal

¼* ¼ Normalization in 19/20 patients ¼ [ (in responding patients) ¼ Y (after 1 month of therapy) ¼*

sTF, soluble tissue factor; FVIII, factor VIII; VWF, von Willebrand factor; FXIIa, factor XII activated; [, increased; Y, decreased; ¼, stable.

2 trial [47]. While renal cancer is not as commonly associated with VTE as other cancers, the underlying malignancy may be contributing to the overall risk. One possible scenario that seems plausible to explain this high rate of VTE is as follows. Following endothelial cell injury induced by intravenous chemotherapy, the coagulation cascade is triggered, thrombin is generated and VEGF is released from both injured endothelium and activated platelets [48]. Thrombin is also known to upregulate VEGF receptor expression. As VEGF acts as a maintenance factor for the endothelium, the presence of an antiangiogenic agent may impair the capacity for endothelial injury repair. The ongoing endothelial disruption exposes subendothelial thrombogenic components (e.g. collagen, elastin, basement membrane, etc.) and leads to exuberant platelet adhesion and thrombosis. Based on their in-vitro observations, Kaushal et al [49] suggested that thalidomide may be procoagulant not by enhancing doxorubicin-mediated endothelial injury, but by increasing the expression of protease-activated receptor 1, which is expressed on endothelial cells and platelets and is important in the regulation of cellular morphology. Another debated topic is the possible role of eythropoietic agents in the development of thrombosis. In fact, Steurer et al [50] described thrombotic complications (one fatal DVT/PE, two DVTs) in three of the first seven patients enrolled on a study of patients with myelodysplastic syndrome receiving thalidomide and darbepoietin-alpha. In other studies, however, recombinant human erythropoietin did not increase the VTE rate in myeloma patients treated with thalidomide [51] or lenalidomide. For example, in a recent study of patients treated with aspirin thromboprophylaxis, VTE developed in 8% of patients, independently from the concomitant use of erythropoietin [52]. Antagonists of VEGF or its receptors Bevacizumab Bevacizumab (Avastin) is a recombinant, humanized monoclonal antibody directed against VEGF, which was approved by the US Food and Drug Adminstration in February 2004 for the treatment of metastatic colon cancer and non-small-cell lung cancer (excepted squamous histology). This is the best known and most widely used VEGF inhibitor and it has been included in many regimens in combination with chemotherapy. Novel toxicities emerged with bevacizumab use, including hypertension, haemorrhage, ATE, VTE and bowel perforation. In particular, the toxicity profile in relation to coagulation indicates both a pronounced haemorrhagic and thrombotic predisposition (see Table 4). These apparent disparate toxicities can both result theoretically from endothelial cell perturbations induced by the drug, given the increased susceptibility of tumour-associated new blood vessels with both thrombosis and increased permeability (‘leaking’) (see review by Dvorak and Rickles [61]). The perturbation of the endothelium may derive from non-physiological endothelial cell apoptosis due to inhibition of VEGF.

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Table 4 Incidence of thrombotic or bleeding complications in cancer patients during treatment with bevacizumab and chemotherapy (modified from Elice et al, 2008 [3]). Tumour

Grade 3–4 bleeding episodes

Venous thromboembolic events (%) Arterial thromboembolic events (%) Reference

Bevacizumab (5 or 10 mg vs control) þ fluorouracil þ leucovirin Bevacizumab (vs placebo) þ irinotecan þ fluorouracil þ leucovirin Bevacizumab (7.5 or 15 mg/kg vs placebo) þ carboplatin þ paclitaxel Bevacizumab (vs placebo) þ fluorouracil þ leucovirin Bevacizumab þ irinotecan þ cisplatin

Metastatic colorectal cancer

0/35 in low-dose, 3/32 (9%) in high-dose, 0/35 in controlb 3.1% vs 2.5% (NS)

8/35 (23%) in arm 1, 12/32 (6%) in arm 2, 2/35 (6%) in controlb 19.4% vs 16.2% (NS)

5/32 (16%) in low-dosea 1/34 (3%) in high-dose, 0/32 in control 5/100 (5%) vs 3/104 (3%)b

4/32 (12%) in low-dose and 6/35 (18%) in high-dose, 3/35 (9%) in control arm 8/100 (8%) vs 11/104 (11%), NS

10/100 (10%) vs. 5/104 (5%)b

Not specified

11/50 (22%)

3/26 (11%)

1/299 (0.4%) vs 1/215 (0.5%)

7/229 (3%) vs 6/215 (3%)

Metastatic colorectal cancer (813 patients)

Advanced or metastatic non-small-cell lung cancer Metastatic colorectal cancer Metastatic or unresectable gastric cancer Bevacizumb (vs placebo) þ Relapsed metastatic capecitabine breast cancer Bevacizumb (vs placebo) þ Advanced or metastatic paclitaxel þ carboplatin non-small-cell lung cancer (not squamous) Bevacizumab (vs placebo) þ Metastatic colorectal oxaliplatin þ fluorouracil þ cancer leucovirin

1/35 (3%) in arm 1, 2/32 (6%) in arm 2, 1/35 (3%) in controlb

Kabbinavar 2003 [53] Hurwitz, 2004 [54]

Johnson, 2004 [55]

Kabbinavar, 2005 [56] Shah, 2005 [57]

Miller, 2005 [58]

10/427 (2.3%) vs 2/441 (0.5%)a 23/427 (5%) vs 14/441 (3%)a

Not reported

Cohen, 2007 [59]

3.4% vs 0.4%a; 1 fatal event

09% vs 0.4% (NS)

Giantonio, 2007 [60]

NS, not significantly different. a difference between treatment arms was statistically significant. b statistical comparison was not reported for single adverse events.

16.3% vs 9.2%a

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Therapy

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This hypothesis is based on the observation that VEGF is necessary for the maintenance of a functional endothelium [48,62]. Abnormal apoptosis of endothelial cells leads to exposure of the highly prothrombotic basement membrane and to loss of integrity of the endothelium with subsequent haemorrhage. The blocking of the VEGF signalling pathway can also cause thrombosis through a platelet-dependent mechanism. In fact, it has been observed that VEGF signalling is essential for production of the naturally occurring platelet function inhibitors prostaglandin I-2 (PGI-2) and nitric oxide (NO). Reduced levels of PGI-2 and NO may lead to increased platelet activation and increased incidence of ATE [63]. Table 4 summarizes the thromboembolic complications (VTE and ATE) observed in some clinical trials with bevacizumab combined with chemotherapy. The VTE and ATE rates are variable in the different trials, and a significant increase in thrombosis in patients treated with bevacizumab is not consistently demonstrated. Although an analysis of pooled data from three randomized trials failed to show a statistically significant increase in thrombotic events in a recent analysis of pooled data of 1745 patients from five randomized trials, the addition of bevacizumab to chemotherapy was associated with an increased risk of ATE (overall incidence 3.8% with bevacizumab vs 1.7% in the chemotherapy-alone group), but not VTE [64]. Most ATE episodes described were myocardial or cerebrovascular events. On multivariate analysis, only exposure to bevacizumab, age 65 years or a prior history of ATE were identified as significant risk factors, although cardiovascular risk assessment was suboptimal in most patients [64]. Interestingly, bleeding events were frequently reported in all studies. A higher incidence of epistaxis and haematuria was observed in the bevacizumab arm of two trials in patients with metastatic renal cancer [65] or metastatic colorectal cancer [53]. Although mild (Grade 1 and 2) epistaxis was a common complication of bevacizumab treatment (up to 53%) [53], the incidence of Grade 3 and 4 bleeding or thrombotic episodes was not increased significantly in a Phase 3 randomized trial [54] including 813 patients with metastatic colorectal cancer. In a Phase II trial, Johnson et al [55] randomized 99 patients with advanced, untreated non-small-cell lung cancer to a three-arm study evaluating patients treated with carboplatinum and paclitaxel with or without the addition of bevacizumab (at a dose of 7.5 mg/kg or 15 mg/kg). Surprisingly, some form of bleeding occurred in 23 of 32 patients (72%) given the 7.5-mg/kg dose, including five of six life-threatening episodes of haemoptysis; 19 of 35 patients (54%) given the 15-mg/kg dose; and four of 32 patients (12.5%) in the control arm. The authors suggested that the life-threatening haemorrhagic events may have been related to the central location of the tumours, the rapidity of tumour response to therapy and/or to the squamous cell histology. Although bevacizumab-dependent bleeding events are mainly mild, this toxicity becomes very important when one considers a prophylactic strategy to prevent ATE; indeed, the use of antiplatelet or anticoagulant drugs could further enhance the risk for bleeding complications. SU5416 (semaxibin) SU5416 is a synthetic molecule that inhibits VEGF receptor-1 and -2 (VEGFR-1 and VEGFR-2) signalling. This molecule is an example of the potential of these agents for producing unacceptable vascular toxicity and, therefore, the clinical development of this drug was abandoned by the manufacturer. The initial studies with SU5416 used as a single agent in patients with solid tumours demonstrated a 6–15% VTE rate, which is not significantly increased from the basal rate in this group of patients [66,67]. However, in a dose-finding study, Kuenen et al [68] combined this agent with gemcitabine and cisplatinum (agents with known prothrombotic potential) in 19 patients with various advanced solid tumours; the authors reported nine ATEs and VTEs in eight patients and the study was therefore terminated. Coagulation parameters were investigated in cancer patients treated with SU5416 alone, and the results suggested that SU5416 caused endothelial cell activation, as shown by the significant increase of soluble E-selectin, VWF and TF [69]. The authors demonstrated a concomitant activation of coagulation parameters and a decline in platelet count in those patients in whom SU5416 was combined with gemcitabine and cisplatinum [70]. The investigators postulated that once starved of VEGF, endothelial cells become activated and, thus, more susceptible to the damage imposed by the trio of therapeutic agents. Furthermore, they suggested that platelets, as a source of VEGF, may have a role in maintaining vascular integrity in these patients.

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Table 5 Thormbotic and haemorrhagic complications observed during the treatment of cancer patients with the anti-angiogenic agents sunitinib and sorafenib. Therapy

No. patients Type of cancer

Sunitinib (SU11248) 28 207

375 (vs 360) 84 63

Sorafenib (BAY 43-9006)

42 202 137 451 (vs 452)

Sorafenib (BAY 43-9006) þ doxorubicin Sorafenib (BAY 43-9006) þ gemcitabine

34

42

Rate of VTEa Rate of ATEa Rate of bleeding eventsa

Solid tumours 4% GIST (randomized 0 vs placebo)

0 0

Renal cell ca. (randomized vs interferon) Metastatic colorectal cancer Lung cancer (NSCLC)

0

0

<10%

<10%

0

0

Solid tumours 0 (Phase I) Renal cell ca. 0 Hepatocellular ca. 0

0 0 0

Renal cell ca. (randomized vs placebo) Solid tumours

0

3% vs <1%b

0

0

Solid tumour þ pancreatic ca. (Phase I)

12% (fatal ATE in 1 pt)

0 7% Grade I–II epistaxis vs 0% in placebob Epistaxis Grade III 1% vs 0% (NS); all grades 12% vs 1% <10% 5% Grade IV–V (pulmonary and cerebral) 0

Reference Faivre, 2006 [71] Demetri, 2006 [72]

Motzer, 2007 [73]

Saltz, 2007 [74] Socinski, 2008 [75]

Moore, 2005 [76]

4% fatal intracranial haemorrhage in 1 pt 3% vs 2% (NS); 15% vs 8% including Grade I–IIb 0

Ratain, 2006 [77] Abou-Alfa, 2006 [78]

2%

Siu, 2006 [81]

Escudier, 2007 [79]

Richly, 2006 [80]

VTE, venous thromboembolism; ATE, arterial thromboembolism; MI, myocardial infarction; TIA, transient ischaemic attack; ca., carcinoma; NSCLC, non-small-cell lung cancer; NS, not significant; pt, patient; GIST, gastrointestinal stroma tumors. a Only Grade 3 or 4 events are reported if not otherwise specified. b significantly different between the two groups.

SU11248 (sunitinib) and BAY 43-9006 (sorafenib) A different toxicity profile has been reported for sunitinib and sorafenib, which share similar mechanisms of action. Sunitinib (or SU11248) is a small-molecule multi-target tyrosine kinase inhibitor that blocks the signalling of multiple cell surface receptors such as VEGFR-1, -2 and -3; fms-like tyrosine kinase 3 (FLT-3); stem cell factor receptor cKIT; colony stimulating factor receptor (CSF-1R) and RET (rearranged during transfection). Sunitinib was approved by the US Food and Drug Administration for the treatment of locally advanced/metastatic renal cell carcinoma and imatinibresistant gastrointestinal stromal tumours. The incidence of thromboembolic complications is low for this drug, although a few cases of ATE, particularly myocardial infarction or cardiac ischaemia, have been reported (see Table 5). However, a slight increase in bleeding complications has also been observed, mainly Grade I and II epistaxis. Three fatal bleeding episodes were reported in a Phase II study of 63 patients with lung cancer, and two haemorrhages (one pulmonary and one cerebral) were considered to be drug related [75]. In assessing the complications of the multi-kinase inhibitor sorafenib (BAY 43-9006), another small-molecule tyrosine kinase inhibitor that blocks the intracellular domain of cell surface VEGF receptors such as VEGFR-2 and-3, PDGFR-beta, cKIT and FLT-3, haemorrhagic complications, mainly mild epistaxis, appear to be more relevant than thromboembolism (see Table 5). However, in a randomized trial comparing sunitinib with placebo in patients with advanced renal cell carcinoma, arterial complications (particularly cardiac ischaemia) were more common in the sorafenib arm [79]. Differences in the toxicity profile of molecules of the same class may be explained by the different spectrum of target receptors and the different affinity of the inhibitors for their receptors. However, since the thrombotic potential of thalidomide, IMiDs and SU-5416 only became evident in association with polychemotherapy, close monitoring of potential thromboembolic complications

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should continue in future trials, particularly when these agents are used in combination with chemotherapy. Other tyrosine kinase inhibitors Other molecules of this class are in clinical development (e.g. vatalanib, CHIR-258, KRN951), and both thrombotic and haemorrhagic complications have been observed in Phase I or II clinical trials. However, in the absence of randomized trials, it is not possible to establish a clear causal association between administration of these drugs and vascular toxicities. PTK787/ZK222584 (vatalanib) is a tyrosine kinase inhibitor at a more advanced stage of clinical development; indeed, it has been tested with promising results in Phase I and II trials in patients with colorectal cancer, breast carcinoma and imatinib-resistant gastrointestinal stromal tumours [82–84]. ATE and VTE rates were apparently low in these trials. However, these data are still premature, as the number of patients analysed to date is very small. Vatalanib has also been investigated in a Phase III trial in combination with FOLFOX4 (5-fluorouracil, leucovirin, oxaliplatin containing regimen) in previously untreated patients with colorectal cancer. A clinical advantage for the vatalanib arm was only demonstrated in a subset of patients [85]. The safety profile of this combination was described as comparable with that of FOLFOX4 alone [86]. Other agents For other anti-angiogenic agents, variable rates of thrombotic and haemorrhagic events have been reported. For instance, different vascular complications were reported in the first clinical trials with prinomastat, an anti-angiogenic matrix metalloproteinase (MMP) inhibitor, used alone or in combination with chemotherapy. Proteolysis of the basement membrane by MMP (particularly with MMP-2) is an essential step in angiogenesis, allowing endothelial cells to proliferate in the tumourassociated fibrin matrix. Prinomastat inhibits the activation of MMP-2. In patients with lung cancer treated with prinomastat and chemotherapy, the rate of ATE or VTE was 5% [87,88]. However, the trial reported by Heath et al [89], using prinomastat as pre-operative treatment with radio- and chemotherapy before surgery for oesophageal adenocarcinoma, was terminated early after the observation of three episodes of VTE in the first seven patients enrolled. The combination of multiple treatment modalities (chemotherapy, radiotherapy, anti-angiogenic agent) administered over a short period of time, together with the relatively small patient sample, may explain the extremely high VTE rate of 43% (not confirmed in other trials). Few thromboembolic complications have been described with squalamine (up to 7% VTE [90]), recombinant human endostatin (up to 4% VTE [91]) and angiostatin (up to 8% VTE [92]); three agents which inhibit proliferation and migration of endothelial cell angiogenesis through multiple mechanisms. A new class of anti-angiogenic agents is represented by the vascular-disrupting agents, which target the aberrant existing vasculature of tumours. Myocardial ischaemia, decline of left venticular ejection fraction and pulmonary embolism were dose-limiting toxicities in a Phase I study with ZD6126, a novel tubulin-targeting agent with antivascular activity [92]. Particular monitoring of cardiac function and signs of cardiac ischaemia is warranted in trials with these new vascular-targeting agents. Clinical implications It is widely accepted that cancer patients are at a heightened risk for thrombosis, and quite possibly also for haemorrhage in case of therapeutic anticoagulation. Thus, preventive measures, especially during surgical procedures, periods of immobility and possibly during chemotherapy treatment via indwelling venous catheters, are warranted. The observation of an increased risk of VTE or ATE with the new anti-angiogenic drugs requires consideration of thromboprophylaxis in ambulatory cancer patients treated with these drugs. However, it remains to be clarified if thromboprophylaxis should be administered to all patients, and which is the best prophylaxis in this setting; uniform recommendations for this latter indication have not been developed, pending additional evidence from randomized controlled trials of various forms of thromboprophylaxis [93,94].

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The majority of data on VTE prophylaxis come from the experience with thalidomide in multiple myeloma, and suffer generally from the lack of prospective randomized trials. Although no controlled clinical trial exists to guide recommendations, it is generally accepted that thromboprophylaxis is appropriate in selected patients treated with thalidomide, particularly those receiving concurrent chemotherapy (at any time) and newly diagnosed patients treated with a combination of thalidomide and dexamethasone. The options for prophylaxis of VTE include low-molecular-weight heparin (LMWH), low-dose warfarin, full-dose warfarin with target international normalized ration of INR 2–3, and aspirin. The LMWH enoxaparin (at a dose of 40 mg/day) appeared to abrogate the prothrombotic effect of the combination of thalidomide and doxorubicin in two studies of newly diagnosed myeloma patients, who have the highest risk of VTE, whereas low-dose warfarin (1 mg/day) did not appear to affect the rate of VTE [26,45]. This observation has been confirmed in a series from Europe, in which the LMWH nadroparin reduced the VTE rate to 10% in newly diagnosed myeloma patients treated with thalidomide, dexamethasone and doxorubicin [95]. In contrast to the experience of Weber et al [45] and Zangari et al [26] with 1.0 mg of warfarin, Cavo et al [96] reported that fixed, low-dose warfarin (1.25 mg/day) resulted in effective thromboprophylaxis for newly diagnosed patients treated with thalidomide and dexamethasone. Interestingly, preliminary beneficial results have also been reported with the use of aspirin. For example, Baz et al [97] reported the results of a relatively small, nonrandomized comparison trial of the following interventions in three groups of patients: (1) 81 mg aspirin/day, started at the initiation of chemotherapy, dexamethasone and thalidomide; (2) 81 mg aspirin/day, started after treatment was initiated; and (3) no aspirin. Overall, 26 episodes of VTE occurred in 103 subjects (25%), a rather high overall percentage, with 19% in Group 1, 15% in Group 2 and 58% in Group 3, showing a reduction of VTE with the use of aspirin (P < 0.001 by X2 test). Salimichokami[98] added aspirin 200 mg/day to chemotherapy with thalidomide in 30 patients with prostate cancer, and noted a lower-than-anticipated DVT rate of 6.6%. However, all of these results must be validated in randomized controlled trials. Such prospective studies are ongoing to evaluate which is the most effective and safe prophylaxis in newly diagnosed patients. More experience with aspirin is available for the thalidomide derivative lenalidomide. While aspirin appears to be effective in reducing the VTE risk in some trials (Table 2), it is difficult to evaluate the efficacy of any intervention not assessed in a randomized, controlled trial since the VTE rate without prophylaxis reported by various centres is widely discrepant (Table 2). A lower-than-anticipated VTE rate (9%) was reported in relapsed myeloma patients when aspirin was added to a combination of lenalidomide and chemotherapy [38]. A similar low incidence of VTE was observed in elderly, newly diagnosed myeloma patients receiving oral melphalan, prednisone and lenalidomide when aspirin prophylaxis was included in the protocol [37]. For bevacizumab and other anti-angiogenic drugs, the presence of both thrombotic and haemorrhagic events makes it much more problematic to prevent VTE or ATE with anticoagulant or antiplatelet drugs. In the case of bevacizumab, the available information suggests that caution should be exercised with use of this agent in older patients with a history of cardiovascular disease, who are reported to have the highest risk of ATE [64]. The high incidence of mucosal bleeding in these patients, however, suggests that aspirin should be used with caution. That said, to date, patients treated with aspirin for arterial thromboprophylaxis while receiving bevacizumab have not demonstrated an increased prevalence of haemorrhage in a retrospective analysis of pooled data from three randomized trials [99]. In another analysis, aspirin use caused only a slight increase in reported bleeding events (1.3-fold), but appeared effective in preventing bevacizumab-induced arterial thromboembolic complications [64]. In a subgroup of patients treated with bevacizumab and concomitant full-dose warfarin for thrombotic events, bleeding complications did not appear to be significantly increased, suggesting that it may be safe to administer full-dose oral anticoagulation even during bevacizumab therapy [100]. Although these studies are provocative and suggest the possibility of safe thromboprophylaxis for selected patients, the data are very preliminary and need to be confirmed in prospective trials. Concluding remarks New toxicities affecting haemostasis and coagulation have emerged with the use of anti-angiogenic agents in cancer patients. The pathophysiology of these complications seems to be related to the

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intrinsic mechanism of action of these drugs, but it is not possible to predict the toxicity of a new drug as different molecules of the same class of drugs have induced very different toxicity profiles. Therefore, reporting of thrombotic or haemorrhagic complications is mandatory for new anti-angiogenic agents utilizing both pre- and post-marketing surveillance. Thromboembolism and bleeding risk appear to be a reasonable trade-off for efficacy in a patient with advanced cancer. However, when effective therapies are ultimately moved into front-line regimens with resultant exposure of many more patients, the risk of these complications may become unacceptable. Based on preliminary results, antithrombotic prophylaxis seems to be indicated in high-risk patients, particularly those exposed to the combination of anti-angiogenic drugs and chemotherapy, and those with intrinsic risk factors for VTE or ATE (age, previous history, other cardiovascular risk factors). Given the increased risk of haemorrhage induced by some of these agents, caution is required and patients should be followed closely during the administration of prophylactic antiplatelet or anticoagulant agents. Practice points  many new biological agents with anti-angiogenic properties appear to be associated with an increased risk for thrombosis, especially when administered to newly diagnosed cancer patients in combination with standard chemotherapy  a clear association with increased venous thromboembolic risk has been demonstrated for thalidomide, lenalidomide and semaxibin (SU5416), whereas bevacizumab, sunitinib and sorafenib seem to be associated more frequently with arterial thrombotic complications (evidence is less strong for sunitinib and sorafenib)  the use of thromboprophylaxis is recommended for cancer patients treated with a combination of thalidomide (or lenalidomide) and chemotherapy or dexamethasone. Evidence from randomized clinical trials to suggest a specific prophylactic strategy is lacking; however, LMWH is more commonly used to prevent venous thrombosis in patients treated with thalidomide, while aspirin has been mainly used with lenalidomide  mild bleeding complications are very common with bevacizumab, sunitinib and sorafenib, and require caution in the use of anticoagulants or aspirin for thromboprophylaxis

Research agenda  to define the pathogenesis of thrombosis associated with anti-angiogenic agents  to define the vascular toxicity profile of any new anti-angiogenesis agent  to define the best prophylaxis to prevent venous or arterial events without increasing bleeding complications significantly in randomized, controlled trials Conflict of interest statement None declared. References [1] Edwards RL, Klaus M, Matthews E, et al. Heparin abolishes the chemotherapy-induced increases in plasma fibrinopeptide A levels. Am J Med 1990;89:25–8. [2] Mailloux A, Grenet K, Bruneel A, et al. Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis. Eur J Cell Biol 2001;80:442–9. [3] Elice F, Jacoub J, Rickles FR, et al. Hemostatic complications of angiogenesis inhibitors in cancer patients. Am J Hematol 2008;83:862–70. [4] Falanga A, Rickles FR. The pathogenesis of thrombosis in cancer. New Oncol Thromb 2005;1:9–16. [5] Winn R, Harlan J. The role of endothelial cell apoptosis in inflammatory and immune diseases. J Thromb Haemost 2005;3:1815–24.

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