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Sun, M.; Bhaskar, S.M.M. Cancer-Related Stroke Management. Encyclopedia. Available online: https://encyclopedia.pub/entry/43885 (accessed on 27 July 2024).
Sun M, Bhaskar SMM. Cancer-Related Stroke Management. Encyclopedia. Available at: https://encyclopedia.pub/entry/43885. Accessed July 27, 2024.
Sun, Ming-Yee, Sonu M. M. Bhaskar. "Cancer-Related Stroke Management" Encyclopedia, https://encyclopedia.pub/entry/43885 (accessed July 27, 2024).
Sun, M., & Bhaskar, S.M.M. (2023, May 05). Cancer-Related Stroke Management. In Encyclopedia. https://encyclopedia.pub/entry/43885
Sun, Ming-Yee and Sonu M. M. Bhaskar. "Cancer-Related Stroke Management." Encyclopedia. Web. 05 May, 2023.
Cancer-Related Stroke Management
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24097981

The underlying aetiopathophysiology of cancer-related strokes and thromboembolisms differs from that of noncancer-related strokes, which makes treating cancer-related strokes and thromboembolisms a distinct clinical challenge. This necessitates the development of novel, individualised diagnostic and treatment strategies.

cancer stroke thromboembolism anticoagulation prevention reperfusion cerebrovascular disorders

1. Therapeutic or Preventive Management of Stroke in Cancer Patients

Overall, amongst both cancer and noncancer patients, the incidence of ischaemic and nonischaemic strokes remain consistent at 85% and 15%, respectively [1]. The highest risk of an ischaemic stroke after cancer is within the first month of cancer diagnosis, with stage 4 cancer patients facing a 10-fold increased risk in this period compared to the normal population [2]. For haemorrhagic stroke, the risk was greatest in the first 6 months after diagnosis, at almost 2 times the normal population [3]. Another important clinical consideration is atrial fibrillation (AF) in cancer patients who develop stroke [4]. About 2–5% of cancer patients have AF at the time of diagnosis, making it yet another common condition in this population [5][6][7]. A case-controlled study of cancer patients who experience stroke/transient ischaemic attack (TIA) with matched cancer patients without stroke/TIA found that AF, prior ischaemic stroke, ongoing cancer therapy, dyslipidaemia, and renal disease are independent risk factors for stroke/TIA [7]. The study also indicated that a higher CHA2DS2-VASc score significantly potentiates the risk in people with active cancer independent of AF [7]. This study had several limitations including a retrospective design and a small sample size. Further studies on the interrelationship among AF, stroke, and cancer may provide insights into the management of this high-risk subgroup of patients. The assessment of the risk factors identified in this study may guide preventive strategies in cancer patients who develop stroke/TIA. Timely preventive and therapeutic management of stroke in cancer patients is essential in both improving their prognosis and in reducing the burden that these diseases individually and combined place on the health system. Cancer-specific stroke risk prediction scores/tools need to be developed to aid the prevention of stroke/TIA [7]. Strategies for the prophylactic and emergent management of stroke in cancer patients are discussed below.

2. Reperfusion Therapy for Stroke in Cancer Patients

Reperfusion therapy, intravenous thrombolysis (IVT), and endovascular thrombectomy (EVT) are currently the mainstay of acute management of ischaemic stroke patients [8]. Reperfusion therapy for stroke involves the administration of drugs to dissolve blood clots. The tissue plasminogen activator (tPA) is the most commonly used thrombolytic drug. The treatment with tPA works by dissolving the clot and restoring blood flow to the affected area of the brain. However, the use of tPA in cancer patients can be complicated by several factors including thrombocytopenia, impaired coagulation, and the need for additional monitoring. However, limited studies have been conducted on the effectiveness of IVT or EVT in stroke patients with active malignancy, and those that have been conducted have used small sample sizes [9][10][11][12][13]. Hence, treatment guidelines for stroke in cancer patients are not well established. The 2019 guidelines from the American Heart Association and American Stroke Association suggest that acute ischaemic stroke patients with systemic cancer and reasonable (>6 months) life expectancy may benefit from IVT [14]. No such recommendations are available for EVT in patients with acute ischaemic stroke and active cancer [15]. A substudy of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN) Registry provided Class I evidence that patients with active cancer undergoing EVT for acute ischaemic stroke (AIS) had significantly worse functional outcomes at 90 days relative to those without active cancer. Authors also reported an increased risk of recurrent stroke in cancer patients [11]. A study by Joshi et al. found that the functional outcomes and mortality at 90 days of patients following EVT for AIS with and without cancer were similar in a propensity-matched analysis [10]. Cancer patients, on the other hand, had a much greater risk of haemorrhagic transformation (HT) [10]. An analysis of the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) registry on 1338 patients who underwent reperfusion therapy, comprising 62 patients (4.6%) with active cancer, 78 patients (5.8%) with nonactive cancer, and 1198 patients (89.5%) with no history of cancer revealed similar adverse events and 24 h neurological improvement in patients with active cancer relative to other groups [16]. However, patients with active cancer were linked to poorer long-term functional outcomes, vis-à-vis functional independence at 3 months and mortality at 6 months. A systematic review comprising 18 retrospective studies on the safety and efficacy of MT in cancer patients revealed EVT is safe in cancer patients with acute ischaemic stroke, however, with higher mortality at 90 days and lower 90-day functional independence [17]. Another meta-analysis, aided by machine learning, on the safety and outcomes of reperfusion therapy, IVT or EVT in AIS patients with or without active cancer reported comparable clinical outcomes of IVT and procedural outcomes of EVT, indicating reperfusion therapy may benefit a select group of AIS patients with active cancer [18]. However, IVT was associated with an increased risk of symptomatic intracerebral haemorrhage (sICH) in AIS patients with active cancer. Furthermore, in active cancer patients treated with EVT for AIS, higher mortality and fewer odds of favourable outcomes were observed [18]. Interestingly, a recent study leveraging the National Inpatient Sample (NIS), a large inpatient database from the United States, showed that in contemporary medical practice settings, acute ischaemic stroke patients with comorbid cancer or metastatic cancer treated with EVT had similar rates of intracranial haemorrhage and favourable/routine discharges as patients without cancer [19]. However, patients with metastatic cancer were associated with significantly higher rates of in-hospital mortality compared to patients without cancer [19]. Indeed, the efficacy of EVT in cancer patients presenting with stroke merits further investigation. Furthermore, efforts to reduce treatment delays in providing time-critical reperfusion therapies to acute stroke patients, including those with pre-existing cancer, are also needed [20][21].

3. Anticoagulation

The preventive and therapeutic management of stroke in cancer patients is essential in improving prognosis and in reducing the burden that these diseases individually and combined place on the health system.
Cancer patients undergoing chemotherapy may be at increased risk of venous thromboembolism (VTE) [22][23]. Identifying patients at high risk of VTE is crucial for prophylactic treatment strategies, such as anticoagulation. In comparison to matched controls, patients with cancer-related stroke exhibit greater levels of coagulation, platelet, and endothelial dysfunction as well as more circulating microemboli [24]. A multicentre prospective cohort study of adult patients (N = 50) with AIS and cancer found that the primary outcome of a composite of recurrent arterial/VTE or death occurred in 43 (86%) of the individuals [25]. The composite of recurrent arterial/VTE or mortality was associated with the levels of D-dimer (Hazards Ratio (HR), 1.6), P-selectin (HR, 1.9), sICAM-1 (HR, 2.2), sVCAM-1 (HR, 1.6), and microemboli (HR, 2.2). Recurring AIS was linked to the D-dimer level (HR, 1.2). For the stroke-only group, only one biomarker (P-selectin) and for the cancer-only group, only thrombin–antithrombin, were shown to be uniquely linked. These findings imply that indicators of embolism and hypercoagulability may be linked to poor clinical outcomes in people with cancer-related AIS [25]. Further research on haematologic and embolic prognostic biomarkers is warranted. In clinical practice, a biomarker signature may need to take into account factors including unambiguous interpretability, testing cost, and convenience in addition to predictive accuracy [26]. Concentrating on a subset of well-characterised biomarkers may aid in minimising costs.
Two landmark randomised clinical trials (RCTs) indicated that VTE prophylaxis with direct oral anticoagulants (DOACs), following a risk assessment, significantly reduced the rate of VTE during chemotherapy [27][28]. The 2021 guidelines from the American Society of Hematology recommend stratification of cancer patients according to their VTE risk prior to chemotherapy, as well as considering patient-specific factors, using the Khorana risk score, which takes into account the cancer phenotype [29]. More recently, the 2022 International Clinical Practice Guidelines published by the International Initiative on Thrombosis and Cancer (ITAC) also provided indications for treatment and prophylaxis of cancer-associated thrombosis [30]. The following are key recommendations (grade 1A or 1B): (1) low-molecular-weight heparins (LMWHs) for initial (first 10 days) and maintenance therapy of cancer-associated thrombosis; (2) in the absence of significant drug–drug interactions or gastrointestinal absorption impairment, DOACs are indicated for the initial treatment and maintenance of cancer-associated thrombosis in patients who are not at elevated risk of gastrointestinal or genitourinary bleeding; (3) use of LMWHs or DOACs to treat cancer-related thrombosis for a minimum of 6 months; (4) prophylactic treatment with LMWHs for an extended period of time (4 weeks) to prevent postoperative VTE after major abdominopelvic surgery, if there is no significant bleeding risk; and (5) use of LMWHs or direct oral anticoagulants (apixaban or rivaroxaban) is indicated for primary prevention of VTE in ambulatory patients with locally advanced or metastatic pancreatic cancer undergoing anticancer treatment and have a low likelihood of bleeding [30].
The American Society of Oncology (ASCO) Clinical Practice guidelines also provide indications for prophylaxis and treatment of VTE in patients with cancer [31]. They indicate pharmacologic thromboprophylaxis to hospitalised patients with active malignancy in the absence of bleeding or other contraindications. Whilst routine pharmacologic thromboprophylaxis was not indicated to all outpatients with cancer, they recommended thromboprophylaxis with apixaban, rivaroxaban, or LMWH in high-risk outpatients with cancer (Khorana score of 2 or higher before starting a new systemic chemotherapy regimen). Furthermore, they also indicated pharmacologic thromboprophylaxis with either unfractionated heparin (UFH) or LMWH to all patients with malignant disease undergoing surgical intervention.
Patients with cancer and VTE should receive anticoagulation for a minimum of 6 months [32]. However, the National Comprehensive Cancer Network (NCCN) guidelines recommend a minimum duration of 3 months. In patients with cancer-associated VTE, a meta-analysis of randomised trials indicates a decreased risk of recurrent VTE albeit with a higher risk of bleeding compared to LMWH [33]. The 2021 Guidelines for the Secondary Prevention of Ischaemic Stroke released by the American Heart Association/American Stroke Association incorporates a section on malignancy, with recommendations being for patients with ischaemic stroke or TIA in the setting of AF and cancer, and DOACs are preferred over warfarin for stroke prevention [34]. They also called for action and highlighted the need for more specific guidelines on the type of anticoagulation across specific cancers and for how to treat patients who are on anticoagulation but still experience a stroke and the effect of LMWH.

4. Antiplatelet Therapy

In the absence of an embolic source, antiplatelet therapy is indicated in patients with malignancy and ischaemic stroke [35]. Antiplatelets should also be considered as a preventive therapy, as they can decrease platelet aggregation and thus impede potential thrombus formation [2]. As platelets form the basis of the haemostatic plug, which adheres to vascular lesions, targeting these main effector cells of coagulation and thrombosis could be paramount [36]. Damaged endothelium secretes von Willebrand factor (vWF) and other thrombotic mediators, which activate platelet adhesion and aggregation. Furthermore, increased platelet counts are a risk factor for VTE in cancer patients, particularly those undergoing concurrent chemotherapy [37]. Agents, such as acetylsalicylic acid, clopidogrel, phosphodiesterase inhibitors, and glycoprotein IIb/IIIa inhibitors, are conventional therapies in the treatment of arterial thrombosis and may apply to the scenario of stroke in cancer patients, warranting further research [37].
For patients without a need for anticoagulation, antiplatelet therapy may be initiated. Anticoagulation is more appropriate for patients with a Factor V Leiden disorder, with a large-vessel dissection or AF (cardiogenic embolism/thrombophilic conditions). Antiplatelet therapy is preferred also in lesions that are characterised by atherosclerosis and endothelial injury [38]. Dual antiplatelet therapy (DAPT) may need to be discontinued in cancer patients who have received percutaneous coronary intervention (PCI) or experienced an acute coronary syndrome (ACS) to restart anticancer treatment, perform surgery, or even have biopsies [39][40]. Furthermore, the optimal duration of DAPT in cancer patients remains a challenge owing to the increased risks of thrombosis and haemorrhage associated with cancer [41]. By using optical coherence tomography (OCT) to assess the stent strut coverage, the decision around early DAPT discontinuation can be considered in high-risk patients [42].
Furthermore, histological studies into the molecular features of thrombi in cancer patients who experienced stroke reveal that they tend to be higher in platelet fraction and lower in erythrocyte in comparison to inactive cancer or control groups [43][44]. Patients with vegetation also showed high platelet and low erythrocyte fractions. This points to the importance and role of antiplatelet therapy in the context of cancer patients at a higher risk of stroke. Though there is still limited literature available in this area [45][46], more studies that focus on analysing thrombus and clot morphology in patients with stroke and cancer will inform the selection of the most efficacious treatment option.

5. Lifestyle Management

The identification of independent stroke risk factors in cancer patients is essential, given that the majority of patients in the studies observed above undergoing radiotherapy and chemotherapy experienced multiple confounding factors of hypertension, hyperlipidaemia, diabetes mellitus, and tobacco use [47]. Managing modifiable factors, such as hypertension, hyperlipidaemia, and diabetes, should be concurrent with any sort of pharmacological treatment, as well as lifestyle modifications, including regular physical activity, healthy diet, hydration, weight management, compression stockings, and smoking cessation counselling [48][49].

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