Ischemic Stroke in Cancer: Mechanisms, Biomarkers, and Implications for Treatment

Abstract

Ischemic stroke is an important cause of morbidity and mortality in cancer patients. The underlying mechanisms linking cancer and stroke are not completely understood. Long-standing and more recent evidence suggests that cancer-associated prothrombotic states, along with treatment-related vascular toxicity, such as with chemotherapy and immunotherapy, contribute to an increased risk of ischemic stroke in cancer patients. Novel biomarkers, including coagulation, platelet and endothelial markers, cell-free DNA, and extracellular vesicles are being investigated for their potential to improve risk stratification and patient selection for clinical trials and to help guide personalized antithrombotic strategies. Treatment of cancer-related stroke poses unique challenges, including the need to balance the risk of recurrent stroke and other thromboembolic events with that of bleeding associated with antithrombotic therapy. In addition, how and when to restart cancer treatment after stroke remains unclear. In this review, we summarize current knowledge on the mechanisms underlying ischemic stroke in cancer, propose an etiological classification system unique to cancer-related stroke to help guide patient characterization, provide an overview of promising biomarkers and their clinical utility, and discuss the current state of evidence-based management strategies for cancer-related stroke. Ultimately, a personalized approach to stroke prevention and treatment is required in cancer patients, considering both the underlying cancer biology and the individual patient's risk profile.

Keywords

cancer - acute ischemic stroke - biomarkers - stroke mechanisms - cancer-related stroke

Patients with active cancer face an increased risk of developing acute ischemic stroke (AIS), and this risk correlates with cancer's histopathology and stage.[1] [2] Whereas some AIS patients with cancer have an identifiable traditional stroke mechanism (TSM), the underlying etiology remains undetermined in 32 to 51% of cases.[1] [3] [4] [5] [6] Cancer-related stroke mechanisms are diverse and may involve hypercoagulability, direct tumor invasion of blood vessels, immunosuppression, and cancer therapy-related factors, including prothrombotic effects and cardiotoxicity of chemotherapy and radiation-induced vasculopathy.[7] Increasingly administered immunotherapies promote atherosclerosis and may result in an increased arterial thromboembolic risk.[8] In addition, having a cancer-related mechanism (alone or with a TSM) is associated with an increased risk of cerebrovascular recurrence.[9] Thus, studying cancer-related mechanisms of AIS in cancer patients is crucial for better identifying high-risk patients for primary prevention as well as tailoring oncological and antithrombotic strategies before and after AIS.

Recent studies have highlighted the importance of biomarkers in predicting stroke risk in cancer patients. Elevated D-dimer levels have been associated with increased cancer activity, hypercoagulability, increased stroke risk, and cerebrovascular recurrence, and may serve as a marker of occult cancer in AIS patients.[7] [10] [11] [12] [13] In addition, neutrophil extracellular traps (NETs), extracellular vesicles (EVs), and markers of platelet and endothelial activation have been investigated in AIS patients with cancer.[14] [15] These biomarkers may help clinicians and researchers better characterize AIS patients with cancer and potentially enable risk stratification for prospective studies, but their current use in routine clinical practice is limited.

Regarding treatments of AIS in cancer patients, international guidelines provide only general indications on reperfusion therapies,[16] [17] and the best secondary antithrombotic strategy after AIS in patients with cancer is still debated. Currently, no clear evidence suggests that anticoagulation is preferable to antiplatelet therapy in all AIS patients with cancer, except possibly in those with elevated D-dimer levels.[18] Some planned and ongoing prospective studies on AIS patients with cancer will provide guidance in this regard.[10] [19]

In this review, we discuss the mechanisms of AIS in cancer patients, propose an etiological classification system for cancer-associated stroke, highlight radiological and laboratory biomarkers in cancer patients with AIS, and discuss existing data on reperfusion therapies and secondary prevention in this population.

Stroke Mechanisms in Cancer Patients

Stroke Mechanisms in Cancer Patients

The debate over the pathogenesis of stroke in cancer patients stems from the fact that both TSMs and cancer-related mechanisms contribute to the development of stroke in these patients. Cancer and its treatments can promote TSMs, such as atherosclerosis, small-vessel disease, and cardiac embolism.[20] Additionally, shared risk factors for cancer and ischemic stroke (e.g., smoking, obesity, alcohol, and inflammation)[21] contribute to heightened stroke risk in cancer patients, while cancer treatments can cause stroke through numerous mechanisms (i.e., radiation therapy that may accelerate atherosclerosis[22] [23]). Moreover, solid tumors of the lung or heart (cardiac myxoma or sarcoma) can rarely invade pulmonary veins and cardiac chambers and cause stroke through tumor embolism.[24] [25]

A 2010 study on 161 patients with cancer and AIS reported that patients with cancer and TSMs had a similar distribution of stroke subtypes to those of stroke patients without cancer, suggesting that these cancer–stroke patients should be categorized as having cancer-unrelated mechanisms and treated accordingly.[3] We recently described findings in a larger cohort of 5,986 AIS patients, including 365 with cancer, of which 42% presented with cancer-related mechanisms only or concomitantly with TSMs.[9] This may motivate clinicians to use a detailed classification of cancer-related stroke subtypes along with TSMs that aims to help in the diagnostic and clinical decision-making process (see [Table 1]).

Table 1 Proposed criteria for acute ischemic stroke mechanisms related to cancer or its treatment

Mechanisms	Criteria	Refs.
Cancer-associated
Hypercoagulability	• At least two of the following:   – Recurrent unexplained arterial and/or venous thrombotic events while patient has active cancer (independent of whether PFO present)   – Radiological multifocal nonlacunar (>1 territory) stroke lesions, either simultaneous or acute and subacute (not chronic)   – Blood markers of hypercoagulability: ≥1 of the following: D-dimer level >4 μg/mL on admission, and/or presence of monomers at any stage during the current stroke-related hospitalization, and/or thrombocytosis >1,000 G/L, and/or hyperleukocytosis >100 G/L  • Nonbacterial thrombotic endocarditis with valvular vegetations detected on echocardiography and negative work-up for infective endocarditis.	[7] [13] [18] [37] [40] [48]
Direct tumor invasion of blood vessels	• Tumor embolization: evidence of centrally located lung tumor, or primary or secondary intracardiac tumor (echo, postmortem), or invasive head and neck cancer with distal occlusion and histopathological evidence of tumor emboli (retrieved during EVT, or postmortem, or metastasis on follow-up imaging at site of embolic stroke)  • Leptomeningeal carcinomatosis:   – Stroke predominantly in deep structures (presumably from neoplastic infiltration of Virchow–Robin perivascular spaces and perforator arteries), and   – Evidence of leptomeningeal enhancement on brain MRI, and/or tumor cell in CSF, and/or postmortem leptomeningeal carcinomatosis  • Brain intravascular lymphoma: histopathological evidence on brain biopsy or postmortem  • Direct vessel infiltration: radiologically or histologically confirmed arterial invasion of tumor mass (e.g., glioblastoma, invasive astrocytoma, metastases in brain infiltrating vessels, or invasive head and neck cancer with occlusion of cervical arteries)	[7] [24] [51] [52] [53] [54] [55] [56]
Immunosuppression favoring infections that cause stroke	Cancer-related immunosuppression leading to systemic or CNS infections that cause stroke (such as infectious endocarditis, sepsis, bacterial meningitis, opportunist infections)	[7] [10]
Cancer therapy-related
Chemotherapy and hormone therapy	Chemotherapies (including target therapies, e.g., tyrosine kinase inhibitors) and hormone therapies with at least moderate evidence of association with an increased risk of cardiovascular events	[61]
Cancer-therapy related immunosuppression favoring infections that cause stroke	Cancer therapy-related immunosuppression leading to systemic or CNS infections that cause stroke (such as infectious endocarditis, bacterial meningitis, opportunist infections)	[7]
Cardiac failure with a reduced ejection fraction	Reduced ejection fraction <35% attributed exclusively to past chemotherapy (e.g., anthracycline) and/or radiotherapy (e.g., chronic constrictive pericarditis)	[70] [71]
Radiotherapy	Past radiotherapy: remote (>1 year, independently of dose) radiation:  • To head/neck/mediastinum with demonstrated large artery arteriopathy leading to the ischemic territory (≥50% stenosis, and/or high-risk plaque radiology) insufficiently explained by ≥2 vascular risk factors  • To head, with small-vessel cerebral arterial pathology not sufficiently explained by ≥2 vascular risk factors	[23] [86]
Surgical or endoscopic therapeutic approaches	Stroke onset during or within 24 hours of the surgical endoscopic procedure without any other definite cause.	[171]
Cancer diagnostic-related
Surgical or endoscopic diagnostic procedures	Stroke onset during or within 24 hours of the diagnostic procedure for cancer without any other definite cause.	[92] [93] [94]

Abbreviations: CNS, central nervous system; EVT, endovascular treatment; MRI, magnetic resonance imaging; PFO, patent foramen ovale.

One of the most relevant points of discussion regards the classification of cancer-related stroke as a subtype of embolic stroke of undetermined source (ESUS). This topic has already been thoroughly covered in another review.[10] In the following subsections, we will briefly summarize the topic of ESUS and cancer and then discuss our proposed diagnostic framework for different subtypes of cancer-related stroke.

“Stroke of Undetermined Origin” and Cancer

Stroke of undetermined origin may occur in cancer and noncancer patients; most of them qualify as “ESUS,” which refers to a concept conceived for patients with nonlacunar ischemic stroke whose cause remained cryptogenic after standard diagnostic evaluation. This notion was created in part as a basis for randomized trials comparing traditional antiplatelet therapy to novel oral anticoagulant therapy for secondary stroke prevention. The underlying hypothesis was that most ESUS resulted from thromboembolic mechanisms arising from atherothrombotic and cardiac sources, supporting the idea of a potential benefit of anticoagulant over antiplatelet therapy in these patients. Two large randomized clinical trials failed to show the superiority of direct oral anticoagulants (DOACs) over aspirin for treating ESUS patients.[26] [27] This has prompted stroke experts to subdivide ESUS patients into subgroups, such as those with biomarker evidence for atrial cardiopathy currently being investigated in the ARCADIA trial (AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke),[28] and patients with cancer.

Approximately 10% of ESUS are estimated to be due to cancer, although this percentage may be higher in certain Asian populations.[29] [30] [31] Conversely, this proportion could also be lower as the relationship between cancer and stroke may be incidental in some cases, particularly considering the variable definition of cancer within studies. Recent data indicate that 2 to 10% of patients with ESUS are diagnosed with cancer within a year of their stroke,[12] [32] [33] and about half of the ischemic strokes in cancer patients are classified as ESUS, a proportion higher than in patients without cancer.[3] [34] A more structured classification of ESUS in cancer patients would likely reduce this percentage. We recently presented such a classification system,[2] suggesting specific criteria for considering a stroke as cancer-related ([Table 1]) based on a review of the literature and pathophysiological considerations. By applying these criteria, the percentage of stroke of undetermined origin was reduced to 16% (9% ESUS, 7% non-ESUS) in our study[9] compared to a range between 31 and 51% in previous research studies.[5] [6] [34]

ESUS in patients with cancer is typically associated with fewer traditional risk factors and a higher stroke severity than ESUS in noncancer patients.[5] Features associated with underlying cancer in stroke patients include smoking, unexplained weight loss, infarcts in all vascular territories, increased D-dimer and C-reactive protein, anemia, and lower nutritional status.[31] [32] [33] [35] In line with these results, a recent score aiming to predict occult cancer in AIS patients (OCCULT-5 score) comprised ESUS, multiterritorial infarcts, and high D-dimer levels in addition to age ≥77 years and female sex as predicting variables.[36] However, it remains debated whether and how ESUS patients should be screened for cancer and how early detection could change management and outcomes.

Cancer-Associated Mechanisms

Different authors have thoroughly discussed stroke etiology in cancer patients, mostly distinguishing between hypercoagulable and nonhypercoagulable mechanisms.[10] [37] [38] Whereas much research has focused on characterizing hypercoagulability in these patients,[13] [18] [39] other less frequent mechanisms have been more difficult to define. Diagnostic ascertainment in this subgroup is even more complex as cancer patients may not only present with traditional vascular risk factors and stroke mechanisms, but also overlapping cancer-related mechanisms, directly linked to the underlying tumor or diagnostic/therapeutic approaches. To help physicians define better the etiology of stroke in cancer patients with AIS, we propose the classification framework described in [Table 1], which includes three main pathophysiological categories: (1) directly cancer-associated; (2) cancer therapy-related; and 3) cancer diagnostic-related.

Regarding directly cancer-associated mechanisms, stroke due to hypercoagulability may be a definable disease entity, as characteristic features have emerged in studies of diverse populations.[3] [4] [5] Patients with hypercoagulability often have multiterritorial infarcts (i.e., three-territory sign) and laboratory findings suggestive of coagulopathy, such as elevated D-dimer, and, as recently documented, fibrin monomers, prothrombin fragment 1.2, and thrombin–antithrombin complex.[11] [40] [41] In the proposed schema, we selected those markers that were more extensively studied and more readily available in clinical practice, i.e., D-dimer and fibrin monomers. Among 362 AIS patients with cancer (newly diagnosed or known cancer), we found a presumed hypercoagulable mechanism in about one-fourth of cases, with female gender, previous stroke/transient ischemic attack, and metastatic disease as associated factors from multivariable analyses.[42] Hypercoagulability can cause a stroke by promoting clot formation from the venous system (i.e., Trousseau syndrome), which then leads to paradoxical embolism through a patent foramen ovale. In addition, thrombus formation on cardiac valves (nonbacterial thrombotic endocarditis [NBTE]) and in the arterial circulation can occur (intravascular coagulopathy).[37] Pathophysiologically, cancer-related thromboembolic events are believed to be caused in part by the abnormal activity of cytokines, tissue factor, cancer procoagulants, and cancer mucins. The acceleration of the coagulation cascade is facilitated by tissue factor and procoagulants, while platelets are activated by inflammatory cytokines and cancer-derived mucin[37] ([Fig. 1]).

Fig. 1 Schematic representation of the coagulation cascade and its presumed interactions with cancer-related prothrombotic factors in acute ischemic stroke patients with active cancer. In pathological conditions such as cancer states, inflammatory cytokines can trigger endothelial cell activation, leading to the release of von Willebrand factor (VWF) and surface expression of tissue factor (TF), and inducing the release of TF from monocytes. The activation of endothelial cells impairs anticoagulation mechanisms, whereas the upregulation of TF elicits the coagulation cascade. VWF released from endothelial cells enhances platelet adhesion, contributing to the generation of clots. Other important activators of coagulation include cancer procoagulants (proteases directly activating factor X) and macromolecules acting on the contact phase such as DNA, RNA, neutrophil extracellular traps (NETs), and short-chain polyphosphates (sc-PolyPs) released by activated platelets. Understanding the complex interplay between cancer cells and the coagulation system is crucial for unraveling the hypercoagulability state in many cancer patients with AIS and for developing effective and patient-tailored treatment strategies for cancer-related thromboembolic events. AIS, acute ischemic stroke; NETosis, neutrophil extracellular trap-osis

The hypercoagulable state associated with cancer is supported by the fact that most AIS patients with cancer have elevated levels of plasma D-dimer. This is a nonspecific marker of hypercoagulability and a product of fibrin clot degradation that provides a sensitive measure of the degree of coagulation cascade activation and thrombus formation.[13] Elevated D-dimer levels may indicate the presence of an occult tumor in AIS patients with cancer and an undetermined underlying mechanism of stroke[31] and are associated with a presumed hypercoagulability, early neurological deterioration within 72 hours of AIS, and a poor prognosis in association with various cancer types.[43] [44] [45] Different cancer-associated factors may affect the presence of hypercoagulability including cancer type and histopathological characteristics, cancer staging, and the interval between cancer diagnosis and stroke.[34] [46] [47] Adenocarcinoma is the histological type most commonly associated with cancer-related stroke, particularly in patients with lung cancer, and is associated with increased risk of stroke recurrence.[1] Cancer-related strokes are more frequent when metastases are present at the first event.[37] Hematological malignancies can also cause AIS through prothrombotic processes, including myeloproliferative neoplasms such as polycythemia vera, essential thrombocythemia, leukemia-associated blast crisis with hyperleukocytosis, and plasma cell dyscrasias causing hyperviscosity syndromes.[48] [49] [50]

Patients with cancer can experience stroke due to various mechanisms unrelated to hypercoagulability. Although rare, tumor embolism can lead to AIS. This typically occurs in patients with primary or metastatic lung cancers that invade the pulmonary veins or cardiac chambers and embolize to the brain,[25] [51] and in invasive head and neck cancers. A pathophysiological clue to this mechanism is the formation of metastasis at the site of prior embolization. Primary central nervous system (CNS) tumors or brain metastases can cause intracranial vessel compression or dissection thereby disrupting arterial flow and leading to ischemia in distal territories.[52] [53] Leptomeningeal carcinomatosis can trigger cerebral ischemia through invasion of perivascular spaces by neoplastic cells, followed by vessel wall infiltration, or induced vasospasm.[54] [55] Malignant hematologic tumors, such as intravascular lymphoma, can directly obstruct blood vessels.[24] [56] [57]

Additionally, accumulating evidence suggests that cancer is a risk factor for atrial fibrillation, likely due to shared risk factors and increased inflammation that may link cancer to left atrial cardiomyopathy.[58]

Patients with cancer commonly develop immunosuppression from the tumor itself, cancer treatment including chemotherapies and steroids as well as cancer-associated malnutrition, and chemotherapy.[59] The ensuing infections can trigger stroke, particularly in older individuals.[39] In addition, septic emboli from infective endocarditis is highly prevalent in patients with cancer due to frequent immunosuppression, invasive procedures, and chronic indwelling catheters.[7] [60]

Cancer Diagnostic Procedure and Treatment-Related Mechanisms

In addition to cancer itself, cancer-related diagnostic procedures and cancer treatments—chemotherapy, hormone therapy, immunotherapy, radiotherapy, and surgery—can be associated with AIS. Pharmacological cancer therapies can play a pathophysiological role in stroke with different degrees of evidence and various mechanisms. In our classification, we considered cancer drugs with at least a moderate level of evidence for an association with ischemic stroke as a potential stroke mechanism according to a recent publication.[61] For the drugs not included in this review, we performed a search for potential associations with cerebrovascular events using various sources of information, including summaries of product characteristics,[62] Micromedex, PubMed, and Meyler's Side Effects of Drugs.[63] Cancer drugs were considered prothrombotic according to the same criteria used in our recent review.[61]

Platinum-based compounds may be associated with an increased stroke risk due to the release of prothrombotic microparticles from cancer cells, such as EVs and cell-free DNA.[64] [65] [66] Inhibitors of the vascular endothelial growth factor pathway can predispose to thromboembolic events by reducing endothelial cell regenerative capacity, increasing local prothrombotic molecules (e.g., prostacyclins), and heightening the risk of hypertension.[67] The cardiac effects of different cancer chemotherapies may lead to AIS. For instance, anthracyclines can lead to acute and chronic cardiomyopathy, taxanes may have arrhythmogenic effects and trastuzumab can be directly cardiotoxic or potentiate the cardiotoxic effect of anthracyclines.[68] [69] In addition, oncological treatments and their related infectious complications can produce cardiomyopathy (such as Takotsubo cardiomyopathy) or myocarditis with low ejection fraction, leading to thrombus formation and subsequent embolization.[70] [71]

Chemotherapies and steroids, commonly used as adjuvants to decrease the risk of nausea and vomiting, may also cause immunosuppression leading to systemic or CNS infection that may cause stroke (such as infectious endocarditis, bacterial meningitis, and opportunistic infections).[7] In our cohort of 260 known cancer patients, we found that 22% of them had AIS associated with a prothrombotic chemotherapy (only or in addition to other stroke mechanisms).[42] As mentioned above, a substantial proportion of stroke in cancer patients may be related to chemotherapy; for this reason, we believe that the choice of whether to discontinue cancer therapy during hospitalization for AIS and whether, how, and when to resume it at discharge should be carefully weighed up and discussed by a multidisciplinary team considering the type of drug, stage of cancer, possible competing mechanisms of AIS, and risk/benefit ratio. Although several specific agents are associated with an increased risk of stroke (e.g., L-asparaginase, bevacizumab, platinum-based compounds, receptor tyrosine kinase inhibitors, e.g., sunitinib, inhibitors of BCR-ABL, breakpoint cluster region protein-tyrosine kinase protein ABL1 [BCR-ABL], such as nilotinib),[72] [73] the overall role of chemotherapy in stroke pathogenesis is still debated. In a recent large retrospective study of 5,887 cancer patients undergoing chemotherapy compared with 13,119 nonchemotherapy patients, the former group had an 84% higher risk of stroke in unadjusted analyses. However, after adjustment for cancer status, this difference became negligible, suggesting that in an unstratified population of cancer patients, advanced cancer may be more relevant than chemotherapy in determining stroke risk.[74] For further information on the association between chemotherapies and stroke, we refer to the topical review by Grover et al.[73]

Some hormonal treatments and immunotherapies for cancer have been associated with ischemic stroke, although the level of evidence for most compounds is low.[8] [61] [75] The GnRH (gonadotropin-releasing hormone) agonists goserelin and leuprolide are two androgen deprivation drugs used in the treatment of prostate cancer that increase the risk of developing diabetes mellitus and atheromatous plaque instability.[76] The U.S. Food and Drug Administration label includes a warning for vascular events, including stroke.[61] Patients with breast cancer undergoing treatment with tamoxifen are at increased risk of venous and arterial thromboembolic events (ATEs).[73] [77] The presumed pathogenic mechanisms may include the reduction of coagulation factors such as antithrombin, protein C, or protein S,[78] but data are inconclusive. Whereas one study found no differences in blood levels of these factors,[78] another indicated that tamoxifen decreased levels of antithrombin and protein S, but not protein C.[79] In addition, tamoxifen induced resistance to activated protein C[80] [81] and increased levels of factor VIII, factor IX, and von Willebrand factor (VWF).[79]

In clinical trials, the relative (1.9; 95% confidence interval [CI]: 0.7–4.9) and absolute risks of ATEs with immunotherapy is low.[82] However, real-world cohort studies indicate a 1-year ATE rate of 1.8 to 4.5%.[83] [84] [85] Notably, these observations do not signify causality with these treatments, and could simply represent an epiphenomenon related to the underlying cancer. As high-quality evidence for ATEs in cancer patients receiving immunotherapies is limited, we have not included prothrombotic immunotherapies in our classification ([Table 1]). However, the potentially high rates of thromboembolic complications in these cohorts warrant further investigation.

Radiation therapy, a key component of many cancer treatment plans, may accelerate atherosclerosis and cause progressive and irreversible vascular injury, leading to AIS from either small- or large-vessel disease.[23] [86] Aortic arch atheroma, myocardial dysfunction, and valvopathy may be other potential causes of cancer-related stroke, as thoracic radiation is commonly performed in breast and lymphoma cancers.[87] In addition, irradiation of head and neck cancers often includes the supra-aortic arteries, increasing the risk of late cerebrovascular complications.[88] Although radiation therapy usually takes years to produce luminal stenosis, it can cause arterial injury and accelerate and destabilize atherosclerotic plaques within months, particularly when combined with the proinflammatory effects of cancer.[89] As survival of cancer patients increases, aortic and large artery atherosclerosis may become an increasingly common cause of cancer-related stroke, especially among childhood and young adult cancer survivors.[90] [91] Diagnostic or treatment-related cancer surgery and endoscopic procedures can also cause cancer-related stroke by tumor embolism, direct arterial injury, and secondary cardiac arrhythmias.[92] [93] [94]

Oncological Biomarkers in AIS Patients

Magnetic Resonance Imaging and Transcranial Doppler

Multiterritorial lesions in all brain vascular territories are more frequently found in patients with cancer-related stroke.[95] In a retrospective study comparing AIS patients with underlying malignancy to those with atrial fibrillation as the cause of stroke, the presence of bilateral anterior circulation and posterior circulation acute infarctions on magnetic resonance imaging (MRI), known as the “three-territory-sign,” was considerably more frequent in the malignancy group.[96] This sign predicted the presence of occult cancer in AIS patients with an undetermined etiology with a specificity of 0.65 and a sensitivity of 0.92.[97] Susceptibility-weighted imaging (SWI) imaging on MRI detects local distortion of the magnetic field induced by paramagnetic substances, such as red blood cells (RBCs) entrapped in thrombi in patients with large vessel occlusions (LVOs), resulting in a hypointense signal defined as the “susceptibility vessel sign” (SVS).[98] Since thrombi in cancer patients typically have lower RBC fractions,[99] the absence of SVS may be another biomarker of occult cancer. However, a recent study by Beyeler et al on 40 AIS patients with cancer found that the absence of SVS was associated with having a cancer but could not predict occult cancer better than clinical predictors.[100] A more refined SVS analysis using quantitative susceptibility mapping may increase the predictive power of this model.[101]

As described previously (see “Stroke Mechanisms in Cancer Patients”), NBTE is another possible mechanism of cancer-related stroke linked to hypercoagulability. This condition is characterized by the formation of sterile platelet–fibrin vegetations on cardiac valves, particularly in patients with metastatic cancer.[102] In a large autopsy series conducted at a cancer center in the United States, NBTE was the primary mechanism in cancer patients with symptomatic AIS, despite often being undetected premortem.[60] A recent cohort study spanning two decades reported that only 42 out of more than 650,000 echocardiograms performed at a large tertiary-care center showed signs of NBTE,[103] whereas autopsy studies on the adult population suggest an incidence between 1 and 1.6%.[104] [105] [106] Transesophageal echocardiography is superior to transthoracic echocardiography in detecting NBTE,[103] but this may not be feasible in many cancer patients with AIS due to bleeding risk, reduced consciousness, or palliative goals of care. Transcranial Doppler ultrasound is a promising radiological biomarker for cancer-related AIS. A prospective study on 74 patients using transcranial Doppler found that 58% of cancer patients with ESUS had evidence of cerebral microemboli that were associated with increased levels of D-dimer, adenocarcinoma histology, and were frequently bilateral, suggesting a potential cardiac source.[39] More recently, another prospective study including 50 patients with AIS and cancer documented microembolic signals in 16 patients, significantly more than in matched patients with stroke- and cancer-only.[15]

Laboratory: Circulating Biomarkers

Since cancer-associated stroke may represent a distinct subgroup of stroke, it is important to consider the diverse range of potential laboratory biomarkers associated with this mechanism. This is a rapidly evolving field, where biomarkers may be divided into two groups: general markers of inflammation, coagulation, platelet and endothelial activation, and cancer-related pathological processes ([Table 2]). The pathobiology responsible for the acquired hypercoagulable state in some cancer patients is complex and varies based on cancer site and histology, involving multiple interconnected factors ([Fig. 1]).

Table 2 Selected studies on laboratory biomarkers in patients with acute ischemic stroke and active cancer

Biomarker type	Definitions or examples	Methods and findings (M = methods; F = findings)	Refs.
General markers of inflammation, coagulation, platelet, and endothelial activation
Markers of coagulation, platelet, and endothelial activation.	Coagulation: D-dimer, thrombin–antithrombin; platelet function: P-selectin; endothelial activation: thrombomodulin, sICAM-1, sVCAM-1.	M: 50 prospectively enrolled patients with solid cancer and AIS (cancer-plus-stroke) compared with 50 cancer-only and 50 stroke-only patients. Blood samples collected 72–120 hours after stroke onset. F: cancer-plus-stroke patients had higher levels of different biomarkers. D-dimer, P-selectin, ICAM-1, sVCAM-1 associated with recurrent thromboembolism (arterial/venous), or death. D-dimer was the only marker associated with recurrent AIS.	[14] [15]
		M: 120 retrospectively collected patients with cryptogenic stroke, including 12 with occult cancer. F: AIS patients with occult cancer had significantly higher D-dimer levels and these predicted the presence of an occult neoplasm.	[5]
Neutrophil/lymphocyte ratio (NLR)	Ratio of the absolute number of neutrophils to number of lymphocytes; a value >5 is considered increased. NLR may reflect a cancer-related inflammatory response, which correlates with worse prognosis in some cancer types and AIS patients with LVOs.	M: 69 retrospectively sampled cancer patients with AIS within 2 years of cancer diagnosis. Possibly also included patients with inactive cancer. NLR calculated within 1 month of cancer diagnosis. F: elevated NLR was associated with higher ischemic stroke risk within 2 years of cancer diagnosis (7% per 1 point increase), regardless of cancer site and stage. In the subgroup with NLR > 15, risk of stroke was nearly eightfold higher.	[112]
Cancer-related pathological processes
Extracellular vesicles	Small, circular membrane fragments from the cell surface or secreted from the endosomes. Circulating EVs may play a role in cancer progression by favoring metastatic spreading, neovascularization, and thrombogenesis.	M: 155 retrospectively collected patients with cancer and cancer (cancer related or TSMs) versus 158 control patients (stroke only, cancer only, and healthy subjects). Measurements of D-dimer levels and EVs expressing markers in the serum, including tissue factor. F: cancer cell-derived EVs may cause cancer-related coagulopathy (as defined by D-dimer levels) independently from TF.	[119]
		M: 114 prospectively collected patients with active lung cancer and stroke. Measurements of cancer-derived EVs in the serum within 7 days of stroke. F: patients with lung adenocarcinoma had higher EV levels than other histologic types, and these induced shorter, dose-dependent clotting times in vitro.	[120]
Neutrophil extracellular traps	Meshwork of decondensed chromatin released by neutrophils upon activation involved in the innate immune response to pathogens. In cancer patients, they may act as scaffolds for tumor progression and spreading and contribute to cancer-associated thrombosis.	M: 138 prospectively collected patients: 38 with cancer and cancer-related stroke, 27 cancer controls, 40 stroke controls, and 33 healthy controls. Measurements of plasma DNA and nucleosomes as markers of NETs and D-dimer levels (cut-off ≥2 μg/mL to consider coagulopathy). F: plasma DNA and nucleosome levels were significantly higher in cancer-related strokes and correlated with coagulopathy.	[124]
		M: 31 prospectively sampled patients with AIS (12 with increased hsTnT as cases, and 19 with lower hsTnT as controls), including 8 patients with cancer. Measurement of various blood markers within 2 days of admission, such as citrullinated histone H3 (H3Cit, a specific marker of NETs). F: AIS patients with cancer had higher H3Cit levels; this correlated with the prothrombin–antithrombin complex, P-selectin (another marker of prothrombotic state).	[123]
Mucins	Glycosylated proteins produced by epithelial tissues, including some carcinomas. Mucins are considered nonspecific tumor markers. Carcinomatous mucin may trigger procoagulant states by interacting with P-selectin on platelets.	M: 77 patients with cancer and AIS divided into hypercoagulation and nonhypercoagulation groups (cut-off, D-dimer levels >3 μg/mL). Measurements of CEA, CA19-9, and CA125 (>2-fold increase from the upper limit of the standard to reach statistical significance). F: increased CA125 level predicted hypercoagulability versus control group (fivefold higher odds).	[125]
		M: 70 retrospectively collected patients with gastric cancer and cancer-related stroke versus 140 nonstroke patients with gastric cancer. Measurements of CEA, CA125, CA153, and CA199 in routine blood work-up (timing not specified). F: increased CA125 was associated with a higher probability of having stroke in patients with gastric cancer.	[126]

Abbreviations: AIS, acute ischemic stroke; cancer, active cancer; CA19-9, carbohydrate antigen 19-9; CA125, carbohydrate antigen-125; CEA, carcinoembryonic antigen; EV, extracellular vesicle; hsTnT, high-sensitivity troponin; LVO, large vessel occlusion; NETs, neutrophil extracellular traps; sICAM-1, soluble intercellular adhesion molecule-1, sVCAM-1, soluble vascular cell adhesion molecule-1 TF, tissue factor; ; TSM, traditional stroke mechanism.

General Markers of Inflammation, Coagulation, Platelet, and Endothelial Activation

Markers of inflammation, coagulation, platelet, and endothelial activation are altered in AIS patients with cancer.[15] Tissue factor produced by cancer cells is increased in cancer patients and contributes to arterial thromboembolism.[107] In addition, 4 to 16% of all patients with cancer have concurrent venous thromboembolism[108] [109] [110] associated with high plasma D-dimer, which is often used as a biomarker of hypercoagulability, particularly at very high levels.[4] Other relevant pathophysiological mechanisms include the alteration of endothelial wall integrity and adhesiveness ([Table 2]). Cancer increases the level of soluble thrombomodulin, which decreases the anticoagulant thrombomodulin at the endothelial surface.[111] Moreover, cancer increases the amount of VWF, a molecule involved in platelet–platelet and platelet–collagen adhesion.[111] A recent prospective study comparing 50 AIS patients with cancer with matched cancer-only and stroke-only groups explored the association of various laboratory biomarkers of coagulation (D-dimer, thrombin–antithrombin), platelet (P-selectin), and endothelial activation (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], soluble vascular cell adhesion molecule-1 [sVCAM-1]) with recurrent arterial and venous thromboembolism and death.[15] With respect to the reference groups, the levels of D-dimer, P-selectin, and sICAM-1 and sVCAM-1 were significantly higher in AIS patients with cancer.[14] These biomarkers were all correlated with the outcome measures, but only increased D-dimer levels (hazard ratio: 1.2; 95% CI: 1.0–1.5) were significantly associated with recurrent AIS in the group of AIS patients with cancer.[15] This aligns with previous results supporting the value of D-dimer in predicting recurrent stroke in patients with AIS of undetermined origin,[11] and warrants further investigations for its use as a marker of recurrence in the cancer subpopulation.

The neutrophil-to-lymphocyte ratio (NLR) may be a valuable biomarker in AIS patients with cancer ([Table 2]). The NLR is easily calculated by dividing the number of blood neutrophils by the number of lymphocytes, and a value >5 is considered increased.[112] This ratio may reflect a cancer-related inflammatory response, which has been shown to correlate with prognosis in patients with colorectal and small-cell lung carcinoma,[113] [114] and has been associated with worse prognosis in patients with LVO and AIS.[115] Recently, Kawano et al highlighted that each 1-unit increase in the NLR obtained within 1 month from cancer diagnosis is associated with a 7% higher risk of subsequent AIS.[112] Moreover, a rising NLR between days 1 and 3 from the index stroke predicts early neurological deterioration in cancer patients with ESUS,[116] suggesting that inflammation plays a role in the clinical worsening in these patients. These results have been recently confirmed in a systematic review (particularly in the Asian population).[117] Interestingly, we calculated the NLR in our cohort of 365 cancer patients and found that an increased NLR is associated with having cancer, worse functional outcome at 3 months, and higher mortality over 1 year.[9] Altogether, these data support the potential value of the NLR to identify cancer patients at higher risk of AIS and its use as a low-cost and readily available prognostic marker of morbidity in cancer patients with AIS.

Cancer-Related Pathological Processes

Biomarkers associated with cancer-related pathological processes comprise diverse groups of macromolecules, such as EVs, NETs, and mucin-related biomarkers. Circulating EVs refer to lipid-bound structures secreted by cells that can carry proteins, nucleic acid, and lipid molecules and that can exert a multitude of biological functions, such as a triggering role in the coagulation cascade.[118] In a prospective study carried out in Korea called OASIS-Cancer (Optimal Anticoagulation Strategy in Stroke Related to Cancer), cancer patients with ESUS had higher levels of cancer-secreted EVs compared to AIS patients with TSMs, stroke-only and cancer-only patients.[119] EVs correlated with increased D-dimer levels and promoted coagulation independently of the tissue factor pathway, the primary cellular initiator of blood coagulation. In addition, levels of EVs were associated with adenocarcinoma histology in patients with lung cancer, but not with cancer stage.[120]

NETs are net-like structures primarily composed of DNA–histone complexes from neutrophils ([Table 2]). They are part of the innate immune response, promote platelet and coagulation activity, and are upregulated in AIS patients with cancer.[119] [121] Activated neutrophils can release decondensed chromatin that acts as a scaffold for the adhesion of platelets, RBCs, and fibrinogen and can trigger the intrinsic and extrinsic coagulation pathways.[122] Patients with cancer-related stroke had increased levels of markers of NETs (circulating DNA, citrullinated histone H2 and H3), and these were correlated with platelet activity, thrombin–antithrombin, P-selectin, and D-dimer levels, suggesting their role in cancer-related hypercoagulability.[123] [124] In addition, increased levels of EVs can trigger the formation of NETs in cancer-related thrombosis.[119]

The role of mucinous biomarkers in arterial thromboembolism has been investigated in case reports and small cohorts.[125] [126] [127] Carcinomatous mucins may trigger thrombosis by interacting with P- and L-selectins, thereby inducing the formation of platelet-rich thrombi.[128] In a small study on 77 AIS patients with cancer divided into hypercoagulable and nonhypercoagulable groups based on D-dimer levels, the former showed elevated levels of CA125, and this was associated with hypercoagulable stroke mechanisms.[125] However, these results may reflect selection bias due to the unsystematic measurements of CA125 in this cohort.

Thrombi Composition

Clots in AIS can be retrieved using mechanical thrombectomy and provide clues regarding the underlying stroke mechanism. A histopathologic study of thrombi from AIS patients revealed that cancer patients had higher platelet proportions and lower erythrocyte fractions (so-called “white clots”) than patients with inactive cancer or no cancer.[129] Also, the cancer group had significantly higher platelet counts. When considering subgroups by etiology, four patients had NBTE and seven were categorized as ESUS, and both groups had higher platelet counts. In another study, white clots in cancer patients were independently associated with increased D-dimer levels and worse prognosis compared to “red clots” (RBCs-rich thrombi).[99] Although based on small studies, these results indicate that platelet dysfunction plays an important role in cancer-related stroke.

Stroke and Cancer Treatments in AIS Patients with Cancer

Acute Reperfusion Treatments

Intravenous Thrombolysis

Few high-quality data are available on the benefit of intravenous thrombolysis (IVT) in AIS patients with cancer. The existing literature is mostly limited to cohort studies and case series, which may be affected by selection and publication biases. American Heart Association guidelines state that IVT is not recommended for patients with gastrointestinal cancer or intra-axial tumors but may be used for patients with extra-axial intracranial tumors or other systemic malignancies and with a life expectancy of at least 6 months.[16] Meanwhile, European guidelines state that nonmetastatic cancer patients likely obtain similar relative benefit from IVT to noncancer patients.[16] [17]

The most recent and largest studies on the topic have provided conflicting results on thrombolysis efficacy and safety. In 2020, a meta-analysis of 15 retrospective studies found that cancer patients had similar outcomes to noncancer patients in terms of favorable neurological outcome, symptomatic intracranial hemorrhage (ICH), major bleeding, and 3-month mortality.[130] Subgroups by cancer type did not show significant differences. Conversely, a 2021 meta-analysis highlighted potential safety concerns on the use of IVT in cancer patients, specifically the risk of symptomatic ICH, which was 10 times higher in cancer patients.[131] The discrepancy between the two studies may depend on differing selection criteria: the former study included case series, whereas the latter excluded them. In a large dataset of 32,576 AIS patients treated with IVT and comprising 807 cancer patients (hematologic, solid, with and without metastasis), IVT was not associated with increased hospital mortality or ICH risk.[132] Unsurprisingly, metastatic cancer was associated with worse outcomes, but cancer subtypes had no impact on symptomatic ICH rates. In another retrospective study on 93 cancer patients with gastrointestinal tumors, ICH rates and other IVT-related serious complications were comparable with the noncancer group.[133] These data will probably not change the recommendations for patients with active gastrointestinal cancers receiving IVT, but they might stimulate further studies on some subgroups of AIS patients with cancer.

Regarding intracranial tumors and IVT, the guidelines distinguish between intra-axial (e.g., glioblastoma, metastasis) and extra-axial (meningioma) neoplasms. The available small cohort studies and case series are restricted to no more than 100 reported cases.[134] [135] [136] [137] [138] In one study, no substantial complications for intracranial extra-axial tumors were reported, whereas one patient out of five with intra-axial tumors treated with IVT developed symptomatic ICH.[139] Overall, IVT seems reasonably safe and effective in most cancer patients, except for patients with intra-axial intracranial tumors and possibly patients with gastrointestinal tract malignancies.

Endovascular Treatment

Endovascular treatment (EVT) is an established therapy for AIS patients with LVO within 24 hours from stroke onset.[140] However, cancer patients were generally excluded from the pivotal randomized trials, and evidence for EVT in cancer patients is mostly available through retrospective cohorts and case series. Two cohort studies reported similar recanalization rates between cancer and noncancer patients,[141] [142] but the clot in cancer patients may be more difficult to retrieve, possibly due to higher platelet, fibrin, and VWF content organized into dense interwoven aggregates comprising all three components.[143] [144] [145] [146] Particularly, VWF-rich thrombi are resistant to tissue plasminogen activator and the administration of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), a physiological metalloprotease able to cleave VWF, results in greater recanalization rates in murine models of AIS.[146] As VWF contributes to thrombogenesis by binding to the glycoprotein Ib (GpIb)α receptor on platelets, inhibitors targeting the GpIbα–VWF interaction such as caplacizumab (a divalent nanobody) could theoretically represent novel IVT approaches[147] administered before or after EVT. To date, no clinical data on stroke are available, but caplacizumab recently demonstrated efficacy in a patient with myocardial infarction and intra-stent thrombosis resistant to standard antithrombotics.[148]

A recent metanalysis of observational studies indicated that cancer patients may present higher disability, hemorrhagic transformation, and death rates after EVT compared with noncancer patients.[149] In subgroup analyses from the MR CLEAN registry, 124 cancer patients treated with EVT (4.8% of the 2,583 total population) had a worse prestroke disability, with one-fourth receiving palliative care. The recanalization and symptomatic ICH rates were similar to noncancer patients, but the cancer group presented higher disability, mortality, and recurrent ischemic stroke at 3 months after adjustment for potential confounders.[150] In most studies on AIS cancer patients and stroke, increased mortality may be more related to the underlying cancer than AIS or reperfusion treatments. Metastatic disease and a cancer diagnosis within the previous 2 years have been associated with increased short-term mortality risk in cancer–stroke patients treated with EVT.[151]

Overall, the safety and efficacy of EVT in this population are still up for debate. Careful consideration is necessary when selecting patients with cancer for EVT of LVO, as this group is heterogeneous, with patients varying greatly in status and comorbidities, including life expectancy. In many comprehensive stroke centers, patients with LVO and disabling neurological deficits are typically not excluded from EVT if they meet all other criteria. However, patients receiving palliative care may represent a different subset of patients unlikely to benefit from EVT. Therefore, a more individualized approach to selecting patients with cancer for EVT is encouraged, focusing on demographic, clinical, and cancer-related factors to have realistic expectations of medium- and long-term outcomes and considering patients' wishes and goals of care.

Cancer patients are generally one-third to one-half less likely to receive IVT or bridging therapy than patients without cancer.[9] Increased anticoagulation use, perceived higher bleeding risk, higher prestroke disability, shorter life expectancy, more frequent comorbidities, and contraindications in cancer patients, as well as conservative recommendations by American guidelines against treatment for some tumor types (gastrointestinal or intra-axial brain tumors) may explain these differences.[16] Conversely, there might not be a disparity in EVT rates between cancer and noncancer patients.[152]

Long-Term Secondary Prevention Therapies

Current guidelines do not provide specific recommendations for selecting antithrombotic treatments after AIS in cancer patients. While high-quality data have emerged for the prevention of venous thromboembolism in oncological patients,[153] cancer patients with arterial thromboembolism may have unique underlying pathophysiology, making these findings difficult to extrapolate.[123] [154] Most available data for antithrombotic strategies in cancer patients with AIS stem from retrospective or small prospective pilot studies. These are summarized in [Table 3].

Table 3 Studies comparing antithrombotic strategies in acute ischemic stroke patients with active cancer

Ref.	Study population and secondary prevention antithrombotic drug	Study type	Stroke mechanism	Primary outcomes (O), findings (F), and comments (C)
[162]	543 cancer patients: 254 rivaroxaban vs. 289 aspirin.	Prospective, subgroup analyses of NAVIGATE-ESUS trial, multicenter	ESUS as per protocol definition	O: recurrent ischemic stroke, major bleeding, and all-cause mortality. F: the two groups had similar efficacy outcomes; the aspirin group had less major bleeding. C: not specified whether cancer was active.
[18]	268 cancer patients stratified on D-dimer levels: 203 anticoagulation (89 LMWH, 113 heparin/warfarin) and 51 antiplatelets.	Prospective, OASIS-CANCER study, single center	Undetermined (72%); traditional causes (28%)	O: overall and 1-year survival. F: higher D-dimer levels correlated with reduced survival; 1-year survival was increased if reduction of D-dimer <3 μg/mL was achieved following anticoagulation. No antiplatelet group.
[156]	20 cancer patients: 10 LMWH vs. 10 aspirin.	Prospective, TEACH trial, multicenter	Undetermined (75%); traditional causes (25%)	O: feasibility (enrollment rate among 100 eligible patients for which the lower bound 95% CI exceeded 30%). F: no significant differences between groups in terms of major bleeding, thromboembolic events, and survival. C: six patients in the enoxaparin group crossed-over due to injection-related discomfort (4/6).
[1]	263 cancer patients: 102 antiplatelet (92 aspirin); 90 anticoagulation (78 LMWH). 20 patients received both.	Retrospective, single center	Undetermined (51%); traditional causes (36%), other rare causes, including cancer-related (15%)[a]	O: recurrent thromboembolic events (composite of recurrent ischemic stroke, myocardial infarction, systemic embolism, TIA, or venous thromboembolism). F: cancer had high rate of recurrent thromboembolic events, but this did not differ significantly when comparing cancer patients by antithrombotic strategies.
[155]	79 cancer patients: LMWH 29 vs. warfarin 50.	Retrospective, single center	All cancer-related (defined as having cancer and stroke not explained by TSM).	O: change in D-dimer levels from baseline following anticoagulation. F: the enoxaparin group presented significantly lower levels of D-dimer at follow-up. C: follow-up measurement of D-dimer not standardized.
[44]	48 cancer patients: 41 LMWH vs. 7 DOAC (dabigatran and rivaroxaban)	Retrospective, single center	All undetermined; excluded patients with TSMs	O: early neurologic deterioration, early radiologic recurrence, 3-month disability (mRS at 3 months), 3-month mortality, cardiocerebrovascular recurrence, and bleeding complications. F: no difference in outcomes between the two treatment groups. C: lack of control group and unbalanced number of patients in both groups.
Planned/ongoing studies
[19]	40 cancer patients (estimated): edoxaban vs. LMWH	Prospective, ENCHASE clinical trial, multicenter	All cancer-related strokes excluding patients presenting TSMs, primary brain tumors, or presumed vascular occlusion due to tumor.	O: interval change of serum D-dimer level between days 0 and 7. C: ongoing.
[10]	Cancer patients (estimated number NA): apixaban vs. aspirin	Prospective, TEACH2, clinical trial, multicenter	All ESUS	O: composite of major ischemic and major hemorrhagic events at 1-year of follow-up. C: planned and awaiting funding.

Abbreviations: cancer, active cancer; DOAC, direct oral anticoagulant; ENCHASE, Edoxaban for the Treatment of Coagulopathy in Patients with Active Cancer and Acute Ischemic Stroke; ESUS, embolic stroke of undetermined source; LMWH, low-molecular-weight heparin; mRS, modified Rankin Scale; NA, not available; NAVIGATE-ESUS, New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus Aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source; TEACH, Enoxaparin versus Aspirin in Patients with Cancer and Stroke; TIA, transient ischemic attack; TSM, traditional stroke mechanisms.

^a Percentages have been rounded up; thus, the total sum exceeds 100%.

Anticoagulation

Anticoagulant therapy for AIS patients with cancer-related stroke is often administered empirically in clinical practice based on theoretical considerations and results from pilot studies. In a prospective study on 74 AIS patients with cancer, anticoagulant use was associated with reduced D-dimer levels during hospitalization, particularly in cancer patients without TSMs. Further, patients with persistently high D-dimer levels despite treatment were more likely to develop stroke recurrence.[39]

In the prospective OASIS study on 268 AIS patients with cancer, those with reduced D-dimer levels following anticoagulation had higher survival at 1 year.[18] Regarding specific anticoagulants, low-molecular-weight heparin (LMWH) has been the most studied drug.[155] [156] [157] Although LMWH may be more effective than vitamin K antagonists (VKAs) in reducing D-dimer levels and stroke recurrence (3.4% in the LMWH vs. 16% in the VKA),[155] it may be associated with injection-related discomfort and treatment discontinuation.[156] In a pilot trial (TEACH), 20 AIS patients with cancer were randomized to receive subcutaneous LMWH or aspirin. The primary aim was to assess the feasibility of larger clinical trials. Patient aversion to injections frequently led to enrollment failure, and 40% of patients randomized to enoxaparin crossed over to the aspirin group because of discomfort on injection.

Due to their convenience, DOACs are increasingly being used for the treatment of cancer-related stroke. As shown in many randomized clinical trials, oral factor Xa inhibitors have comparable efficacy and safety to LMWH for preventing recurrent VTE and major bleeding, calling for similar investigations in cancer patients with AIS.[158] [159] Recent guidelines now recommend DOAC as a maintenance treatment in select cancer patients to prevent VTE recurrence.[160] [161] DOACs have only been studied in small uncontrolled cohorts of cancer and AIS, suggesting comparable safety and efficacy to LMWH.[157] A randomized clinical trial comparing the DOAC edoxaban to LMWH is ongoing (ENCHASE trial [Edoxaban for the Treatment of Coagulopathy in Patients with Active Cancer and Acute Ischemic Stroke]).[19] This trial aims to investigate the potential of individualized anticoagulation therapy by serial measures of factor Xa activity and anti-factor Xa activity before and after administering anticoagulants to patients. In the United States, a multicenter, double-blinded, randomized trial (TEACHH2, Trial of Apixaban versus Aspirin in Cancer Patients with Cryptogenic Ischemic Stroke) is being planned to compare the safety and efficacy of apixaban versus aspirin in patients with cancer and ESUS (defined according to conventional criteria).[10]

Antiplatelet Agents

Some findings support the use of antiplatelet therapy over anticoagulation in AIS patients with cancer. In a retrospective study of 172 AIS patients with cancer, 102 received antiplatelet and 90 anticoagulation at discharge (and some both). There were no differences between groups in the odds of developing recurrent stroke, recurrent thromboembolism, or death.[10] [34] In our cohort followed at the Lausanne University Hospital, Switzerland, we found in multivariable analyses that antiplatelet therapy upon discharge after AIS—but not anticoagulation—was associated with a 30% reduction in the 1-year risk of cerebrovascular recurrence.[9] When comparing the subgroups of AIS patients with known cancer versus noncancer patients, anticoagulation at discharge was not associated with lower death rates or recurrent cerebrovascular events over 1 year.[42] These results, however, may be confounded by indication, as patients considered to be at higher risk of stroke recurrence or with worse prognosis may have received anticoagulation more often. In the NAVIGATE ESUS randomized trial (comparison of rivaroxaban to aspirin in ESUS patients), 543 patients (7.5%) had history of cancer, although it was not reported whether these cancers were active. The risk of recurrent stroke between treatment groups was not significantly different. If anything, aspirin may have performed better at secondary prevention. Additionally, the risk of major bleeding was more than doubled in the cancer patients randomized to rivaroxaban.[162]

Altogether, current data do not indicate a clear advantage of anticoagulant or antiplatelet therapy in patients with cancer and ischemic stroke. Prospective studies are crucial to answer this question, and, as indicated previously, data from VTE studies in cancer patients may not translate to patients with arterial thromboembolism. The issue of anticoagulation after AIS is especially relevant in cancer patients who face high rates of major bleeding, especially if brain tumors are present.[163] [164] Moreover, major bleeding confers an increased mortality risk in cancer patients, which is already high in older patients with medical comorbidities (e.g., renal insufficiency), thrombocytopenia, gastrointestinal cancers, and metastatic disease, all factors common in cancer-related stroke.[165]

Another potential antithrombotic strategy for cancer patients with AIS is the combination of antiplatelet and anticoagulant therapy, which has proved beneficial in high-risk populations with atheromatous disease.[166] As both platelet function and the coagulation cascade are altered in cancer patients, this dual pathway inhibition strategy could theoretically more comprehensively address the underlying prothrombic mechanisms in this population. However, because the combination significantly increases the risk of bleeding,[166] a recommendation for this approach does not seem prudent at this stage. Further, combination therapy may even be contraindicated if other concurrent abnormalities are present (e.g., thrombocytopenia).[167]

Restarting Cancer Treatment after Stroke

While antithrombotics play a vital role in the secondary prevention of patients with cancer, addressing the underlying cancer through directed cancer treatments, especially cytoreductive and targeted therapies, may be even more relevant. Indeed, a cancer-related hypercoagulable mechanism seems to be closely associated with the activity and extent of the underlying tumor[42] and may play a role in cerebrovascular recurrences.[1] In our cohort, we found that having a metastatic disease was independently associated with an almost fivefold higher odds of having a presumed hypercoagulable stroke mechanism (as defined in [Table 1]).[42] Therefore, reducing cancer activity seems paramount and it may be the only option to prevent further thromboembolic events. Accordingly, the use of cytoreductive drugs (e.g., hydroxyurea) in a large cohort of patients with myeloproliferative neoplasms presenting with AIS (at diagnosis or within the preceding 2 years) cuts the risk of recurrent ischemic stroke by more than half.[168]

Unfortunately, two issues make the reduction of cancer activity in AIS patients challenging in clinical practice: first, oncologists are often reluctant to prescribe cancer treatments after stroke, as many of them are associated with an increased risk of thrombosis. If cancer patients prefer aggressive treatments, have a good functional status, and therapeutic oncological options are available, it might be recommended to restart cancer treatments as soon as possible to mitigate cancer-mediated hypercoagulability and the risk of stroke recurrence. In line with the American Society of Clinical Oncology recommendations, cancer patients with advanced disease and with good performance status, measured as an Eastern Cooperative Oncology Group score of 1 or less (symptomatic, but fully ambulatory or asymptomatic), should benefit more from chemotherapy than more disabled cancer patients.[169] Because most stroke patients with cancer have metastatic disease (58% in our cohort)[42] and AIS may further reduce performance status, the decision to restart cancer therapies in these cases should be weighed up between the treating neurologists and oncologists, who should thoroughly discuss the patient's treatment goals, functional status, and overall risks and benefits. Second, patients may refuse aggressive treatments or further oncological treatments may not be available. Whereas the latter becomes less likely as more therapeutic options come on the market, both situations require the treating physician to elucidate long-term goals of care.

Conclusion

In recent years, important advances have refined our understanding of the intertwined and complex relationship between cancer and stroke. A deeper investigation of the role of laboratory biomarkers such as D-dimer and thrombin–antithrombin, which are increased because of hypercoagulable mechanisms, and NETs, which can directly cause prothrombotic states, will further refine our understanding of cancer-related stroke mechanisms. Hopefully, this will lead to a better distinction between populations at high and low risk of AIS and facilitate patient selection for clinical trials. This could also enable better informed decisions regarding secondary prevention strategies. In this regard, DOACs are now being tested in prospective studies in cancer patients with AIS, and new drugs that inhibit factor XI—an intrinsic pathway factor involved more in thrombosis than in hemostasis—may become an additional option to reduce thromboembolic risk without increasing bleeding rate.[170]

Finally, the role of cancer treatments before and after AIS needs to be clarified. Although chemotherapy in general may not be associated with increased stroke risk,[74] specific cancer drugs likely do increase this risk.[61] Guidelines on whether, how, and when to restart these therapies after AIS are lacking. Additionally, hormonal and immunological therapies may also affect the risk of arterial thromboembolism,[61] [83] but current data are conflicting and limited. Given the increased survival of cancer patients over the last two decades making secondary complications such as AIS more frequent and impactful, further progress in this field is crucial.

Conflict of Interest

None declared.

Acknowledgments

The authors would like to thank Melanie Price Hirt, PhD, for English language editing.

• References

• 1 Navi BB, Singer S, Merkler AE. et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology 2014; 83 (01) 26-33
• 2 Costamagna G, Hottinger A, Milionis H. et al. Clinical and demographic characteristics, mechanisms, and outcomes in patients with acute ischemic stroke and newly diagnosed or known active cancer. Neurology 2023; 100 (24) e2477-e2489
• 3 Kim SG, Hong JM, Kim HY. et al. Ischemic stroke in cancer patients with and without conventional mechanisms: a multicenter study in Korea. Stroke 2010; 41 (04) 798-801
• 4 Schwarzbach CJ, Schaefer A, Ebert A. et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke 2012; 43 (11) 3029-3034
• 5 Gon Y, Okazaki S, Terasaki Y. et al. Characteristics of cryptogenic stroke in cancer patients. Ann Clin Transl Neurol 2016; 3 (04) 280-287
• 6 Grazioli S, Paciaroni M, Agnelli G. et al. Cancer-associated ischemic stroke: a retrospective multicentre cohort study. Thromb Res 2018; 165: 33-37
• 7 Dardiotis E, Aloizou AM, Markoula S. et al. Cancer-associated stroke: pathophysiology, detection and management (Review). Int J Oncol 2019; 54 (03) 779-796
• 8 Moik F, Ay C. Venous and arterial thromboembolism in patients with cancer treated with targeted anti-cancer therapies. Thromb Res 2022; 213 (Suppl. 01) S58-S65
• 9 Costamagna G, Hottinger AF, Milionis H. et al. Oral presentations. Eur J Neurol 2022; 29 (S1): 46-168
• 10 Navi BB, Kasner SE, Elkind MSV, Cushman M, Bang OY, DeAngelis LM. Cancer and embolic stroke of undetermined source. Stroke 2021; 52 (03) 1121-1130
• 11 Choi KH, Kim JH, Kim JM. et al. d-Dimer level as a predictor of recurrent stroke in patients with embolic stroke of undetermined source. Stroke 2021; 52 (07) 2292-2301
• 12 Gon Y, Sakaguchi M, Takasugi J. et al. Plasma D-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. Eur J Neurol 2017; 24 (03) 503-508
• 13 Ohara T, Farhoudi M, Bang OY, Koga M, Demchuk AM. The emerging value of serum D-dimer measurement in the work-up and management of ischemic stroke. Int J Stroke 2020; 15 (02) 122-131
• 14 Navi BB, Sherman CP, Genova R. et al. Mechanisms of ischemic stroke in patients with cancer: a prospective study. Ann Neurol 2021; 90 (01) 159-169
• 15 Navi BB, Zhang C, Sherman CP. et al. Ischemic stroke with cancer: hematologic and embolic biomarkers and clinical outcomes. J Thromb Haemost 2022; 20 (09) 2046-2057
• 16 Powers WJ, Rabinstein AA, Ackerson T. et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50 (12) e344-e418
• 17 Berge E, Whiteley W, Audebert H. et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J 2021; 6 (01) I-LXII
• 18 Lee MJ, Chung JW, Ahn MJ. et al. Hypercoagulability and mortality of patients with stroke and active cancer: the OASIS-CANCER study. J Stroke 2017; 19 (01) 77-87
• 19 Bang OY. Edoxaban for the treatment of coagulopathy in patients with active cancer and acute ischemic stroke: a pilot study. (ENCHASE Study). clinicaltrials.gov; 2018. Accessed March 07, 2023 at: https://clinicaltrials.gov/ct2/show/NCT03570281
• 20 Navi BB, Iadecola C. Ischemic stroke in cancer patients: a review of an underappreciated pathology. Ann Neurol 2018; 83 (05) 873-883
• 21 Conen D, Wong JA, Sandhu RK. et al. Risk of malignant cancer among women with new-onset atrial fibrillation. JAMA Cardiol 2016; 1 (04) 389-396
• 22 Santoro F, Tarantino N, Pellegrino PL. et al. Cardiovascular sequelae of radiation therapy. Clin Res Cardiol 2014; 103 (12) 955-967
• 23 Plummer C, Henderson RD, O'Sullivan JD, Read SJ. Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. Stroke 2011; 42 (09) 2410-2418
• 24 Yamamoto A, Kikuchi Y, Homma K, O'uchi T, Furui S. Characteristics of intravascular large B-cell lymphoma on cerebral MR imaging. AJNR Am J Neuroradiol 2012; 33 (02) 292-296
• 25 Navi BB, DeAngelis LM, Segal AZ. Multifocal strokes as the presentation of occult lung cancer. J Neurooncol 2007; 85 (03) 307-309
• 26 Diener HC, Sacco RL, Easton JD. et al; RE-SPECT ESUS Steering Committee and Investigators. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med 2019; 380 (20) 1906-1917
• 27 Hart RG, Sharma M, Mundl H. et al; NAVIGATE ESUS Investigators. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018; 378 (23) 2191-2201
• 28 Kamel H, Longstreth Jr WT, Tirschwell DL. et al. The AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke randomized trial: Rationale and methods. Int J Stroke 2019; 14 (02) 207-214
• 29 Ntaios G, Perlepe K, Lambrou D. et al. Prevalence and overlap of potential embolic sources in patients with embolic stroke of undetermined source. J Am Heart Assoc 2019; 8 (15) e012858
• 30 Sanossian N, Djabiras C, Mack WJ, Ovbiagele B. Trends in cancer diagnoses among inpatients hospitalized with stroke. J Stroke Cerebrovasc Dis 2013; 22 (07) 1146-1150
• 31 Kim SJ, Park JH, Lee MJ, Park YG, Ahn MJ, Bang OY. Clues to occult cancer in patients with ischemic stroke. PLoS One 2012; 7 (09) e44959
• 32 Cocho D, Gendre J, Boltes A. et al. Predictors of occult cancer in acute ischemic stroke patients. J Stroke Cerebrovasc Dis 2015; 24 (06) 1324-1328
• 33 Selvik HA, Bjerkreim AT, Thomassen L, Waje-Andreassen U, Naess H, Kvistad CE. When to screen ischaemic stroke patients for cancer. Cerebrovasc Dis 2018; 45 (1–2): 42-47
• 34 Navi BB, Singer S, Merkler AE. et al. Cryptogenic subtype predicts reduced survival among cancer patients with ischemic stroke. Stroke 2014; 45 (08) 2292-2297
• 35 Uemura J, Kimura K, Sibazaki K, Inoue T, Iguchi Y, Yamashita S. Acute stroke patients have occult malignancy more often than expected. Eur Neurol 2010; 64 (03) 140-144
• 36 Beyeler M, Birner B, Branca M. et al. Development of a score for prediction of occult malignancy in stroke patients (Occult-5 score). J Stroke Cerebrovasc Dis 2022; 31 (08) 106609
• 37 Bang OY, Chung JW, Lee MJ, Seo WK, Kim GM, Ahn MJ. OASIS-Cancer Study Investigators. Cancer-related stroke: an emerging subtype of ischemic stroke with unique pathomechanisms. J Stroke 2020; 22 (01) 1-10
• 38 Lun R, Siegal D, Ramsay T, Dowlatshahi D. Cancer and stroke: what do we know and where do we go?. Thromb Res 2022; 219: 133-140
• 39 Seok JM, Kim SG, Kim JW. et al. Coagulopathy and embolic signal in cancer patients with ischemic stroke. Ann Neurol 2010; 68 (02) 213-219
• 40 Refaai MA, Riley P, Mardovina T, Bell PD. The clinical significance of fibrin monomers. Thromb Haemost 2018; 118 (11) 1856-1866
• 41 Nahab F, Sharashidze V, Liu M. et al. Markers of coagulation and hemostatic activation aid in identifying causes of cryptogenic stroke. Neurology 2020; 94 (18) e1892-e1899
• 42 Costamagna G, Hottinger AF, Milionis H. et al. Clinical and demographic characteristics, mechanisms, and clinical in patients with acute ischemic stroke and newly diagnosed or known active cancer. Neurology 2023; 100 (24) e2477-e2489
• 43 Fujinami J, Ohara T, Kitani-Morii F. et al. Cancer-associated hypercoagulation increases the risk of early recurrent stroke in patients with active cancer. Cerebrovasc Dis 2018; 46 (1-2): 46-51
• 44 Nam KW, Kim CK, Kim TJ. et al. D-dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer. Eur J Neurol 2017; 24 (01) 205-211
• 45 Ay C, Dunkler D, Pirker R. et al. High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica 2012; 97 (08) 1158-1164
• 46 Chen PC, Muo CH, Lee YT, Yu YH, Sung FC. Lung cancer and incidence of stroke: a population-based cohort study. Stroke 2011; 42 (11) 3034-3039
• 47 Zaorsky NG, Zhang Y, Tchelebi LT, Mackley HB, Chinchilli VM, Zacharia BE. Stroke among cancer patients. Nat Commun 2019; 10 (01) 5172
• 48 Hashem H, Muhsen BA. Hyperleukocytosis-induced stroke and tonsillar herniation: case report. Ann Med Surg (Lond) 2021; 70: 102776
• 49 Arboix A, Besses C, Acín P. et al. Ischemic stroke as first manifestation of essential thrombocythemia. Report of six cases. Stroke 1995; 26 (08) 1463-1466
• 50 Abdel-Rahman I, Murphy C. Recurrent ischaemic stroke unveils polycythaemia vera. BMJ Case Rep 2015; 2015: bcr2014207625
• 51 Navi BB, Kawaguchi K, Hriljac I, Lavi E, DeAngelis LM, Jamieson DG. Multifocal stroke from tumor emboli. Arch Neurol 2009; 66 (09) 1174-1175
• 52 Aoki N, Sakai T, Oikawa A, Takizawa T, Koike M. Dissection of the middle cerebral artery caused by invasion of malignant glioma presenting as acute onset of hemiplegia. Acta Neurochir (Wien) 1999; 141 (09) 1005-1008
• 53 Pina S, Carneiro Â, Rodrigues T. et al. Acute ischemic stroke secondary to glioblastoma. A case report. Neuroradiol J 2014; 27 (01) 85-90
• 54 Gutiérrez ML, Carrasco-Moro R, Ruz-Caracuel I, San Millán JSM. Stroke secondary to leptomeningeal carcinomatosis with radiologic signs of arterial invasion. Surg Neurol Int 2022; 13: 290
• 55 Klein P, Haley EC, Wooten GF, VandenBerg SR. Focal cerebral infarctions associated with perivascular tumor infiltrates in carcinomatous leptomeningeal metastases. Arch Neurol 1989; 46 (10) 1149-1152
• 56 Anbil S, Fenerty K, Feng Z, Doughty R, El-Farra NS. Intravascular large B cell lymphoma as a cause of multifocal cryptogenic stroke. Am J Med 2021; 134 (10) 1236-1237
• 57 Rota E, Pitino A, Pastorino R, Gallesio I, Morelli N. Intravascular large B-cell lymphoma: a forgotten stroke “mimic”. Acta Neurol Belg 2020; 120 (03) 745-746
• 58 Vinter N, Christesen AMS, Fenger-Grøn M, Tjønneland A, Frost L. Atrial fibrillation and risk of cancer: a Danish population-based cohort study. J Am Heart Assoc 2018; 7 (17) e009543
• 59 Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 2013; 11 (02) 223-233
• 60 Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985; 64 (01) 16-35
• 61 Marto JP, Strambo D, Livio F, Michel P. Drugs associated with ischemic stroke: a review for clinicians. Stroke 2021; 52 (10) e646-e659
• 62 Home - electronic medicines compendium (emc). Accessed October 19, 2022 at: https://www.medicines.org.uk/emc
• 63 Meyler's Side Effects of Drugs. 16th ed. Accessed May 11, 2022 at: https://www.elsevier.com/books/meylers-side-effects-of-drugs/aronson/978-0-444-53717-1
• 64 Lysov Z, Dwivedi DJ, Gould TJ, Liaw PC. Procoagulant effects of lung cancer chemotherapy: impact on microparticles and cell-free DNA. Blood Coagul Fibrinolysis 2017; 28 (01) 72-82
• 65 Li SH, Chen WH, Tang Y. et al. Incidence of ischemic stroke post-chemotherapy: a retrospective review of 10,963 patients. Clin Neurol Neurosurg 2006; 108 (02) 150-156
• 66 Barceló R, Muñoz A, López-Vivanco G. Prospective evaluation of major vascular events in patients with nonsmall cell lung carcinoma treated with cisplatin and gemcitabine. Cancer 2005; 104 (05) 1110-1111 , author reply 1111
• 67 Zuo PY, Chen XL, Liu YW, Xiao CL, Liu CY. Increased risk of cerebrovascular events in patients with cancer treated with bevacizumab: a meta-analysis. PLoS One 2014; 9 (07) e102484
• 68 Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: part 1. J Am Coll Cardiol 2017; 70 (20) 2536-2551
• 69 Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced cardiotoxicity. Maedica (Buchar) 2013; 8 (01) 59-67
• 70 Yoon GJ, Telli ML, Kao DP, Matsuda KY, Carlson RW, Witteles RM. Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies are clinicians responding optimally?. J Am Coll Cardiol 2010; 56 (20) 1644-1650
• 71 Belzile-Dugas E, Eisenberg MJ. Radiation-induced cardiovascular disease: review of an underrecognized pathology. J Am Heart Assoc 2021; 10 (18) e021686
• 72 Kucuk O, Kwaan HC, Gunnar W, Vazquez RM. Thromboembolic complications associated with L-asparaginase therapy. Etiologic role of low antithrombin III and plasminogen levels and therapeutic correction by fresh frozen plasma. Cancer 1985; 55 (04) 702-706
• 73 Grover SP, Hisada YM, Kasthuri RS, Reeves BN, Mackman N. Cancer therapy-associated thrombosis. Arterioscler Thromb Vasc Biol 2021; 41 (04) 1291-1305
• 74 Kitano T, Sasaki T, Gon Y. et al. The effect of chemotherapy on stroke risk in cancer patients. Thromb Haemost 2020; 120 (04) 714-723
• 75 Drobni ZD, Alvi RM, Taron J. et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 2020; 142 (24) 2299-2311
• 76 Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010; 102 (01) 39-46
• 77 Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991; 9 (02) 286-294
• 78 Pemberton KD, Melissari E, Kakkar VV. The influence of tamoxifen in vivo on the main natural anticoagulants and fibrinolysis. Blood Coagul Fibrinolysis 1993; 4 (06) 935-942
• 79 Cosman F, Baz-Hecht M, Cushman M. et al. Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res 2005; 116 (01) 1-13
• 80 Eilertsen AL, Liestøl S, Mowinckel MC, Hemker HC, Sandset PM. Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system. Thromb Haemost 2007; 97 (06) 938-943
• 81 Rühl H, Schröder L, Müller J. et al. Tamoxifen induces resistance to activated protein C. Thromb Res 2014; 133 (05) 886-891
• 82 Wang TF, Khorana AA, Carrier M. Thrombotic complications associated with immune checkpoint inhibitors. Cancers (Basel) 2021; 13 (18) 4606
• 83 Moik F, Chan WE, Wiedemann S. et al. Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood 2021; 137 (12) 1669-1678
• 84 Ando Y, Hayashi T, Sugimoto R. et al. Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors. Invest New Drugs 2020; 38 (04) 1200-1206
• 85 Sussman TA, Li H, Hobbs B, Funchain P, McCrae KR, Khorana AA. Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival. J Immunother Cancer 2021; 9 (01) e001719
• 86 Scott AS, Parr LA, Johnstone PAS. Risk of cerebrovascular events after neck and supraclavicular radiotherapy: a systematic review. Radiother Oncol 2009; 90 (02) 163-165
• 87 Jiang Z, Elkind M, Lucky M, Fekete Z. Stroke in a young man: a late complication of radiation therapy. BMJ Case Rep 2019; 12 (02) e228029
• 88 Donnellan E, Griffin BP, Johnston DR. et al. Rate of progression of aortic stenosis and its impact on outcomes in patients with radiation-associated cardiac disease: a matched cohort study. JACC Cardiovasc Imaging 2018; 11 (08) 1072-1080
• 89 Xu J, Cao Y. Radiation-induced carotid artery stenosis: a comprehensive review of the literature. Intervent Neurol 2014; 2 (04) 183-192
• 90 Campen CJ, Kranick SM, Kasner SE. et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke 2012; 43 (11) 3035-3040
• 91 Fullerton HJ, Stratton K, Mueller S. et al. Recurrent stroke in childhood cancer survivors. Neurology 2015; 85 (12) 1056-1064
• 92 Apostolakis E, Koletsis EN, Panagopoulos N, Prokakis C, Dougenis D. Fatal stroke after completion pneumonectomy for torsion of left upper lobe following left lower lobectomy. J Cardiothorac Surg 2006; 1 (01) 25
• 93 Kamiya-Matsuoka C, Cachia D, Yust-Katz S. et al; Anderson Cancer Center. Ischemic stroke in patients with gliomas at the University of Texas-M.D. J Neurooncol 2015; 125 (01) 143-148
• 94 Jacob L, Kostev K. Cancer is associated with intraoperative and postprocedural complications and disorders. J Cancer Res Clin Oncol 2016; 142 (04) 777-781
• 95 Schwarzbach CJ, Fatar M, Eisele P, Ebert AD, Hennerici MG, Szabo K. DWI lesion patterns in cancer-related stroke–specifying the phenotype. Cerebrovasc Dis Extra 2015; 5 (03) 139-145
• 96 Nouh AM, Staff I, Finelli PF. Three territory sign: an MRI marker of malignancy-related ischemic stroke (Trousseau syndrome). Neurol Clin Pract 2019; 9 (02) 124-128
• 97 Guo L, Wang L, Liu W. Ability of the number of territories involved on DWI-MRI to predict occult systemic malignancy in cryptogenic stroke patients. J Stroke Cerebrovasc Dis 2020; 29 (07) 104823
• 98 Park MG, Oh SJ, Baik SK, Jung DS, Park KP. Susceptibility-weighted imaging for detection of thrombus in acute cardioembolic stroke. J Stroke 2016; 18 (01) 73-79
• 99 Ikeda H, Ishibashi R, Kinosada M. et al. Factors related to white thrombi in acute ischemic stroke in cancer patients. Neuroradiol J 2023; 36 (04) 453-459
• 100 Beyeler M, Belachew NF, Kielkopf M. et al. Absence of susceptibility vessel sign in patients with malignancy-related acute ischemic stroke treated with mechanical thrombectomy. Front Neurol 2022; 13: 930635
• 101 Chen J, Zhang Z, Nie X. et al. Predictive value of thrombus susceptibility for cardioembolic stroke by quantitative susceptibility mapping. Quant Imaging Med Surg 2022; 12 (01) 550-557
• 102 Yoo J, Choi JK, Kim YD. et al. Outcome of stroke patients with cancer and nonbacterial thrombotic endocarditis. J Stroke 2020; 22 (02) 245-253
• 103 Zmaili MA, Alzubi JM, Kocyigit D. et al. A contemporary 20-year cleveland clinic experience of nonbacterial thrombotic endocarditis: etiology, echocardiographic imaging, management, and outcomes. Am J Med 2021; 134 (03) 361-369
• 104 Deppisch LM, Fayemi AO. Non-bacterial thrombotic endocarditis: clinicopathologic correlations. Am Heart J 1976; 92 (06) 723-729
• 105 Llenas-García J, Guerra-Vales JM, Montes-Moreno S, López-Ríos F, Castelbón-Fernández FJ, Chimeno-García J. Nonbacterial thrombotic endocarditis: clinicopathologic study of a necropsy series [in Spanish]. Rev Esp Cardiol 2007; 60 (05) 493-500
• 106 Steiner I. Nonbacterial thrombotic endocarditis–a study of 171 case reports [in Czech]. Cesk Patol 1993; 29 (02) 58-60
• 107 Hisada Y, Mackman N. Tissue factor and cancer: regulation, tumor growth, and metastasis. Semin Thromb Hemost 2019; 45 (04) 385-395
• 108 Khorana AA, Mackman N, Falanga A. et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022; 8 (01) 11
• 109 Eichinger S. Cancer associated thrombosis: risk factors and outcomes. Thromb Res 2016; 140 (Suppl. 01) S12-S17
• 110 Ha J, Lee MJ, Kim SJ. et al. Prevalence and impact of venous and arterial thromboembolism in patients with embolic stroke of undetermined source with or without active cancer. J Am Heart Assoc 2019; 8 (21) e013215
• 111 Blann AD, Dunmore S. Arterial and venous thrombosis in cancer patients. Cardiol Res Pract 2011; 2011: 394740
• 112 Kawano T, Sasaki T, Gon Y. et al. High neutrophil/lymphocyte ratio at cancer diagnosis predicts incidence of stroke in cancer patients. Brain Commun 2021; 3 (02) fcab071
• 113 Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005; 91 (03) 181-184
• 114 Kang MH, Go SI, Song HN. et al. The prognostic impact of the neutrophil-to-lymphocyte ratio in patients with small-cell lung cancer. Br J Cancer 2014; 111 (03) 452-460
• 115 Goyal N, Tsivgoulis G, Chang JJ. et al. Admission neutrophil-to-lymphocyte ratio as a prognostic biomarker of outcomes in large vessel occlusion strokes. Stroke 2018; 49 (08) 1985-1987
• 116 Nam KW, Kim TJ, Kim CK. et al. Temporal changes in the neutrophil to lymphocyte ratio and the neurological progression in cryptogenic stroke with active cancer. PLoS One 2018; 13 (03) e0194286
• 117 Sarejloo S, Kheradjoo H, Haghi SE. et al. Neutrophil-to-lymphocyte ratio and early neurological deterioration in stroke patients: a systematic review and meta-analysis. BioMed Res Int 2022; 2022: 8656864
• 118 Doyle LM, Wang MZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells 2019; 8 (07) 727
• 119 Bang OY, Chung JW, Lee MJ. et al. Cancer cell-derived extracellular vesicles are associated with coagulopathy causing ischemic stroke via tissue factor-independent way: the OASIS-CANCER study. PLoS One 2016; 11 (07) e0159170
• 120 Chung JW, Cho YH, Ahn MJ. et al. Association of cancer cell type and extracellular vesicles with coagulopathy in patients with lung cancer and stroke. Stroke 2018; 49 (05) 1282-1285
• 121 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
• 122 Almeida VH, Rondon AMR, Gomes T, Monteiro RQ. Novel aspects of extracellular vesicles as mediators of cancer-associated thrombosis. Cells 2019; 8 (07) 716
• 123 Thålin C, Demers M, Blomgren B. et al. NETosis promotes cancer-associated arterial microthrombosis presenting as ischemic stroke with troponin elevation. Thromb Res 2016; 139: 56-64
• 124 Bang OY, Chung JW, Cho YH. et al. Circulating DNAs, a marker of neutrophil extracellular traposis and cancer-related stroke: the OASIS-Cancer study. Stroke 2019; 50 (10) 2944-2947
• 125 Maezono-Kandori K, Ohara T, Fujinami J, Makita N, Tanaka E, Mizuno T. Elevated CA125 is related to stroke due to cancer- associated hypercoagulation. J Stroke Cerebrovasc Dis 2021; 30 (12) 106126
• 126 Long H, Qin K, Chen J. et al. Biomarkers of gastric cancer-related ischemic stroke and its underlying pathogenesis. Medicine (Baltimore) 2018; 97 (17) e0493
• 127 Okazaki K, Oka F, Ishihara H, Suzuki M. Cerebral infarction associated with benign mucin-producing adenomyosis: report of two cases. BMC Neurol 2018; 18 (01) 166
• 128 Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110 (06) 1723-1729
• 129 Park H, Kim J, Ha J. et al. Histological features of intracranial thrombi in stroke patients with cancer. Ann Neurol 2019; 86 (01) 143-149
• 130 Huang S, Lu X, Tang LV, Hu Y. Efficacy and safety of intravenous thrombolysis for acute ischemic stroke in cancer patients: a systemic review and meta-analysis. Am J Transl Res 2020; 12 (08) 4795-4806
• 131 Eun MY, Jeon ET, Seo KD, Lee D, Jung JM. Reperfusion therapy in acute ischemic stroke with active cancer: a meta-analysis aided by machine learning. J Stroke Cerebrovasc Dis 2021; 30 (06) 105742
• 132 Murthy SB, Karanth S, Shah S. et al. Thrombolysis for acute ischemic stroke in patients with cancer: a population study. Stroke 2013; 44 (12) 3573-3576
• 133 Inohara T, Liang L, Kosinski AS. et al. Thrombolytic therapy in older acute ischemic stroke patients with gastrointestinal malignancy or recent bleeding. Eur Stroke J 2020; 5 (01) 47-55
• 134 Singh K, Mowla A, Mehla S. et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients with preexisting intracranial neoplasms: a case series. Int J Stroke 2015; 10 (03) E29-E30
• 135 Rubinshtein R, Jaffe R, Flugelman MY, Karkabi B, Lewis BS. Thrombolysis in patients with a brain tumour. Heart 2004; 90 (12) 1476
• 136 Dafer RM, Paleologos N, Lynch D. Intravenous thrombolysis for ischemic stroke in recurrent oligodendroglioma: a case report. J Stroke Cerebrovasc Dis 2014; 23 (05) 1235-1238
• 137 Schwarzbach CJ, Ebert A, Hennerici MG, Neumaier-Probst E, Platten M, Fatar M. Off-label use of IV t-PA in patients with intracranial neoplasm and cavernoma. Ther Adv Neurol Disord 2018; 11: 1756285617753423
• 138 Neil W, Ovbiagele B. Intravenous thrombolysis in ischemic stroke patients with intracranial neoplasms: two cases and a literature review. Case Rep Med 2011; 2011: 503758
• 139 Etgen T, Steinich I, Gsottschneider L. Thrombolysis for ischemic stroke in patients with brain tumors. J Stroke Cerebrovasc Dis 2014; 23 (02) 361-366
• 140 Turc G, Tsivgoulis G, Audebert HJ. et al. European Stroke Organisation (ESO)-European Society for Minimally Invasive Neurological Therapy (ESMINT) expedited recommendation on indication for intravenous thrombolysis before mechanical thrombectomy in patients with acute ischemic stroke and anterior circulation large vessel occlusion. J Neurointerv Surg 2022; 14 (03) 209-227
• 141 Cho BH, Yoon W, Kim JT. et al. Outcomes of endovascular treatment in acute ischemic stroke patients with current malignancy. Neurol Sci 2020; 41 (02) 379-385
• 142 Lee EJ, Bae J, Jeong HB, Lee EJ, Jeong HY, Yoon BW. Effectiveness of mechanical thrombectomy in cancer-related stroke and associated factors with unfavorable outcome. BMC Neurol 2021; 21 (01) 57
• 143 Jolugbo P, Ariëns RAS. Thrombus composition and efficacy of thrombolysis and thrombectomy in acute ischemic stroke. Stroke 2021; 52 (03) 1131-1142
• 144 Jung S, Jung C, Hyoung Kim J. et al. Procedural and clinical outcomes of endovascular recanalization therapy in patients with cancer-related stroke. Interv Neuroradiol 2018; 24 (05) 520-528
• 145 Staessens S, Denorme F, Francois O. et al. Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance. Haematologica 2020; 105 (02) 498-507
• 146 Denorme F, Langhauser F, Desender L. et al. ADAMTS13-mediated thrombolysis of t-PA-resistant occlusions in ischemic stroke in mice. Blood 2016; 127 (19) 2337-2345
• 147 Gauberti M, Martinez de Lizarrondo S, Vivien D. Thrombolytic strategies for ischemic stroke in the thrombectomy era. J Thromb Haemost 2021; 19 (07) 1618-1628
• 148 Stalder G, Chatte A, De Rossi N, Yerly P, Alberio L, Eeckhout E. Caplacizumab for treating subacute intra-stent thrombus occurring despite efficacious double anti-platelet treatment and anticoagulation: a case report. Eur Heart J Case Rep 2023; 7 (02) ytac497
• 149 Caimano D, Letteri F, Capasso F. et al. Endovascular treatment in patients with acute ischemic stroke and cancer: systematic review and meta-analysis. Eur Stroke J 2022; 7 (03) 204-211
• 150 Verschoof MA, Groot AE, de Bruijn SFTM. et al; MR CLEAN Registry Investigators. Clinical outcome after endovascular treatment in patients with active cancer and ischemic stroke: a MR CLEAN registry substudy. Neurology 2022; 98 (10) e993-e1001
• 151 Letteri F, Pracucci G, Saia V. et al. Endovascular treatment in patients with acute ischemic stroke and comorbid cancer: analysis of the Italian Registry of Endovascular Treatment in Acute Stroke. Stroke Vasc Intervent Neurol 2023; 3: e000423
• 152 Chatterjee A, Merkler AE, Murthy SB. et al. Temporal trends in the use of acute recanalization therapies for ischemic stroke in patients with cancer. J Stroke Cerebrovasc Dis 2019; 28 (08) 2255-2261
• 153 Gervaso L, Dave H, Khorana AA. Venous and arterial thromboembolism in patients with cancer: JACC: CardioOncology State-of-the-Art Review. JACC Cardiooncol 2021; 3 (02) 173-190
• 154 De Stefano V. Arterial thrombosis and cancer: the neglected side of the coin of Trousseau syndrome. Haematologica 2018; 103 (09) 1419-1421
• 155 Jang H, Lee JJ, Lee MJ. et al. Comparison of enoxaparin and warfarin for secondary prevention of cancer-associated stroke. J Oncol 2015; 2015: 502089
• 156 Navi BB, Marshall RS, Bobrow D. et al. Enoxaparin vs aspirin in patients with cancer and ischemic stroke: the TEACH pilot randomized clinical trial. JAMA Neurol 2018; 75 (03) 379-381
• 157 Nam KW, Kim CK, Kim TJ. et al. Treatment of cryptogenic stroke with active cancer with a new oral anticoagulant. J Stroke Cerebrovasc Dis 2017; 26 (12) 2976-2980
• 158 Agnelli G, Becattini C, Meyer G. et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382 (17) 1599-1607
• 159 Raskob GE, van Es N, Verhamme P. et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
• 160 Falanga A, Ay C, Di Nisio M. et al; ESMO Guidelines Committee. Electronic address: [e-mail]. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol 2023; 34 (05) 452-467
• 161 Lyman GH, Carrier M, Ay C. et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021; 5 (04) 927-974
• 162 Martinez-Majander N, Ntaios G, Liu YY. et al; NAVIGATE ESUS investigators. Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial. Eur J Neurol 2020; 27 (05) 841-848
• 163 Mantia C, Uhlmann EJ, Puligandla M, Weber GM, Neuberg D, Zwicker JI. Predicting the higher rate of intracranial hemorrhage in glioma patients receiving therapeutic enoxaparin. Blood 2017; 129 (25) 3379-3385
• 164 Kamphuisen PW, Beyer-Westendorf J. Bleeding complications during anticoagulant treatment in patients with cancer. Thromb Res 2014; 133 (Suppl. 02) S49-S55
• 165 Angelini DE, Radivoyevitch T, McCrae KR, Khorana AA. Bleeding incidence and risk factors among cancer patients treated with anticoagulation. Am J Hematol 2019; 94 (07) 780-785
• 166 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
• 167 Falanga A, Leader A, Ambaglio C. et al. EHA guidelines on management of antithrombotic treatments in thrombocytopenic patients with cancer. HemaSphere 2022; 6 (08) e750
• 168 De Stefano V, Carobbio A, Di Lazzaro V. et al. Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms. Blood Cancer J 2018; 8 (03) 25
• 169 ECOG-ACRIN Cancer Research Group. ECOG performance status scale. Accessed March 05, 2023 at: https://ecog-acrin.org/resources/ecog-performance-status/
• 170 Weitz JI, Eikelboom JW. What is the future of factor XI inhibitors?. Circulation 2022; 146 (25) 1899-1902
• 171 Grisold W, Oberndorfer S, Struhal W. Stroke and cancer: a review. Acta Neurol Scand 2009; 119 (01) 1-16

Publication History

Article published online:
28 July 2023