|REVIEW & CASE REPORT
|Year : 2020 | Volume
| Issue : 5 | Page : 17-25
Peripheral artery disease and stroke
Concetta Zito1, Roberta Manganaro1, Scipione Carerj1, Francesco Antonini-Canterin2, Frank Benedetto3
1 Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, Azienda Ospedaliera Universitaria “Policlinico G. Martino”, Messina, Italy
2 Rehabilitation Cardiology Unit, Motta di Livenza, Treviso, Italy
3 Cardiology Department, Hospital ‘Bianchi Melacrino Morelli’ Reggio Calabria, Italy
|Date of Submission||14-Jan-2019|
|Date of Acceptance||23-Feb-2019|
|Date of Web Publication||10-Apr-2020|
Prof. Concetta Zito
Department of Clinical and Experimental Medicine, Division of Cardiology, University of Messina, Via Consolare Valeria 98124, Messina
Source of Support: None, Conflict of Interest: None
Peripheral artery disease (PAD) and stroke can occur as vascular complication of anticancer treatment. Although the mechanisms, monitoring, and management of cardiotoxicities have received broad attention, vascular toxicities remain often underrecognized. In addition, the development of new chemotherapeutic drugs bears the risk of vasotoxicities that are yet to be identified and may not be realized with short-term follow-up periods. The propensity to develop PAD and/or stroke reflects the complex interplay between patient's baseline risk and preexisting vascular disease, particularly hypertension and diabetes, while evidence for genetic predisposition is increasing. Chemotherapeutic agents with a prominent vascular side effect profile have been identified. Interruption of vascular endothelial growth factor (VEGF) inhibitors (VEGFIs) signaling (i.e., bevacizumab) is associated with vascular toxicity and clinical sequelae such as hypertension, stroke, and thromboembolism beyond acute coronary syndromes. Cisplatin and 5-fluorouracil are the main drugs involved in the stroke risk. In addition, circulating concentrations of VEGF are reduced by cyclophosphamide administered at continuous low doses, which might underpin some of the observed vascular toxicity, such as stroke, as seen in patients treated with VEGF inhibitors. The risk of stroke is also increased after treatment with anthracyclines that can induce endothelial dysfunction and increase arterial stiffness. Proteasome inhibitors ( bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), approved for use in multiple myeloma, carry a black box warning for an increased risk of stroke. Finally, head-and-neck radiotherapy is associated with a doubled risk of cerebrovascular ischemic event, especially if exposure occurs in childhood. The mechanisms involved in radiation vasculopathy are represented by endothelial dysfunction, medial necrosis, fibrosis, and accelerated atherosclerosis. However, BCR-ABL tyrosine kinase inhibitor (TKI), used for the treatment of chronic myeloid leukemia (CML), is the main antineoplastic drugs involved in the development of PAD. In particular, second- and third-generation TKIs, such as nilotinib and ponatinib, while emerging as a potent arm in contrasting CML, are associated with a higher risk of PAD development rather than traditional imatinib. Factors favoring vascular complication are the presence of traditional cardiovascular risk factors (CVRF) and predisposing genetic factors, high doses of BCR-ABL TKIs, longer time of drug exposure, and sequential use of potent TKIs. Therefore, accurate cardiovascular risk stratification is strongly recommended in patient candidate to anticancer treatment associated with higher risk of vascular complication, in order to reduce the incidence of PAD and stroke through CVRF correction and selection of appropriate tailored patient strategy of treatment. Then, a clinical follow-up, eventually associated with instrumental evaluation through vascular ultrasound, should be performed.
Keywords: Arterial stiffness, atherosclerosis, endothelial dysfunction, stroke, thrombosis
|How to cite this article:|
Zito C, Manganaro R, Carerj S, Antonini-Canterin F, Benedetto F. Peripheral artery disease and stroke. J Cardiovasc Echography 2020;30, Suppl S1:17-25
|How to cite this URL:|
Zito C, Manganaro R, Carerj S, Antonini-Canterin F, Benedetto F. Peripheral artery disease and stroke. J Cardiovasc Echography [serial online] 2020 [cited 2022 Aug 13];30, Suppl S1:17-25. Available from: https://www.jcecho.org/text.asp?2020/30/5/17/282280
| Introduction|| |
Peripheral artery disease (PAD) and stroke can occur as vascular complication of different anti-cancer treatment. Particularly, vascular endothelial growth factor inhibitors (VEGFI) (i.e. bevacizumab) are associated with clinical sequelae such as hypertension, stroke and thromboembolism beyond acute coronary syndromes, while BCR-ABL tyrosine-kinase inhibitor (TKIs), used for the treatment of chronic myeloid leukaemia (CML) are the main anti-neoplastic drugs involved in the development of PAD. The development of vascular toxicity is obviously influenced also by traditional cardiovascular risk and predisposing genetic factors. Vascular damage is also observed as complication of other anticancer treatment such as cyclophosphamide, antracyclines and head and neck radiotherapy.
An accurate cardiovascular risk-stratification is, thus, strongly recommended in patient candidate to anti-cancer treatment associated with higher risk of vascular complication, in order to correct CVRF and select appropriate tailored-patient strategy of treatment. Then a clinical follow-up, eventually associated to instrumental evaluation through vascular ultrasound, should be performed.
In the subsequent paragraphs we will focus on peripheral artery disease and stroke, describing etiopathogenesis, diagnosis and therapeutic management.
| Peripheral Artery Disease|| |
Incidence and pathophysiology
Peripheral artery disease (PAD) can occur as complication secondary to anticancer treatment, with an incidence of up to 30%. BCR-ABL tyrosine kinase inhibitor (TKI), used for the treatment of chronic myeloid leukemia (CML), is the main antineoplastic drugs involved in the development of PAD being responsible for the development of vascular adverse events. Due to the emerging resistance against imatinib, considered a “gold standard” of treatment of patients with newly diagnosed CML, more effective TKIs, including nilotinib, dasatinib, bosutinib, and ponatinib, have been developed and are successfully used in daily practice.,,, Their superior efficacy with a major antileukemic activity is, however, accompanied by the development of adverse effects, due to the expression of several targets also in nonhematopoietic cells. Vascular damage is an emerging type of clinically relevant complications in patients receiving second- or third-generation BCR-ABL1 TKIs and includes coronary artery disease, cerebral ischemic disease (stroke), and PAD.,,, The exact incidence of vascular complications is still debated, but according to the most studies, emerging data are the following: (1) the frequency of vascular adverse events increases over time, (2) it is higher in patients treated with higher doses of nilotinib ((800 vs. 600 mg daily) or ponatinib (45 mg vs. 30 or 15 mg daily), and (3) there is a certain correlation between preexisting cardiovascular risk factors (CVRF) and vascular complications.,,, The various TKIs have distinct vascular safety profiles, most likely due to each compound's different kinase inhibition profiles and nonkinase targets. Even if nilotinib and ponatinib are the BCR-ABL TKIs more involved in the development of vascular damage, recent data suggest that vascular disease can also occur in CML patients treated with dasatinib or bosutinib, but with a lower incidence (<5% of patients)., On the contrary, the incidence of vascular complications in patients treated with imatinib appears to be low, interestingly <1% of patients. Imatinib was found to improve the fasting blood glucose level; thus, it can explain a possible protective effect of imatinib on the formation of atherosclerotic plaque and the related cardiovascular diseases. When evaluating the risk of PAD development in such patients treated with BRC-ABL TKIs, different factors have to be considered [Table 1]. First, the presence of preexisting CVRF, such as hypertension, diabetes mellitus, dyslipidemia, smoke, and preexisting vascular disease. Another relevant factor affecting the development of vascular complication is the dose of TKIs, with increased risk at higher doses. Therefore, lowering the dose of drug administered can reduce the incidence of vascular adverse effects. Moreover, shorting the time of exposure to these TKIs can lower the risk of PAD and stroke. In addition, the sequential use of certain TKIs, such as nilotinib and ponatinib, increases the risk of vascular complications; thus, it has been suggested to avoid it if possible., Finally, genetic risk factors may predispose for vascular occlusive disease in patients treated with nilotinib or ponatinib; however, only little is known about these factors. Due to the relative rapid onset of vascular complications in patients under TKIs treatment (within 12 months after starting therapy), it has been hypothesized a direct effect of drugs on vascular cells. Some studies have postulated that TKIs can induce a vasospasm on rapid stenosis formations in arteries; however, now, there is a strong evidence about proatherogenic effects on endothelial cells., It was demonstrated that nilotinib and ponatinib may promote the expression of proatherogenic surface adhesion receptors on human umbilical vein-derived endothelial cells in vitro., Moreover, neoangiogenesis plays a pivotal role in vascular repair processes which are fundamental in favoring survival and recanalization of affected arteries. Both nilotinib and ponatinib have an antiangiogenic activity and inhibit proliferation and survival of human endothelial cells in vitro. In addition, nilotinib treatment resulted in an unbalanced pro-/anti-inflammatory network in a clinical cohort of patients who received either imatinib or nilotinib, which could lead to a proatherothrombotic predisposition, another possible driver of vascular complications. It was also reported that nilotinib might induce metabolic disorders, in particular, increased fasting glucose and cholesterol levels, associated with the increased risk of developing vascular occlusive events.,, Nilotinib treatment is also associated with hypothyroidism, which can affect lipid and glucose metabolism. Even if the exact cellular interactions and mechanism underlying nilotinib-induced hyperglycemia and hypercholesterolemia remain unknown, these metabolic changes can favor the development of atherosclerosis in patients with CML. Finally, all these spectrums of actions exerted by BRC-ABL TKIs can explain the elevated risk of PAD developments in patients treated with these drugs, especially if the previous mentioned risk factors are also present. Hypertension is a main side effect of all three major antivascular endothelial growth factor (VEGF) drugs (bevacizumab, sorafenib, and sunitinib). Mechanisms of arterial hypertension include both functional (inactivation of endothelial nitric oxide synthase and production of vasoconstrictors such as endothelin-1) and anatomic (capillary rarefaction) modifications, which lead to vasoconstriction and an increase in peripheral vascular resistance. All these effects may induce increased arterial stiffness, which increased risk of PAD, especially in patients who received TKIs. VEGF inhibitors (VEGFIs) are also associated with an absolute increase in risk of arterial and venous thrombosis and thromboembolism of 1.5%–4%.
|Table 1: Clinical risk factors contributing/predisposing to the occurrence of vascular adverse event in chronic myeloid leukemia patients treated with nilotinib or ponatinib|
Click here to view
Diagnostic and therapeutic management
BCL-ABL kinase inhibitors have transformed the prognosis of CML; thus, many patients taking TKIs for CML will be on therapy for 10 years or longer. Therefore, it is essential for physicians to prevent and manage acute and chronic vascular complications associated with these agents. The first step in the prevention and diagnosis of PAD secondary to anticancer treatment is represented by accurate cardiovascular risk stratification, searching for preexisting CVRF and cardiovascular disease. Hence, the assessment of CVRF implemented by clinical visit and ankle–brachial index measurement is strongly recommended.
A simple ABCDE algorithm is an established tool to reduce cardiovascular events in the general population and has already been recommended to prevent cardiovascular disease in survivors of breast cancer. Similarly, Moslehi and Deininger proposed an ABCDE step to prevent cardiovascular disease in patients with CML treated with a TKI [Table 2]. This strategy allows identifying patients at higher risk of developing vascular complication and which can thus benefit of some precautions, such as selection of the optimal second- or third-line TKI and doses. Due to the high risk of development of PAD, it should be avoided to administrate nilotinib and ponatinib as a first-line therapy in patients with multiple CVRF if other agents are available.
|Table 2: ABCDE steps to prevent cardiovascular disease in patients with chronic myeloid leukemia treated with a tyrosine kinase inhibitor|
Click here to view
In this context, different strategies have been proposed [Table 3]. One is to start with imatinib in most patients and to switch to second-line TKI only when a suboptimal or no response is seen or the patient is at high risk to transform to accelerated phase (AP)/blast phase (BP). Another possibility in high-risk patients (for both, AP/BP risk and vascular complication risk) is to start with bosutinib or to administer bosutinib after 3–6 months of imatinib therapy. An alternative is the possibility of inducing a stable molecular response (MR) with nilotinib, dasatinib or ponatinib, followed by 2 years of therapy with imatinib or bosutinib. However, this strategy does not prevent at all the possibilities of PAD development because usually, several months are necessary before reaching a deep MR. An interesting alternative can be the rotational therapy, consisting in a combination of a potent but high-risk TKI (nilotinib or ponatinib) with a safer agent (imatinib or bosutinib) in 1–3 month intervals., All these strategies, however, need to be tested in large clinical randomized trial. Once PAD has occurred, the management relies first on the grade of vascular disease. In case of Fontaine stages I or II, patients require risk factor control and periodic clinical, metabolic, and hemodynamic follow-up. In these cases, it is possible to maintain therapy with nilotinib or ponatinib, usually at low doses. It could be suggested to start therapy with aspirin, and antidiabetic drugs or cholesterol-lowering agents, or antihypertensive drugs, could be added if metabolic disorders or hypertension develop. However, the development of high-grade PAD is a more challenging question, due to the problems related to interruption of potent BCR-ABL TKIs therapy. In some cases, it is possible to switch to TKIs with safer vascular profile (imatinib or bosutinib). In selected patients with deep and long-lasting MR (MR4 or deeper), discontinuation of TKI treatment may be an option. Moreover, revascularization should be individualized and discussed in a multidisciplinary meeting with experts in hematology, vascular surgery, and cardio-oncology.,
|Table 3: Proposed strategies to minimize the risk of vascular adverse event evolution in patients with chronic myeloid leukemia|
Click here to view
In patients undergoing VEGFI, a practical algorithm has been recently proposed for assessing risk of hypertension and monitoring the occurrence of this complication during therapy [Table 4].
|Table 4: Cardiovascular risk assessment and monitoring during vascular endothelial growth factor inhibitors|
Click here to view
| Stroke|| |
Incidence and pathophysiology
Stroke and transient ischemic attacks can occur in patients who have cancer with patterns and risk factors similar to noncancer patients. Although not at higher risk of hemorrhagic stroke, patients with cancer are at higher risk of thromboembolic events including those related to paradoxical embolization and indwelling catheters. Hypercoagulability may play a role in some patients but not in general. Moreover, cerebrovascular disease, such as transient ischemic attack and ischemic stroke, can complicate in particular head-and-neck radiotherapy [Table 5]. The risk of stroke is, in fact, increased, at least doubled, after mediastinal, cervical, or cranial radiotherapy, with the exception of adjuvant neck radiotherapy for breast cancer where carotid exposure is minimal., The risk of developing cerebrovascular disease is higher when radiotherapy exposure occurs in childhood than in adulthood. Radiation vasculopathy is the precursor to ischemic stroke in patients who have been treated with head-and-neck radiotherapy for cancer., Chronic radiation vasculopathy affecting medium and large intra- and extra-cranial arteries is characterized by increasing rates of hemodynamically significant stenosis. The pathogenesis of radiation-induced cerebrovascular complication, however, is not totally known, and there are two main hypotheses. In particular, while some authors consider radiation occlusive vasculopathy as a form of accelerated atherosclerosis, others considered it as a distinct disease secondary to the initial radiation insult to the vasa vasorum.,,,, Fonkalsrud et al. analyzed the evolution of radiation vasculopathy in canine femoral arteries after a net dose of 40 Gray. By 48 h, there was extensive endothelial damage with nuclear disruption, platelet aggregation, and fibrin deposition; the intima and media remained intact, but the adventitia already showed minor fibrosis and hemorrhage. By 1 week, no normal endothelial cells were seen, and by 3 weeks, there was destruction of the internal elastic lamina and marked thickening of the endothelium. By 6 weeks, the media was hypocellular. By 4 months, there was focal necrosis and fibrosis of the media, accompanied by chronic inflammation and minimal thrombosis of the adventitia. The medial and adventitial fibrosis narrowed the vessel lumen. It is also known that irradiation induces an increase in oxidative stress involved in the formation of vascular damage. Some pro-inflammatory molecules (cytokines and growth factors) can stimulate radio-induced endothelial proliferation, fibroblast proliferation, collagen deposition, and hence the fibrosis leading to the development of atheromas. Endothelial damage secondary to irradiation induces the secretion of thrombomodulins, which, together with other pro-inflammatory molecules, increase the attraction of leukocytes on the endothelium (chemotaxis), resulting in subendothelial inflammatory infiltrate. The pathophysiology of radiation-induced vasculopathy can be, thus, summarized in the following mechanisms occurring in medium and large vessels: vasa vasorum occlusions with medial necrosis and fibrosis, adventitial fibrosis, and accelerated atherosclerosis, leading to increased carotid stiffness and intima–media thickness and advanced atherosclerosis (occurring >10 years after radiotherapy)., However, while it is clear that no doses of radiotherapy can be considered safe, there is no exhaustive information if and which dose can be safer.
Even if radiotherapy is the main “iatrogenic” cause of cerebrovascular accident (CVA) in patients affected by cancer, it is not the only. Likewise, not all, but some chemotherapeutic agents and new target therapy have been associated with a risk of stroke in neoplastic patients. Cisplatin and 5-fluorouracil (5-FU) are the main drugs involved. More than 30 years ago, Goldhirsch et al. reported an acute CVA in a patient receiving a cisplatin-based treatment. Other case reports followed.,,, The physiopathogenesis is probably multifactorial. Cisplatin is responsible of a hypercoagulability state secondary to a cisplatin-induced reduction of C-reactive protein and increased von Willebrand factor and tissue factor level. This may explain why, in some cases, no cause of ischemic stroke can be identified; whereas, in other cases, local cranial artery thrombosis can occur to the point of acute complete occlusions.
Moreover, cisplatin induces endothelial dysfunction responsible of increased intima–media thickness and reduced production of nitric oxide and may cause nephrotoxicity with renal magnesium wasting that leads to vasoconstriction. 5-FU is an antineoplastic agent which has also been connected with increased incidence of ischemic strokes, and cases are also reported following combined treatment with both 5-FU and cisplatin., It was demonstrated that 5-FU causes direct endothelium-independent vasoconstriction of vascular smooth muscle in vitro. However, ischemic stroke has to be differentiated from leukoencephalopathy with stroke-like presentation which is a rare complication of chemotherapeutic agents including 5-FU and is characterized by specific findings on cerebral magnetic resonance.,,
Given the outlined side effect profile of arterial thrombosis, bleeding, and hypertension, concerns for stroke risk have been raised for VEGFI. In Phase I and II trials of VEGFI, ischemic stroke and intracranial hemorrhage occurred at a rate of 1.9% each with bevacizumab and in 0% and 3.8% of patients receiving VEGF receptor TKIs, respectively.
A retrospective review of the Food and Drug Administration MedWatch database of adverse events indicated that cranial bleeds accounted for 12.9% of all bleeding events with bevacizumab (which were 6.8% of all adverse events) and were fatal in half of the cases.
The greatest risk actors were additional use of medications associated with bleeding and thrombocytopenia, whereas central nervous system tumors and metastases do not seem to increase the risk of intracranial bleeding. The combination of bevacizumab with 5-FU- or carboplatin-based therapies may more than double the overall incidence of arterial thromboembolic events, especially in those ≥65 years of age or with a previous arterial thromboembolic event.
In this analysis of combination therapies, as many as half of all acute ischemic events were strokes or transient ischemic attacks.
Structural vascular abnormalities such as atherosclerosis or dissections as underlying mechanisms are rarely reported. Finally, even if cases of CVA after treatment with bevacizumab were reported, the meta-analysis conducted by Ranpura et al. concluded for any increased relative risk of stroke with bevacizumab therapy. Similarly, although significant carotid artery disease can be noted with sorafenib, this seems to be the exception rather than the rule in patients presenting with stroke while undergoing therapy with VEGF signaling pathway TKIs. However, probably a higher risk of cerebral ischemic events has to be expected due to endothelial injury secondary to inhibition of VEGF signaling and subsequent risk of arterial thrombosis, typical of this group of drugs.,
Anthracyclines, more commonly associated with cardiac toxicity, may also increase the risk of stroke through several pathophysiological mechanisms involving carotid arteries such as oxidative stress, vascular inflammation, and apoptosis. Indeed, anthracyclines can induce both an acute and chronic carotid damage, the first related to endothelial dysfunction and increase of smooth muscle tone and the second to accelerated atherosclerosis and increased collagen synthesis. More than 15 years ago, experimental models demonstrated that the exposure of animal arteries to doxorubicine for 1 to 10 weeks is able to lead apoptosis of smooth muscle cells and increased medial and adventitial thickness, and these data were confirmed later. These reparative processes secondary to the chemical stress lead to structural changes within the vessel wall and extracellular matrix with increased collagen deposition and vessel wall calcification, ultimately resulting in reduced arterial compliance and increased stiffness. More recently, it has been detected through magnetic resonance imaging, in individuals receiving anthracyclines for breast cancer, an early (≈3 months) and abrupt increase of arterial stiffness, and interestingly, this effect was dose, age, and CVRF independent. Moreover, the increase of arterial stiffness can be persistent at 12 months after therapy.,, Furthermore, patients survived for ≥5 years after diagnosis of leukemia, lymphomas, central nervous system tumors, and sarcomas of leukemia treated with standard chemotherapy show lower carotid distensibility and compliance, indicating increased arterial stiffness when compared to controls. All these results demonstrate thus that early in life, cancer survivors previously treated with anthracyclines have arterial changes indicating increased risk for premature atherosclerosis and stroke.
An increased incidence of stroke has been demonstrated in patients with multiple myeloma (MM) undergoing immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide. These agents inhibit the production of interleukin-6 (IL-6), which is a growth factor for MM cells. They also activate apoptotic pathways through caspase-8-mediated cell death and regulate the activity of molecules that affect apoptosis through c-Jun terminal kinase-dependent release of cytochrome-c and SMAC into the cytosol of cells. The exact mechanism of the increased clot risk with this class of agents is not known. It has been suggested that this is a direct effect of the drugs on endothelial cell activation, and this is possibly synergistic with the increased risk of thrombosis related to MM. The latter may be mediated by increased IL-6 and tumor necrosis factor-alpha found in MM.
A moyamoya disease-like process has also been implied as a potential side effect of interferon-α. A posterior reversible encephalopathy syndrome can emerge as an acute cerebral event with headache, confusion, visual symptoms, and seizures. The characteristic finding is posterior cerebral white matter edema on neuroimaging attributable to impaired autoregulation of the cerebral vasculature. It is often noted with severe hypertension, and numerous cases have been reported for patients who have cancer undergoing drug therapy, in particular, with VEGFI and the proteasome inhibitor bortezomib.
Diagnostic and therapeutic management
Patients treated with head and/or neck radiotherapy should undergo cerebrovascular ultrasound, especially beyond 5 years after irradiation, and then follow-up should be performed at least every 5 years or earlier if atherosclerosis is detected. Of note, carotid lesions secondary to radiotherapy are often more extensive and commonly involve longer segments of the carotid arteries. Computed tomography angiography is, also, routinely used to evaluate carotid, subclavian, and aortic diseases related to radiation therapy. To date, no randomized trial has assessed the medical treatment option for primary or secondary stroke prevention in this patients' group. A strict control of traditional CVRF should be strongly recommended, and antiplatelet treatment may be considered. Significant carotid stenosis may be treated by surgery or stenting.,,,, Even if neither approach appears to be clearly superior, different studies showed a higher incidence of restenosis after carotid angioplasty and stenting of radiation-induced vascular stenosis, compared to surgical results.,,
The relationship linking increased arterial stiffness with atherosclerosis and risk of stroke is well recognized. Accordingly, it is reasonable to advocate that efforts should be directed at monitoring increased arterial stiffness and managing CVRF in cancer patients treated with drugs which may potentially impair vascular elasticity (i. e., anthracyclines and anti-VEGFR). Applanation tonometry and/or echotracking are two main available modalities in clinical practice for this purpose [Figure 1]. Moreover, being Pulse wave velocity (PWV), an independent predictor of cardiovascular morbidity and stroke, we can better stratify patients' prognosis. Nonetheless, larger prospective studies are needed to determine the predictive value of PWV in this population and its utility as a screening modality. Unsolved problems on this issue are detailed in [Table 6].
|Figure 1: Measurement of beta-index and PWV through echotracking at baseline and 3 months after starting chemotherapy with anthracyclines, showing increased arterial stiffness at 3-month follow-up|
Click here to view
|Table 6: Unsolved problem for including arterial stiffness assessment within the stoke risk management in cancer patients|
Click here to view
In patients at risk of ischemic stroke, undergoing treatment with platinum compounds is important to manage CVRF to prevent vascular ischemia. Carboplatin, second-generation platinum, shows an improved toxicity profile. Additional agents, for example, vitamins, selenium, resveratrol, and melatonin reduce endothelial cell oxidative stress and inhibit inflammation, thus exerting beneficial effects by suppressing cisplatin-related oxidative injury.
Patients with cancer who have signs or symptoms of stroke should be managed based on published guidelines. This entails a a head computed tomography to address the question of a hemorrhagic event or intracranial tumors (metastases). If negative, the decision on revascularization is to be made. Importantly, patients with cancer per se are not at a higher risk of intracerebral hemorrhage when undergoing thrombolytic therapy. However, patients who experience a thrombotic stroke as a consequence of chemotherapy have not been rigorously studied in fibrinolysis trials. Low platelet count (<100,000) and abnormal plasma glucose (<50 or >400 mg/dL) are contraindications to lytic therapy that can be quite relevant for patients who have cancer. Further, workup of underlying pathologies such as thrombotic occlusion, critical stenosis, or dissection by imaging of the cerebral vasculature should be pursued on as needed. A 12-lead ECG should be obtained to assess for atrial fibrillation and an echocardiogram to assess for a patent foramen ovale, valve abnormalities, regional wall abnormalities, and aneurysms as potential sources of thromboembolism. An emergency neurology referral should be made at the onset of presentation. Care decisions (acute and long term) are to be made in the context of the patients' overall prognosis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al
. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC committee for practice guidelines: The task force for cancer treatments and cardiovascular toxicity of the European society of cardiology (ESC). Eur Heart J 2016;37:2768-801.
O'Hare T, Eide CA, Deininger MW. Bcr-abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007;110:2242-9.
Radich JP. Monitoring response to tyrosine kinase inhibitor therapy, mutational analysis, and new treatment options in chronic myelogenous leukemia. J Natl Compr Canc Netw 2013;11:663-6.
Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, et al.
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N
Engl J Med 2006;354:2542-51.
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al.
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N
Engl J Med 2006;354:2531-41.
Aichberger KJ, Herndlhofer S, Schernthaner GH, Schillinger M, Mitterbauer-Hohendanner G, Sillaber C, et al.
Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol 2011;86:533-9.
Kim TD, Rea D, Schwarz M, Grille P, Nicolini FE, Rosti G, et al.
Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 2013;27:1316-21.
Le Coutre P, Rea D, Abruzzese E, Dombret H, Trawinska MM, Herndlhofer S, et al.
Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst 2011;103:1347-8.
Mirault T, Rea D, Azarine A, Messas E. Rapid onset of peripheral artery disease in a chronic myeloid leukemia patient without prior arterial disorder: Direct relationship with nilotinib exposure and clinical outcome. Eur J Haematol 2015;94:363-7.
Valent P, Hadzijusufovic E, Hoermann G, Füreder W, Schernthaner GH, Sperr WR, et al.
Risk factors and mechanisms contributing to TKI-induced vascular events in patients with CML. Leuk Res 2017;59:47-54.
Giles FJ, Mauro MJ, Hong F, Ortmann CE, McNeill C, Woodman RC, et al.
Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: A retrospective cohort analysis. Leukemia 2013;27:1310-5.
Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre P. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 2015;125:901-6.
Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, et al.
Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012;26:2197-203.
le Coutre PD, Hughes TP, Mahon FX, Kim DW, Steegmann JL, Shah NP, et al.
Low incidence of peripheral arterial disease in patients receiving dasatinib in clinical trials. Leukemia 2016;30:1593-6.
Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogné JM. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: A systematic review and meta-analysis. JAMA Oncol 2016;2:625-32.
Breccia M, Muscaritoli M, Aversa Z, Mandelli F, Alimena G. Imatinib mesylate may improve fasting blood glucose in diabetic ph+chronic myelogenous leukemia patients responsive to treatment. J Clin Oncol 2004;22:4653-5.
Mayer K, Gielen GH, Willinek W, Müller MC, Wolf D. Fatal progressive cerebral ischemia in CML under third-line treatment with ponatinib. Leukemia 2014;28:976-7.
Bocchia M, Galimberti S, Aprile L, Sicuranza A, Gozzini A, Santilli F, et al.
Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients. Oncotarget 2016;7:72311-21.
Quintás-Cardama A, Kantarjian H, Cortes J. Nilotinib-associated vascular events. Clin Lymphoma Myeloma Leuk 2012;12:337-40.
Gover-Proaktor A, Granot G, Shapira S, Raz O, Pasvolsky O, Nagler A, et al.
Ponatinib reduces viability, migration, and functionality of human endothelial cells. Leuk Lymphoma 2017;58:1455-67.
Rea D, Mirault T, Cluzeau T, Gautier JF, Guilhot F, Dombret H, et al.
Early onset hypercholesterolemia induced by the 2nd
-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Haematologica 2014;99:1197-203.
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al.
Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N
Engl J Med 2010;362:2251-9.
Racil Z, Razga F, Drapalova J, Buresova L, Zackova D, Palackova M, et al.
Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia. Haematologica 2013;98:e124-6.
Li W, Croce K, Steensma DP, McDermott DF, Ben-Yehuda O, Moslehi J. Vascular and metabolic implications of novel targeted cancer therapies: Focus on kinase inhibitors. J Am Coll Cardiol 2015;66:1160-78.
Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 2015;33:4210-8.
Gugliotta G, Castagnetti F, Breccia M, Gozzini A, Usala E, Carella AM, et al.
Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia. Am J Hematol 2016;91:617-22.
Valent P, Herndlhofer S, Schneeweiß M, Boidol B, Ringler A, Kubicek S, et al.
TKI rotation-induced persistent deep molecular response in multi-resistant blast crisis of ph+CML. Oncotarget 2017;8:23061-72.
Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, Cohnert T, et al
. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European society for vascular surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: The European stroke organization (ESO) the task force for the diagnosis and treatment of peripheral arterial diseases of the European society of cardiology (ESC) and of the European society for vascular surgery (ESVS). Eur Heart J 2018;39:763-816.
Fokkema M, den Hartog AG, Bots ML, van der Tweel I, Moll FL, de Borst GJ. Stenting versus surgery in patients with carotid stenosis after previous cervical radiation therapy: Systematic review and meta-analysis. Stroke 2012;43:793-801.
De Bruin ML, Dorresteijn LD, van't Veer MB, Krol AD, van der Pal HJ, Kappelle AC, et al.
Increased risk of stroke and transient ischemic attack in 5-year survivors of hodgkin lymphoma. J Natl Cancer Inst 2009;101:928-37.
Woodward WA, Durand JB, Tucker SL, Strom EA, Perkins GH, Oh J, et al.
Prospective analysis of carotid artery flow in breast cancer patients treated with supraclavicular irradiation 8 or more years previously: No increase in ipsilateral carotid stenosis after radiation noted. Cancer 2008;112:268-73.
Brada M, Burchell L, Ashley S, Traish D. The incidence of cerebrovascular accidents in patients with pituitary adenoma. Int J Radiat Oncol Biol Phys 1999;45:693-8.
Dorresteijn LD, Kappelle AC, Boogerd W, Klokman WJ, Balm AJ, Keus RB, et al.
Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol 2002;20:282-8.
Levinson SA, Close MB, Ehrenfeld WK, Stoney RJ. Carotid artery occlusive disease following external cervical irradiation. Arch Surg 1973;107:395-7.
Hayward RH. Arteriosclerosis induced by radiation. Surg Clin North Am 1972;52:359-66.
Cheng SW, Ting AC, Wu LL. Ultrasonic analysis of plaque characteristics and intimal-medial thickness in radiation-induced atherosclerotic carotid arteries. Eur J Vasc Endovasc Surg 2002;24:499-504.
Zidar N, Ferluga D, Hvala A, Popović M, Soba E. Contribution to the pathogenesis of radiation-induced injury to large arteries. J Laryngol Otol 1997;111:988-90.
Nardelli E, Fiaschi A, Ferrari G. Delayed cerebrovascular consequences of radiation to the neck. A clinicopathologic study of a case. Arch Neurol 1978;35:538-40.
Fonkalsrud EW, Sanchez M, Zerubavel R, Mahoney A. Serial changes in arterial structure following radiation therapy. Surg Gynecol Obstet 1977;145:395-400.
Louis EL, McLoughlin MJ, Wortzman G. Chronic damage to medium and large arteries following irradiation. J Can Assoc Radiol 1974;25:94-104.
Fajardo LF. The pathology of ionizing radiation as defined by morphologic patterns. Acta Oncol 2005;44:13-22.
Goldhirsch A, Joss R, Markwalder TM, Studer H, Brunner K. Acute cerebrovascular accident after treatment with cis-platinum and methylprednisolone. Oncology 1983;40:344-5.
Digklia A, Voutsadakis IA. Acute cerebrovascular accident after cisplatin treatment in a patient taking letrozole. Chemotherapy 2012;58:435-8.
Gamble GE, Tyrrell P. Acute stroke following cisplatin therapy. Clin Oncol (R Coll Radiol) 1998;10:274-5.
Serrano-Castro PJ, Guardado-Santervás P, Olivares-Romero J. Ischemic stroke following cisplatin and 5-fluorouracil therapy: A transcranial doppler study. Eur Neurol 2000;44:63-4.
Lange J, Audebert HJ, Endres M, Rocco A. Cisplatin-related cerebral infarction in testicular germ cell cancer: Short report of three cases andPin testicular germ cell cancer: Short report of three cases and pathomechanism. Clin Neurol Neurosurg 2017;152:76-7.
Sekijima T, Tanabe A, Maruoka R, Fujishiro N, Yu S, Fujiwara S, et al.
Impact of platinum-based chemotherapy on the progression of atherosclerosis. Climacteric 2011;14:31-40.
El Amrani M, Heinzlef O, Debroucker T, Roullet E, Bousser MG, Amarenco P. Brain infarction following 5-fluorouracil and cisplatin therapy. Neurology 1998;51:899-901.
Kinno R, Kii Y, Uchiyama M, Owan Y, Yamazaki T, Fukui T. 5-fluorouracil-induced leukoencephalopathy with acute stroke-like presentation fulfilling criteria for recombinant tissue plasminogen activator therapy. J Stroke Cerebrovasc Dis 2014;23:387-9.
Li J, Lee JJ, Chu E, Baehring JM. Reversible leukoencephalopathy with stroke-like presentation in a patient with 5-dihydropyrimidine dehydrogenase deficiency treated with continuous 5-fluorouracil infusion. Clin Colorectal Cancer 2012;11:215-7.
Nguyen MT, Stoianovici R, Brunetti L. Chemotherapy induced stroke mimic: 5-fluorouracil encephalopathy fulfilling criteria for tissue plasminogen activator therapy. Am J Emerg Med 2017;35:1389-90.
Fraum TJ, Kreisl TN, Sul J, Fine HA, Iwamoto FM. Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. J Neurooncol 2011;105:281-9.
Letarte N, Bressler LR, Villano JL. Bevacizumab and central nervous system (CNS) hemorrhage. Cancer Chemother Pharmacol 2013;71:1561-5.
Sandler A, Hirsh V, Reck M, von Pawel J, Akerley W, Johnson DH. An evidence-based review of the incidence of CNS bleeding with anti-VEGF therapy in non-small cell lung cancer patients with brain metastases. Lung Cancer 2012;78:1-7.
Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, et al.
Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007;99:1232-9.
Domenico G, Vincenza T, Emiddio B, Dino T, Franco MC, Bruno D. Afatal brain stroke in patient with advanced breast cancer treated with bevacizumab: A Case report. World J Oncol 2010;1:252-4.
Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: A meta-analysis of randomized controlled trials. Acta Oncol 2010;49:287-97.
Kuenen BC. Analysis of prothrombotic mechanisms and endothelial perturbation during treatment with angiogenesis inhibitors. Pathophysiol Haemost Thromb 2003;33 Suppl 1:13-4.
Di Lisi D, Madonna R, Zito C, Bronte E, Badalamenti G, Parrella P, et al.
Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond. Int J Cardiol 2017;227:11-7.
Murata T, Yamawaki H, Hori M, Sato K, Ozaki H, Karaki H. Chronic vascular toxicity of doxorubicin in an organ-cultured artery. Br J Pharmacol 2001;132:1365-73.
Chaosuwannakit N, D'Agostino R Jr., Hamilton CA, Lane KS, Ntim WO, Lawrence J, et al.
Aortic stiffness increases upon receipt of anthracycline chemotherapy. J Clin Oncol 2010;28:166-72.
Drafts BC, Twomley KM, D'Agostino R Jr., Lawrence J, Avis N, Ellis LR, et al.
Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc Imaging 2013;6:877-85.
Grover S, Lou PW, Bradbrook C, Cheong K, Kotasek D, Leong DP, et al.
Early and late changes in markers of aortic stiffness with breast cancer therapy. Intern Med J 2015;45:140-7.
Dengel DR, Kelly AS, Zhang L, Hodges JS, Baker KS, Steinberger J. Signs of early sub-clinical atherosclerosis in childhood cancer survivors. Pediatr Blood Cancer 2014;61:532-7.
Gao Y, Ma G, Liu S, Teng Y, Wang Y, Su Y. Thalidomide and multiple myeloma serum synergistically induce a hemostatic imbalance in endothelial cells in vitro
. Thromb Res 2015;135:1154-9.
Herrmann J, Yang EH, Iliescu CA, Cilingiroglu M, Charitakis K, Hakeem A, et al.
Vascular toxicities of cancer therapies: The old and the new – An evolving avenue. Circulation 2016;133:1272-89.
Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bogaert J, Davin L, et al
. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: A report from the European Association of cardiovascular imaging and the American Society of Echocardiography. J Am Soc Echocardiogr 2013;26:1013-32.
Gujral DM, Shah BN, Chahal NS, Senior R, Harrington KJ, Nutting CM. Clinical features of radiation-induced carotid atherosclerosis. Clin Oncol (R Coll Radiol) 2014;26:94-102.
Al-Mubarak N, Roubin GS, Iyer SS, Gomez CR, Liu MW, Vitek JJ. Carotid stenting for severe radiation-induced extracranial carotid artery occlusive disease. J Endovasc Ther 2000;7:36-40.
Ting AC, Cheng SW, Yeung KM, Cheng PW, Lui WM, Ho P, et al.
Carotid stenting for radiation-induced extracranial carotid artery occlusive disease: Efficacy and midterm outcomes. J Endovasc Ther 2004;11:53-9.
Friedell ML, Joseph BP, Cohen MJ, Horowitz JD. Surgery for carotid artery stenosis following neck irradiation. Ann Vasc Surg 2001;15:13-8.
Protack CD, Bakken AM, Saad WE, Illig KA, Waldman DL, Davies MG. Radiation arteritis: A contraindication to carotid stenting? J Vasc Surg 2007;45:110-7.
Shin SH, Stout CL, Richardson AI, DeMasi RJ, Shah RM, Panneton JM. Carotid angioplasty and stenting in anatomically high-risk patients: Safe and durable except for radiation-induced stenosis. J Vasc Surg 2009;50:762-7.
Ricco JB, Marchand C, Neau JP, Marchand E, Cau J, Fébrer G. Prosthetic carotid bypass grafts for atherosclerotic lesions: A prospective study of 198 consecutive cases. Eur J Vasc Endovasc Surg 2009;37:272-8.
Moreo A, Vallerio P, Ricotta R, Stucchi M, Pozzi M, Musca F, et al.
Effects of cancer therapy targeting vascular endothelial growth factor receptor on central blood pressure and cardiovascular system. Am J Hypertens 2016;29:158-62.
Seok JM, Kim SJ, Song P, Chung CS, Kim GM, Lee KH, et al.
Clinical presentation and ischemic zone on MRI in cancer patients with acute ischemic stroke. Eur Neurol 2012;68:368-76.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]