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. 

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

Abstract Since stroke is often associated with cancer, acute stroke patients with cancer undergoing endovascular therapy (EVT) are not uncommon. Reportedly, the proportion of such cases is approximately 6%–7% of all stroke EVT cases. Ischemic stroke in patients with active cancer (cancer-associated stroke) includes not only strokes caused by cancer-related hypercoagulability but also coincident strokes due to common etiologies, strokes associated with tumor emboli, direct tumor invasion of blood vessels, and strokes associated with cancer therapy. Stroke caused by cancer-related hypercoagulability itself encompasses various entities, including paradoxical embolism, stroke due to nonbacterial thrombotic endocarditis, and in situ arterial occlusion due to disseminated intravascular coagulation or thrombotic microangiopathy. Thus, diverse mechanisms contribute to cancer-associated stroke, emphasizing the need to consider individualized treatment strategies for acute cases involving large vessel occlusion. Observational studies have shown that EVT for cancer-associated stroke results in poorer clinical outcomes, but with comparable rates of successful reperfusion and symptomatic intracranial hemorrhage when compared with stroke patients without cancer. This suggests that denying patients EVT solely on the basis of comorbid active cancer is inappropriate, and decision-making should be shared with the patients and their families, preferably through a multidisciplinary team approach. Thrombi retrieved from patients with stroke caused by cancer-related hypercoagulability have unique characteristics, being predominantly platelet rich and difficult to retrieve. Preprocedural imaging and serum biomarkers, including the hyperdense vessel sign on non-contrast CT, susceptibility vessel sign on T2* or susceptibility-weighted MRI, three-territory sign on MRI, and D-dimer levels, are valuable in evaluating the stroke subtype and thrombus features. Thrombectomy techniques, such as contact aspiration and stent retriever monotherapy, have shown varying degrees of effectiveness for stroke caused by cancer-related hypercoagulability, warranting further study. After reperfusion therapy, appropriate treatment for the prevention of stroke recurrence should be initiated, considering the specific stroke subtypes. In conclusion, cancer-associated stroke encompasses diverse subtypes, and thrombi associated with stroke caused by cancer-related hypercoagulability present various challenges for thrombectomy. Individualized treatment approaches based on underlying mechanisms are essential for improving outcomes in acute stroke patients with active cancer. Optimization of preprocedural diagnosis, EVT techniques, and secondary prevention of stroke caused by cancer-related hypercoagulability will lead to better management of these patients and enhance their quality of life.

Cancer-Associated Stroke and Acute Endovascular Reperfusion Therapy

HomeStroke: Vascular and Interventional NeurologyVol. 3, No. 3Thrombectomy in Patients With Active Malignancy Open AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessEditorialPDF/EPUBThrombectomy in Patients With Active Malignancy James E. Siegler and Thanh N. Nguyen James E. SieglerJames E. Siegler *Correspondence to: James E. Siegler, MD, Cooper Neurological Institute, Cooper University Hospital, Camden, NJ 08103. Email: E-mail Address: [email protected]Thanh N. Nguyen, MD, Department of Neurology, Radiology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118. Email: E-mail Address: [email protected] https://orcid.org/0000-0003-0287-3967 , Cooper Neurological Institute, , Cooper University Hospital, , Camden, , NJ, , Cooper Medical School of Rowan University, , Camden, , NJ, Search for more papers by this author and Thanh N. NguyenThanh N. Nguyen *Correspondence to: James E. Siegler, MD, Cooper Neurological Institute, Cooper University Hospital, Camden, NJ 08103. Email: E-mail Address: [email protected]Thanh N. Nguyen, MD, Department of Neurology, Radiology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118. Email: E-mail Address: [email protected] https://orcid.org/0000-0002-2810-1685 , Boston Medical Center, , Boston University Chobanian and Avedisian School of Medicine, , Boston, , MA, Search for more papers by this author Originally published2 May 2023https://doi.org/10.1161/SVIN.123.000835Stroke: Vascular and Interventional Neurology. 2023;3:e000835Patients with stroke and comorbid cancer represent a unique population at heightened risk of stroke.1 Several direct and indirect associations likely account for this risk, including older age of individuals with versus without cancer, concomitant stroke risk factors associated with certain cancers (eg, prior tobacco use), use of specific chemotherapeutics (which may be prothrombotic), radiation (leading to large‐artery vasculopathy or cerebral microvascular injury), or predisposition to infection as a consequence of immunosuppression, which can contribute to thrombosis. Furthermore, the cancer itself can lead to a relative state of hypercoagulability. For these reasons, between 1% and 15% of patients with cancer will experience a cerebrovascular event (stroke or intracranial hemorrhage).2, 3 These neurological complications not only impair quality of life but also contribute to disability and may preclude ongoing or additional disease‐modifying oncological care. Unfortunately, many patients with cancer are excluded from short‐term interventional trials in stroke; therefore, the benefit of emergent reperfusion is less well established in this population. That said, there is no biological plausibility as to why endovascular treatment may be futile in appropriately selected patients with stroke attributable to large‐vessel occlusion (LVO) and concomitant cancer. A term that has developed in place of “futile reperfusion” is “reperfusion without functional independence” as many of these patients can still have quality of life.4Using real‐world data from the prospective Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS), including >4500 patients, Letteri et al summarize their experience with thrombectomy in patients with stroke who have comorbid cancer. Propensity‐score matching was used to reduce the risk of confounding by treatment indication.5 Across the total cohort, the investigators reported no difference in the technical success of thrombectomy in patients with versus without cancer (Thrombolysis in Cerebral Infarction scores 2b–3 of 74% versus 75%; P=0.84), nor was there a difference in the rate of symptomatic intracerebral hemorrhage (8% versus 7%; P=0.53). Rates of technical success and symptomatic intracerebral hemorrhage were similar in the propensity‐matched cohort (71% versus 73% and 4% versus 7%, respectively).After propensity‐score matching (n=152 in cancer and noncancer groups), the probability of achieving functional independence at 3 months (modified Rankin Scale score of 0–2) was high and was no different between those with versus without cancer (39% versus 38%; P=0.91). Furthermore, these rates are comparable to those reported from another prospective thrombectomy real‐world registry (SVIN [Society of Vascular and Interventional Neurology] Registry, modified Rankin Scale score 0–2, 37%)6 and randomized trial data reported by the Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration (46%; P=0.12 [immediate test of proportions]).7In addition to demonstrating the technical and functional outcomes with thrombectomy in this population, Letteri et al contribute to the growing body of epidemiologic literature in cancer‐associated stroke. Among the nested cohort of 130 patients with reported timing of cancer diagnosis, nearly two‐thirds (62%) experienced the incident LVO stroke >2 years following their diagnosis of cancer. Compared with patients who experience an acute LVO within 1 year or 1 to 2 years, the 3‐month mortality rate was least among those with a stroke >2 years after diagnosis with cancer (25% if >2 years versus 45% if within 1 year versus 50% within 1–2 years; P=0.02). Although this 25% mortality rate is still higher than what has been reported from the HERMES meta‐analysis of patients with anterior circulation LVO (15%),7 and the mortality rate was higher in patients with comorbid cancer than those without cancer, two‐thirds of patients with cancer remained alive at 3 months following thrombectomy and more than half of survivors achieved functional independence.Currently, societal guidelines recommend thrombectomy in select patients according to the criteria set forth by published clinical trials,8, 9 which often excluded patients with comorbid cancer. On the basis of the available evidence to support thrombectomy for many trial‐ineligible populations,10, 11, 12, 13 there may be no equipoise in randomizing patients with cancer to medical management. Therefore, no trials are anticipated to put this question to rest, and many patients with cancer may be excluded from endovascular intervention if current guidelines are rigidly followed.14 In patients with cancer who are on the hospice pathway or with widely metastatic disease, the ethical question of who one should treat is another question and likely best addressed on an individual basis with the patient's family, and based on the available resources. Certainly, for some patients with cancers associated with severe immediate disability and harboring a more malignant prognosis, thrombectomy may not provide any meaningful improvement in function. It may prolong survival with greater disability, greater anticipated end‐of‐life care costs, and more emotional distress for caregivers and next of kin. For patients with cancer that is detected early, or that may be more treatment responsive, thrombectomy may improve the chances of a functional recovery sufficient for the patient to tolerate cancer treatment. Although the data from Letteri et al reflect observational experience and nonrandomized treatment allocation, the generally favorable outcomes following thrombectomy in this large cohort of patients with comorbid cancer argue strongly for endovascular intervention in this population. That said, the decision to proceed with endovascular intervention must take into consideration the patient's premorbid disability, probability of a good functional recovery, and overall goals of care. In patients with minimal or no prestroke disability and a reasonable quality of life with (or without) treatment of their underlying cancer, endovascular thrombectomy for anterior LVO is likely to yield better outcomes when compared with medical management alone.Sources of FundingNone.DisclosuresDr Nguyen reports advisory board with Idorsia.AcknowledgmentsNone.Footnotes*Correspondence to: James E. Siegler, MD, Cooper Neurological Institute, Cooper University Hospital, Camden, NJ 08103. Email: Siegler.[email protected]comThanh N. Nguyen, MD, Department of Neurology, Radiology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118. Email: Thanh.[email protected]orgThe opinions expressed in this article are not necessarily those of the editors, the American Heart Association, or the Society of Vascular and Interventional Neurology.REFERENCES1 Zaorsky NG, Zhang Y, Tchelebi LT, Mackley HB, Chinchilli VM, BE Zacharia. Stroke among cancer patients. Nat. Commun. 2019; 10:5172. Available from: https://doi.org/10.1038/s41467‐019‐13120‐6Google Scholar2 Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine. 1985; 64:16–35.CrossrefMedlineGoogle Scholar3 Navi BB, Reiner AS, Kamel H, Iadecola C, Elkind MSV, Panageas KS, DeAngelis LM. Association between incident cancer and subsequent stroke. Ann. Neurol. 2015; 77:291–300. Available from: https://doi.org/10.1002/ana.24325CrossrefMedlineGoogle Scholar4 Seker F, Qureshi MM, Möhlenbruch MA, Nogueira RG, Abdalkader M, Ribo M, Caparros F, Haussen DC, Mohammaden MH, Sheth SA, et al. Reperfusion Without Functional Independence in Late Presentation of Stroke With Large Vessel Occlusion. Stroke. 2022; 53:3594–3604.LinkGoogle Scholar5 Letteri F, Giovanni P, Valentina S, Fabrizio S, Paolo MA, Valerio DR, Rossana T, Maurizio A, Bracco S, Alessandro DV, 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 Interv Neurol. 2022; 0:e000423.LinkGoogle Scholar6 Haussen DC, Al‐Bayati AR, Mohammaden MH, Sheth SA, Salazar‐Marioni S, Linfante I, Dabus G, Starosciak AK, Hassan AE, Tekle WG, et al. The Society of Vascular and Interventional Neurology (SVIN) mechanical thrombectomy registry: methods and primary results. Stroke Vasc Interv Neurol. 2022; 2:e000234. Available from: http://doi.org/10.1161/svin.121.000234LinkGoogle Scholar7 Goyal M, Menon BK, van Zwam WH, Dippel DWJ, Mitchell PJ, Demchuk AM, Dávalos A, Majoie CBLM, van der Lugt A, de Miquel MA, et al. Endovascular thrombectomy after large‐vessel ischaemic stroke: a meta‐analysis of individual patient data from five randomised trials. Lancet2016; 387:1723–1731.CrossrefMedlineGoogle Scholar8 Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, 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:e344–e418.LinkGoogle Scholar9 Eskey CJ, Meyers PM, Nguyen TN, Ansari SA, Jayaraman M, McDougall CG, DeMarco JK, Gray WA, Hess DC, Higashida RT, et al. Indications for the performance of intracranial endovascular neurointerventional procedures: a scientific statement from theCirculation2018; 137:e661–e689.LinkGoogle Scholar10 Abdalkader M, Finitsis S, Li C, Hu W, Liu X, Ji X, Huo X, Alemseged F, Qiu Z, Strbian D, et al. Endovascular versus medical management of acute basilar artery occlusion: a systematic review and meta‐analysis of the randomized controlled trials. J Stroke. 2023; 25:81–91.CrossrefGoogle Scholar11 Siegler JE, Qureshi MM, Nogueira RG, Tanaka K, Nagel S, Michel P, Vigilante N, Ribo M, Yamagami H, Yoshimura S, et al. Endovascular vs medical management for late anterior large vessel occlusion with prestroke disability: analysis of CLEAR and RESCUE‐Japan. Neurology. 2023; 100:e751–e763.CrossrefGoogle Scholar12 Nguyen TN, Abdalkader M, Nagel S, Qureshi MM, Ribo M, Caparros F, Haussen DC, Mohammaden MH, Sheth SA, Ortega‐Gutierrez S, et al. Noncontrast computed tomography vs computed tomography perfusion or magnetic resonance imaging selection in late presentation of stroke with large‐vessel occlusion. JAMA Neurol. 2022; 79:22–31.CrossrefMedlineGoogle Scholar13 de Havenon A, Castonguay A, Nogueira R, Nguyen TN, English J, Satti SR, Veznedaroglu E, Saver JL, Mocco J, Khatri P, et al. Prestroke disability and outcome after thrombectomy for emergent anterior circulation large vessel occlusion stroke. Neurology. 2021; 97:e1914–e1919.CrossrefGoogle Scholar14 Nguyen TN, Raymond J, Nogueira RG, Fischer U, Siegler JE. The problem of restrictive thrombectomy trial eligibility criteria. Stroke. 2022; 53:2988–2990LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails May 2023Vol 3, Issue 3 Article InformationMetrics © 2023 The Authors. Published on behalf of the American Heart Association, Inc., and the Society of Vascular and Interventional Neurology by Wiley Periodicals LLC.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.https://doi.org/10.1161/SVIN.123.000835 Manuscript receivedFebruary 23, 2023Manuscript acceptedMarch 21, 2023Originally publishedMay 2, 2023 Keywordsmedical oncologyEditorialsthrombectomystrokePDF download 

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Thrombectomy in Patients With Active Malignancy

Introduction Patients with cancer (CP) need a different approach to acute ischaemic stroke (AIS) treatment as intravenous thrombolysis (IVT) may be contraindicated. Mechanical thrombectomy (MT) is a treatment of choice for otherwise eligible patients, although the literature on its long-term outcomes in CP is limited. Aim Assessing outcomes of MT-treated AIS patients with concomitant malignancy in a year-long follow-up. Material and methods The study included 593 MT-treated AIS patients admitted in 2019–2021. The group was divided into CP (defined as a diagnosis of malignancy and undergoing/qualified for cancer treatment within previous 5 years) and a control group. The profile of cardiovascular risk factors, stroke severity and discharge, 90-day and 365-day outcomes were compared between the groups. Results CP and controls had a similar profile of cardiovascular risk factors and comparable stroke severity. CP were less frequently treated with IVT (25.7% vs. 59.1%, p < 0.001). There were no differences between the groups in the successful reperfusion rate and occurrence of haemorrhagic complications. Discharge and 90-day outcomes were similar. CP had higher 365-day mortality (48.6% vs. 29.9%, p = 0.024) but the percentage of patients achieving good functional outcome in a year-long observation was comparable. Conclusions Treatment with MT seems beneficial for AIS patients with concomitant malignancy both in short- and long-term observation.

Long-term outcomes of mechanical thrombectomy
in acute ischaemic stroke patients with concomitant
malignancy

Patients with cancer have an increased risk of ischemic stroke compared to the general population. Additionally, these patients have a worse prognosis compared to stroke patients without cancer. Activation of coagulation appears to play a key role in the pathophysiology of ischemic stroke in patients with cancer. However, the underlying mechanisms remain unknown. Moreover, we do not have a way to identify cancer patients with a high risk of stroke and cannot develop prevention strategies. Therefore, there is an urgent need for neurologists and oncologists to develop screening and prevention strategies for stroke in patients with cancer. In this review, we summarize the characteristics of cancer patients at a high risk of stroke, the predictors for the development of stroke and survival in cancer patients, and possible treatments. 

Cancer patients and ischemic stroke


 
 Acute stroke patients with comorbid cancer (CC) are more preferably addressed with endovascular treatment (EVT) than thrombolytic therapy, due to the presumed potential risk of hemorrhagic transformation and systemic bleeding. This study aims to evaluate clinical and procedural outcomes of acute stroke patients with CC receiving EVT.
 
 
 
 Using the Italian Registry of Endovascular Treatment in Acute Stroke, we reviewed prospectively collected data of CC patients treated with EVT from 2011 to 2017. Outcome measures were modified Thrombolysis in Cerebral Infarction score, symptomatic intracranial hemorrhage rate, and 3‐month modified Rankin scale. We also compared CC patients with a control group without cancer (non‐comorbid cancer) receiving EVT and matched the 2 populations with a 1:1 propensity score.
 
 
 
 
 Out of 4598 stroke patients treated with EVT, 165 (3.6%) had a CC. Modified Thrombolysis in Cerebral Infarction 2b‐3 was obtained in 73.8% of CC and 74.5% of non‐comorbid cancer patients (
 P
 =0.84), whereas the rate of symptomatic intracranial hemorrhage rate was 8.2% and 6.9%, respectively. Three‐month all‐cause mortality was 33.3% in CC patients and 18.6% non‐comorbid cancer patients (
 P
 <0.001), and after propensity score was 35.4% and 22.1%, respectively (
 P
 =0.012). In CC patients, the presence of metastasis and a more recent diagnosis of cancer were significantly associated with a higher 3‐month mortality (
 P
 =0.018 and 0.021, respectively). Breast cancer showed a significant correlation with mild or no disability (odds ratio, 3.32; CI, 1.28–8.67;
 P
 =0.014) and less death cases at 3‐months (odds ratio, 0.44; CI, 0.16–1.21;
 P
 =0.114) compared to the other most represented malignancies.
 
 
 
 
 Although 3‐month all‐cause mortality was significantly higher in CC patients, successful recanalization and hemorrhagic transformation rate were comparable in both groups. In cancer patients, a metastatic and active disease seem to be associated with a poorer functional outcome, whereas a diagnosis of breast cancer appears to be more frequent in patients with a mild or no disability at long term.


Endovascular Treatment in Patients With Acute Ischemic Stroke and Comorbid Cancer: Analysis of the Italian Registry of Endovascular Treatment in Acute Stroke

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Endovascular Treatment in Patients With Acute Ischemic Stroke and Comorbid Cancer: Analysis of the Italian Registry of Endovascular Treatment in Acute Stroke